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Wake Forest School of Medicine

Human Research Protection Program and Institutional Review Board

Polices and Procedures

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Contents 1.0 Ethical and Regulatory Mandates for the Protection of Human Research Subjects ............................... 11

The Belmont Report ................................................................................................................................... 11

45 CFR 46 ................................................................................................................................................... 11

21 CFR 50 and 21 CFR 56 ........................................................................................................................... 11

Department of Defense Addendum .......................................................................................................... 11

ICH-GCP ...................................................................................................................................................... 11

Assurance and IRB registration process .................................................................................................... 11

2.0 Institutional Roles in the Protection of Human Subjects ......................................................................... 13

Institutional Official ................................................................................................................................... 13

Institutional Review Board Office .............................................................................................................. 13

Institutional Review Boards ....................................................................................................................... 13

Principal Investigator (PI) ........................................................................................................................... 14

Research Team Members .......................................................................................................................... 14

3.0 IRB Authority and Responsibility ............................................................................................................. 16

Authority of the IRB ................................................................................................................................... 16

Relationship of the IRB to the Research Community ................................................................................ 16

IRB relationship with collaborating institutions and investigators ............................................................ 18

Community Partnerships in Research ........................................................................................................ 19

4.0 IRB Composition and Management ......................................................................................................... 21

Membership and Structure........................................................................................................................ 21

Chairperson ................................................................................................................................................ 21

IRB Members ............................................................................................................................................. 22

Alternate Members.................................................................................................................................... 23

IRB staff and resources .............................................................................................................................. 23

Use of consultants ..................................................................................................................................... 25

IRB Subcommittees .................................................................................................................................... 25

Independent Institutional Review Board ................................................................................................... 25

Training of IRB chairs and members .......................................................................................................... 25

Evaluations ................................................................................................................................................. 26

5.0 Operations of the IRB............................................................................................................................... 28

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Schedule of Meetings ................................................................................................................................ 28

Quorum requirements ............................................................................................................................... 28

Technology use in IRB meetings ................................................................................................................ 28

Agenda ....................................................................................................................................................... 28

Voting requirements .................................................................................................................................. 29

Criteria for IRB approval of research ......................................................................................................... 30

Further review/approval of IRB actions ..................................................................................................... 31

Appeal of IRB decisions .............................................................................................................................. 31

Scientific Validity ........................................................................................................................................ 32

6.0 IRB Record Retention ............................................................................................................................... 34

Written procedures and guidelines ........................................................................................................... 34

IRB membership roster .............................................................................................................................. 34

Minutes of meetings .................................................................................................................................. 34

Procedures for reporting actions to the institution .................................................................................. 35

Retention of documents by the IRB ........................................................................................................... 35

7.0 Determination if an activity qualifies as human subjects research ......................................................... 38

Not human subjects research .................................................................................................................... 38

Definitions .................................................................................................................................................. 38

Criteria for consideration that a study is not human subjects research ................................................... 39

Determination and notification that a study is not human subjects research .......................................... 40

8.0 Initial Submission ..................................................................................................................................... 43

Required materials ..................................................................................................................................... 43

Level of review ........................................................................................................................................... 43

Determination of review type ................................................................................................................... 43

9.0 Full Board Review of Research................................................................................................................. 45

Full board review of research .................................................................................................................... 45

Approval period ......................................................................................................................................... 47

DoD sponsored research ........................................................................................................................... 47

10.0 Expedited Review of Research ............................................................................................................... 49

Determination and notification of expedited status ................................................................................. 49

Approval Period ......................................................................................................................................... 50

Categories of research that may be approved through expedited procedures ........................................ 50

DoD sponsored research ........................................................................................................................... 54

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11.0 Exempt Research ................................................................................................................................... 56

Determination and notification of Exempt status ..................................................................................... 56

Categories of Exempt human subjects research ....................................................................................... 57

Exempt human research involving children .............................................................................................. 60

12.0 Advertisements and Recruiting ............................................................................................................. 61

Recruitment of students, employees, or trainees ..................................................................................... 62

Recruitment of patients ............................................................................................................................. 63

Recruitment by outside researchers ......................................................................................................... 63

Payment of recruitment incentives ........................................................................................................... 63

Recruitment of US military personnel ....................................................................................................... 64

13.0 Amendments or changes to approved research studies ....................................................................... 65

Regulatory Background .............................................................................................................................. 65

Procedures to be followed by the study team .......................................................................................... 65

IRB procedures for reviewing an amendment request ............................................................................. 66

14.0 Continuing Review ................................................................................................................................. 68



IRB procedures for continuing review ....................................................................................................... 69

Administrative closure of protocols due to lack of continuing review ...................................................... 72

Approval period ......................................................................................................................................... 73

15.0 Closure upon completion of research ................................................................................................... 74

Regulatory background .............................................................................................................................. 74


IRB procedures for closing a research study ............................................................................................. 74

Renewal of activity in a closed state .......................................................................................................... 75

16.0 Informed Consent .................................................................................................................................. 76


Definitions .................................................................................................................................................. 77

Informed Consent Process and Required Elements .................................................................................. 79

Documentation of Informed Consent ........................................................................................................ 81

Use of the Short Form Written Consent Document .................................................................................. 81

Waiver of Documentation of Informed Consent ....................................................................................... 82

Waiver of Informed Consent or the Elements of Informed Consent ........................................................ 83

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Additional Signatures ................................................................................................................................. 84

Re-consenting Research Subjects .............................................................................................................. 84

Data retention when participants withdraw from a clinical trial .............................................................. 84

Research involving deception or withholding of information ................................................................... 85

Obtaining Consent Remotely ..................................................................................................................... 86

Adults Unable to Consent .......................................................................................................................... 86

Monitoring the consent process ................................................................................................................ 86

Additional Regulations ............................................................................................................................... 87

Retention of the consent document ......................................................................................................... 87

Compensation for Research Injury in Informed Consent .......................................................................... 88

17.0 Exception from Informed Consent for studies conducted in Emergency Settings ................................ 89


Procedures to Be Followed by Principal Investigators .............................................................................. 89

IRB Procedures ........................................................................................................................................... 92

18.0 Conflict of Interest ................................................................................................................................. 95

Definitions .................................................................................................................................................. 95


Investigator Conflict of Commitment ........................................................................................................ 96

Investigator Conflict of Interest ................................................................................................................. 99

Procedures for disclosure and management ........................................................................................... 101

IRB Member Conflict of Interest .............................................................................................................. 103

Institutional Conflict of Interest ............................................................................................................... 104

19.0 HIPAA ................................................................................................................................................... 107

Definitions ................................................................................................................................................ 107

Regulatory Background ............................................................................................................................ 108

Privacy Rule Identifiers ............................................................................................................................ 109

Using Protected Health Information for Research .................................................................................. 110

Retention of Protected Health Information ............................................................................................ 110

Waiver of Individual Authorization .......................................................................................................... 113

Limited Data Set ....................................................................................................................................... 114

Disclosing a Limited Data Set ................................................................................................................... 116

Receiving a Limited Data Set from outside the institution ...................................................................... 116

Reviews that are Preparatory to Research .............................................................................................. 116

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Research Recruitment under HIPAA ........................................................................................................ 117

Allowable Recruitment Practices ............................................................................................................. 118

Research on Decedents ........................................................................................................................... 118

The IRB’s Role Related to the Privacy Rule .............................................................................................. 118

Other Research Related Topics ................................................................................................................ 120

“Minimum Necessary” Provision and Role-Based Access ....................................................................... 121

Accounting for Research Disclosures ....................................................................................................... 122

Additional Uses and Disclosures of Protected Health Information ......................................................... 122

Certificates of Confidentiality .................................................................................................................. 123

Resources ................................................................................................................................................. 123

20.0 Medical Devices ................................................................................................................................... 125


Determining which devices pose Significant or Non-significant Risk ...................................................... 125

Significant Risk Devices ............................................................................................................................ 126

Non-significant Risk Devices .................................................................................................................... 126

Responsibilities of the Investigator ......................................................................................................... 128

If the IRB decides the study is Significant Risk ......................................................................................... 128

If the IRB decides the study is Non-significant Risk ................................................................................. 128

Reporting IRB determinations of Significant and Non-Significant Risk ................................................... 128

Billing Compliance Issues ......................................................................................................................... 129

Storage and control of Investigational Devices ....................................................................................... 129

21.0 Humanitarian Use Devices ................................................................................................................... 130


Procedures to be followed by the Principal Investigator ........................................................................ 131

HUD Use in Emergency Settings .............................................................................................................. 131

Procedures to be followed by the IRB ..................................................................................................... 133

22.0 Investigational Drugs ........................................................................................................................... 134


Compliance with IND regulations ............................................................................................................ 135

Storage and control of Investigational Drugs .......................................................................................... 136

23.0 Emergency Use of a test article in Life Threatening Situations ........................................................... 138


Definitions ................................................................................................................................................ 139

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Procedures to be followed by the Investigators prior to use: ................................................................. 139

Procedures to be followed by Investigators after use ............................................................................. 141

Non-emergency indications ..................................................................................................................... 143

24.0 Protocol Deviations .............................................................................................................................. 146

Definitions ................................................................................................................................................ 146


Investigator Requirements for Reporting Protocol Deviations to the IRB .............................................. 147

IRB Review of Protocol Deviations ........................................................................................................... 147

Determinations and Required Responses ............................................................................................... 148

25.0 Unanticipated Problems Involving Risks to Subjects or Others/Safety Event Reporting .................... 149

Definitions ................................................................................................................................................ 149


Investigator Requirements for Reporting to the IRB ............................................................................... 150

IRB Responsibilities for Review and Response ........................................................................................ 152

IRB Reporting of Unanticipated problems to appropriate institutional officials, the department or

agency head (or designee), and OHRP .................................................................................................... 154

Other Safety Reports ............................................................................................................................... 154

26.0 Study Suspension or Termination ........................................................................................................ 158

Definitions ................................................................................................................................................ 158


Procedures to be followed by the IRB ..................................................................................................... 158

Responsibilities of the Principal Investigator........................................................................................... 160

Reporting of Suspension or Termination ................................................................................................. 160

27.0 Reporting to External Agencies............................................................................................................ 161


Changes in IRB Membership/Registration ............................................................................................... 163

28.0 Non-compliance ................................................................................................................................... 164

Definitions ................................................................................................................................................ 164


Notification of Potential Serious or Continuing Noncompliance ............................................................ 165

29.0 IRB Authorization Agreements ............................................................................................................ 169


Responsibilities of the IRB ....................................................................................................................... 169

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30.0 Individual Investigator Agreements ................................................................................................. 171




31.0 Multi-site studies where Wake Forest is the lead coordinating center .............................................. 172

Multi-site studies where Wake Forest is the lead coordinating center .................................................. 172

Responsibilities of the Principal Investigator........................................................................................... 172

32.0 Use of the Copernicus IRB ................................................................................................................... 174

Purpose .................................................................................................................................................... 174

Criteria for recommending use of the Copernicus IRB ............................................................................ 174

Procedures ............................................................................................................................................... 174

Responsibility for Copernicus Fees .......................................................................................................... 175

33.0 Procedure for the IRB to serve as the IRB of Record to Sites External to our Institution ................... 176


External Site Investigator Responsibilities ............................................................................................... 176

Wake Forest Investigator Responsibilities ............................................................................................... 177

IRB Administration Responsibilities ......................................................................................................... 178

34.0 Facilitated Review ................................................................................................................................ 180




35.0 Children Involved in Research ............................................................................................................. 181

Who is considered a child? ...................................................................................................................... 181

Definitions ................................................................................................................................................ 181


IRB Considerations ................................................................................................................................... 182

Requirements for permission by parents or guardians and for assent by children ................................ 184

IRB Waiver of Assent and Parental Permission ....................................................................................... 184

Wards of the State ................................................................................................................................... 185

36.0 Research Involving Pregnant Women, Human Fetuses and Neonates ............................................... 189


Conditions required for pregnant women or fetuses to be involved in research ................................... 189

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Conditions required for neonates of uncertain viability and nonviable neonates to be involved in

research ................................................................................................................................................... 190

Neonates of uncertain viability ................................................................................................................ 190

Nonviable neonates ................................................................................................................................. 191

Viable Neonates ....................................................................................................................................... 191

37.0 Research Involving Prisoners ............................................................................................................... 192

Definition of research addressed in this section ..................................................................................... 192

Special considerations for prisoner research .......................................................................................... 192


Additional Consent requirements ........................................................................................................... 196

Certification of prisoner research ............................................................................................................ 197

38.0 Genome Wide Association Studies ...................................................................................................... 200

Purpose .................................................................................................................................................... 200

Definitions ................................................................................................................................................ 200




Withdrawal of Individual Consent ........................................................................................................... 203

39.0 Charges for IRB Review ........................................................................................................................ 204

Fee Structure ........................................................................................................................................... 204

Invoicing Procedures................................................................................................................................ 204

40.0 Compensation for Research Participants ............................................................................................ 206


Guidelines for IRB Review of "Reasonable Compensation" .................................................................... 207

41.0 Research Related Injury ....................................................................................................................... 209


Template Language .................................................................................................................................. 209

42.0 SOP Revisions ....................................................................................................................................... 212

General Description ................................................................................................................................. 212

Procedures ............................................................................................................................................... 212

43.0 Case Reports ........................................................................................................................................ 214

44.0 Application of ICH-GCP Guidance to the conduct of clinical trials ...................................................... 216

Purpose .................................................................................................................................................... 216

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Definitions ................................................................................................................................................ 216

IRB Responsibilities .................................................................................................................................. 217

Informed Consent Requirements ............................................................................................................ 218

Vulnerable Populations ............................................................................................................................ 219

Investigator Qualifications ....................................................................................................................... 219

Investigator Responsibilities .................................................................................................................... 220

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1.0 Ethical and Regulatory Mandates for the Protection of Human

Research Subjects The regulation of human subjects research by the U.S. Department of Health and Human Services (DHHS)

is codified in 45 CFR 46. Because Subpart A of 45 CFR 46 has been adopted by many federal agencies, it is

known as the Common Rule. The Common Rule requires that every institution performing federally-

supported human subjects research file an assurance of protection for human subjects. Wake Forest

University Health Sciences maintains a Federalwide Assurance (FWA) of compliance, approved by the

Office of Human Research Protections (OHRP), for the protection of human subjects in research. Pursuant

to the FWA, human subjects research should conform to the documents described below:

The Belmont Report The Belmont Report elucidates three ethical principles that should guide research:

Respect for persons (applied by obtaining informed consent, respecting privacy and

confidentiality, and affording additional protections for vulnerable populations);

Beneficence (applied by weighing risks and benefits)

Justice (applied by the equitable selection of subjects).

45 CFR 46 The regulation, published by DHHS, codifies basic human subject protection measures

21 CFR 50 and 21 CFR 56 The Food and Drug Administration (FDA) has also codified basic human research protection measures, and

are largely congruent with 45 CFR 46, with some differences that pertain to FDA-regulated research.

Department of Defense Addendum This regulation applies to studies regulated by the Department of Defense.

ICH-GCP This guidance applies to clinical trials conducted in accordance with the ethical principles that have

originated from the Declaration of Helsinki and are consistent with all Good Clinical Practice guidelines.

The Wake Forest IRBs comply with ICH-GCP guidance (E6) only to the extent that is compatible with FDA

and DHHS regulations, unless otherwise specified.

When appropriate, a Principal Investigator will indicate when ICH-GCP standards are to be applied. This

information will be verified by review of the study protocol and confirmed by the Office of Sponsored

Programs when it is contractually required.

Assurance and IRB registration process Wake Forest University Health Sciences, as an institution involved in biomedical and behavioral research,

has in place a set of principles and guidelines that govern the institution, its faculty, staff, IRB members

and staff, and the Institutional Official in the discharge of its responsibilities for protecting the rights and

welfare of human subjects taking part in research conducted at, or sponsored by the institution,

regardless of funding source. Assurances applicable to federally supported or conducted research must,

at a minimum, contain such a statement of principles, which may include an appropriate existing code,

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declaration, and/or statement of ethical principles as formulated by the institution. The Belmont Report

serves as such a document for the Wake Forest University Health Sciences IRB.

The process of assurance also provides institutions the option of applying the Common Rule to all studies

regardless of funding source. Wake Forest University Health Sciences has chosen to apply the Common

Rule to only studies that are supported by the federal agencies.

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2.0 Institutional Roles in the Protection of Human Subjects

Institutional Official The Institutional Official is the Assistant Dean for Research Administration at Wake Forest School of

Medicine.

It is the responsibility of the Institutional Official to oversee the institution’s compliance with federal

regulations related to human subjects research. The Institutional Official hold signature authority for all

regulatory documents submitted to the Department of Health and Human Services and the Office of

Human Research Protections. Signature authority for matters such as Authorization Agreements,

Individual Investigator Agreements, and Data Use Agreements may be delegated to the Director of the

Institutional Review Board (IRB).

The Institutional Official maintains ultimate responsibility for complaints or concerns about the human

research practices.

Institutional Review Board Office The Institutional Review Board (IRB) office is led by the IRB Director. The IRB Director has been identified

as the Human Protections Administrator (HPA) for the institutional FWA, and may serve as an additional

point of contact to OHRP officials. All IRB staff, members, and Chairs report to the Director and through

the Director to the administration and Institutional Official.

The IRB Director holds regular meetings with IRB administrative staff as well as IRB Chairs to discuss

controverted issues and operational processes. The goals of these meetings are to achieve consistency

amongst all staff and chairs, optimize the review process, and update all pertinent members of upcoming

changes and revisions. All activity has the central goal of promoting the protection of human subjects

participating in research.

Institutional Review Boards The Wake Forest School of Medicine IRB holds authority to protect all human subjects involved in research

studies brought before it for review, regardless of the research sponsor, in accordance with its written

policies, procedures, and guidance. This authority holds for all institutions designating the Wake Forest

School of Medicine IRB as the IRB of record, and for all principal and co-investigators named in research

protocols brought before the IRB, regardless of institutional affiliation or location in which the research

will be conducted.

The purpose of the IRB is to protect the safety, rights, and welfare of human subjects, who are participants

in research, with special attention to vulnerable subjects, including but not limited to prisoners, pregnant

women, and children. The safety, rights, and welfare of research subjects is the most important

consideration and prevails over interests of science and society.

The IRB is guided by the ethical principles for the protection of human research participants as set forth in

the Belmont Report and the Declaration of Helsinki. It operates in accordance with the requirements for

human subjects research as set forth in the Code of Federal Regulations at 45 CFR 46 and 212 CFR 50, 56,

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312, and 812 and other applicable federal and state regulations and laws, and the ICH-GCP consolidated

guidelines.

Principal Investigator (PI) The principal investigator is the individual responsible for the conduct of research, and, as such, must

personally conduct or supervise the research. The PI is responsible for ensuring that the research study is

accurately and completely submitted for IRB review; that IRB approval is obtained prior to initiation of

research or before making any changes or additions to the research; that the IRB is informed of new

information (e.g. from the study sponsor) or changes to information previously presented to the IRB, and

work with the IRB to determine if and how new information should be communicated to participants.;

that progress reports are submitted to the IRB as required; that all non-compliance is reported to the IRB;

and that all unanticipated problems or serious adverse events involving risk to human subjects are

reported to the IRB.

The principal investigator is responsible for the delegation of responsibilities of study conduct to other

study team members based on experience and qualifications. Trainees such as medical students,

residents, and fellows are not permitted to have the role of principal investigator, and must have a

sponsor/mentor to support, oversee, and submit their research application.

The principle investigator must complete the Collaborative Institutional Training Initiative (CITI) training

module for the protection of human research subjects. Training modules are selected by each subscribing

institution based on the needs and relevant research topics at their respective institutions. Wake Forest

School of Medicine has selected modules that are relevant to both biomedical and social-behavioral

studies. Principal Investigators are required to complete the Biomedical Investigators version of the

training. CITI training is valid for three years, and must be current before the IRB can grant approval of a

research application.

When following ICH-GCP guidance, the investigator is responsible for the following additional items:

Provide evidence of his/her qualifications through an updated CV or biosketch

Be familiar with the appropriate use of the investigational product, as described in the protocol, in

the current investigator brochure, in the product information, and in other information provided

by the sponsor

Permit monitoring and auditing by the sponsor and inspection by the appropriate regulatory

authority

Ensure the accuracy, completeness, legibility, and timeliness of the date reported to the sponsor

Maintain the clinical trial documents as specified in Essential Documents for Conduct of a Clinical

Trial and as required by the applicable requirements

Retain essential documents for two years following the last approval of a marketing application or

three years since the formal discontinuation of clinical development of the investigational

product.

Research Team Members Every member of the research team is responsible for the ethical conduct of research as outlined in the

Belmont Report. All study team members (students, fellows, residents, nurses, coordinators, and others)

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must formally agree to participate in each protocol review by the IRB and be current in CITI human

subjects protection training. Only the PI is permitted to make the initial submission of a study to the IRB.

Research team members, other than the PI are highly encouraged to complete the biomedical training

modules within CITI, however, the social-behavioral modules are acceptable if the respective team

member’s role in the study will be strictly social-behavioral. CITI training is valid for three years.

Submissions may not be granted approval if all members of the study team do not have current CITI

training.

References

45 CFR 46.103(c)

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3.0 IRB Authority and Responsibility

Authority of the IRB The IRB holds authority for the review, approval, and continuing oversight of all research involving human

subjects brought before the IRB from any institution or individual designating the WFUHS IRB as the IRB of

record by appropriately signed agreements. The IRB functions independently of other institutional entities

regarding the protection of human subjects. IRB members may report undue influence to the IRB Director

or Institutional Official. Response to such reports will be evaluated and responded to individually. The IRB

has the authority to take the actions listed below when appropriate.

The IRB has the authority to approve, require modifications in order to secure approval, disapprove, close

or suspend any research study based upon its considerations for the protection of human subjects. If the

IRB disapproves a research study, it shall provide written notification for its decision and give the

investigator an opportunity to respond in person or in writing.

The IRB has the authority to require progress reports from the investigators and oversee the conduct of

any research study that is approved. The IRB may request a progress report at any time; however,

progress reports will be reviewed at least annually depending on the IRB’s assessment of the risk to

subjects. The IRB has the authority to have the consent process or any aspect of the research be observed

by an IRB member or a third party whom the IRB determines is qualified and appropriate. The IRB has the

authority to obtain all research records and documents associated with an approved study and to audit

the conduct of any research study it approves.

The IRB has the authority to suspend, terminate, or modify approval of any study it has originally approved

in which an unanticipated problem involving risk to the safety, rights, or welfare of human subjects or

others has occurred. Similar action may be taken in the case of serious or continuing noncompliance with

the requirements of any state or federal regulation or serious or continuing noncompliance with the

determinations of the IRB. Any suspension or termination shall be promptly reported in writing to the

investigator, appropriate Institutional Official, and as appropriate to OHRP, the study sponsor, the FDA

and other appropriate federal departments or agencies. Any report of a suspension or termination shall

include the statement of the reason for the IRB’s action. The IRB Director or Institutional Official does

have the authority to suspend research studies until a convened meeting of the IRB can evaluate the study

and issues involved.

The IRB has the authority to place restrictions (including but not limited to length of approval) on any

study based upon its considerations for the protection of human subjects.

Relationship of the IRB to the Research Community The IRB is the primary Institutional Review Board for the Wake Forest Baptist Medical Center. It is charged

with the review of all research proposals involving human subjects originating from the institution’s

faculty, staff, and students. Furthermore, when the IRB is contacted by participants to discuss problems,

obtain information, or offer input, issues will be noted, resolved, or referred to the appropriate

representative within the institution.

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The IRB is a standing committee of Wake Forest Baptist Medical Center. Its members are appointed

annually by the Dean of the School of Medicine in accordance with the Organization and Policies

Handbook of the Wake Forest School of Medicine.

The IRB is administratively part of the Biomedical Research Services and Administration unit, and as such

falls under the administrative responsibility of the Assistant Dean for Research Administration. The IRB

does rely on specialty review of a number of ancillary groups listed below. Approval by all applicable

groups must be obtained prior to IRB approval.

Institutional Biosafety Committee (IBC): On issues regarding the safe and appropriate use of biological

agents, the IRB interacts with the IBC. Approval of both committees is required prior to initiation of the

study.

Medical Radiation Safety: On issues regarding the safe and appropriate use of radiation, the IRB interacts

with the Radiation Safety Committee. Approval of both committees is required prior to initiation of the

study.

Clinical Research Unity (CRU): Protocols that propose the use of the CRU by subjects should be evaluated

and approved by the CRU. The purpose of this review is for space and resource utilization. Approval of

CRU and IRB is required prior to initiation of the study.

Cancer Center Protocol Review Committee (PRC): Protocols involving oncology patients should be

submitted and approved by the PRC. Approval of the PRC and IRB is required prior to initiation of the

study.

Downtown Health Plaza (DHP): Due to the vulnerability of patients seen at DHP, protocols that propose

the use of this facility should be evaluated and approved. Approval by the DHP and IRB are required prior

to initiation of the study.

Institutional Legal Counsel: The IRB Director meets periodically with the institutional legal counsel as well

as representatives of the privacy and compliance offices, IT security, and human resources to discuss

research matters and apply institutional, local, state, and federal laws to research standards.

Creative Communications: Studies that involve the use of advertising and recruitment material must be

approved by the Creative Communications department to ensure appropriate institutional branding and

non-coercive appearances.

Pharmacy: Studies involving the use of drugs, supplements, or other biologics will be reviewed by the

investigational drug services to verify the plans for safe storage, management, and dispensation of the

products being studied.

General Internal Medicine Review Committee: Due to the vulnerability of patients seen in these clinics,

protocols that propose the use of these clinics should be evaluated and approved. Approval of the

committee and the IRB is required prior to study initiation.

Clinical Trials Office: Funded studies or those with potential billing risk to participants must be reviewed

band a Medicare Coverage Analysis completed when applicable.

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Oversight and Outreach: Oversight and Outreach reviews are conducted to ensure that investigators are

conducting the stud protocol in an ethical manner and according to institutional policies and good clinical

practice guidelines. Review can be conducted at random, investigator initiated, for cause, or to

investigate a potential conflict of interest. During the process of review, the monitor will also review the

IRB records to ensure all regulations were followed and appropriately documented in the review process.

Office of Sponsored Programs: Studies that are supported by sponsors must negotiate a clinical trial or

funding agreement with WFUHS. The director of the department, of their designee is responsible for

reviewing contracts to ensure the items below are addressed.

Medical care for research participants with a research-related injury

Timely reporting of events/findings that could affect the safety of participants of influence the

conduct of the study

Provisions for monitoring the data to ensure the safety of participants and for providing data and

safety monitoring reports to WFUHS and the timeframe with which they will be received

Plans for disseminating findings from the research and the roles that researchers and sponsors will

play in the publication or disclosure of results

Plans to let WFUHS know of any study results that could affect the safety of former study

participants once the study has ended

The committees and groups above have separate and independent review responsibilities within the

institution. Representatives are notified via the eIRB software when a study or amendment is submitted

and requires their respective committee’s approval. A study or amendment will not be assigned for

review by the IRB, no matter the review type, until all necessary ancillary approvals have been received.

The IRB also interacts with OHRP and the FDA. The IRB maintains a Federalwide Assurance and

registration with OHRP for the conduct of human subjects research sponsored by the signatory agencies.

The IRB is charged to abide by both federal/national law as well as other applicable laws. In general, state

or local law is more conservative than federal/national law and would overrule the federal/national

requirements. As such the IRB will follow the applicable law that offers the most protection for human

subjects participating in studies conducted at the institution.

IRB relationship with collaborating institutions and investigators The IRB welcomes collaborators from other institutions and community members. When expertise in community culture, knowledge, or experience is pivotal to the success of a research study, focus groups or community collaborators may be needed. Depending on the level of involvement, a community member may be named on a study application or advice the study team as a consultant. Investigators are also encouraged to share results and outcomes of research study with their community collaborators. When an investigator at WFUHS will be collaborating with or studying subjects in a foreign country, additional requirements must be satisfied. If the country of collaboration or investigation has regulations to protect human subjects, then at minimum they must be met in addition to local, state, and federal regulations. If no regulations are in place, then the investigator should apply all ethical, safety, and reporting standards used for local research protocols. Investigators should apply all regulations that apply for domestic studies, to studies conducted in other countries. When appropriate the IRB should communicate with other local IRB representatives regarding initial review, continuing review, modifications, post- approval monitoring, and the handling of complaints, non-compliance and

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unanticipated problems. The IRB should obtain necessary information about the local research context through one or more of the following mechanisms: Personal knowledge of the local context by an IRB member, through direct experience with the research site, its population, and surrounding community

Participation by one or more consultants at convened meetings or through written review. Such consultants should be appropriately qualified with local knowledge of the research context, population, and its surrounding community.

Input from an IRB in the country where the research will take place. If an IRB is not available, an appropriate governmental agency may be consulted. Additional information should be supplied to the IRB describing the credentials and training of international collaborators and the plan to reporting events and to preserve the integrity of study data. The IRB must review all research conducted internationally by its faculty and staff. The investigator should also consult with researchers familiar with the culture differences of international research and consider the different customs, habits, and practices of international study subjects with regard to the process of obtaining informed consent. For research sponsored by the Department of Defense, the institution or the investigator must have permission to conduct research in that country by certification, or local ethics review. Investigators must follow all local laws, regulations, customs, and practices.

Community Partnerships in Research Increasingly research design involves members of the community under study in the design and implementation of this research. These approaches include community engaged research and community based participatory research (CBPR). Community-engaged research encourages the participation and influence of nonacademic researchers in the search for new knowledge. Community members, organizations, and researchers work together in all aspects of the research process. Community-engaged research is done with communities and not on communities. This approach to research recognizes the strengths of the community and builds on those strengths.

Health-related research studies may develop new treatments or find ways to prevent disease, but it can take years before these treatments become available in most clinics, doctors' offices, or community health centers. This is especially true for research that involves disadvantaged communities. Community-Based Participatory Research actively involves the community in the research process. CBPR seeks to directly benefit the public in a process that:

Is a collaborative approach that equitably includes community members, organizations, and researchers in all aspects of the research process

Enhances the understanding of a mutually shared area of public health interest Puts findings into action to improve the health and well-being of community members

In CBPR, community members are also involved in getting the word out about the research and promoting the use of the research findings. This involvement can help improve the quality of life and health care in the community by putting new knowledge in the hands of those who need such information in order to

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make changes.

These processes may present challenges for both researchers and IRBs, including whether the community partners are subjects, members of the research team or both; what training is required; how to manage conflicts of interest; when it is appropriate to establish community advisory boards; how to solicit their input in ongoing involvement; whether and what kind of collaborative agreements are required; and how/when to disseminate results. In many cases it will not be necessary or appropriate to apply the same policies and requirements to community partners that are applied to University-based members of the research team. For example, it may be more appropriate for the principal investigator to provide training that is tailored to the role of community partners (e.g., church members, barbers, community advocates) than it is to require completion of the same online CITI modules that investigators complete. Outreach to the community includes presentations and training to community groups, provision of educational material and community events/health fairs. Feedback is obtained from participants at the conclusion of each training session. These activities are periodically evaluated to assess effectiveness of the program and for planning of additional offerings. References

26 CFR 56.114 45 CFR 46.114 DoDD 3216.2 para. 4.9 SECNAVINST 3900.39D, para. 6i

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4.0 IRB Composition and Management

Membership and Structure Each IRB shall have at least five members. Additional members may be added to have a sufficient number of members to assure adequate review of the submissions made to the IRB. The members appointed to the IRB shall be qualified by experience, expertise, and diversity of background

to assure the complete and thorough review of submissions commonly made to the IRB. The IRB shall

collectively possess the professional competence necessary to review specific research activities and shall

be able to ascertain compliance of applications and proposals with institutional commitments and

regulations, applicable law, standards of professional conduct and practice, and community attitudes. If

the IRB regularly reviews research that involves a vulnerable category of research subjects, it shall have at

least one member knowledgeable about and experienced in working with the category of vulnerable

subjects to which the research applies. Examples of categories of vulnerable research subjects include, but

are not limited to children, prisoners and pregnant women.

The IRB shall maintain diversity of membership. The IRB shall include both men and women. Every effort

will be made to ensure the IRB is ethnically diverse. The IRB shall not consist entirely of members of a

single professional group or entirely of officers, employees or persons otherwise associated with the

institution, apart from their membership on the IRB. The IRB shall include at least one member whose

primary concerns are in nonscientific areas and one member whose primary concerns are in scientific

areas. The IRB shall include at least one member who is not associated with Wake Forest Baptist Medical

Center and who represents the general perspective of participants. An individual will be considered to

have an affiliation with the institutions if they are receiving financial compensation from the institution or

otherwise have a financial interest in the institution. If research involves an FDA regulated article, a

licensed physician must be included in the quorum. Financial compensation for service on the IRB, if

provided, will not be considered to constitute a financial interest in the institutions. The spouse, children,

or parents of individuals affiliated with the institutions will also be considered to be affiliated with the

institution. Students of the institutions will be considered to be affiliated with the institutions regardless

of their financial interest.

WFUHS maintains eight IRBs. Each IRB shall meet the above stated requirements for membership. All IRBs

review all types of research. There are no designated specialty review boards. The Dean may constitute

additional IRBs that comply with the above membership requirements at his/her discretion. Rosters of

the respective boards are reviewed on a periodic basis and updated as needed to ensure appropriate

representation.

Chairperson The Dean of the Wake Forest University School of Medicine shall appoint one member to serve as Chair of

each board.

The Chair shall serve for a term of 3 years and may be reappointed.

Duties

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Ensure compliance with the federal regulations regarding human subjects research (all applicable

OHRP and FDA regulations)

Ensures that the IRB carries out its responsibilities

Serves as a voting member of the IRB and performs all duties of a voting member

Reviews and approves Expedited review applications or establishes designee to do so Provides

leadership to the research community and IRB staff

Represents the IRB at meetings (within the institution, locally, and nationally) Assists in

investigations of research non-compliance

Mediates resolution of disputes involving human research and IRB actions

Keeps the IRB Director and Institutional Official informed of IRB activity and issues related to human

subjects protection

Maintains an understanding of the ethical principles of human research, requirements of federal

regulation, applicable state laws, the institution’s Federalwide Assurance and institutional policies and

procedures for the protection of human subjects

Educates IRB members and investigators on the appropriate conduct of human research and IRB

policies and procedures

Contributes to the development of policies and procedures as well as guidance documents

Acts as a liaison between the IRB, Investigators and the Institutional Official

Works with the IRB Director as needed to resolve administrative concerns

Facilitates meetings and confirms that a quorum of members are present

The Chair serves at the pleasure of the Dean of Wake Forest University School of Medicine and may be

removed at any time with written notice.

IRB Members The Dean of Wake Forest University School of Medicine shall appoint members and alternate members to

the IRB.

Members are ordinarily appointed for a term of three years with approximately one-third of terms

expiring each year. Members may be reappointed for additional terms. The Dean of Wake Forest

University School of Medicine may vary the term of any member at his/her discretion. Individuals

responsible for business development, raising funds, or garnering support for research are prohibited from

serving as members of the IRB or from carrying out day-to-day operations of the review process. IRB

members are prohibited from owning equity in the organization.

Duties

Review, approve, require modifications in order to secure approval, restrict, disapprove, terminate, or

suspend research studies involving human subjects brought before the IRB

Conduct continuing oversight of approved research

Act as primary reviewer for assigned protocols, provide written comments, and lead discussions of the

research study at the convened IRB meeting

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Maintain an effective knowledge of subject populations, institutional, and legal requirements and

other factors that may contribute to a determination of risks and benefits to subjects and subjects’

informed consents

Apply the ethical principles of human research, requirements of federal regulation, applicable state

laws, the institution’s Federalwide Assurance and institutional policies and procedures for the

protection of human subjects

Apply knowledge of research ethics to protect the safety, rights, and welfare of research participants

Apply knowledge to ensure compliance with applicable state and federal regulations and laws

Members are expected to attend all board meetings or provide sufficient notice of anticipated

absence to allow for an alternate member to be notified

Members serve at the pleasure of the Dean of Wake Forest University School of Medicine and may be

removed at any time with written notice

IRB members who serve will be compensated for 5% of their salary in recognition of their service on the

board. IRB chairs who serve will be compensated 10% of their salary in recognition of their service on the

board. Non-employees will not receive any compensation.

IRB members, including non-affiliated members, are covered through the standard liability coverage for its

faculty, staff and volunteers.

Alternate Members The appointment and function of alternate members is the same as that for regular members.

The alternate member’s qualifications are comparable to those of the primary member(s) with whom they

substitute. The IRB roster filed with OHRP identifies the primary member(s) for whom each alternate

member may substitute.

When alternates substitute for a regular member, the alternate member receives for review the same

material that the regular member receives or would have received. The IRB minutes will document when

an alternate member replaces a regular member. When an alternate member substitutes for a regular

member, the regular member cannot vote.

IRB staff and resources The IRB staff consists of the IRB Director, IRB Associate Director, four (4) Protocol Analysts, and 2 exempt

review analysts. All IRB staff are under the supervision of the Assistant Dean for Research Administration

and are evaluated on an annual basis. The IRB administrative staff is housed in administrative office space

within the Medical Center. Administrative offices are equipped with telephones, computers, printers,

copiers, filing systems and other office equipment required to support IRB functions. Computers are

connected to the WFUHS network and the Internet.

The IRB staff is also responsible for the set-up of materials needed to conduct board meetings. The

institution provides the resources required to ensure that the IRB meets regulatory and legal

requirements. The IRB meets in various Medical Center conference rooms that are adequate for protocol

presentations and to facilitate open discussion.

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The Assistant Dean for Research Administration conducts an annual evaluation of the resources available

to the IRB staff. Included in this evaluation will be staffing needs, facilities, office space, and other

resources necessary for the conduct of the office.

In addition to the annual assessment conducted by the Assistant Dean and Director, a number of

committees are chartered, in part, to ensure ongoing evaluation of resources needed in particular areas of

the HRPP. The committees include the Research Advisory Committee (monthly meeting) comprised of

basic and clinical investigators who assess the policies and practices related to research, the Research

Operations Committee (quarterly meeting) comprised of faculty and administrators who evaluate the

institution’s operational functions related to research, the Clinical Trials Task Force (monthly meeting)

made up of research administrators who assess the needs of the human clinical research program and

recommend improvements to upper administration, the Faculty Executive Committee (quarterly meeting)

comprised of department chairs and upper institutional leadership and charged with developing policies

consistent with the clinical, educational ,and research goals of the institution , the Faculty Research

Committee (quarterly meeting) made up of research intensive faculty who provide advice and guidance to

upper administration on policies, practices, and resources will best facilitate high quality research at the

institution, and the HRPP Management Meeting (weekly) comprised of HRPP leadership who engage in

ongoing evaluation of the entire HRPP process. The HRPP is represented on each of these committees and

each of them is officially sanctioned by the Chief Executive Officer, Dean and/or Senior Associate Dean for

Research. The evaluations and recommendations of these groups are reported directly to upper

leadership.

As a whole, these groups evaluate all aspects of the HRPP including but not limited to:

Space

Personnel

HRPP Education Program Legal Counsel

Conflict of Interest

Quality Improvement Plans

Community Outreach

Attendance by non-IRB members

IRB meetings are open to IRB members; whether or not they are in attendance as part of the quorum, IRB

staff members, and the Institutional Official as defined at 45 CFR 46.103(c) or their designee. Other

individuals affiliated with the institution may attend IRB meetings as visitors at the invitation of an IRB

member. The member extending the invitation must be present at the meeting attended by the visitor.

Any IRB member in attendance may call for a vote requiring a visitor to be excused from the meeting.

Visitors do not vote and may not participate in discussion of IRB business unless requested by the IRB.

Visitors may not be present for discussion or vote on any research study where they are listed as an

investigator, co-investigator or where they have an actual or potential conflict of interest.

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The IRB administrative staff provides operational and administrative support to the IRB. The IRB

administrative staff members are employees of the institution. Their specific duties and job requirements

are provided in their job descriptions.

Use of consultants The chairman of the respective board, at his/her discretion, may either defer a protocol review to another

board with more expertise or invite individuals with competence in special areas to assist in the review of

issues that require expertise beyond or in addition to that available on the IRB. The chairman of the

respective board is authorized to request review and/or opinions from ad hoc consultants concerning any

submitted proposal, IRB business or issue presented to the IRB. Such consultants serve at the pleasure of

the IRB, and will be required to complete a conflict of interest questionnaire prior to reviewing a protocol.

The IRB may direct the Chair or other designee to select and appoint the ad hoc consultants at their

discretion or as defined by the IRB. At minimum, ad hoc consultants will be asked to provide a written

statement documenting the review and recommendations to the IRB. This written statement will be

available for review by all voting board members. Ad hoc consultants are not counted towards quorum,

and shall not vote on items brought before the IRB.

The IRB is not bound by the opinion, review or findings of ad hoc consultants but receives their opinions

and reports for information.

IRB Subcommittees The IRB is authorized to establish both standing and ad hoc subcommittees. Such subcommittees serve at

the pleasure of the IRB. The IRB may vote to allow the Chair or other IRB member to appoint the

membership of such subcommittees at their discretion or as defined by the IRB. The role of any

subcommittee shall be established by the IRB, or by the Chair or designated IRB member if so designated

by the IRB. The IRB is not bound by the opinion, review or findings of any subcommittee but receives their

reports for information.

Independent Institutional Review Board In situations where the IRB does not maintain the expertise to review protocols submitted to the Board for

review and approval, such proposals can be designated to an Independent IRB. An Independent IRB may

also be used in situations where there is an Institutional Conflict of Interest which needs to be managed

through the review and approval of an IRB other than the WFUHS IRB. A separate policy details the

process for the designation of an Independent IRB which includes situations where such review may be

appropriate. Additional guidance regarding the use of an Independent IRB can be found under the specific

policy.

Training of IRB chairs and members The IRB Director or designee provides orientation for new members on an annual basis. Current IRB

members are encouraged to attend as well. Each new member receives a packet of IRB reference

materials. The IRB Director, in consult with the IRB Chairs and staff, will determine the content of the

packet. All IRB members must complete the requirements for education in human subjects research

established by the institution. These requirements include the CITI training for IRB members. New IRB

members are also invited to observe a board meeting prior to being listed on the IRB roster. If new

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appointees to the board do not attend the training sessions, they will not be assigned applications to

review and will not be allowed to vote at convened meetings until training has been completed with the

IRB Director or staff.

For research sponsored by the Department of Defense, initial and continuing research ethics education for

all personnel who conduct, review, approve, oversee, support, or manage human subject research is

required. Education should be appropriate for individual’s level of involvement, duties, and

responsibilities.

The IRB Director, in consult with the IRB Chairs and staff, will establish means and materials that meet

continuing education requirements. The IRB Director periodically provides IRB members copies of articles

related to issues relevant to human research from various sources. Copies of these articles are maintained

in the IRB Office.

The IRB Office maintains a library of reference material, books and conference material for the use of IRB

members, IRB staff, researchers and others interested in human research.

Evaluations Board members will be asked to periodically complete an anonymous online survey to evaluate the

effectiveness of the IRB Chair as well as IRB staff. Likewise, a survey will be sent to Chairs and IRB staff to

evaluate the effectiveness of each board member on the Chair and Staff member’s board. In addition, a

random sample of investigators will be sent an anonymous survey evaluating the effectiveness of the IRB.

Categories included in the survey may include but are not limited to, timeliness of response, compliance

with federal regulations, usefulness of templates and other research material, preparedness for convened

meetings, quality of educational opportunities, and meeting conduct. Based on the responses to this

survey each member will receive individual feedback, and the IRB staff will focus education topics and

training based on the responses and feedback from the evaluation results. Meeting attendance, as well as

the timeliness and quality of protocol reviews will be regularly tracked by IRB staff for their assigned board

members. This information will also inform the evaluation process and educational needs of board

members.

The HRPP will undergo an annual assessment to evaluate compliance with policies and identify areas of

poor quality or inefficiency. This assessment will be conducted by the IRB Director with assistance from

the Human Research Monitoring and Oversight Specialist, and other designated staff members as needed.

One goal of this assessment is to ensure compliance with applicable federal, state, and institutional

regulations. This can be done by a review of meeting minutes from each board in order to assess the

needs for quorum and the appropriate vote counts and documentation for each agenda item. If areas for

improvement are identified, the IRB Director will provide staff and board members with appropriate

education on the area(s) in need of improvement, in order to ensure compliance. A second goal of this

evaluation will be to monitor the efficiency of the review process. An example of this assessment will be

calculating the average number of days from submission to approval of initial applications, amendments,

and continuing reviews. A summary of findings and reports will be filed and stored in the HRPP office for

future comparison and evaluation of progress. A third goal of the evaluation is to assess the plan and

methods for enhancing the understanding of participants, prospective participants and communities.

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References:

21 CFR 56.107

45 CFR 46.107

DoDD 3216.2, para 4.5

SECNAVINST 3900.39D para. 6a(2)

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5.0 Operations of the IRB

Schedule of Meetings The IRB shall meet at regular intervals to discuss submitted proposals in detail and reach a decision on

each submission. A schedule of regular IRB meetings is established by the IRB Director in consultation with

IRB Chairs, and will be published annually. The date, time, and place of each meeting is provided to

members as part of the review material distributed prior to each meeting. The schedule will provide for

an IRB meeting four days per week. Each committee will meet on alternating weeks, and therefore a total

of sixteen to twenty meetings will be held each month to ensure the timely review or re-review of

research.

The IRB Director or any IRB Chair may call the IRB into special session outside the published schedule of

meetings. If the IRB is appropriately constituted at such special meetings the IRB may review and act on

protocol submissions and conduct any other business.

Quorum requirements A simple majority of the membership listed in the most current version of the IRB’s OHRP Assurance

constitutes a quorum, and is required to convene a meeting and for each vote on a protocol. The quorum

must include at least one member whose primary expertise are in nonscientific areas and at least one

member whose primary expertise is in scientific areas. If at any time during the meeting a quorum is lost

the Board may not vote on material until a quorum is reestablished. The Chair or designee will establish

that the requirements for a quorum are met and maintained throughout the meeting. The Protocol

Analyst will document in the electronic IRB system (eIRB) that quorum was obtained and maintained

through the meeting. This information will be documented in the minutes of the meeting.

Technology use in IRB meetings A laptop computer will be provided for each IRB member during the meeting in order to facilitate

reference to each protocol submission and reviewer checklist during discussion. The electronic submission

and IRB record system (eIRB) will be made available to Board members at all times for review of submitted

protocols prior to the meeting. The system will be accessible from any device with internet access and the

appropriate individual account login and password for member convenience. Teleconferencing or video-

conferencing may be used to allow for the attendance of one or more members who cannot physically

attend the meetings. When utilizing teleconference or videoconference technology, the members will

present the studies assigned to them, discuss concerns and vote on all studies, as they would if they were

physically present. Members who will be participating in the meeting remotely will have access to all

study materials through eIRB the same as members who attend in person.

Agenda The agenda will be generated by the electronic submission system (eIRB) and will consist of the material

submitted and ready for review by the end of business approximately seven days prior to the next Board

meeting. All IRB members will have access to the agenda and all submission materials prior to the

meeting in order to view material and conduct reviews. In rare instances, exceptions may be made to add

a research study to the agenda less than seven days prior to the meeting, when circumstances warrant.

The total number of items to be reviewed, including protocols, noncompliance issues, and unanticipated

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problems, will vary at each meeting. IRB staff will assign studies to members for review and will ensure

that each member is comfortable with the number of studies assigned to him or her so that research is

carefully reviewed. Each agenda will contain the list of submissions reviewed and approved by the

expedited process. For the expedited studies, the agenda will contain the study title, the name of the

principal investigator, the Primary IRB Reviewer, the date of approval and a link to the study workspace in

eIRB, where the full IRB record is stored.

The material provided to members for review will consist of the entire IRB file, via the electronic IRB

record system (eIRB). The IRB application will consist of all information necessary to evaluate the study,

including but not limited to:

The purpose of the research;

The scientific rationale for conducting the study;

The setting in which the research will be conducted;

Whether prospective participants will be vulnerable to coercion or undue influence;

The inclusion/exclusion criteria;

Participant recruitment and enrollment procedures;

The information contained in any advertisement;

The mode and final version of all advertising;

A description of the procedures being performed already for diagnostic or treatment purposes

(standard of care procedures).

The amount and timing of payments to participants;

The risks and potential benefits of participation in the research

Voting requirements Voting may only occur when a properly constituted quorum is established. Members may vote for,

against, abstain or recuse from voting. A member may abstain from any vote without a need to state a

reason. Abstaining members continue to count toward a quorum. Members who are the principal

investigator, listed co-investigator or who have a potential or actual conflict of interest should recuse

themselves rather than abstain. In such instances, that individual will not be counted toward IRB quorum

requirements for the review of that protocol. The minutes will indicate when a member leaves the

meeting for reasons other than to recuse and is not present for the vote. The member will not be listed as

having voted for, against or abstain. If an investigator, co-investigator or other individual associated with a

research study being considered by the IRB is present as a visitor, they must not be present during the

discussion and vote for that research study.

A separate vote is taken and recorded for each protocol. Voting is limited to duly appointed IRB members

in attendance at a properly convened meeting.

Decisions are based on a majority vote of the members in attendance at a convened meeting. Majority is

defined here as greater than or equal to 51% of members in attendance. If a majority vote for or in the

affirmative, the motion passes or carries; otherwise the motion does not pass or fails. All members in

attendance at a convened meeting have full voting rights for all items of business, except if they are

required to recuse themselves for actual or potential conflicts of interest. The minutes will list the number

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voting for, against, abstaining and recusing. The identity of members who recuse themselves from a vote

will be listed in the minutes. Chairs will vote on all protocols for which they do not have a real or perceived

conflict of interest. In the case of a tie vote, the IRB may defer to another board.

Criteria for IRB approval of research In order to approve research, the IRB must find that:

1. Risks to subjects are minimized:

a. By using procedures which are consistent with sound research design and which do not

unnecessarily expose subjects to risk, and

b. Whenever appropriate, by using procedures already being performed on the subjects for

diagnostic or treatment purposes

2. Risks to subjects are reasonable in relation to the anticipated benefits, if any, to subjects, and the

importance of the knowledge that may reasonably be expected to result. In evaluating risks and

benefits, the IRB should consider only those risks and benefits, the IRB should consider only those

risks and benefits that may result from the research (as distinguished from risks and benefits of

therapies subjects would receive even if not participating in the research). The IRB should not

consider possible long-range effects of applying knowledge gained in the research (for example,

the possible effects of the research on public policy) as among those research risks that fall within

the purview of its responsibility. The IRB should consider physical, psychological, social, economic,

and legal risks.

3. Selection of subjects is equitable. In making this assessment the IRB should take into account the

purposes of the research and the setting in which the research will be conducted and should be

particularly cognizant of the special problems of research involving vulnerable populations, such

as children, prisoners, pregnant women, mentally disabled persons, or economically or

educationally disadvantaged persons. The IRB should also consider the Inclusion/Exclusion criteria

as well as the proposed recruitment and enrollment procedures, as well as the amount and timing

of payment to participants.

4. Informed consent will be sought from each prospective subject or the subject’s legally authorized

representative, in accordance with, and to the extent required by 45 CFR 46.116 or 21 CFR 50.25

5. Informed consent will be appropriately documented, in accordance with , and to the extent

required by 45 CFR 46.117 or 21 CFR 50.27

6. When appropriate, the research plan makes adequate provisions for monitoring the data collected

to ensure the safety of subjects. The IRB may consider the following criteria to determine whether

data and safety monitoring is required: studies involving greater than minimal risk, large study

populations, multi-site studies, research involving dangerous procedures, research with a high

chance of study termination.

7. When appropriate, the research plan makes adequate provisions to protect the privacy of subjects

and to maintain the confidentiality of data

8. When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such

as children, prisoners, pregnant women, mentally disabled persons, or economically or

educationally disadvantaged persons, additional safeguards have been included in the study to

protect the rights and welfare of these subjects, in order to be approved

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9. The IRB considers the purposes of the research, scientific or scholarly rationale, procedures to be

performed, and the difference in standard of care treatment vs. research protocol procedures.

10. The IRB must also find that the research study has adequate resources necessary to protect

participants, including:

Adequate time for the researchers to conduct and complete the study

Adequate number of qualified staff

The professional qualifications, experience and training of the investigators to conduct the research

study

Adequate facilities

Adequate access to the study population to allow for the necessary recruitment

Availability of any medical or psychological resources participants may need as a consequence of the

research

When the research is supported by the Department of Defense, the IRB should consider the appointment

of a research monitor if the study is greater than minimal risk, although the IRBs can require this for a

portion of the research or studies involving no more than minimal risk if appropriate. The independent

research monitor will be appointed by name. The research monitor has the authority to:

Stop a research study in progress

Remove individuals from a study.

Take any steps to protect the safety and well-being of subjects until the IRBs can assess the events.

When following ICH-GCP guidance, the investigator informs the participant’s primary physician about the

participant’s participation in the clinical trial if the participant has a primary physician and if the

participant agrees to the primary physician being informed. Furthermore, although a participant is not

obliged to give his or her reasons for withdrawing prematurely from a clinical trial, the investigator makes

a reasonable effort to ascertain the reason, while fully respecting the participant’s rights.

Further review/approval of IRB actions Research studies approved by the IRB may be subject to further review and approval or disapproval by

officials of the institution. These officials may not approve any research study that has been disapproved

by the IRB or that has not received full approval by the IRB. No external body, Institutional Official or other

individual may approve the conduct of a research study that has not received the full approval of the IRB.

The decision of the IRB to disapprove a research study cannot be overturned by an external body,

Institutional Official or other individual.

Appeal of IRB decisions To appeal a decision of the IRB, an Investigator must send a written statement with the reasons for appeal

to the IRB Chair of the Board which disapproved the study or the IRB Director. This statement will be

distributed to all members of the IRB and the research study will be scheduled for reconsideration at a

future IRB meeting of a different board. The investigator will be invited to attend this meeting to give a

presentation of information supporting his/her reason for appeal and will respond to any question posed

by the IRB. The IRB may establish by vote, limits on the extent and length of the investigators

presentation. The IRB will discuss and vote on the research study and the investigator’s appeal. No further

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appeal of this decision is then possible. An investigator may not further appeal an IRB decision regarding

an appeal. The investigator must not be present for the discussion or vote on their appeal.

Appeals of IRB decisions must be made within 30 days the investigator receiving written notice of the IRB

decision. If reconsideration is granted the study would be considered by a neutral IRB within the

institution that is free of any potential conflicts of interest.

Scientific Validity Proposed research will be evaluated to protect human subjects, but also will be evaluated for scientific

validity, either by the IRB or an external entity. When a study is unsponsored, the IRB will serve to provide

a scientific and ethical review. IRB members will follow the same guidance as used for National Institute

of Health reviewers when conducting a review of scientific validity and will be documented in the

reviewer’s checklist. Examples of the items under consideration include the use of procedures consistent

with sound research design and the whether the design of the study is expected yield the expected

knowledge.

For research sponsored by the Department of Defense, that is non-exempt, the IRB must consider the

scientific merit of the research. The IRB may rely on outside experts to provide an evaluation of the

scientific merit. Substantive amendments to approved research undergo scientific review prior to IRB

review.

When following ICH-GCP guidance, reviewers should evaluate the available nonclinical and clinical

information on an investigational product is adequate to support the proposed clinical trial. Reviewers

should also determine if clinical trials are scientifically sound based on the protocol provided.

References:

45 CFR 46.111

45 CFR 46.108(b)

45 CFR 46.107(e)

45 CFR 46.115(a)(2)

45 CFR 46.112

21 CFR 56.111

21 CFR 56.108(c)

21 CFR 56.107(e)

21 CFR 56.115(a)(2)

21 CFR 56.112

ICH-GCP 2.4

ICH-GCP 2.5

ICH-GCP 3.1.3

ICH-GCP 4.3.3

ICH-GCP 4.3.4

ICH-GCP 4.8.3

SECNAVINST 3900.39D, para 8c(6)

FDA Self-Evaluation checklist for IRBs - 1998

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6.0 IRB Record Retention

Written procedures and guidelines The IRB will prepare, maintain, follow, and retain written procedures for all of its functions and operations

including:

Conducting initial and continuing review of research

Reporting its findings and actions to the investigator and the institution

Determining which projects require review more often than annually and which projects need

verification from sources other than the investigator that no material changes have occurred since

previous review

Ensuring prompt reporting to the IRB of changes in research activity

Ensuring that during the period for which IRB approval has already been given, no change in the

approved research may be initiated without prior IRB review and approval, except when necessary to

eliminate apparent immediate hazards to the human subjects

Ensuring prompt reporting to the IRB, appropriate Institutional Officials, Sponsor, Office of Human

Research Protections, and the Food and Drug Administration, as applicable, of any unanticipated

problems involving risks to human subjects or others, any instances of serious or continuing

noncompliance with these regulations or requirements, relevant determinations made by the IRB, or

any suspension or termination of IRB approval for the research.

IRB membership roster The IRB shall prepare and maintain a list of IRB members and alternates identified by name, earned

degree, representative capacity, indication of experience sufficient to describe each member’s chief

anticipated contributions to IRB deliberations, and any relationship between each member and the

Institution. Changes in IRB membership shall be reported promptly by the IRB Director or representative

to OHRP. The IRB membership roster will be provided by the IRB Office to investigators, sponsors, funding

agencies, and regulatory agencies as required by regulation or contract. Copies of the IRB membership

roster may be obtained through Freedom of Information from OHRP by any other individuals.

Minutes of meetings The IRB shall prepare and maintain adequate documentation of IRB activities by recording minutes of IRB

meetings in sufficient detail to show:

Attendance at the meetings

When an alternate member is a proxy for a primary member

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A separate list of any consultants, guests, or others who attended each meeting

Separate deliberations, actions and votes for each protocol undergoing review by the convened IRB

The basis for requiring changes in or disapproving research

A written summary of the discussion of controverted issues and their resolution

Documentation, including protocol-specific information, justifying:

o A consent procedure which does not include or which alters some or all of the required

elements of informed consent

o Waiving the requirement to obtain informed consent

o Waiving the requirement to obtain individual authorization

o Approving research involving pregnant women, human fetuses, or neonates Approving

research involving prisoners

o Approving research involving children

The frequency of continuing review, as appropriate to the degree of risk, and/or time interval for

submission of progress reports

When following FDA regulations, the rationale for significant risk/non-significant risk decisions for

medical devices

The vote on all IRB actions including the number of members voting for, against, abstaining or recusing

for actual or potential conflict of interest. Recused members shall be listed by name and the reason for

recusal.

When following DHHS regulations, the justification of any deletion or substantive modification of

information concerning risks or alternative procedures contained in the DHHS-approved sample

consent document.

Procedures for reporting actions to the institution The IRB shall prepare monthly reports of all new applications approved for that particular month which will

be sent to appropriate institutional representatives. This report will include all pertinent findings and

actions of the IRB as well as investigations of serious and/or continuing non-compliance with human

subjects research.

Retention of documents by the IRB The IRB shall prepare and maintain adequate documentation of IRB activities for at least 6 years after

study closure. All records shall be accessible for inspection and copying by authorized representatives of

the federal agencies (OHRP, FDA) or the sponsor at reasonable times and in a reasonable manner. Records

are stored in a way that protects confidentiality. IRB records for a protocol are organized to allow a

reconstruction of a complete history of IRB actions related to the review and approval of the research

protocol. For each protocol reviewed by the IRB, the retained records shall include:

The research proposal reviewed

Any accompanying grant application, investigator brochures or external scientific evaluations

Copies of all correspondence between the IRB and the investigators Recruitment materials

The approved consent documents and if applicable the approved assent documents

Reports of any unanticipated problems involving risks to subjects or others, including adverse events

and/or injuries

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Records of initial and continuing review

Records of review of additions, revisions and amendments to the protocol and/or consent documents,

investigator brochure, etc., and if applicable the assent documents

Data and safety monitoring reports

Progress reports submitted by investigators and statements of significant new findings provided to

subjects

Emergency use reports

Documentation of study closure

Documentation of non-compliance

Scientific evaluations, when these are provided by an entity other than the IRB

For research applications reviewed by expedited procedure, the IRB will maintain records of:

The justification for using the expedited procedures and the specific permissible category

Actions taken by the reviewer

Any findings required by laws, regulations, codes, and guidance

For research applications approved as Exempt, the IRB will maintain records of:

The justification for exemption determinations

Actions taken by the reviewer

Any findings required by laws, regulations, codes, and guidance

For protocols that are withdrawn or closed prior to enrolling a subject, IRB records will be maintained for

at least three years after withdrawal/closure.

Budgets, accounting records, and study data are not retained by the IRB. The principal investigator is

responsible for retaining documentation pertaining to budgets, accounting records, and study data, and

making these records available upon request to the Institutional Official or their designee, or regulatory

agencies.

References:

45 CFR 46.108(a)

45 CFR 46.115

45 CFR 46.116(d)

45 CFR 46.117(c)

45 CFR 46.204-207

45 CFR 46.305-306

45 CFR 46.404-407

45 CFR 164.512(i)(2)(ii)

45 CFR 164.530(j)

21 CFR 50.50-56

21 CFR 56.108

21 CFR 56.115

ICH-GCP 3.2.2

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ICH-GCP 3.4

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7.0 Determination if an activity qualifies as human subjects research

Not human subjects research Certain types of research activities may be designated as Not Human Subjects Research (NHSR), and hence

are not governed by federal regulations for the protection of human research subjects (45 CFR Part 46) and

do not require review and approval by the IRB. Investigators who believe their research activities involves

data about humans, qualifies as NHSR are strongly advised to seek the advice and counsel of the IRB

before engaging in any research activities in order to determine whether the research may be designated

NHSR. Conducting human subjects research without IRB approval, even if it is mistakenly thought to be

NHSR, can jeopardize the entire Human Subjects Protection Program and lead to serious penalties by

federal authorities as well as individual sanctions.

Definitions Research is defined by several agencies. Activities that meet any of these definitions are considered to be

research. Listed below are the agency specific definitions for research.

DHHS: a systematic investigation, including development, testing, and evaluation, designed to

develop or contribute to generalizable knowledge

Systematic Investigation refers to an activity that involves a prospective research plan

which incorporates data collection, either quantitative or qualitative, and data analysis to

answer a research question.

Generalizable knowledge refers to information that is produced for the purposes of

dissemination to a scientific audience outside of the population served by the covered

entity. Some examples include information collected for the purposes of doctoral theses;

presentation at a scientific meeting or conference; submission to or publication in a

scientific journal; and Internet postings.

FDA: Any experiment that involves a test article and one or more human subjects, and that either

must meet the requirements for prior submission to the Food and Drug Administration under

section 505 (i) or 520 (g) of the Federal Food, Drug, and Cosmetic Act or need not meet the

requirements for prior submission to the Food and Drug Administration under these sections of

the Federal Food, Drug, and Cosmetic Act, but the results of which are intended to be later

submitted to, or held for inspection by, the Food and Drug Administration as part of an application

for a research or marketing permit. The terms research, clinical research, clinical study, study, and

clinical investigation are synonymous for purposes of FDA regulations. (21 CFR 50.3(c), 21 CFR

56.102(c)).

DoD: an activity, for research purposes, where there is an intervention or interaction with a human

being for the primary purpose of obtaining data regarding the effect of the intervention or

interaction

Belmont Report: an activity designed to test a hypothesis [and] permit conclusions to be drawn

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Human Subjects are defined differently by several agencies. Individuals that meet any of these definitions

are considered to be the object of the research at WFUHS. Listed below are the agency specific definitions

for research.

DHHS: obtains (1) data through intervention or interaction; (2) identifiable private information

FDA: Human subject means an individual who is or becomes a participant in research, either as a

recipient of the test article or as a control. A subject might be either a healthy individual or a

patient. For research involving medical devices a human subject is also an individual on whose

specimen an investigational device is used.

When medical device research involves in vitro diagnostics and unidentified tissue specimens, the

FDA defines the unidentified tissue specimens as human subjects.

Intervention or interaction refers to both physical procedures by which data are gathered

(for example, venipuncture) and manipulations of the subject or the subject's environment

that are performed for research purposes (for example, conducting a focus group).

Interaction also includes communication or interpersonal contact between the principal

investigator and subject.

Identifiable Private Information refers to

1) information obtained from or about subject (s) that is individually identifiable,

that is be used by a third party to directly identity subject (s) (for example, names,

addresses, social security numbers). The OHRP considers private information or

specimens to be individually identifiable when they can be linked to specific

individuals by the investigators either directly or indirectly by a coding system.

2) Information which has been provided for specific purposes by an individual and

which the individual can reasonably expect will not be made public (for example, a

medical histories and records).

3) Information about subject’s behavior that occurs in a context in which an

individual can reasonably expect that no observation or recording is taking place.

Obtaining here refers to an investigator’s use, study, or analysis for research purposes of identifiable

private information or identifiable specimens for research purposes, including private information or

identifiable specimens already in the possession of the investigator.

Criteria for consideration that a study is not human subjects research A study can NOT be considered to be Not Human Subjects Research if

1) The research involves obtaining in the future, any identifiable private information or identifiable specimens

for research purposes

2) The research involves pregnant women, human fetuses, embryonic stem cells, in vitro fertilization, or

prisoners

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A study MAY be considered to be Not Human Subjects Research if

1) It does not meet the federal definition of research (for example, a case report or a quality

improvement project). In such cases, investigators are encouraged to consult IRB guidance regarding

case reports and quality improvement/assurance projects.

2) It does not involve the use of data, information, or biological specimens obtained from human

subjects, whether living or deceased (for example, studies using biochemicals, using laboratory

animals, or non-human cell lines).

3) It involves the use of data, medical records, publicly obtainable information, or specimens obtained

from individuals who are no longer living. However in certain circumstances before a determination of

NHSR is issued, investigators may be required to furnish the IRB with the methodologies that will be

used to assure that the individuals under study are in fact deceased, and may still be subject to the

HIPAA and Privacy Rule regulations.

4) It involves the use of data that does not contain ANY codes or links to identifiable information. This can

be obtained via the safe harbor method (removal of all links, codes, and HIPAA identifiers) or through

consultation with a qualified statistician that the identities of subjects are secure and cannot readily be

linked to the study data.

5) It involves the use of only coded private information or specimens if the following conditions are met

a) the private information or specimens were not collected specifically for the currently proposed

research project by interaction or intervention with living individuals

b) the investigators cannot readily ascertain the identity of the individuals to whom the coded private

information or specimens pertain because

i) the key to decipher the code is destroyed before the research begins

ii) the investigators and the holder of the key enter into an agreement prohibiting the release of

the key to the investigators under any circumstances, until the individuals are deceased

iii) IRB-approved written policies and operating procedures for a repository or data management

center prohibit the release of the key to the investigators under any circumstances, until

individuals are deceased

iv) there are other legal requirements prohibiting the release of the key to the investigators, until

the individuals are deceased

Note that if the investigator(s) at any time obtain the uncoded private information or specimens, or

unexpectantly learn the identity of one or more living individuals or believes it is important to determine

the identity of one or more of the individuals, the research becomes human subjects research as defined

by the federal regulations. If such events occur, the investigator should file a protocol deviation and an

amendment. The IRB will then review the protocol under the appropriate review category before further

research may be conducted.

Determination and notification that a study is not human subjects research The IRB Director, IRB Chair, or a qualified designee of the Chair is responsible for determining whether a

submission qualifies as NHSR under the federal regulations and guidance provided by OHRP, and may

require modifications to the submission prior to making that determination.

Investigators have the ability to conduct research that does not involve human subjects without seeking

IRB approval, however if there is any doubt as to whether a project qualifies as human subjects research,

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then they should always err on the side of caution and submit an application to the IRB. If submitted to the

IRB, researchers may not initiate a study prior to receiving a memorandum from the IRB declaring it to be

NHSR or approved human subjects research. Each project requires a separate review and determination

for NHSR. Please note, that if an official determination statement is required from the IRB for publication

purposes, this can only be granted prior to initiation of the research project. The IRB cannot review

research that has already occurred.

Research conducted on deceased people is still subject to HIPAA privacy laws if PHI is collected as part of

the research study. A research application must be submitted for IRB review because the IRB serves as the

Privacy Board. In order to maintain the confidentiality of the research data, a research study application

should be submitted to the IRB to list the data being collected. Research only involving deceased persons

will be considered NHSR, but protections for PHI must be in place.

If the submission is determined to be NHSR, the IRB will send the principal investigator a written or

electronic notification which will include: 1) a statement that the IRB has determined the research to be

NHSR; 2) a statement that the IRB must be informed of any changes to a project, so that it can determine

whether the project continues to meet the requirements for NHSR. If the submission requires any

modification, the investigator is notified of the needed changes. The requested changes should be made

within 30 days of the request; otherwise the submission may be withdrawn and a new submission required

for the research study to be conducted. A memorandum with the information listed above is provided only

after changes have been made, reviewed, and approved by the IRB Director, IRB Chair, or designee. The

IRB is informed of all submissions determined to be NHSR as information items on future agendas.

If it is determined that a submission does not meet the criteria for NHSR, the IRB will notify the principal

investigator and the submission will be referred for review through either exempt procedures, expedited

procedures, or full board review along with the reviewer’s comments and any reviewer recommendation

for consideration and final determination.

Research studies declared NHSR by the IRB must be conducted in the same ethical manner and with the

same respect for the privacy and confidentiality of research subjects as those studies approved by the Full

IRB or by Expedited and Exempt Review.

When following DoD requirements, non-exempt classified must be conducted following the requirements

of Instruction 3216.02 13.

References:

21 CFR 50.3(c)

21 CFR 50.3(g)

38 CFR 16.102(d)

38 CFR 16.102(f)

45 CFR 46.101

45 CFR 46.102(d)

45 CFR 46.102(f)

DoD Directive 3216.2 E2.1

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8.0 Initial Submission

Required materials All applications submitted for IRB review are screened for complete documentation as well as a

preliminary review by IRB office staff. If concerns or omissions are noted, then the application is returned

to the investigator through the eIRB system. For applications to be reviewed by the full IRB, board

members will be assigned protocols to review prior to their scheduled meeting. All submissions, no matter

the review type are required to submit the following material, when applicable:

completed e-IRB application and submitted by the Principal Investigator

completion of conflict of interest questions by all study team members

written protocol document

if industry sponsored, then a written protocol document is required

If federally sponsored, then a written protocol using the WFUHS template is required (a grant

document is not an acceptable substitute in lieu of a protocol document)

consent or assent document(s) containing compounded HIPAA language when applicable

fact or information sheets

recruitment materials

questionnaires, focus group guides, scripts or other data collection forms

other materials specific to the proposed study (grant application, investigator’s brochure, sponsor

correspondence with a regulatory agency such as the FDA regarding test item risk)

documentation of review from other committees or institutions

data use agreements

documentation of IRB approval from a study coordinating site

FDA regulatory documentation when an IND or IDE is involved

Level of review The possible review types are described below and correspond to the level of potential risk of harm to the

subjects within the proposed research. Each type of review is discussed in more detail in its respective

section of this document.

Full board Review

Expedited Review

Exempt Review

Facilitated Review

Not Human Subjects Research

VA Collaboration

Determination of review type The electronic submission system (eIRB) will guide investigators to the appropriate review category based

on the level of risk and potential benefits associated with the study protocol. Upon submission, IRB staff

and/or board will review the entire application. If the staff or committee does not agree with the level of

review selected by the investigator, a different level may be suggested, and the application returned to the

investigator for revision.

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9.0 Full Board Review of Research

Full board review of research Complete applications received by the IRB Office are assigned for review at the next available IRB meeting.

An application may be assigned for review by an IRB other than the next available IRB by the IRB Staff, IRB

Director or IRB Chair to ensure review by an IRB with appropriate experience and expertise necessary to

conduct a thorough review of the research or to facilitate IRB workflow. Applications may be returned to

the principal investigator without IRB review if they are determined to be incomplete or contrary to

regulations or policies and procedures. In such case the principal investigator will be informed of the

deficiency in the initial submission.

At least one primary reviewer will be assigned to each protocol scheduled for initial review by the full IRB.

Additional primary reviewers may be assigned to each submission based on the complexity of the

application/protocol and the need to ensure adequate review. Reviewers will be assigned by the IRB

Protocol Analyst responsible for the respective board in consultation with the IRB Director, IRB Chair or

designee, as needed, to ensure that protocols are reviewed by board members with appropriate expertise.

An IRB Protocol Analyst will also evaluate each protocol and ensure that at least one IRB member

knowledgeable about or experienced in working with vulnerable populations will be present at the

meeting when research involves such subjects, or has provided commentary for consideration by the

board.

Before the scheduled meeting, for each initial submission the primary reviewer(s), and all IRB members

including alternates scheduled to attend in place of a regular member, will receive all submitted materials

including but not limited to the full protocol, any recruitment materials intended to be heard or seen by

the potential subject(s), the proposed informed consent document and if applicable the assent document,

the investigator’s brochure if one exists, and any relevant grant applications to allow them to make the

determinations required by 45 CFR Part 46.111 and 21 CFR Part 56.111. Applications are assigned to

primary reviewers, for an in- depth review, in advance of the scheduled board meeting. Applications will

be viewable through the eIRB, the electronic protocol submission software. All IRB members will have

access to the meeting agenda and associated documents in advance of the meeting through the eIRB

system. Primary reviewer(s) are encouraged to request additional information from the investigators,

prior to the meeting either anonymously through IRB staff or directly if this is needed to complete their

review. The primary reviewer(s) will review the proposal prior to the scheduled meeting and will provide

written comments and concerns about the submission to the IRB Office. All IRB members are expected to

review submissions so that they can individually determine whether the research meets regulator criteria

for approval.

At the scheduled meeting each protocol will be presented by a primary reviewer in sufficient detail to

allow consideration by the full IRB, followed by the comments of any other primary reviewers. The IRB

Chair will present or may designate a member of the IRB or IRB staff to present the protocol if a primary

reviewer(s) is not available but has provided their written comments. The written comments of any

reviewers not present at the meeting will be presented. Following presentation by the primary reviewer(s),

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the IRB Chair will open the floor for discussion and deliberation by the full IRB. Following discussion and

deliberation, the IRB Chair will ask for a recommendation on the course of action. Any IRB member may

put forth a motion.

At the scheduled meeting each protocol will be presented by a primary reviewer in sufficient detail to

allow consideration by the full IRB, followed by the comments of any other primary reviewers. The IRB

Chair will present or may designate a member of the IRB or IRB staff to present the protocol if a primary

reviewer(s) is not available but has provided their written comments. The written comments of any

reviewers not present at the meeting will be presented. Following presentation by the primary reviewer(s),

the IRB Chair will open the floor for discussion and deliberation by the full IRB. Following discussion and

deliberation, the IRB Chair will ask for a recommendation on the course of action. Any IRB member may

put forth a motion.

The IRB may reach one of the following decisions regarding each protocol:

Approval as submitted and the duration of approval.

Approval with minor modifications and the duration of approval. Minor modifications must require

only simple attention to and concurrence by the principal investigator. This action authorizes the IRB

Chair or designee to grant final approval upon verification that the principal investigator has made the

specified modifications.

Postpone: this action defers discussion and action on the application due to the primary reviewers

being absent from the meeting and having not submitted their comments.

Table: This action proposes further review by the full IRB pending major revisions to the application,

receipt of additional information related to the application, or when substantial issues have been

identified that require the response of the principal investigator to IRB concerns. Any time the IRB

requests substantive clarifications or modification that may affect the risk determination or any other

regulatory criteria for approval of a proposed study; it should be tabled and reviewed again by a

convened meeting of the full board. Upon full IRB review of the requested materials or response, a

new motion will then be put forth for vote.

Disapproval: This action indicates the IRB believes approval of the protocol is unwarranted.

Resubmission of a previously disapproved protocol requires full IRB review and approval.

The decision of the IRB regarding each application will be provided to the principal investigator

electronically or in writing. If the application is approved, the principal investigator will be notified of the

type of review, the expiration date of IRB approval, that IRB review will be required before any changes are

made unless necessary to eliminate any apparent immediate hazard to the subjects, that continuing

review is required if the project will continue beyond the approval period and the requirement to report

promptly any unanticipated problems involving risks to subjects to the IRB.

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If the application is approved with minor changes, the principal investigator will be notified of the required

changes. The requested changes should be made within 30 days of the date concerns were communicated

by the IRB Office. A full approval memorandum with the information listed above will be provided only

after the minor changes have been made and reviewed and approved by the Chair or designee. If the

application is postponed or tabled, the principal investigator will be notified of the reason and any

information or changes that are required should be submitted to the IRB within 60 days. Any response to a

postponed or tabled application must be returned to a convened IRB for further consideration and action.

Tabled applications are generally returned to the IRB that initially tabled the application. Applications that

are postponed due to the absence of the primary reviewers are typically scheduled for the next available

IRB meeting to reduce any further delays in starting the research project. Applications which are tabled

can be scheduled for review at another board. An IRB asked to review a postponed application that it did

not initially review may, at the discretion of the chair, decline to consider the postponed application and

refer it back to the IRB that reviewed it initially.

If an application is disapproved, the principal investigator will be notified of the reason and the process for

appealing the decision.

Approval period All research studies approved by the full board are subject to continuing review at an interval appropriate

to the degree of risk but not to exceed every 12 months. The date of the convened IRB meeting at which

the protocol was reviewed and approved either without changes or contingent upon specified changes is

the date from which the duration of approval is set. The study will be approved for a maximum of 364 days

from the date of initial approval. For example if a study approval date is set on 1/1/2010, then the study

will expire if not renewed by 12/31/2010. A memorandum of approval and stamped informed consent

form are issued only after all specified changes have been made to the IRB’s satisfaction. No part of the

protocol can be initiated until full IRB approval is received by the principal investigator.

DoD sponsored research When following Department of Defense requirements, the following must be promptly (no longer than

within 30 days) reported to the DoD human research protection officer:

When significant changes to the research protocol are approved by the IRB.

The results of the IRB continuing review.

Change of reviewing IRB.

When the organization is notified by any Federal department, agency, or national organization that

any part of an HRPP is under investigation for cause involving a DoD- supported research protocol.

References:

45 CFR 46.103(b)(4)

45 CFR 46.111

21 CFR 50.25(b)(5)

21 CFR 56.111

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DoD: Instruction 3216.02 4.b.4

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10.0 Expedited Review of Research

Federal regulations identify certain categories of research activities involving human subjects that may

qualify for expedited review under the federal regulations for the protection of human research subjects

(45 CFR 46 and 21 CFR 56).

Criteria for consideration of expedited review

To qualify for Expedited review status, a research study must meet two criteria:

1. The research cannot place the subjects at any greater than minimal risk

2. It MUST fall entirely within one or more of the nine categories for expedited review

Determination and notification of expedited status An expedited review process may be utilized in accordance with the federal regulations (45 CFR

Part 46 and 21 CFR Part 56). An investigator may submit research studies, amendments or changes to

existing research studies, and continuing review of approved research studies for expedited review. The

same materials are required for review regardless of whether it is ultimately reviewed under the full board

or expedited process. An application initially reviewed by the full IRB may be reviewed through expedited

review processes if it is no greater than minimal risk to the subjects and qualifies according to the federal

regulations under category 8 or 9. The IRB is not required to review research proposals through the

expedited review process, even if it appears to qualify under the federal regulations for such review. The

decision to review an application through the expedited review process or to refer to the full IRB for

review is made by the IRB Director and/or IRB Chairs, or designee.

The IRB Chair or their designee is responsible for the expedited review of IRB applications. They may

approve the application or require modifications to the application, protocol, consent and accompanying

documents prior to approval. A reviewer’s checklist will be completed for each application to document

the reviewer’s comments, concerns, and recommendations. The IRB Chair or their designee may not

disapprove submissions through the expedited review process. If a study is not able to be approved by

expedited review procedures, the principal investigator is notified and the submission is referred to the full

IRB along with the reviewer’s comments and recommendations for consideration and final determination.

The full IRB is informed of all submissions approved through expedited processes as informational items on

the meeting agenda that is distributed via eIRB for each meeting. Each item will have a link to the

complete study application from the agenda.

The principal investigator is notified electronically or in writing of the outcome of the expedited review. If

the submission is approved, the principal investigator is notified of the type of review, the category within

which the study qualifies, the expiration date of IRB approval, that IRB review is required before any

changes are made unless necessary to eliminate an apparent immediate hazard to the subjects, that

continuing review is required if the project will continue

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beyond the approval period and the requirement to report promptly any unanticipated problems

involving risks to subjects. If the submission requires modification, the principal investigator is

notified of the needed changes. The requested changes should be made within 30 days of the date

concerns are submitted to the study team. The study team can ask for an extension, otherwise the

application may be withdrawn and a new application is required for the research study to be

conducted. A full approval memorandum with the information listed above, along with a stamped

informed consent (if applicable), is provided only after changes have been made, reviewed, and

approved by the Chair or designee.

IRB members who possess relevant scientific expertise and experience and have participated on the

IRB as a full voting member for at least two years may be designated by the IRB Chair as the primary

and sole reviewer and approver of expedited submissions. The IRB Director and Associate Director are

appointed as alternate members of the IRB and may serve as alternate for the Chair or as his or her

designee as sole reviewer and approver of submissions processed under expedited procedures.

The federal requirements for informed consent (or its waiver, alteration, or exception) apply

regardless of whether the research study is reviewed through expedited procedures or at a convened

meeting of the full IRB. Expedited review procedures may not be used for classified research, or

where identification of the subjects and/or their responses would reasonably place them at risk of

criminal or civil liability or be damaging to the subjects’ financial standing, employability, insurability,

reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so

that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.

Approval Period Approvals are valid for the duration specified by the IRB, but cannot exceed 12 months. The date that

the application is forwarded for approval by the Chair or designee is the date from which the duration

of approval is set. No part of the protocol can be initiated until full approval is received by the

principal investigator.

Categories of research that may be approved through expedited procedures Research activities that (1) present no more than minimal risk to human subjects, and (2) involve only

procedures listed in one or more of the following categories, may be reviewed by the IRB through the

expedited review procedure authorized by 45 CFR 46.110 and 21 CFR 56.110. The activities listed

should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on

this list merely means that the activity is eligible for review through the expedited review procedure

when the specific circumstances of the proposed research involve no more than minimal risk to

human subjects.

The categories in this list apply regardless of the age of subjects, except as noted.

The expedited review procedure may not be used where identification of the subjects and/or

their responses would reasonably place them at risk of criminal or civil liability or be damaging to

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the subjects’ financial standing, employability, insurability, reputation, or be stigmatizing, unless

reasonable and appropriate protections will be implemented so that risks related to invasion of

privacy and breach of confidentiality are no greater than minimal.

The expedited review procedure may not be used for classified research involving human

subjects.

The standard requirements for informed consent (or its waiver, alteration, or exception) apply

regardless of the type of review--expedited or convened-- utilized by the IRB.

Survey research conducted under Department of Defense typically requires separate review and

approval. When appropriate, the research protocol is reviewed and approved by the IRB prior to

Department of Defense approval.

Categories one (1) through seven (7) pertain to both initial and continuing IRB review.

1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met.

Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required.

(Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability

of the risks associated with the use of the product is not eligible for expedited review.)

Research on medical devices for which (i) an investigational device exemption application (21 CFR

Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical

device is being used in accordance with its cleared/approved labeling.

2) Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows:

i) from healthy, non-pregnant adults who weigh at least 110 pounds. For these subjects,

the amounts drawn may not exceed 550 ml in an 8 week period and collection may not

occur more frequently than 2 times per week; or

ii) from other adults and children, considering the age, weight, and health of the subjects,

the collection procedure, the amount of blood to be collected, and the frequency with

which it will be collected. For these subjects, the amount drawn may not exceed the

lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more

frequently than 2 times per week.

Although the physical risks of these procedures may be low, special care should be taken with

pediatric populations with regard to volume of blood and frequency of needle sticks. If at all possible,

additional blood for research purposes should be collected at the time of a clinical sample.

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3) Prospective collection of biological specimens for research purposes by noninvasive means.

Examples:

i) hair and nail clippings in a non-disfiguring manner;

ii) deciduous teeth at time of exfoliation or if routine patient care indicates a need for

extraction;

iii) permanent teeth if routine patient care indicates a need for extraction;

iv) excreta and external secretions (including sweat);

v) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing

gumbase or wax or by applying a dilute citric solution to the tongue;

vi) placenta removed at delivery;

vii) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor;

viii) supra- and subgingival dental plaque and calculus, provided the collection procedure is

not more invasive than routine prophylactic scaling of the teeth and the process is

accomplished in accordance with accepted prophylactic techniques;

ix) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth

washings;

x) sputum collected after saline mist nebulization.

Specimens collected for use in research involving DNA testing or in search of a new way to test

pathology should be considered potentially sensitive, should be reviewed carefully, and may require

referral to the full board for review.

4) Collection of data through noninvasive procedures (not involving general anesthesia or sedation)

routinely employed in clinical practice, excluding procedures involving x-rays or microwaves.

Where medical devices are employed, they must be cleared/approved for marketing. (Studies

intended to evaluate the safety and effectiveness of the medical device are not generally eligible

for expedited review, including studies of cleared medical devices for new indications.) Examples:

i) physical sensors that are applied either to the surface of the body or at a distance and do

not involve input of significant amounts of energy into the subject or an invasion of the

subject’s privacy;

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ii) weighing or testing sensory acuity;

iii) magnetic resonance imaging;

iv) electrocardiography, electroencephalography, thermography, detection of naturally

occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler

blood flow, and echocardiography;

v) moderate exercise, muscular strength testing, body composition assessment, and flexibility

testing where appropriate given the age, weight, and health of the individual.

This is a very detailed list of procedures which would qualify as minimal risk. However, the population

being studied must be considered in the evaluation of the study under expedited review. For example,

some of these tests and procedures may be appropriate for middle aged adults, but would be at higher

risk for a more debilitated disease cohort.

5) Research involving materials (data, documents, records, or specimens) that have been collected, or

will be collected solely for non-research purposes (such as medical treatment or diagnosis), or (2)

have already been collected for either non-research or research purposes, provided the materials

were not collected for the currently proposed research. (NOTE: Some research in this category may

be exempt from the HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(4). This

listing refers only to research that is not exempt.)

For example, category 5 research studies will allow investigators to collect laboratory values from a

search of medical records. Category 5 will also allow investigators to conduct a secondary data analysis

on research data previously collected at this institution under a separate protocol, or collected at a

different institution with the appropriate data sharing plans in place.

6) Collection of data from voice, video, digital, or image recordings made for research purposes.

Investigators should use caution when applying category 6 to ensure that the identity of the subjects is

protected sufficiently and reduce the risk of harm associated with a breach of confidentiality.

7) Research on individual or group characteristics or behavior (including, but not limited to, research on

perception, cognition, motivation, identity, language, communication, cultural beliefs or practices,

and social behavior) or research employing survey, interview, oral history, focus group, program

evaluation, human factors evaluation, or quality assurance methodologies. (NOTE: Some research in

this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR

46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.)

Survey research is commonly employed by social/behavioral researchers. Researchers should be

cognizant of potential breach of confidentiality and well as possibly stigmatizing subjects based on the

content of surveys, questionnaires, and interviews.

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8) Continuing review of research previously approved by the convened IRB as follows:

i) where (i) the research is permanently closed to the enrollment of new subjects; (ii) all

subjects have completed all research-related interventions; and (iii) the research remains

active only for long-term follow-up of subjects; or

ii) where no subjects have been enrolled and no additional risks have been identified; or

iii) where the remaining research activities are limited to data analysis.

For example, studies may be expedited under category 8 if subject enrollment and follow-up are

complete and the study remains open for subsequent analysis only.

9) Continuing review of research, not conducted under an investigational new drug application or

investigational device exemption where categories two (2) through eight (8) do not apply but the IRB

has determined and documented at a convened meeting that the research involves no greater than

minimal risk and no additional risks have been identified.

As indicated previously, initial review of research by expedited methods is limited to only those activities

that fall within category 1-7. However, at the time of initial full board review, the IRB may decide that the

study is no more than minimal risk and can be reviewed through expedited procedures at subsequent

review periods, unless the Board requests that future study submissions be reviewed at a convened

meeting.

DoD sponsored research Surveys performed on Department of Defense (DoD) personnel must be submitted, reviewed, and

approved by the Department of Defense after the research protocol is reviewed and approved by the IRB.

For any DoD-supported researcher, the following must be promptly (no longer than 30 days) reported to

the DoD human research protection officer:

When significant changes to the research protocol are approved by the IRB.

The results of the IRB continuing review.

Change of the reviewing IRB.

When the organization is notified by any Federal department, agency or national organization

that any part of an HRPP is under investigation for cause involving a DoD- supported research

protocol.

References:

45 CFR 46.108(b)

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45 CFR 46.110

21 CFR 56.110 OPNAVINST 5300.8B

SECNAVINST 3900.39D, para. 6e

Instruction 3216.02 4.b.4

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11.0 Exempt Research

Federal regulations identify certain categories of research activities involving human subjects that may

qualify for exemption from the federal regulations for the protection of human research subjects.

Criteria for consideration of Exempt status

To be considered for Exempt status, a research study must meet the following four criteria and the

procedures must fall into one of six exempt categories prescribed by federal regulations outlined below.

The four criteria for consideration are:

1) The research cannot place subjects at greater than minimal risk

2) The selection of subjects is equitable

3) There are adequate provisions to maintain the confidentiality of the data.

4) The research CANNOT involve pregnant women, human fetuses, in vitro fertilization, or prisoners

Please Note: The federal regulations outlined in 21 CFR Part 50 and 21 CFR Part 56 which cover research

under FDA oversight, do not allow for the IRB to designate research. Furthermore, the IRB prohibits

studies involving pregnant women, human fetuses, or in vitro fertilization from being reviewed under

exempt procedures. Due to the vulnerability associated with these populations, studies involving these

types of subjects may be reviewed by expedited or full board processes.

Determination and notification of Exempt status The IRB Director, IRB Chair or a qualified IRB Staff Member is responsible for conducting an evaluation of

the submitted material and determining whether or not a submission meets the criteria for exempt

research, and may require modifications to the submission prior to making that determination. The

investigator should complete an eIRB application with the information requested through the electronic

submission system to obtain an exemption determination. Specific items that may be applicable to a

submission are listed in section 8.1 of this document. If it is determined that a submission does not meet

the criteria for exempt status, the IRB will notify the principal investigator and the submission will be

referred for review through either expedited procedures or by the full board review along with the

reviewer’s comments and any reviewer recommendation for consideration and final determination.

Investigators do NOT have the authority to make an independent determination that research involving

human subjects is exempt, and may not initiate a research study prior to receiving a memorandum from

the IRB approving its exempt status. Each project requires a separate review and approval for exemption.

If the submission is determined to be exempt, the IRB will send the principal investigator a written or

electronic notification which will include: 1) the date of IRB approval; 2) the date of expiration of IRB

approval; 3) the exempt category under which the research has been determined to be exempt: 4) a

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statement that the IRB must be informed of any changes to a project, so that it can determine whether

the project continues to meet the requirements for exemption, ;5) , a statement that the principle

investigator must report promptly any unanticipated problems to the IRB. If the submission requires

modification, the principal investigator is notified of the needed changes.

A memorandum with the information listed above is provided only after changes have been made and

reviewed and approved by the IRB Director, IRB Chair, or designee. If the submission is determined to not

be exempt, the principal investigator is notified and instructed on steps to be taken to approve the

research project. The full board is informed of all submissions determined to be exempt by listing them

on the meeting agenda and providing an electronic link to all study specific documents. The IRB requires

renewal of research studies declared exempt every three years.

Research studies declared Exempt by the IRB must be conducted in the same ethical manner and with the

same respect for the privacy and confidentiality of research subjects as those studies approved by the full

IRB or by Expedited Review. If there are interactions with participants, there will be a consent process

that will disclose such information as:

• The activity is research

• A description of the procedures

• That participation is voluntary

• Name and contact information for the Researcher

Research studies involving participants that would fall under subpart B of the DHHS regulations will apply

the same exemptions as 45 CFR 46.101(b)(1-6). Research studies involving participants that fall under

subpart D of the DHHS regulations will apply the exemptions related to 45 CFR 46.101(b)(1) and 45 CFR

46.101(b)(3-6).

Categories of Exempt human subjects research Categories of Research that may be exempt through the provisions of 45 CFR 46.101(b) (1)-(6) are as

follows:

Category 1: Research conducted in established or commonly accepted educational settings, involving

normal educational practices, such as (i) research on regular or special educational instructional

strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques,

curricula, or classroom management methods.

For this exempt category to apply, investigators must provide evidence that the educational practices to

be studied are frequently used educational practices carried out in a place where such practices are

commonly accepted to. Commonly accepted settings are not limited to schools. For example, a car may

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be a commonly accepted setting for a driver education program. A clinic may be a commonly accepted

setting for a medical student or resident education program. A repair facility may be a commonly

accepted setting for a technician education program.

Children, as well as adults, may be subjects of such studies.

Category 2: Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement),

survey procedures, interview procedures or observation of public behavior, unless: (i) information

obtained is recorded in such a manner that human subjects can be identified, directly or indirectly

through identifiers linked to the subjects; and (ii) any disclosure of the human subjects’ responses outside

the research could reasonably place the subjects at risk of criminal or civil liability, or be damaging to the

subjects’ financial standing, employability, or reputation.

For this exempt category to apply, investigators must provide evidence that the collected data are

recorded in such a way that no information can be linked to a subject either directly, such as by recording

names, codes, or social security numbers, or indirectly, such as by recording information that contains

clues to subjects’ identity.

If the data CAN be linked to subjects, the research still may be exempt provided the data does not include

sensitive information that could reasonably place the subjects at risk of criminal or civil liability, or be

damaging to the subjects’ financial standing, ability to gain or maintain employment, or reputation.

Research involving observation of public behavior is usually exempt, unless the investigator participates

in the public behavior, or manipulates the environment in order to elicit certain kinds of public behavior.

Category 3: Research involving the use of education tests (cognitive, diagnostic, aptitude, achievement),

survey procedures, interview procedures, or observation of public behavior that is not exempt under

Exemption category (2) (above) of this section if: (i) The human subjects are elected or appointed public

officials or candidates for public office; or (ii) federal statutes require, without exception, that the

confidentiality of the personally identifiable information will be maintained throughout the research and

thereafter.

Public officials are not considered to be entitled to the same degree of privacy that applies to private

individuals. For this exempt category to apply, investigators must provide evidence that the research

involves only education tests, or survey, interview or observation of the public behavior of public officials.

Note that such research may qualify for exemption even though the research may involve significant risks

for subjects.

If the research is intended to include educational tests, surveys interviews or observation of public

behavior carried out under specific federal programs supported by the Department of Justice or the

National Center for Education Statistics of the U.S. Dept. Of Education, then it may qualify for exemption.

This exception is allowed because other federal law regulates the security of information in these

programs.

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If studies are conducted using federal databases operated by the agencies identified above, the

investigator should check with the agency to determine whether their research qualifies for exemption.

This information should be communicated to the IRB.

Category 4: Research involving the collection or study of existing data, documents, records, pathological

specimens, or diagnostic specimens, if these sources are publicly available or if the information is

recorded by the investigator in such a manner that subjects cannot be identified, directly or through

identifiers linked to the subjects.

For this exempt category to apply, investigators must provide evidence that ALL the data, documents,

records or specimens to be used in the research are already in existence at the time of review by the IRB,

and that all the data has been recorded in such a manner that subjects cannot be identified directly or

indirectly.

Category 5: Research and demonstration projects which are conducted by or subject to approval of

[federal] department or agency heads, and which are designed to study, evaluate, or otherwise examine

(i) public benefit or service programs; (ii) procedures for obtaining benefits or services under these

programs; (iii) possible changes or alternatives to those programs or procedures; or (iv) possible changes

in methods or levels of payments for benefits or services under those programs.

This exemption addresses the need to evaluate methods of administering certain federal programs. For

this exempt category to apply, investigators must provide evidence that the proposed research is

intended to evaluate methods for administration of federal programs authorized under the Social

Security Act, Medicare, Medicaid or other public benefit programs, then it may qualify for exemption.

The principal investigator must provide the IRB with a letter from the relevant federal department or

agency head before this category of exemption can be granted.

Category 6: Taste and food quality evaluation and consumer acceptance studies, (I) if wholesome food

without additives is consumed, or (ii) If a food is consumed that contains a food ingredient at or below

the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or

below the level found to be safe by the Food and Drug Administration (FDA) or approved by the

Environmental Protection Agency (EPA) or the Food Safety and Inspection Service of the U.S. Department

of Agriculture (USDA).

This exemption pertains to food testing. For this exempt category to apply, investigators must provide

evidence that the research involves the examination of consumer taste and acceptance of 1) unprocessed

naturally occurring foods, or 2) processed foods containing added ingredients, agricultural chemicals, or

environmental contaminant at or below the level found to be safe by the FDA, EPA, or USDA.

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Exempt human research involving children All exemptions, except exemption 2, are uniformly applicable to children. However under

Exemption 2, educational testing is applicable to children, but research involving survey or interview

procedures or observations of public behavior is NOT applicable to children, except for research involving

observation of public behavior when the investigator(s) do not participate in the activities being

observed.

References:

21 CFR 56.104(d)

45 CFR 46.101(b)(1-6)

45 CFR 46.102(f)

45 CFR 46.201(b)

45 CFR 46.301(a)

45 CFR 46.401(b)

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12.0 Advertisements and Recruiting

The IRB considers advertising for research study subjects to be the start of the subject selection and

informed consent process. Advertising for research study subjects is defined as advertising that is

intended to be seen or heard by prospective subjects to solicit their participation in a study. All research

study advertisements must be reviewed and approved by the IRB prior to their use. The mode of

advertisement should be communicated to the IRB, and final copies of printed and audio/visual

advertisements must be submitted for review. The IRB must review and approve the final advertisement

as potential research subjects will see it.

Advertisements may be reviewed through expedited procedures. All advertisements reviewed through

expedited procedures will be reported to the IRB as information items at a convened meeting. Final

copies of all advertising materials will be reviewed by representatives of the Creative Communications

department.

All advertisements for research subjects must contain the following four elements:

1. The institution or facility conducting the research

The identification of the research facility should be in compliance with policies and procedures of the

facility.

The use of any logos should be in compliance with the policies and procedures associated with the

use of the logos.

2. The condition under study and/or the purpose of the research

The advertisement must state that subjects are being recruited for a “Research Study.” The IRB

expects the words “Research Study” to be used to describe what subjects are being recruited for.

Advertising for recruitment into investigational research studies should not use terms such as “new

treatment,” “new medication” or “new drug” without clearly explaining that the test article is

investigational. No indication should be made that the drug or device being studied is safe or effective for

the purposes being studied. Claims regarding the equivalence or superiority to other drugs or devices

should also not be made when advertising a research study.

3. The name and phone number of the department, section, or office to contact for further information

regarding the study. The advertisement should include information about eligibility criteria and the

purpose of the study.

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4. The IRB study number should appear in all advertisements. For video, the IRB number should appear in

either the opening or the closing frame. For audio material, the IRB number should be given at some time

during the advertisement.

The following items may be included at the investigator’s or the IRB’s discretion

1. In summary form, the key criteria that will be used to determine eligibility for the study.

2. A brief list of participation benefits, if any. The benefits should not be more than what is outlined in the

consent and/or protocol.

The advertisement should not state or imply a certainty of favorable outcomes as a result of

participation.

No claims should be made, either explicitly or implicitly that the drug, biological, device, test,

procedure, or intervention is safe or effective for the purposes under investigation.

No claims should be made, either explicitly or implicitly that the drug, biological, device, test,

procedure, or intervention is known to be equivalent or superior to any other drug, biological, device, test,

procedure, or intervention.

Exculpatory language should not be included in any advertisements.

Advertisements should not promise “free medical treatment” when the intent is only to say research

subjects will not be charged for taking part in the investigation.

Advertisements may state that research subjects will be paid and the amount they will be paid.

However, the advertisement should not emphasize the payment or the amount to be paid for

participation by such means as larger or bold type.

The IRB may disallow advertisement of the exact amount a research subject will be paid if it is felt to

be unduly coercive.

3. The time or other commitment required of the subjects.

Recruitment of students, employees, or trainees Direct recruitment of students, employees or trainees is not generally allowed due to potentially coercive

power structure with the University environment. Mass distribution of informational materials such as

mass emails, flyers, or other means may be evaluated by the IRB for use in recruitment. The IRB must

determine that the manner of delivery and the contents do not in any way imply that an individual’s

decision has any bearing on his or her relationship with instructors, employers, or mentors.

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Recruitment of patients It is preferable that patients are informed of opportunities to participate in research by someone they

recognize as having a reason to know their medical history. “Cold calls” from strangers should generally be

avoided. A letter of introduction from a direct care provider is usually an acceptable method of

disseminating information regarding research opportunities to patients and can provide contact

information for the study investigators. In the rare circumstances in which direct contact of patients by an

investigator not involved in their care is the only practicable means of recruitment, care should be taken

to construct the recruitment approach to best respect the privacy of the patients.

Recruitment by outside researchers Outside researchers may not solicit at Wake Forest Baptist Medical Center without first contacting the IRB

for a determination as to whether the research would engage the institution in research activity. The

determination can be made by the IRB Director, IRB Chair, or designee. The IRB Director or Chair may

require a University collaborator in order for the research activities to take place on the institutional

campuses. Proof of approval from an external IRB will be required for outside investigators to conduct

recruitment or other activities at the University. The IRB Director or Chair may determine that research

activities by outside investigators are not appropriate for conduct on campuses and may disallow the

conduct of these research activities on institutional premises.

Payment of recruitment incentives The Institutional Review Board does not permit direct payment in cash or kind to any individual (e.g. study

coordinator, house officer, nurse, pharmacist, other physician) for the recruitment of research study

subjects. The Board views such payments as inappropriate and a conflict of interest. Recruitment bonuses

paid directly to individuals are inappropriate, since the study is paying personnel for recruitment duties

and other associated responsibilities. Recruitment bonuses may also influence referral of subjects to

certain protocols, at the exclusion of other protocols, which Board views as a conflict of interest.

Wake Forest School of Medicine (WFUSM) policy does not permit individuals to receive payments or

benefits in exchange for referrals. [Wake Forest School of Medicine Standards of Excellence]. Recruitment

of study participants is viewed as a referral. Therefore, WFUSM policy does not permit a sponsor of a

research study to directly pay (in cash or kind) any School employees.

One acceptable practice would be to pool such additional payments. These payments should be made to

the School (not an individual) and deposited into a School account. These funds could then be used

professional development activities such as attendance at continuing education programs or appropriate

professional meetings. Distribution of pooled funds should be under appropriate, pre-established

guidelines for professional activities and not as individual incentives.

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Recruitment of US military personnel When following a DoD addendum and the research involves U.S. military personnel, undue influence

should be minimized for research participants by the following:

Officers are not permitted to influence the decision of their subordinates.

Officers and senior non-commissioned officers may not be present at the time of recruitment.

Officers and senior non-commissioned officers have a separate opportunity to participate.

When recruitment involves a percentage of a unit, an independent ombudsman is present

When research involves U.S. military personnel, limitations on dual compensation are as follows:

Prohibit an individual from receiving pay from more than one position for more than 40 hours of work

in one calendar week (e.g. an individual cannot receive payment for being in a research project during

normal duty hours). Participation and payment not on normal duty hours is allowed.

The policy includes temporary, part-time, and intermittent appointments.

References:

45 CFR 46.110(b)

45 CFR 46.108(b)

21 CFR 56.110(b)

Dual Compensation Act, 24 U.S.C 3-1,

DoDD 3216.2, para. 4.4.4;

SECNAVINST 3900.39D, para. 6a(6)

ICH-GCP: 3.1.8

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13.0 Amendments or changes to approved research studies

Regulatory Background Federal regulations state that there should written procedures for ensuring prompt reporting to the IRB of

any changes in research activities, and that changes in approved research may not be initiated without IRB

review and approval, except where necessary to eliminate apparent immediate hazards to human

subjects.

IRB review and approval is required before an investigator can implement any changes in an approved

research protocol except in the situation described above. This includes, but is not limited to, changes in

the informed consent document, protocol document, investigator’s brochure (if applicable),

advertisements, any other research study-related documents that have been reviewed and approved by

the IRB, and any changes in the research team or environment that affects their ability to safely conduct

the study. This policy also applies to any changes in the status of the principal investigator and research

team which impact upon conflict of interest issues. Changes in subject recruitment and follow-up status

should also be reported to the IRB in the form of an amendment.

It is the principal investigator’s responsibility to insure that all changes in an approved protocol, consent

form, or other research study related documents are submitted as amendments for IRB review and

approval before they are implemented. Initiating ANY changes in an active protocol before the

amendments has received IRB approval is a violation of both Federal law and institutional policy, and

could subject the investigators to serious consequences. After receipt of IRB approval, the principal

investigator is then responsible for insuring that the most recently- approved version of the informed

consent and other study-related documents are used. Approval of an amendment does not reset the

expiration date, and a continuing review must still be completed within the appropriate time window.

Procedures to be followed by the study team To amend an IRB approved consent form, the research team member must submit an amendment request

via eIRB that includes:

A description of the proposed change(s) and the rationale for the change(s)

A copy of the revised documents highlighting the proposed changes. It is recommended that the

revised document should include the version number or date in the document footer.

A clean copy of the newly revised documents, including the consent forms for watermarking.

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NOTE: The revised consent form, once approved, is effective only until the ORIGINAL expiration or

renewal date of the research study.

Multiple changes to different parts of the IRB application may be submitted at one time.

Investigators may submit changes in study personnel through a separate Personnel Amendment.

However, the Principal Investigator must be changed through an Application Amendment because these

types of changes often include changes to the consent forms and/or protocol documents.

IRB procedures for reviewing an amendment request Upon receipt of an amendment request, IRB staff will review the application for completeness;

amendments which are incomplete or do not have all required documents will not be considered by the

IRB and will be returned without review. Amendment requests are classified as follows:

A. Minor Revisions

Minor revisions involve changes in procedures that present no more than minimal risk to subjects or do

not increase the risks to subjects, and/or revisions that do not constitute a significant alteration of the

study design. Minor revisions include, but are not limited to, changes in study team members, corrections

of grammatical and typographical errors in the protocol or consent form, changes in telephone numbers,

or deletion of survey questions. Minor revisions may qualify for expedited review under 45 CFR

46.110(b)(2). Minor revisions may be reviewed by a designated board member or alternate with

appropriate expertise and experience and reported to the full board as information items on the agenda.

The final determination of whether or not an amendment qualifies for expedited review is at the

discretion of the IRB Director, the IRB Chair, or designee. All amendments approved by expedited

procedures will be presented to a convened IRB as information and included in the minutes. Amendments

cannot be disapproved by expedited procedures. Amendments that do not meet the requirements for

expedited review, or that for any other reason cannot be approved through expedited procedures, will be

presented to the IRB for discussion and vote at a fully convened IRB meeting.

B. Major (Substantive) Revisions

Major Revisions involve changes in procedures which increase the risk to subjects, changes in the

protocol which significantly affect the nature or purpose of the study, or changes that are otherwise

determined not to meet the criteria for expedited review. Such revisions must be reviewed by at least one

member of the IRB and presented and voted upon at a fully convened IRB meeting. All of the IRB

members on the board reviewing the changes will have access to the modified documents via the eIRB

system. Major revisions include, but are not limited to, changes in the recruitment plan, changes in study

eligibility criteria, addition of procedures that have a greater than minimal risk, and revisions to the

consent form including the addition of newly identified risks or side effects. Note that changes in inclusion

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criteria must be approved by the IRB by the amendment process before any subjects may be enrolled who

do not meet the inclusion criteria outlined in the currently approved protocol. If an amendment to a

protocol previously approved as expedited causes the protocol to no longer qualify for expedited review,

the IRB may elect to re-classify the protocol to be reviewed by the full board. If so, up to three board

members could be assigned to review the proposed changes. The IRB also reserves the right to request

that the investigator submit a new application if deemed appropriate.

C. Revisions Implemented Immediately for Safety Reasons

Amendments that must be made immediately to insure research subject safety are an exception to the

requirement for IRB approval prior to implementation. The principal investigator should use his/her

judgment when determining if an amendment must be implemented immediately to ensure research

subject safety. If this occurs, the IRB Director or IRB Chair must be notified immediately; an amendment

request must follow within 24 hours. The request will be considered by the full IRB to determine whether

each change was consistent with ensuring the subject’s continued welfare.

Following review of the requested amendment, the principal investigator will be notified of IRB approval,

any required modifications, clarifications or conditions, or disapproval. If changes to the consent form

have been approved, a watermarked copy of the revised consent form will accompany the approval

notification. Amendments cannot be implemented without final approval from the IRB.

References:

45 CFR 46.103(4)(iii)

45 CFR 46.110(b)(2)

21 CFR 56.108(a)(3-4)

21 CFR 56.110(b)

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14.0 Continuing Review

Regulatory Background Federal regulations 45 CFR 46.109(e); 21 CFR 56.109(f) require that all research protocols approved by the

IRB be subject to continuing review at least every 365 days, or at shorter intervals determined by the IRB,

appropriate to the degree of risk. More frequent review is appropriate when the risks to subjects require

close monitoring. Factors to consider include:

Nature of risks posed by the research

Degree of uncertainty regarding risks involved

Vulnerability of the subject population

Experience of the investigator

IRB’s previous history with the investigator and/or sponsor Projected rate of enrollment

Whether the studies involve novel therapies

The continuing review process must be substantive and meaningful. Review by the convened IRB, with

separate deliberations, actions, and votes for each protocol, is required unless the research meets criteria

for review through expedited procedures under 45 CFR Part 46.110 and 21 CFR 56.110. At the discretion

of the IRB, research activities are subject to audit and verification from sources other than the principal

investigator to ensure that no substantive changes have occurred since the last IRB review of the protocol,

informed consent document, and other pertinent materials.

Procedures to be followed by the study team A. Application for Continuing Review

To request continuing review of a protocol, the principal investigator or designee should complete an

appropriate request via eIRB. Requests for continuing review of a protocol should be received no less than

30 days prior to the annual renewal date. Requests for continuing review that are submitted to the IRB

less than 30 days prior to the annual renewal date are not guaranteed to receive approval before they

expire. Requests that are incomplete or lack necessary supporting documentation will be returned

without review, and are likewise not guaranteed to receive approval by the date of expiration.

B. Consequences of Failure to Obtain Continuing Renewal of a Protocol

Continuing review and re-approval of research must occur on or before the date IRB approval is to expire.

Failure to submit a complete continuing review application in a timely manner may result in

administrative closure of the protocol. Should this occur, then ALL research activity must cease – including

recruitment/enrollment of human subjects, continued collection of data or specimens, analysis of data or

specimens previously collected, and all interventions or interactions with enrolled human research

participants, unless doing so would pose a risk to the participants. Continuation of any research after the

expiration date constitutes noncompliance with federal regulations and institutional policy, and could

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subject the principal investigator and research team to serious sanctions. Additional detailed information

regarding study closure can be found in the IRB Study Closure Policy.

C. Notification of Annual Continuing Renewal

eIRB will automatically send notification to the principal investigator and study team advising of an

approaching protocol annual continuing renewal 60 days and 30 days before the approval expiration date.

This notification is made as a courtesy only; whether or not the notification ultimately comes to the

attention of the principal investigator, it remains his/her responsibility to maintain a record of the

expiration date of IRB approval and submit a timely continued renewal accordingly.

IRB procedures for continuing review A. Continuing Review by Full Board

If approved, a new expiration date will be created based on the new date of approval. For continuing

review of protocols that are not eligible for expedited review, the IRB staff will designate at least one

member of the IRB as the primary reviewer for each protocol. The primary reviewer and all other board

members will receive and review a copy of the complete protocol including any modifications previously

approved by the IRB and a status report on the progress of the research, including:

The number of subjects accrued

A summary of unanticipated problems involving risks to subjects or others, withdrawals of subjects

from the research, reason for withdrawals, and any complaints about the research that have accrued

since the last IRB review

A summary of any relevant recent literature, interim findings, and amendments or modifications to

the research since the last review

Any relevant multi-center trial reports including reports from Data Safety Monitoring Boards

Any other relevant information, especially information about risks associated with the research

A copy of the current informed consent document and if applicable, the newly proposed consent

document

A summary of minor deviations occurring over the past year

At the time of the board meeting, all IRB members will have access via eIRB to the protocol summary, the

complete protocol, including any modifications previously approved by the IRB, the status report, and

relevant IRB minutes from prior deliberations of convened IRB meetings.

In conducting the continuing review, the IRB will ensure:

• That the required determinations for the approval of research regarding risks, potential benefit, informed

consent and safeguards for human subjects continue to be met

• The currently approved or proposed consent document is still accurate and complete

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• That subjects are provided any significant new findings that may relate to the their willingness to continue

participation [45 CFR Part 46.116(b)(5)].

The IRB may reach one of the following decisions regarding each continuing review submission considered

by the full IRB:

• Approval as submitted and the duration of approval.

• Provisional approval with minor modifications and the duration of approval. Minor modifications must

require only simple attention to and concurrence by the principal investigator. This action authorizes the

IRB Chair or designee to grant final approval upon verification that the principal investigator has made the

specified modifications.

• Postpone: This action defers discussion and action on the application because the primary reviewer(s) are

absent from the meeting and have not provided any written comments.

• Table: This action proposes further review by the full IRB pending major revisions to the application,

receipt of additional information related to the application, or when substantial issues have been

identified that require the response of the principal investigator to IRB concerns. Upon full IRB review of

the requested materials or response, a motion will then be put forth for vote to approve, approve with

minor modifications or disapprove the research protocol.

• Disapproval: This action indicates the IRB believes approval of the protocol is unwarranted.

Resubmission of a previously disapproved protocol requires full IRB review and approval.

The decision of the IRB regarding each continuing review submission will be communicated to the

principal investigator. If the submission is approved, the principal investigator will be notified of the type

of review, the expiration date of IRB approval, that IRB review is required before any changes are made

unless necessary to mitigate apparent immediate hazards to subjects, that continuing review is required if

the project will continue beyond the approval period, and the requirement to report promptly any

unanticipated problems involving risks to subjects.

If the continuing review submission is provisionally approved with minor changes, the principal

investigator is notified of the required changes. The requested changes should be made within 30 days of

the date that the concerns have been transmitted to the study team. If the protocol expires before the

principal investigator addresses the requested changes, the IRB will administratively close the protocol.

Once all required changes have been made and accepted by the IRB Chair or designee, a full approval

memorandum with the information listed above is provided.

If the continuing review submission is postponed or tabled, the principal investigator is notified of the

reason and any information or changes that are required. The principal investigator should respond within

30 days of the date concerns are submitted to the study team. If the protocol expires before the principal

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investigator addresses the requested changes, the IRB will administratively close the protocol. Any

response to a postponed/tabled submission must be returned to a convened IRB for further consideration

and action. Postponed/tabled continuing review submissions are generally returned to the IRB which first

reviewed them; however, such submissions may be assigned to a different IRB with the approval of the

initial primary reviewer(s). An IRB asked to review a deferred/tabled submission that it did not initially

review may, by majority vote, decline to consider the deferred/tabled submission and refer it back to the

IRB that reviewed it initially.

If a continuing review submission is disapproved, the principal investigator is notified of the reason and

the process for appealing the decision.

A study may receive a continuing review for less than 12 months. Some reasons for this action include but

are not limited to: new information regarding the study, increased risk, or jeopardizing subjects rights or

welfare.

B. Continuing Review by Expedited Procedures

Research studies that have been initially approved by expedited review can be renewed by expedited

procedures, unless changes in the protocol have been made that affect subject safety, rights, welfare, or

risk.

Research studies initially approved by full board review will normally undergo review by the full IRB;

however, expedited review procedures may be used under the following conditions:

1. no subjects have been enrolled to date and no interim changes in the protocol have been made

that affect subject safety, rights, welfare, or risk; OR (b) the research is permanently closed to

enrollment of new subjects, all subjects have completed research related interventions, and the

research remains active only for long-term follow up of subjects; OR (c) the remaining research

activities are limited to data analysis only.

2. the research is not conducted under an investigational new drug application or investigational

device exemption; AND (b) categories 2 through 8 of the expedited review categories do not

apply; AND (c) the IRB has determined and documented at a convened full board meeting that the

research involves no greater than minimal risk; AND (d) and no additional risks have been

identified since the original approval.

For continuing review through expedited review procedures, the IRB Chair or designated IRB member(s)

will receive and review all of the above-referenced documentation for continuing review of research

studies, including the complete protocol. Following review of these materials the Chair or designee may

reach one of the following decisions:

• Approval as submitted and the duration of approval.

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• Approval with minor modifications and the duration of approval. Minor modifications must require only

simple attention to and concurrence by the principal investigator. This action authorizes the Chair or

designee to grant final approval upon verification that the principal investigator has made the specified

modifications.

• Refer to the full IRB for consideration

Continuing review submissions reviewed through expedited procedures cannot be disapproved by the

Chair or designee.

Administrative closure of protocols due to lack of continuing review If a protocol is administratively closed due to the lack of continuing review, the principal investigator is so

notified. If continuing review and re-approval do not occur before the date the approval expires, the IRB

will extend a 30 day re-activation period. If the continuing review is completed within 30 days after the

expiration date and a re-activation form is submitted, a new protocol application is not required. The

investigator should stop all research activity during this lapse of IRB approval. Documentation of this lapse

will be noted in a memo to the investigator, and a new approval and expiration date will be set based on

the date of re-activation. If the investigator does not complete the re-activation form and continuing

review within 30 days a new application must be submitted for review and approval. Upon submission of

a new protocol, a new renewal date will be set based on the date at which the protocol is approved or

approved with minor concerns. Approvals are valid for the duration specified by the IRB, but cannot

exceed 12 months.

If an investigator chooses not to re-activate the study and fails to submit a study closure report within 60

days of expiration, he/she may be deemed to be in non-compliance with institutional policy. In addition,

until such non-compliance issues are satisfactorily addressed, the IRB may decline to consider any new

research proposals on which that individual is listed as principal or co- investigator.

A closure report form includes the following information:


A summary of adverse events and any unanticipated problems involving risks to subjects or others and

any withdrawal of subjects from the research or complaints about the research since the last IRB

review



Any relevant multi-center trial reports


A copy of the current informed consent document

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Approval period If a protocol is approved by the IRB for 12 months on 1/1/2010, the expiration date for that study would

be 12/31/2010. If a continuing review is not completed prior to 11:59:59 on 12/31/2010, then the study

would be administratively closed by the IRB staff.

Continuing review and re-approval of research must occur on or before the date when IRB approval

expires. When a continuing review is completed a new approval/expiration date of no greater than 364

days will be established. If a study is approved greater than 30 days prior to its previous expiration date, a

new approval date will be based upon the date of the convened meeting or the date of review by the IRB

chair or designee. It is the IRB policy to establish a date of no greater than 364 days for each continuing

review based on the date of re-approval.

References:

45 CFR 46.109(e)

45 CFR 46.116(b)(5)

21 CFR 56.109(f)

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15.0 Closure upon completion of research

Regulatory background Per 1998 FDA Information Sheet, investigators are required to report to the IRB when a study is closed.

Once a study has reached the point where follow-up of human subjects AND data analysis is complete, the

principal investigator may choose to close the study.

Once a study has been closed, ALL research activity must cease: human research participants cannot be

recruited or enrolled; there can be no further intervention, interaction, or follow-up with previously

enrolled human research participants; and there can be no continued collection, analysis, use, or transfer

of data or specimens that were previously collected as part of the research protocol. However, the

principle investigator and study team continue to have the responsibility for maintaining the privacy and

confidentiality of data related to the study.

Procedures to be followed by the study team To close or end IRB approval of a completed study, the principal investigator must provide a final status

report to the IRB that includes:


A summary of adverse events and any unanticipated problems involving risks to subjects or others,

any withdrawal of subjects from the research, or complaints about the research that have accrued

since the last IRB review



Any relevant multi-center trial reports, including reports from chartered DSMBs


A copy of the current informed consent document

When following ICH-GCP guidelines, the following should apply as well:

If the investigator terminates or suspends a clinical trial without prior agreement of the Sponsor, the

investigator must inform the institution, Sponsor, and the IRB.

If the IRB terminates or suspends approval of the clinical trial, the investigator promptly notifies the

Sponsor.

Upon completion of the clinical trial, the investigator informs the institution, the IRB and the

regulatory authority responsible for the trial.

IRB procedures for closing a research study

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Upon receipt and review if these material, the IRB Office will provide the principal investigator with

acknowledgment of the study closure, and will finalize the study closure in eIRB. All study closures are

reported to a convened IRB as information.

Renewal of activity in a closed state Once a study has been closed, for any reason, the principle investigator must submit a

new protocol application to the IRB for review and approval should he/she wish to renew ANY research

activity related to the study- including any intervention or interaction with previously recruited subjects;

accessing, analyzing, or transmitting any data which has been stored as part of the study; or review of

subjects' clinical records for research purposes.

References:

21 CFR 56.108(a)(3)

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16.0 Informed Consent

Regulatory Background Informed consent is a requirement of non-exempt human subjects research. Informed consent

is a document as well as a process, both of which are equally important. Obtaining consent is an ongoing

process between the investigator (or designee) and prospective subjects whereby information is

exchanged and the subject is given the opportunity to ask questions. In most cases, federal regulations

require informed consent and documentation of the consent process. In certain circumstances, however,

a waiver may be granted.

Unless signed informed consent is waived or not required by the IRB or federal regulations, investigators

may not conduct research involving human subjects unless legally effective informed consent of the

subject or the subjects' legally authorized representative has been obtained. Informed consent is legally

effective if it is both obtained from the subject or the subject’s legally authorized representative and

documented in a manner that is consistent with the HHS protection of human subject’s regulations and

with applicable laws of the jurisdiction in which the research is conducted. Wake Forest School of

Medicine institutional policy requires a signature, date, and a notation of the time a consent form is

signed. There are no provisions for waiving the documentation of informed consent for FDA regulated

research.

An investigator shall seek such consent only under circumstances that provide the prospective subject or

the legally authorized representative sufficient opportunity to consider whether or not to participate and

that minimize the possibility of coercion or undue influence.

The information that is given to the subject or legally authorized representative shall be in language

understandable to the subject or legally authorized representative. Therefore, it is not appropriate to

consent a subject who speaks a language other than English with a consent form written in the English

language. Subjects or legally authorized representatives whose primary language is not English should be

consented and provided with a copy of the consent form in their native language.

No informed consent may include any exculpatory language, through which the subject or representative

is made to waive or appear to waive any of the subjects' legal rights, or releases or appears to release the

investigator, the sponsor, the institution or its agents from liability for negligence. Exculpatory statements

include statements in which a subject is asked to agree to or accept something that is unfavorable to the

subject.

The informed consent requirements in this policy are not intended to preempt any applicable Federal,

State, or local laws which require additional information to be disclosed in order for informed consent to

be legally effective. In addition, nothing in this policy is intended to limit the authority of a physician to

provide emergency medical care, to the extent the physician is permitted to do so under applicable

Federal, State, or local law.

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Definitions

Assent is the affirmative agreement of a child or individual with impaired consent capacity to participate

in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.

Legally Authorized Representative (LAR) means an individual or judicial or other body authorized under

applicable law to consent on behalf of a prospective subject to the subject’s participation in the

procedure(s) involved in the research. The signature of a LAR may be used in research studies where the

subject is incompetent or otherwise unable to provide informed consent (e.g., unconscious). The IRB

considers the ethical principles outlined in the Belmont Reports when considering whether or not a

research study is allowed to obtain the consent of the LAR. When the IRB approves consent by an LAR, a

signature line and date must be included in the signature section of the informed consent document. A

description of the LARs relationship to the subject must also be included.

The issue as to who can be an LAR is determined by the laws of the jurisdiction in which the research is

conducted (e.g., local or state law). North Carolina has such law that addresses consent by someone other

than the subject for participation in research. The IRB relies on the Medical Center policy for obtaining

informed consent for treatment, surgical operations and procedures (PPB-BRD-04) which states the order

of an LAR. The IRB identifies who can be an LARs in the following order:

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It is the responsibility of the research team to assess the LAR status prior to enrolling a subject in a

research trial which has been approved by the IRB. The status (the relationship to the subject) must be

documented on the informed consent form. The use of an LAR to consent on behalf of a potential research

subject must be outlined in the IRB application and approval must be granted by the IRB.

In situations where the research participant could not sign the informed consent document due to

unconsciousness or similar state, and whose LAR signed the informed consent document on their behalf,

the research participant should be informed of the research study at the earliest possible time. The

research subject should be consented to continue their participation in the research study or given the

opportunity to stop their participation.

Minor, as defined by NC State Law, are subjects less than 18 years of age unless emancipated, in the

armed forces, or legally married. Minors cannot consent to participate in research. Parents, either

biological or adoptive, may give permission for a minor to participate in research. In the absence of a

parent, a court appointed legal guardian may give permission for a minor to participate in research. A legal

guardian is defined as an individual who is authorized under applicable State or local law to consent on

behalf of a child to general medical care. The IRB is responsible for deciding whether written assent is

required in proposed research activities. Assent means a child’s affirmative agreement to participate in

research. Mere failure to object should not, absent affirmative agreement, be construed as assent. A

minor’s written assent is required for children 7-17 years of age, unless waived by the IRB. The IRB would

consider the following three circumstances when determining whether or not a waiver of written assent is

appropriate:

1. the capability of some or all of the children is so limited that they cannot reasonably be consulted;

2. the intervention or procedure involved in the research holds out the prospect of direct benefit to the

health or well-being of the children and is available only in the context of the research;

3. the research meets the same conditions as those for waiver or alteration of informed consent in research

involving adults, as specified in the regulations

Based on such considerations as the child’s age, maturity, and degree of literacy, the IRB will decide what

form of documentation, if any, is most appropriate. If adolescents are involved in research where a

consent form would have been used if the subjects were adults, it would generally be appropriate to use a

similar form to document an adolescent’s assent. Therefore, it may be appropriate for the minor

adolescent to sign the consent form along with their LAR.

The foregoing applies to studies in North Carolina. For studies that will be conducted in other states or

countries, the investigator will be expected to determine local requirements for legally authorized

representatives, minors, and guardians in consultation with the University Legal Counsel.

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Informed Consent Process and Required Elements

The documentation of informed consent as outlined below is required unless the IRB has specifically

waived the requirement under applicable federal regulations.

A proposed informed consent document must be submitted to the IRB with an explanation of how the

informed consent process will be carried out prior to the initiation of research.

All study personnel who are authorized to obtain informed consent must be included in the IRB

application and CITI certified.

The IRB has an informed consent template on its website, and also found in the Appendix of this

document. Investigators are encouraged to use this template as a guide when developing the consent

form.

The proposed consent form must include the following required elements

1. A statement that the study involves research

2. An explanation of the purposes of the research

3. The expected duration of the subject’s participation in the research

4. A description of the procedures to be followed

5. Identification of any procedures which are experimental

6. A description of any reasonable foreseeable risks or discomforts to the subject

7. A description of any benefits to the subject or to others which may reasonably be expected from the

research

8. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be

advantageous to the subject;

9. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be

maintained; and if applicable, a statement of the possibility that the Food and Drug Administration may

inspect the records

10. A statement that the monitor, the auditor, the IRB, and the regulatory authority will be granted direct

access to the participant’s original medical records for verification of clinical

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trial procedures or data, without violating the confidentiality of the participant, to the extent permitted by

the applicable laws and regulations and that, by signing a written consent form, the participant or the

participant’s legally acceptable representative is authorizing such access.

11. For research involving more than minimal risk, an explanation as to whether any compensation is available

if injury occurs, whether any medical treatments are available if an injury occurs, and, if so, what they

consist of, or where further information may be obtained. See the Research Related Injury Policy for

additional information.

12. An explanation of whom to contact for answers to pertinent questions about the research and research

subject’ rights, and whom to contact in the event of a research-related injury to the subject; and

13. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits

to which the subject is otherwise entitled, and the subject may discontinue participation at any time

without penalty or loss of benefits to which the subject is otherwise entitled.

Additional elements of informed consent to be included when appropriate are:

1. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo

or fetus, if the subject is or may become pregnant) which are currently unforeseeable;

2. Anticipated circumstances under which the subject’s participation may be terminated by the investigator

without regard to the subject’s consent;

3. Any additional costs to the subject that may result from participation in the research;

4. The consequences of a subject’s decision to withdraw from the research and procedures for orderly

termination of participation by the subject;

5. A statement that significant new findings developed during the course of the research which may relate to

the subject’s willingness to continue participation will be provided to the subject; and

6. The approximate number of subjects involved in the study.

7. Study treatment(s) and the probability of random assignment to placebo or to each treatment

8. The IRB may require that information be given to research subjects when in its judgment the information

would meaningfully add to the protection of the rights and welfare of subjects

9. The amount and schedule of payments if applicable.

The IRB considers the following when determining whether or not to include the items referenced above:

1. Risks to subjects

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2. The length and extent of the study

3. Whether the study includes multiple sites or occurs at a single site

When following ICH-GCP guidance, investigators and research staff must provide all the disclosures and

follow the requirements pertaining to consent covered by ICH-GCP.

Documentation of Informed Consent The documentation of informed consent as outlined below is required unless the IRB has specifically

waived the requirement under applicable federal regulations.

Informed consent shall be documented by the use of a written informed consent document.

The informed consent document must be signed and dated by the subject or the subject’s legally

authorized representative. If a subject’s legally authorized representative consents on their behalf, a

statement of the relationship of the LAR to the subject must be outlined.

The version of the informed consent most recently approved by the IRB must be used.

A copy of the signed informed consent shall be given to the person signing the document.

The consent document must embody the elements of informed consent required by federal regulations as

outlined above. This form may be read to the subject or the subject's legally authorized representative,

but in any event, the investigator shall give either the subject or the representative adequate opportunity

to read it before it is signed by the subject or legally authorized representative.

If the sponsor or IRB requires a witness to the consenting process in addition to the witness to the

participant’s signature and if the same person needs to serve both capacities, a note to that effect will be

placed under the witness’s signature line.

Use of the Short Form Written Consent Document The IRB also allows for the use of a short form written consent document. A short form

is a summary of the research being performed and would not embody all of the required elements of an

informed consent document. A short form states that the elements of informed consent required by

federal regulations have been presented orally to the subject or the subject's legally authorized

representative. The researcher will give either the participant or representative adequate opportunity to

read the consent document before it is signed. A short form may be used as a substitute if potential

subjects are blind, illiterate, or have other conditions preventing them from obtaining legally effective

consent. When this method is used all the following conditions must be met:

There shall be a witness to the oral presentation

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For participants who do not speak English, the witness should be conversant in both English and

the language of the participant.

The IRB shall approve a written copy of what is to be said to the subject or the representative.

The short form itself is to be signed by the subject or the legally authorized representative For

FDA-regulated research, the subject or the subject’s LAR signs and personally dates the short form

The witness shall sign and personally date both the short form and a written copy of what was said

to the subject or the representative. The witness’s signature hereby attests that the information in

the consent form and any other written information was accurately explained to, and apparently

understood by, the subject of the subject’s LAR, and that informed consent was freely given by the

subject or the subject’s LAR.

The person actually obtaining consent shall sign a written copy of what was said to the subject or

the representative

A written copy of what was said to the subject or the representative shall be given to the subject

or the representative, in addition to a copy of the short form

Waiver of Documentation of Informed Consent The IRB may waive the requirement for the investigator to obtain a signed consent form for some or all

subjects if it finds either:

That the only record linking the subject and the research would be the consent document and the

principal risk would be potential harm resulting from a breach of confidentiality. Each subject will

be asked whether he or she wants documentation linking them with the research, and the

subject’s wishes will govern; or

That the research presents no more than minimal risk of harm to subjects and involves no

procedures for which written consent is normally required outside of the research context.

Studies that follow FDA regulations and guidance may be eligible for a waiver of documentation of the

consent process only under circumstances that meet criteria number 2 above.

In cases in which the documentation requirement is waived, the IRB may require the investigator to

provide subjects with a written statement regarding the research. This written statement should include

the purpose of the research, the investigator’s contact information should the subject have additional

questions after their participation in the research, and contact information for the Institutional Review

Board should the subject have questions regarding their rights as research subjects. This written

statement must be reviewed by the IRB prior to being provided to participants.

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The IRB considers the ethical principal of respect for persons when determining whether or not a waiver of

the documentation of informed consent is appropriate. Respect for persons requires the recognition of the

individual as an autonomous agent and protection of the individual with diminished capacity.

Waiver of Informed Consent or the Elements of Informed Consent The IRB may approve a consent procedure which does not include, or which alters, some or all

of the elements of informed consent set forth in this section, or waive the requirements to obtain

informed consent provided the IRB finds and documents that:

The research involves no more than minimal risk to the subjects;

The waiver or alteration will not adversely affect the rights and welfare of the subjects;

The research could not practicably be carried out without the waiver or alteration; and

Whenever appropriate, the subjects will be provided with additional pertinent information after

participation.

The waiver criteria are not appropriate for research involving drugs and devices that are regulated by the

FDA. This is true for informed consent and for parental permission forms.

The IRB can also waive informed consent if:

The research or demonstration project is to be conducted by or subject to the approval of state or local

government officials and is designed to study, evaluate, or otherwise examine:

public benefit or service programs;

• procedures for obtaining benefits or services under those programs;

• possible changes in or alternatives to those programs or procedures; or

• possible changes in methods or levels of payment for benefits or services under those programs;

the research could not practicably be carried out without the waiver or alteration.

If a waiver of consent is granted by the IRB, this will be communicated to the investigator in their approval

memo, and also a record will be maintained in the electronic study file.

When research is sponsored by the Department of Defense, if the research subject meets the definition of

“experimental subject,” policies and procedures prohibit a waiver of the consent process unless a waiver is

obtained from the Secretary of Defense. An experimental subject is defined as an activity for research

purposes, where there is an intervention or interaction with a human being for the primary purpose of

obtaining data regarding the effect of the intervention or interaction (32 CFR.210.102(f)). Examples of

interventions or interactions include, but are not limited to: a physical procedure, a drug, a manipulation

of the subject or the subject’s environment, the withholding of an intervention that would have been

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undertaken if not for the research purpose. If the research subject does not meet the definition of

“experimental subjects,” policies and procedures allow the IRBs to waiver the consent process.

The Assistant Secretary of Defense for Research and Engineering may waive the requirements for consent

when all of the following are met:

The research is necessarily to advance the development of a medical product for Military Services.

The research might directly benefit the individual experimental subject.

The research is conducted in compliance with all other applicable laws and regulations.

Additional Signatures The Common Rule as outlined in 45 CFR 46 does not require a witness signature, or the signature of the

principal investigator, when the research subject signs a standard informed consent document which

embodies all of the required elements. Federal regulations require the signature of the subject or the

subject’s legally authorized representative (LAR) and the date on which the subject or their LAR sign the

informed consent document.

Re-consenting Research Subjects The federal regulations do not specifically address the re-consenting of subjects; however, they

do require that research subjects be provided with any significant new findings developed during the

course of the research which may relate to the subjects willingness to continue participation. While not

specifically addressed in the regulations, the Belmont Report provides an additional ethical requirement to

provide research subjects with significant new findings that might affect their long-term health even after

they have completed participation in a research study. Neither the federal regulations nor the Belmont

Report provide guidance on the type or extent of documentation required to satisfy these regulatory or

ethical responsibilities.

The IRB requires that research subjects be re-consented to participate in research studies when changes to

the research protocol affect the safety, rights and welfare of the subjects or the subjects’ willingness to

continue participation in the study. For example, amendments filed with the IRB related to research

related risks, would require re-consenting of the research subjects. When filing an amendment,

investigators should outline their plans for re-consenting subjects when changes to the protocol and

consent would affect the safety, rights and welfare of research subjects.

Minor changes to the informed consent document including but not limited to typographical errors, would

not require the re-consenting of research subjects.

Data retention when participants withdraw from a clinical trial Investigators should give participants a variety of options with regard to the management and

confidentiality of study data once a participant withdraws from a trial.

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When a participant withdraws from a study, the data collected on the participant to the point of

withdrawal remains part of the study database and may not be removed. The consent document cannot

give the participant the option of having data removed. Investigators should either include options of

withdrawal in the initial consent document, or have a separate document, that has been approved by the

IRB prior to use, that describes the following options for date integrity following withdrawal.

A researcher may ask a participant who is withdrawing whether the participant wishes to provide

continued follow-up and further data collection subsequent to their withdrawal from the interventional

portion of the study. Under this circumstance, the discussion with the participant would distinguish

between study-related interventions and continued follow-up of associated clinical outcome information,

such as medical course or laboratory results obtained through non-invasive chart review, and address the

maintenance of privacy and confidentiality of the participant’s information.

The researcher must obtain the participant’s informed consent for this limited participation in the study

(assuming such a situation was not described in the original informed consent form). The IRB must

approve the addendum consent document.

If a participant withdraws from the interventional portion of a study and does not consent to continued

follow-up of associated clinical outcome information, the researcher must not access for purposes related

to the study the participant’s medical record or other confidential records requiring the participant’s

consent. However, a researcher may review study data related to the participant collected prior to the

participant’s withdrawal from the study, and may consult public records, such as those establishing

survival status.

Research involving deception or withholding of information Some research designs may require the withholding of information from human subjects.

Research involving deception or withholding of information must be reviewed by the IRB with common

sense and sensitivity. The withholding of information by researchers is different from the practice of

deception, in which researchers provide false or misleading information to subjects. Studies involving

deception need to be carefully reviewed by the IRB to ensure that the deception is justified through an

examination of the risks and benefits of that deception. Furthermore, the IRB should ensure that, when

appropriate, the subjects will be debriefed. Before approving a study that involves deception, the IRB

should determine that the subject population is suitable and that the deception involved in the study

would not alter a subject’s assessment of risk to himself/herself if he/she was aware of the deception at

the time he/she agreed to participate.

Deception can only be permitted where the IRB finds and documents that waiver or alteration of the

informed consent requirements is justified according to 45 CFR 46.116(d). The IRB must document that the

following criteria have been satisfied:

The research involves no more than minimal risk to the subjects;

The waiver or alteration will not adversely affect the rights and welfare of the subjects; The

research could not practicably be carried out without the waiver or alteration;

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Whenever appropriate, the subjects will be provided with additional pertinent information after

participation.

Obtaining Consent Remotely In some cases, investigators may not be able to have face to face contact with potential study participants,

LARs, or parents granting permission to participate in research. In such cases, the investigator may still

obtain consent remotely. In order to obtain legally effective consent, the investigator or member of the

study team should provide two copies of the approved consent form to the participant/LAR/parent. After

received, the investigator should speak with the participant/LAR/parent on the telephone, presenting the

elements of consent, the content of the study, and answer any questions. At the end of the discussion, the

investigators should advice the participant/LAR/parent to sign and date one form and return it. The second

form should be kept by the participant/LAR/parent for documentation. Upon receipt of the signed form,

the investigator should sign and date with the current date, and add a note detailing the date discrepancy.

No study procedures will begin until the IRB approved method of obtaining consent is completed.

Adults Unable to Consent When investigators are likely to approach adults who lack the ability to consent, the IRB

evaluates the following:

The proposed plan for assessment of the capacity to consent is adequate.

Assent of the subjects is a requirement, and if so, whether the plan for assent is adequate.

Examples of research subjects who are adults and unable to assent are the decisionally impaired and

mentally handicapped.

When adult subjects are unable to consent, a legally authorized representative may consent on their

behalf. The criteria for who may qualify as an LAR are determined by state law. The listing of approved

classes of individuals that may serve as an LAR is included in section 16.3 of this document.

Monitoring the consent process The IRB has the authority to observe and monitor the consent process as a method to protect subjects.

The IRB may consider monitoring the consent process in the following circumstances:

An investigator has had previous non-compliance cases for failure to obtain consent in accordance

with the regulations.

The research will involve subjects who are cognitively impaired or unable to consent.

An investigator is conducting his or her first research project.

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The IRB may observe the consent process in person with the study team and subject present, or may

review consent records and source documentation to ensure the methods used to obtain consent were

appropriate.

Additional Regulations In order to comply with ICH-GCP guidance, when alternative procedures or treatments are available to a

subject, information about the potential benefits and risks of these alternative procedures or treatments

must be included in the consent. The monitor, auditor, IRB, and regulatory authority will be granted direct

access to the subject’s original medical records for verification of clinical trial procedures or data, without

violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations.

It must be clear in the consent form that by signing a written consent form, the subject’s legally acceptable

representative is authorizing such access.

For research sponsored by the Department of Defense, IRBs must determine that the disclosure includes

that provisions for research-related injury follow the requirements of the DoD component.

When following FDA requirements, there is a statement that a description of the clinical trial will be

available on http://www.clinicaltrials.gov as required by U.S. law. The website will not include information

that can identify the participant. At most the website will include a summary of the results. The participant

can reach the website at any time.

Retention of the consent document The HHS protection of human subjects regulations require institutions to retain records of IRB activities

and certain other records frequently held by investigators for at least three years after completion of the

research (45 CFR 46.115(b)). In addition, other regulations may apply and require retention of these

records for a longer period of time. Documentation of the informed consent of the subjects - either the

signed informed consent form or the short form and the written research summary - are records related to

conducted research that are typically held by investigators and must be retained for at least three years

after completion of the research, unless the IRB waived the requirement for informed consent or the

requirement for documentation of informed consent (45 CFR 46.117).

If investigators have been designated to retain certain records (e.g., informed consent documents signed

by subjects) on behalf of the institution as required by the HHS regulations at 45 CFR 46.115(b), they must

retain the records in some form. Such records may be preserved in hardcopy, electronic or other media

form and must be accessible for inspection and copying by authorized representatives of HHS at

reasonable times and in a reasonable manner (45 CFR 46.115(b)). Retention of multiple copies of each

record is not required. Investigators should follow the institution’s policies and procedures for retaining

records. If investigators who have been designated to retain records on behalf of the institution leave that

institution, the investigators and the institution should identify the successor responsible for maintaining

those institutional records, either at the original institution or wherever the records are relocated, for the

period of time required under HHS regulations at 45 CFR 46.115(b).

http://www.clinicaltrials.gov/

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Compensation for Research Injury in Informed Consent As required by 45 CFR 46.116, an explanation of compensation in the case or research related injury is

required in studies of greater than minimal risk. For studies that are sponsored by non- profit or federal

entities, Wake Forest has established an insurance policy which is included in the consent form. For

studies that are sponsored by for-profit entities, it is important that the description of compensation and

liability in the informed consent document be consistent with the terms agree to in the Clinical Trials

Agreement between the institution and the sponsor. Therefore, the IRB may approve either the template

language established by the institution or the following statement, if the terms of the contract have not

been negotiated at the time of review:

Injury language will be provided following completion of negotiation and approval by Sponsor and

WFUHS.

If the above statement is employed by an investigator, it will be noted in their approval letter that subjects

should not be enrolled in the study until an amendment has been submitted, verified with the contract,

and approved by the IRB.

Please Note: If a subject is injured as a result of participation in a research study, Wake Forest School of

Medicine does not allow for coverage by the sponsor contingent upon first billing of the subject’s

insurance. For example, accepting payment for any costs to treat a study related injury that the subject’s

insurance does not cover is not permitted. Sponsors are expected to provide the same level of injury

liability coverage to all subjects regardless of their ability to pay treatment costs through other means.

References:

21 CFR 50.20

21 CFR 50.25

21 CFR 50.27

21 CFR 56.109(c)

45 CFR 46.109(c)

45 CFR 46.116

45 CFR 46.117

DoDD 3216.2 para. 5.3.4

DoDD 3216.2 para. 4.2 SECNAVINST 3900.39D, para 6a(5) ICH-GCP 2.9

ICH-GCP 3.1.5

ICH-GCP 3.1.9

ICH-GCP 4.3.4

ICH-GCP 4.8.1-4.8.7

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17.0 Exception from Informed Consent for studies conducted in

Emergency Settings

Regulatory Background Persons with life-threatening conditions who can neither give informed consent nor refuse

enrollment in a study have diminished autonomy, and thus constitute a vulnerable population. Therefore

special consideration and additional protective procedures are warranted for the IRB the review, approval,

and conduct of research conducted in emergency settings.

FDA and OHRP regulations provide a narrow exception to the usual requirements, and that informed

consent be obtained from human subjects, or their legally authorized representatives (LAR), prior to

initiation of an experimental intervention. This exception applies to a limited class of research activities

involving human subjects who are in need of emergency medical intervention, but who cannot give

informed consent because of their life-threatening medical condition, and who do not have a legally

authorized person to represent them. The intent of the regulation is to allow the safe and ethical conduct

of research in life-threatening conditions for which available treatments are unproven or unsatisfactory,

while establishing additional protections for the rights and welfare of subjects who cannot provide

informed consent.

Note that these exception regulations DO NOT apply to research involving fetuses, pregnant women, and

human in vitro fertilization and research involving prisoners. These regulations do not preempt state or

local law. When a study is following DoD regulations, an exception from consent in emergency medicine is

prohibited unless a waiver is obtained from the Secretary of Defense.

Procedures to Be Followed by Principal Investigators Requests for research that fall within this emergency informed consent exemption often take longer

periods of time to review, therefore investigators should plan ahead. Principal Investigators who plan to

conduct research protocols in an emergency setting where it may not be possible to obtain consent from

the subject or their legally authorized representative, and when the research involves a Food and Drug

Administration (FDA) regulated drug or device are strongly encouraged to consult with the Director of the

IRB and the IRB Chair(s) in preparing their applications. The investigator may also wish to attend the IRB

meetings where the protocol is reviewed to answer questions and concerns raised by the members of the

Board. Meetings with other Institutional representatives, such as public affairs or legal affairs, may also be

necessary.

In the protocol the principle investigator must provide assurance and justification that following key

conditions are met:

1. The human subjects who will be studied will be in a life-threatening situation

2. Available treatments for the condition under study are unproven or unsatisfactory

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3. Collection of valid scientific evidence is necessary to determine the safety and effectiveness of the

proposed investigational interventions

4. Obtaining informed consent form some or all subjects is not feasible because:

a. Some subjects will not be able to give informed consent as a direct consequence of their medical

condition, for example they are unconscious;

b. To be maximally effective in saving life or limb, the investigational intervention must be administered

before it is feasible to obtain consent from the subject’s legally authorized representatives;

c. There is no reasonable way to prospectively identify, in a reasonable time frame, which individuals are

likely to become eligible for participation in the study

5. Participation in the research holds out the prospect of a direct benefit to the subjects

6. The study could not practicably be carried out without the waiver of informed consent

In the protocol the principle investigator must also provide a detailed description of how the following

required procedures will be carried out:

1. Concurrence of a Licensed Physician. Because 21 CFR 50.24 permits an exception from the requirement

for informed consent for a group of subjects, the case-by-case independent determination is replaced by

the general concurrence of a licensed physician to the enrollment of potential subjects. This physician

must be someone "who is a member of or consultant to the IRB and who is not otherwise participating in

the clinical investigation" (Sec. 50.24(a)). The option to use a consultant to the IRB provides flexibility, for

example, when the physician member(s) cannot participate in the deliberation and voting due to conflict

of interest. Because the documented concurrence of the physician is required for approval of these

studies, the IRB will ensure that meeting minutes specifically record his/her affirmative vote.

2. Ongoing Attempts to Obtain Consent. Researchers planning to conduct research that does not include the

informed consent of all subjects must present a plan describing how they will attempt to obtain consent

from the subjects and/or their legally authorized representatives on an ongoing basis throughout the

conduct of the study and at the conclusion of the research. It is also required that information be provided

about the clinical investigation to the subject's legally authorized representative or to a relative, if feasible,

if the subject dies before consent has been obtained. Investigators must describe how they will document

and summarize their attempts to contact family members to obtain their consent if obtaining informed

consent is not feasible and a legally authorized representative is not reasonably available; this information

will required at the time of continuing review.

3. Community Consultation. The FDA requires that investigators will provide an opportunity for the

community from which research subjects may be drawn so that they may understand the proposed clinical

investigation and its risks and benefits and have an opportunity to ask questions, raise concerns, and voice

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objections. Thus, consultation with appropriate community representatives must occur before the

research begins.

For example, the principal investigator could schedule a public meeting in the community to discuss the

protocol. At least one member of the IRB must attend the public meetings to assess the public perception

of the research. The IRB may wish to establish a panel of members of the community from which the

subjects will be drawn to gain input. The IRB could add ad hoc members to the board who are not

affiliated with the institution and are representative of the community; or develop other mechanisms to

ensure community involvement and input into the IRB decision making process. It is likely that multiple

methods may be needed in order to provide the supplemental information that the IRB will need from the

community to review the proposal. The IRB will consider the plans for this community consultation in

reviewing the investigation, and may decide, among other things, that it is appropriate to attempt to

exclude certain groups from participation in the investigation, or that wider community consultation and

discussion is needed.

4. Public Disclosure. Appropriate public disclosure must occur before initiating the study, and also at the

completion of the study. It is the responsibility of the principal investigator to disclose information to the

public; however, the IRB is responsible for determining the information to be disclosed. This information

could include, but may not necessarily be limited to, the information that is found in the informed consent

document, the investigator's brochure, and the research protocol. The IRB will consider how best to

publicly disclose, prior to commencement of the clinical investigation, sufficient information to describe

the investigation's risks and benefits. Initial disclosure of information will occur during the community

consultation process.

It is also necessary to provide comprehensive summary data from the completed trial to the research

community in order to permit other researchers to assess the results of the clinical investigation. Sufficient

information may be contained in a scientific publication of the results of the completed investigation; in

other instances, a publication may need to be supplemented by additional information. Information to be

disclosed must include the demographic characteristics (age, gender, and race) of the research population.

Following publication, the IRB will be responsible for determining appropriate mechanisms for providing

this information, possibly supplemented by a lay description, to the community from which research

subjects were drawn.

5. A separate IND or IDE. Protocols involving an exception to the informed consent requirement must be

performed under a separate investigational new drug application (IND) or investigational device

exemption (IDE) that clearly identifies such protocols as protocols that may include subjects who are

unable to consent. The submission of those protocols in a separate IND/IDE is required even if an IND for

the same drug product or an IDE for the same device already exists. Applications for investigations under

this section may not be submitted as amendments under 312.30 or 812.35 of this chapter.

6. Independent Data Monitoring Committee. An independent data and safety monitoring committee is

required to assure that if it becomes clear that the benefits of the investigational intervention are

established, or that risks are greater than anticipated, or that the benefits do not justify the risks of the

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research, the investigation can be modified to minimize those risks or the clinical investigation can be

halted.

IRB Procedures FDA regulations allow the IRB to review, approve, and process continuing review of a research

study without requiring that informed consent be obtained from all research subjects ONLY IF the IRB finds

to its satisfaction and documents that EACH of the following requisites are met:

1. The human subjects to be studied in the protocol will be in a life-threatening situation

2. Available standard of care treatments are unproven or unsatisfactory, and the collection of new scientific

data, including data from randomized placebo-controlled investigations, is necessary to determine the

safety and effectiveness of the proposed intervention(s)

3. Participation in the research has the potential of direct benefit to the subjects because:

a. Subjects are facing a life-threatening situation that necessitates intervention;

b. Appropriate animal and other preclinical studies have been conducted, and the information derived from

those studies and related evidence support the potential of the intervention to provide a direct benefit to

the individual subjects;

c. The risks associated with the investigation are reasonable in relation to what is known about the medical

condition of the potential class of subjects; the risks and benefits of standard or care therapy, if any; and

what is known about the risks and benefits of the proposed intervention or treatment.

4. Obtaining informed consent from all subjects is not feasible because:

a. Some subjects will not be able to give informed consent as a direct consequence of their medical

condition, for example they are unconscious;

b. To be maximally effective in saving life or limb, the intervention under investigation must be administered

before it is feasible to obtain consent from the subjects' legally authorized representatives;

c. There is no reasonable way to prospectively identify, in a reasonable time frame, which individuals are

likely to become eligible for participation in the clinical investigation.

d. The principle investigator provides other justifications as to why the proposed investigation could not be

practicably be carried out without the waiver.

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5. The investigator outlines how he or she will attempt to contact a legally authorized representative (LAR)

for each subject who was not consented, within the potential therapeutic window of the investigation, to

seek their consent for the subject, and how if a LAR is not reasonably available, the investigator will

attempt to contact, within the therapeutic window, a family member who is not a LAR, and ask whether

he or she objects to the subject's participation in the clinical investigation. At the time of each continuing

review, the investigator will summarize the efforts that have been made to contact legally authorized

representatives and family members. The investigator will define the length of the potential therapeutic

window in the protocol based on scientific evidence.

The IRB is responsible for ensuring that procedures are in place to inform, at the earliest feasible

opportunity, each subject, or if the subject remains incapacitated, a legally authorized representative of

the subject, or if such a representative is not reasonably available, a family member, of the subject's

inclusion in the clinical investigation, the details of the investigation and other information contained in

the informed consent document. The IRB shall also ensure that there is a procedure to inform the subject,

or if the subject remains incapacitated, a legally authorized representative of the subject’s participation. If

such a representative is not reasonably available, a family member should be notified that he or she may

discontinue the subject's participation at any time without penalty or loss of benefits to which the subject

is otherwise entitled. If a legally authorized representative or family member is told about the clinical

investigation and the subject's condition improves, the subject is also to be informed as soon as feasible. If

a subject is entered into a clinical investigation with waived consent and the subject dies before a legally

authorized representative or family member can be contacted, information about the clinical investigation

is to be provided to the subject's legally authorized representative or family member, if feasible.

6. The application includes an informed consent document that will be used with subjects who can provide

informed consent or with LAR’s of subjects who cannot.

7. The application describes the establishment of an independent data monitoring committee to monitor and

oversee the clinical investigation

8. The application describes the methods for

a. Consulting with representatives of communities where the clinical investigation will be conducted and

from which the subjects will be drawn

b. Disclosing to the communities in which the clinical investigation will be conducted and from which the

subjects will be drawn, before initiating the clinical investigation, of the purpose of the investigation and

its risks and expected benefits

c. Public disclosure of sufficient information following completion of the clinical investigation to inform the

community of the study findings, including the demographic characteristics of the research population and

adverse events.

Separate IND/IDE

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Protocols involving an exception to the informed consent requirement under the FDA regulation for an

Exception from Informed Consent for Studies Conducted in Emergency Settings must be performed under

a separate investigational new drug application (IND) or investigational device exemption (IDE) that clearly

identifies such protocols as protocols that may include subjects who are unable to consent. The

submission of those protocols in a separate IND/IDE is required even of an IND for the same drug product

or an IDE for the same device already exists. Applications for investigations under this section may not be

submitted as amendments under the Investigational New Drug Application regulations or Investigational

Device Exemptions regulations.

Retention of Records

The IRB determinations required by FDA regulation for an Exception from Informed Consent for Studies

Conducted in Emergency Settings must be retained by the IRB for at least 3 years after completion of the

study, and the records shall be accessible for inspection and copying by the FDA and the Office of Human

Research Protections (OHRP) and as required by federal regulation.

Determination that a Study Does Not Meet Criteria for Exception

If the IRB determines that it cannot approve a clinical investigation because the investigation does not

meet the criteria in the exception provided under the FDA regulation for an Exception from substantially

equivalent clinical investigation of the sponsor, and to other IRB's that have been, or are, asked to review

this or a substantially equivalent investigation by that sponsor. Informed Consent for Studies Conducted in

Emergency Settings paragraph or because of other relevant ethical concerns, the IRB must document its

findings and provide these findings promptly in writing to the clinical investigator and to the sponsor of

the clinical investigation. The sponsor of the clinical investigation must promptly disclose this information

to the FDA and to the sponsor's clinical investigators who are participating or are asked to participate in

this or a substantially equivalent clinical investigation of the sponsor, and to other IRB's that have been, or

are, asked to review this or a substantially equivalent investigation by that sponsor.

References:

21 CFR 50.24

45 CFR 46.101(i)

45 CFR 46 Subpart B

45 CFR 46 Subpart C

45 CFR 46 Subpart D

21 CFR 56 Subpart B

21 CFR 56 Subpart C

21 CFR 56 Subpart D

21 CFR 312

21 CFR 812

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18.0 Conflict of Interest

Definitions a. For conflict of commitment Individual means the faculty member or exempt employee who owes a

primary duty of loyalty and support to the Medical School, including part- time appointments. Individual

includes spouse and dependent children.

b. For conflict of interest Individual means the principal investigator/project director, co- investigators,

and any other person who is responsible for the design, conduct, or reporting of research for which

extramural funding is sought, or the person conducting educational or other academic activities such as

consultation. The principal investigator is responsible for identifying to the Office of Research other

persons who are responsible for the design, conduct, and reporting of the research for which extramural

funding is sought, or involved in educational or other academic activities. Individual includes spouse and

dependent children.

A conflict of commitment exists when a faculty member or exempt employee of Wake Forest University

School of Medicine (WFUSM) has a relationship that requires a commitment of time or effort to outside

activities that may potentially result in the Individual’s failure to meet his or her obligations to the School.

Any relationship with an outside entity that requires frequent and/or prolonged hours of effort spent

outside WFUSM may present a conflict of commitment, regardless of amount of remuneration, number of

days, time of day or day of the week.

The term conflict of interest in professional and scientific endeavors refers to a situation in which financial

or other personal considerations may compromise, or have the appearance of compromising, an

Individual’s professional judgment in conducting or reporting research, patient care, or carrying out or

directing other types of School programs. The bias that may result from such conflicts could have impact

not only on the collection, analysis, interpretation and reporting of data, but also on the hiring of staff,

procurement of materials, or other activities influencing the course of the School’s programs. WFSUSM

follows the Public Health Service (PHS) regulations’ definition for significant financial interest set forth in

42 CFR, Part 50, Subpart F (http://grants.nih.gov/grants/compliance/42 CFR 50 Subpart F.htm).

Reportable conflicts of commitment include, but are not limited to ongoing or repetitive arrangements

with outside entities include consulting, speaking, expert opinion, paid court appearances, research,

laboratory testing, and teaching, regardless of the amount of remuneration, the number of days, the time

of day, or day of the week.

Non-reportable conflicts of commitment include writing, membership on peer review panels, and

membership on advisory groups/councils for not-for-profit organizations.

http://grants.nih.gov/grants/compliance/42

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Reportable significant financial interest, meaning receiving anything of value, including, but not

limited to:

All payments for services (e.g., consulting fees, lecture payments, or honoraria) regardless of

value.

Equity interests (e.g., stock ownership, stock options, or other ownership interests) regardless of

value.

Intellectual property rights (e.g., patents, copyrights, and royalties from such rights) regardless of

value.

Fiduciary services (e.g., officer or board member of an outside entity), even if unpaid.

Some examples of non-reportable significant financial interest include: ownership of mutual funds;

salary or reimbursements from the school; income from seminars, lectures, or teaching engagements

sponsored by public or nonprofit entities; income from service on advisory committees or review

panels for public or nonprofit entities (e.g., NIH).

Disclosure is necessary when a foundation is supported by industry.

Regulatory Background Requirements set forth in 42 CFR, Part 50, Subpart F and other Federal guidelines (National

Science Foundation, National Institutes of Health, Food and Drug Administration) call for disclosure of

personal financial interests by Principal Investigators, Clinical Investigators (co- or sub-investigators),

and others involved in the conduct of research in any way that could bias the design, conduct or

implementation, management, and reporting of research data. The regulations further require that

the University have a mechanism for the investigators to disclose real or potential conflicts and for the

development of a management plan that manages, eliminates, or reduces the potential conflict, if

necessary. The disclosure and management of the conflict must occur before any funds are released

to the grantee institution and contractors (investigator) for expenditures and before any human

subject research may occur.

Investigator Conflict of Commitment A conflict of commitment exists when an Individual with WFUSM has a relationship that requires a

commitment of time or effort to outside activities which may potentially result, either obviously or

implicitly, in the Individual’s failure to meet his or her obligations to the School.

Trust, good faith, and open discussions of controversial issues among colleagues are central to the life

of WFUSM. The relevant outside activities of Individuals must be governed by thoughtful and shared

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consideration of individual circumstances, rather than rigid rules. Reporting and disclosure serve to

protect Individuals from potential conflicts and preserve academic freedom in general.

Purpose

Acceptance of a fulltime appointment entails a commitment to give one's best efforts to furthering

the mission of WFUSM and to assign first priority to its needs and goals. At the same time, WFUSM

recognizes that participation of individuals as principals or consultants in professional organizations,

fiduciaries, government agencies, community organizations, and for- profit companies can serve the

interests of WFUSM. The experience and enhanced status that such participation brings to the

Individual are shared indirectly by WFUSM, and these outside activities often contribute to the

richness and diversity of the academic community. Moreover, as a result of such activities, society will

benefit from the dissemination of knowledge and technology developed within WFUSM.

This policy is intended to promote creative and productive working relationships among the Individual

and relevant outside entities while protecting WFUSM and its Individuals from the conflicts of

commitment that can be created by such affiliations. Relationships with relevant outside entities

should not only benefit that entity, but they must also further the mission of WFUSM and maintain

the integrity and independence of the Individual, the School, and its students.

Policy

Faculty members and exempt employees of WFUSM, in recognizing that their primary professional

responsibility is to WFUSM and the University, will devote their energies to activities that further the

mission of WFUSM.

Although working relationships with outside entities may be beneficial, these relationships may also

create risk. It is therefore crucial that before accepting such a commitment the Individual: be

discriminating (e.g., examine mission, policies and reputation) in selecting outside entities to avoid

compromising WFUSM’s reputation; avoid commitments that could compromise the basic scholarly

independence and freedom of action that are central to university life; and evaluate the time required

by outside commitments and their impact on the Individual’s commitment to WFUSM.

The School requires that Individuals disclose any significant conflicts of commitment annually through

the online Conflict of Interest and Conflict of Commitment disclosure process within 30 days of receipt

of the reminder notification from the Office of Research each April.

Institutional Threshold for Outside Commitments and Prior Approval

The institutional threshold for outside commitments is 26 days per calendar year. The threshold

may vary among individuals and from discipline to discipline. Therefore, based on departmental needs

and responsibilities of the individual the Chair may specify a maximum allowable amount of time or

threshold for outside activities that is compatible with fulfilling primary responsibilities to WFUSM.

(For department chairs and division directors, this determination is made by the Dean).

Outside time commitments and activities exceeding the 26 day threshold, or departmental

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established time threshold, requires prior approval by the chair, and in the case of the chair, prior

approval by the Dean. Thresholds are not intended to put a limit on outside activities.

The regulations and policy are not concerned with the precise timing of the activities, so

all outside activities should be reported regardless of when they occur, e.g., including weekends.

Upon request, a complete written report of all outside activities of an individual may be

requested by the Chair or supervisor, or the Dean in the case of the Chair.

Use of Wake Forest University School of Medicine Name

Since an academic relationship can be of great value to a non-university entity, opportunities for

outside activities may be offered to an Individual in part because of their association with WFUSM. It

must be remembered that there is no way for the Individual to do such activities completely

independent of their affiliation with WFUSM.

Reporting prior to undertaking a secondary commitment serves to protect the Individual,

WFUSM, or both from possible discredit or embarrassment. Thus, faculty and key administrators must

be discriminating in the selection of secondary commitments, regardless of whether they are

professional or non-professional in character, and regardless of whether the obligation is to be

discharged in "off hours" or during vacation.

If a non-university entity wishes to use WFUSM's name, symbols or logos, written approval by the

Dean and General Counsel must be obtained prior to such use. To obtain a copy of WFUSM's

statement on the use of its name, symbols or logos or to request approval, contact the Office of

Technology Asset Management.

Use of facilities or resources

A report must be made if WFUSM will be investing its resources and sharing in the risks of a

venture or in any other way subsidizing the activity, whether or not sharing in any revenues generated

by the activity.

The WFUSM Organization and Policies Handbook governs an Individual’s participation in any

agreement under which an outside entity will profit from the resources (including information) of

WFUSM as well as from the Individual’s personal involvement.

Because consulting arrangements and publication of books involve an Individual’s personal effort,

contracts for publications and payment of related royalties are not subject to sharing of income with

WFUSM, although they still must be reported.

Sharing of intellectual or tangible property

Individuals must report any relationship they are considering or are engaged in with another entity

when the entity anticipates providing financial or other support for the Individual’s work, or when the

entity anticipates utilization of intellectual property (e.g., inventions, know-how) or tangible property

(e.g., research materials) or original works of authorship (e.g., computer software but not textbooks)

of that Individual’s academic work or the work of a subordinate Individual. [See the WFUSM

Inventions and Patent Policy]

Clinical Liability Issues

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Any faculty clinical practice occurring outside of WFUSM or as otherwise specifically directed by

WFUSM is generally not permitted (e.g., moonlighting). Any exception must be reported and approved

prior to initiating the activity.

Verification of professional liability insurance to non-WFUSM entities will be provided only if the

activity is within the scope of employment and after a report is made to, and approved by, the

department chair or supervisor and the Dean.

The existence of malpractice coverage with a carrier other than through WFUSM does not

preclude the requirement that the Individual disclose plans for outside clinical practice and obtain

permission for such activities in the manner prescribed above.

Other Liability Issues

Generally, since consulting is not supervised by WFUSM, WFUSM insurance does not cover

consulting.

WFUSM does not accept liability for activities that are not under the usual supervision and control

of responsible supervisors.

Individuals must be aware that they may incur liability through consulting and should seek

insurance coverage from the entity requesting the activity.

Consulting that is classified specifically by the department chair or supervisor as sufficiently

beneficial to the School may, upon request and administrative approval, be eligible for coverage by

WFUSM’s liability insurance as it applies to employees. Decisions on coverage for these activities will

be made by the Dean after consultation with General Counsel and Risk Management.

Investigator Conflict of Interest Conflicts of interest most frequently arise in connection with research activities, but may also arise

with educational activities (e.g., speaking engagements) or in providing consultation to industry.

Effective interaction between universities conducting research and industry is essential to ensure the

rapid application of scientific discoveries to the needs of the Nation and to maintain the international

competitiveness of domestic industry. Nonetheless, prudent stewardship of public funds includes

protecting sponsored research from being compromised by the conflicting financial and fiduciary

interests of any Individuals responsible for the design, conduct, or reporting of sponsored research in

accordance with PHS regulation 42 CFR, Part 50, Subpart F

(http://grants.nih.gov/grants/compliance/42 CFR 50 Subpart F.htm). Institutional policy seeks to

maintain a reasonable balance between these competing interests, give the School the ability to

identify and manage any conflicting interests that may bias the research, and minimize reporting and

other burdens on the Individuals. In summary, the purpose of this policy is to comply with federal PHS

regulation 42 CFR, Part 50, Subpart F and state regulations and to protect the credibility and integrity

of the School's faculty and staff so that public trust and confidence in the School's activities are

ensured.

Human Subject Research

http://grants.nih.gov/grants/compliance/42

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Since clinical research commonly involves potential risks to human subjects that other types of

research do not, conflicts of interest in research involving human subjects, e.g., clinical trials,

necessitate closer scrutiny. The Institutional Review Board (IRB) will address the rights and welfare of

human study participants (e.g., recruiting, patient contact, and consent). Whereas, the Conflict of

Interest Review Committee (CIRC) generally will address issues of scientific integrity, financial

management, use of university resources and the protection of students and other trainees involved

in the conduct of the proposed study. Investigators and research staff must disclose conflicts of

interest in the IRB application at the time of study submission and when any related financial interests

change. Study team members must report any changes in their conflict of interest status immediately

to the Conflict of Interest Office, the IRB, and the Principal Investigator of the study. The Conflict of

Interest Review Committee will ensure that an appropriate management plan is developed and

implemented. The Principal Investigator will then submit an amendment incorporating the changes

required by the Conflict of Interest Review Committee. The IRB may add additional requirements to

ensure appropriate management of conflicts of interests, but may not lessen those implemented by

the Conflict of Interest Review Committee. The IRB makes the final decision on whether the

management plan is adequate for the protection of research subjects and whether the study may,

therefore, be approved.

The CIRC is advisory to the IRB and may recommend restrictions in the conduct of human subjects

research; however, the IRB may choose to strengthen, but may not independently weaken,

recommendations of CIRC. Effective and efficient management of relationships involving conflicts of

interests in human subject research demands excellent interaction and communication between the

IRB and the CIRC.

Policy

The School has the responsibility to identify, manage, reduce, or eliminate any conflicts of interest that

may be created by personal financial interests of an Individual. Thus, the School requires that

Individuals disclose any significant financial interests annually through the online disclosure process

within 30 days of receipt of the reminder notification from the Office of Research each April and

transactionally through submission of grants, contracts, regulatory protocols and purchases at the

time of each new application.

Upon identifying a potential conflict of interest, the Individual will cooperate with the CIRC, which

has the responsibility to review the relationship creating the conflict of interest to determine if it can

be managed or eliminated.

If human subjects are involved and a potential conflict of interest is found, the IRB and CIRC will

conduct their respective reviews in parallel, and the IRB will hold final approval pending the

completion of the CIRC review, resolution of the issues and recommendations for management are

made.

Public disclosure is required for all publications (including news releases), presentations (including

posters) and media contact related to an Individual’s financial interest in the sponsor of his/her

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research or in the ownership of a related entity or intellectual property, such as new or experimental

drugs, devices or therapies.

Procedures for disclosure and management Annually, beginning April 1, each Individual will complete an online disclosure of his/her

conflicts of interest and conflicts of commitment within 30 days after e-mail notification by the Office

of Research. All disclosures are submitted by Individuals electronically via an easily accessible online

process. The annual disclosure must be reviewed by the Individual’s designated reviewer (department

chair, section head or supervisor) within 90 days after receipt of a reviewer-specific e-mail notification

by the Office of Research.

At any time an event causes a substantial change in external activities, Individuals are required to

electronically update their disclosure within 30 days. Revised disclosures will prompt a new e-mail

notification to the designated reviewer.

An electronic database of annual disclosures and their reviews will be maintained by the Office of

Research. The reports and the database will be accorded the same confidentiality as personnel

records and will be kept on the file server for at least three years after the date of submission of the

final expenditures report or, where applicable, from other dates specified in 45 CFR 74.53(b) for

different situations. The School will hold final approval of any grant or contract applications,

regulatory protocol applications, or purchase orders until all key personnel on the project have

completed the mandatory online conflict of interest and conflict of commitment disclosure.

Disclosure of Conflicts of Commitment

1. Individuals will report their conflicts of commitment as described in the policy.

2. If an individual needs more time commitment to an outside entity than the department- established

threshold, he/she should seek prior approval in writing from his/her department chair or supervisor.

3. Disclosures containing real or apparent conflicts of commitment will be addressed by the Individual’s

department chair or supervisor.

Disclosure of Conflicts of Interest

1. Individuals will report their conflicts of interest as described in the policy.

2. The Office of Research conflict of interest staff shall conduct an initial review of the annual financial

disclosures.

3. If it appears that there may be a conflict of interest as described in the policy, the Individual will

address and manage the conflict as described in the procedures below.

Management of Conflicts of Commitment

1. Each department chair and supervisor has the ability and responsibility to decide the threshold of days

outside of the office allowed for his/her faculty and staff members based on clinical needs, etc.

2. If it appears there may be a conflict in the number of days required for outside activities for

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a faculty or staff member, the department chair and/or supervisor has the responsibility to discuss the

conflict with the Individual to resolve it.

Management of Conflicts of Interest

1. Potential conflicts will be referred to the Conflict of Interest Review Committee (CIRC), a standing

committee appointed by the Dean. The CIRC shall consist of, at a minimum, six faculty members

representing a cross section of clinical and basic science disciplines, and administrators from the Office

of Research.

2. A conflict of interest will be deemed to exist when the CIRC reasonably determines that a Significant

Financial Interest could directly and significantly affect the design, conduct, or reporting of the

proposed sponsored project, or an educational or consulting arrangement. COI staff will have access

to the IRB database, grants and industry relations route forms, and purchase orders to identify

potential conflicts of interest. The Committee shall then determine what conditions or restrictions, if

any, should be imposed by the institution to manage a conflict of interest arising from a disclosed

Significant Financial Interest.

3. Prior to consideration by the CIRC, the individual, in cooperation with the department chair or

supervisor, shall develop a conflict management plan to manage, reduce, or eliminate any conflict of

interest presented by a Significant Financial Interest. Resources for faculty and staff to develop the

management plan are available on the Office of Research web site. The CIRC will review the

management plan and make any changes it considers necessary to manage, reduce, or eliminate the

conflicts of interest.

4. The management plan details the conditions or restrictions imposed upon the Individual in the

conduct of the project or in the relationship with the business enterprise or entity. After approval by

the CIRC, the plan shall be signed by the Individual, all plan participants, the department chair or

supervisor and, on behalf of the School, by the CIRC Chairman and Dean or his designee, and

submitted to the conflict of interest staff within 60 days of CIRC approval. Failure to submit the fully

executed plan within 60 days of approval by the CIRC will be viewed as a management-related

violation and may be subject to sanctions as outlined in the Overview and Background.

5. At least annually in December, a continuation report shall be forwarded to the conflict of interest staff

supporting compliance with the conditions or restrictions outlined in the management plan. After

approval by the CIRC, the continuation report shall be signed by the Individual, all plan participants,

the department chair or supervisor and, on behalf of the School, by the CIRC Chairman and Dean or his

designee, and submitted to the conflict of interest staff within 60 days of CIRC approval. Failure to

submit the fully executed report within 60 days of the due date will be viewed as a management-

related violation and may be subject to sanctions as outlined in the Overview and Background.

6. Conflicts of interests will be satisfactorily managed, reduced, or eliminated in accordance with this

policy within 60 days of identification by the institution, and all reports required regarding the

resolution of the conflict of interest will be submitted to the sponsor prior to expenditure of any funds

under an award. NIH requires the School to report to the NIH Awarding Component the existence of a

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conflicting interest (but not the nature of the interest or other details) found by the School and assure

that the interest has been managed, reduced, or eliminated. NSF only requires the School to report

conflicts that cannot be satisfactorily managed, reduced, or eliminated.

7. The CIRC will communicate management of relationships involving conflicts of interest in human

subjects research effectively and efficiently to the Institutional Review Board. Notification of final

actions taken by either committee will be communicated via electronic memo. The senior IRB

regulatory staff member, or delegated representative, will attend CIRC meetings as a non-voting

member.

8. Records of individual financial disclosures and of actions taken to manage conflicts of interest shall be

retained by the Office of Research until at least three years after the date of submission of the final

expenditures report or, where applicable, from other dates specified in 45 CFR 74.53(b) for different

situations.

9. Collaborators/subrecipients/subcontractors of a research project must provide a certification from

their institutions to WFUSM that they are in compliance with applicable Federal policies regarding

individual Significant Financial Interest disclosure and that their portion of the project is in compliance

with their institutional policies, or comply with this policy.

The Individual should work with each journal or periodical to disclose any relevant personal financial

interests per the publisher’s specific requirements. On presentations, relevant personal financial

interest disclosure should be in plain sight on at least the first or second slide of the presentation, and

a verbal mention during the presentation is recommended. For news releases and news media contact

the Individual should work with WFUBMC Public Relations and Marketing to disclose any personal

financial interests related to research, intellectual property or start-up business being described using

whatever specific language might be required by the Office of Research. The individual must inform

his/her department chair or section head about plans for publicity relating to research, intellectual

property, start-up businesses or other situations in which a conflict of interest may be present.

IRB Member Conflict of Interest Institutional Review Boards (IRBs) hold a position of trust with research subjects, research sponsors,

institutions, their professional bodies and society. This position of trust can be put at risk by conflicts

of interest that may compromise independence, objectivity or ethical duties of loyalty. To maintain

the independence and integrity of ethics review, it is of the highest importance that members of the

IRB avoid real or apparent conflicts of interest. To this end, individuals responsible for business

development are prohibited from serving as members or ex- officio members on the IRB or carrying

out day-to-day operations of the review process. IRB members should identify and address any real or

apparent conflicts of interest in order to maintain the public confidence and trust, discharge

professional obligations and ensure accountability. IRB members complete and sign a Conflict of

Interest disclosure form on an annual basis which is maintained within the Office of Research.

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If an IRB member has a clear conflict of interest when his/her own research project is under review by

the IRB or when he/she have been in direct academic conflict or collaboration with the researcher

whose proposal is under review, then that member should recuse from discussion and voting on the

research study being reviewed. A conflict of interest also exists when an IRB member has significant

financial interest where study outcomes could affect compensation, a proprietary interest in the

tested product, a significant equity interest in the sponsor of the study under consideration, or has

received significant payments of other sorts from the sponsor of the study under consideration as

outlined in this policy.

The IRB Chair will not allow a member to participate in the discussion or vote of any research study in

which the member has a potential or actual conflict of interest, except to provide information as

requested by the IRB. At the beginning of each meeting, the IRB Chair will remind members to recuse

themselves if they have an actual or potential conflict of interest with any submission under review.

To manage conflicts of interest, IRB members may recuse themselves from discussion and vote on

projects where potential or actual conflict of interest exits, or may apply to the Conflict of Interest

Review Committee (CIRC) to determine if a conflict of interest exists and, if so, how it should be

managed. IRB members who recuse due to a conflict of interest are not counted towards quorum. IRB

members with a conflict of interest are documented in the minutes as being absent with an indication

that a conflict of interest was the reason for the absence.

For studies that are reviewed by expedited procedures, unanticipated problems involving risk to

subjects or others, or the review of non-compliance with regulations and local policies, IRB staff

members will not assign these reviews to board members with a documented conflict of interest. If an

undocumented conflict of interest is discovered, the IRB staff will re-assign the items for review by

members without a conflict. If board members are assigned to review items as listed above, it is their

responsibility to inform the IRB staff of potential of actual conflicts if not previously documented.

Institutional Conflict of Interest There are some cases where the Institution has a conflict of interest with its obligation to

protect participants or ensure the credibility of the research. In cases where the Institution has a

potential conflict of interest with a study sponsor, the President of the Institution, in consultation with

the Conflict of Interest Committee and the IRB will determine the best course of management in order

to minimize or limit perceived conflicts.

Definitions

Licensing is the process of granting a licensee the right to utilize specific technologies, patents,

software, know-how or product designs developed at the institution, typically in exchange for royalty

fees to the licensor based on licensed product sales revenue.

Investments are money or capital committed to purchase financial instruments or other assets in

order to gain profitable returns in the form of interest, income or equity for the purpose of enhancing

the value and status of the institution.

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Gifts include non-restricted and designated philanthropic donations to the institution.

Other financial interests include fiduciary responsibilities for institutional officials whereby decisions

made on behalf of an outside entity may not be beneficial to the institution.

Identification of Potential Institutional Conflicts of Interest

Full disclosure and subsequent management of conflicts of interest shall be conducted for key officials

in a leadership role whose decisions may affect departments, centers, institutes or WFUBMC as a

whole. The Dean of the School of Medicine or an appointed designee shall conduct a review of key

official’s annual conflict of interest disclosures with assistance from the Senior Associate Dean for

Administration & Operations. Determination of potential conflicts may be based on the guidance

listed for the following areas:

In Research: Research funded by a sponsor with whom WFUBMC has a significant financial interest or

research involving an investigational product invented or developed at WFUBMC shall be reviewed to

determine if there is a conflict of interest. Most commonly, the CIRC will refer institutional conflicts of

interest in research based on their review of an individual conflict of interest. Circumstances including

one or more of the following related to a research sponsor or investigational product may create ICOI:

a. Potential royalties

b. Licensing activities

c. Equity interest

d. Key officials with significant financial interest

e. Purchasing decisions

f. Gifts to the institution

In Purchasing: Purchasing decisions for a particular technology or device shall not be made by the

party(ies) who invented it, are being funded to study it, or have significant financial interest in the

manufacturer of it. Purchasing decisions include, but are not restricted to the following:

a. The decision to purchase (request for a purchase order)

b. The selection of a supplier

c. The negotiation of a purchasing agreement or contract

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d. In addition to a questionnaire with each purchase order, potential conflicts of interest in purchasing

will be determined by each purchasing committee based on questionnaires of each committee

member. All reported conflicts of interest in purchasing will be reviewed by the Dean of WFUHS or an

appointed designee.

In Licensing a University Technology: Licensing decisions shall be based on competitive bids and not

influenced by institutionally-owned or developed entities, or key officials with significant financial

interest in the licensing entity. Patent applications and licensing agreements will be accompanied by a

conflict of interest questionnaire. All potential conflicts of interest will be referred to the CIRC for

review of individual interests and to the Dean of WFUHS or an appointed designee for review of

institutional interests.

In Gifts: Decisions regarding the use of gifts to the institution shall not be made by any key officials

with a significant financial interest in the donor entity. The Development Office will report all potential

institutional conflicts of interest to the Dean of WFUHS or an appointed designee.

In Investment: Investment decisions made regarding institutional operations and development funding

shall be unrelated to decisions about clinical practice, research or education. The following principles

shall apply:

a. WFUBMC shall limit its equity holding to <5% in any publicly traded company whenever it intends to

pursue research or educational activities with that company.

b. WFUBMC shall have no limit on investment or equity ownership when there is no intention to pursue

research or educational activities with the company.

c. WFUBMC shall have no limit on equity ownership in a privately held company utilizing the institution’s

intellectual property, even if it later becomes publicly traded through an Initial Public Offering.

In Leadership: Leadership decisions involving an outside entity shall not be determined solely by any

key official with a significant financial interest in that entity whose decisions may affect departments,

centers, institutes or WFUBMC as a whole. WFUBMC shall review the decision- making of key officials,

including the Board of Trustees members, who have disclosed:

a. A significant financial interest with a company that is directly or indirectly involved in any part of a

major decision at WFUBMC that could appear to be a conflict of interest.

b. Equity in any entity that could directly or indirectly affect WFUBMC.

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19.0 HIPAA

Definitions Authorization is the granting of rights to access PHI. This is required by HIPAA for disclosures or

uses other than for treatment, payment, or operations (which are covered in the Notice of Privacy

Practices.)

Covered Entity: Under HIPAA, this is a health plan, a health care clearinghouse, or a health care

provider who transmits any health information in electronic form in connection with a HIPAA

transaction.

Data Use Agreements are documents by which the covered entity can obtain satisfactory assurance

that the recipient of the limited data set will use or disclose the PHI for the purposes specified in the

document.

De-identified Data Set is one in which the 18 defined HIPAA identifiers have been deleted. A de-

identified data set is not protected by the Privacy Rule and may be used and disclosed without

restriction.

Disclosure means the release, transfer, provision of, access to, or divulging in any other manner of

information outside the entity holding the information

Health Care Provider is a provider of services, a provider of medical or health services, and any other

person or organization who furnishes, bills, or is paid for health care in the normal course of

business.

Health plan is an individual or group plan that provides, or pays the cost of, medical care.

Health Care Clearing House is a public or private entity that either processes or facilitates the

processing of health information.

Limited data set is one in which direct identifiers have been removed, but certain potential

identifiers remain as defined by the HIPAA Privacy Rule Regulations. A limited Data Set can include

all elements of dates, address, and a unique identifier and must be accompanied by a Data Use

Agreement.

Protected Health Information (PHI) ) is individually identifiable health information that is

transmitted by, or maintained in, electronic media or any other form or medium by a health care

provider, a health plan or health care clearinghouse. This information must relate to: The past,

present, or future physical or mental health, or condition of an individual. The provision of

health care to an individual, or

Payment for the provision of health care to an individual.

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If the information identifies or provides a reasonable basis to believe it can be used to identify an

individual, it is considered individually identifiable information.

Regulatory Background The Health Insurance Portability and Accountability Act of 1996 (HIPAA), Public Law 104-191,

was enacted on August 21, 1996. One requirement of the Act was to establish privacy regulations

governing individually identifiable health information. These regulations, known as the Privacy Rule

(45 CFR parts 160 and 164), became effective April 14, 2003.

The Privacy Rule establishes minimum Federal standards for protecting the privacy of individually

identifiable health information. The Privacy Rule confers certain rights on individuals, including:

Right to receive a written notice about the entity’s privacy practices Right to inspect and

have copied one’s own medical record

Right to amend the record, where appropriate

Right to request confidential communications regarding health information Right to request

that uses and disclosures be restricted

Right to obtain an accounting of all non-routine disclosures

Right to complain about privacy violations to the entity and to the Department of Health and

Human Services

The Privacy Rule governs the use and disclosure of “protected health information.”

Information about the payment for health care also may be PHI. To qualify as PHI, the information

must identify the person directly or be sufficiently specific that the person could be identified. The

Privacy Rule governs all PHI in all forms, whether electronic, paper, medical media, or conversation.

Under the Privacy Rule, PHI may be used only for treatment, payment or operational activities

unless individual authorization is granted or the use is specifically allowed by law. Apart from

treatment activities, providers must use only the “minimum necessary” information to accomplish

the intended purpose. Exceptions to the minimum necessary standard include uses and disclosures

related to treatment, disclosures to the individual patient, and certain disclosures required by law.

Wake Forest University Health Sciences and the North Carolina Baptist Hospital are covered entities

and are subject to the regulations outlined in the HIPAA Privacy Rule.

The HIPAA Privacy Rule outlines the conditions under which Protected Health Information may be

used and disclosed for research purposes. The research provisions of the Privacy Rule apply to both

covered entities that may disclose individually identifiable health information that they created or

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maintain, and to researchers who, as members of a covered entity, may either receive individually

identifiable health information from covered entities or who may create individually identifiable

health information as part of research activities.

Privacy Rule Identifiers The Privacy Rule specifies the following 18 elements as identifiers.

1. Names.

2. All geographic subdivisions smaller than a state, including street address, city, county, precinct, ZIP

Code, and their equivalent geographical codes, except for the initial three digits of a ZIP Code if,

according to the current publicly available data from the Bureau of the Census:

a. The geographic unit formed by combining all ZIP Codes with the same three initial digits contains more

than 20,000 people.

b. The initial three digits of a ZIP Code for all such geographic units containing 20,000 or fewer people

are changed to 000.

3. All elements of dates (except year) for dates directly related to an individual, including birth date,

admission date, discharge date, date of death; and all ages over 89 and all elements of dates

(including year) indicative of such age, except that such ages and elements may be aggregated into a

single category of age 90 or older.

4. Telephone numbers.

5. Facsimile numbers.

6. Electronic mail addresses.

7. Social security numbers.

8. Medical record numbers.

9. Health plan beneficiary numbers.

10. Account numbers.

11. Certificate/license numbers.

12. Vehicle identifiers and serial numbers, including license plate numbers.

13. Device identifiers and serial numbers.

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14. Web universal resource locators (URLs).

15. Internet protocol (IP) address numbers.

16. Biometric identifiers, including fingerprints and voiceprints.

17. Full-face photographic images and any comparable images.

18. Any other unique identifying number, characteristic, or code, unless otherwise permitted by the

Privacy Rule for re-identification.

Using Protected Health Information for Research Any research use of PHI must meet one of two conditions:

Permission is granted by the patient, through a written authorization form

OR

One of the following criteria is met:

a) The information is completely de-identified and no longer governed by the HIPAA Privacy Rule

b) A waiver of the individual authorization requirement is obtained from an institutional review board

(IRB)

c) The information is compiled into a “limited data set” and a data use agreement is executed for the

disclosure of protected health information outside the institution

d) The activity qualifies as “preparatory to research”

e) The researcher is accessing information solely on decedents

Retention of Protected Health Information Research subjects may revoke their research authorization at any time during the research

study. If permission is revoked, the Privacy Rule allows continued use and disclosure of the

information that was obtained prior to the revocation, to preserve the integrity of the study. For

example, the researcher may use the information to account for study withdrawals, to report adverse

events to FDA, or to comply with study audits. Once authorization is revoked, the

subject is withdrawn from the study and no additional information can be collected on this subject by

the investigator. The revocation of an authorization should be submitted to the principal investigator

of the research study. Upon receipt of such revocation, the investigator should submit a copy to the

WFUBMC Privacy Office.

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Written authorization must be kept for a minimum five years after the completion of the study or 6

years from the date the authorization is signed, whichever is the longest.

Written Authorization

Written authorization from the research subject is the default requirement for use of protected

health information in research. Prospective research, such as a clinical trial, generally requires prior

authorization. The authorization differs from informed consent in that the authorization obtains

specific permission to use and disclose protected health information for the research project and

focuses on privacy risks and states how, why, and to whom the PHI will be used and/or disclosed for

research purposes. An Authorization must contain the following specific core elements and required

statements.

A description of the PHI to be used or disclosed, identifying the information in a specific and

meaningful manner.

The names or other specific identification of the person or persons (or class of persons)

authorized to make the requested use or disclosure.

The names or other specific identification of the person or persons (or class of persons) to whom

the covered entity may make the requested use or disclosure.

A description of each purpose of the requested use or disclosure (i.e., for research related

activities)

Authorization expiration date or expiration event that relates to the individual or to the purpose

of the use or disclosure ("end of the research study" or "none" are permissible for research, including

for the creation and maintenance of a research database or repository). The policy of the IRB is five

years after the completion of the study or 6 years from the date the authorization is signed, whichever

is the longest.

Signature of the individual and date. If the individual's legally authorized representative signs the

Authorization, a description of the representative's authority to act for the individual must also be

provided.

A statement of the individual's right to revoke his/her Authorization and how to do so, and, if

applicable, the exceptions to the right to revoke his/her Authorization or reference to the

corresponding section of the covered entity's notice of privacy practices.

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Whether treatment, payment, enrollment, or eligibility of benefits can be conditioned on

Authorization, including research-related treatment and consequences of refusing to sign the

Authorization, if applicable.

A statement of the potential risk that PHI will be re-disclosed by the recipient. This may be a

general statement that the Privacy Rule may no longer protect health information disclosed to the

recipient.

The authorization must be written in plain language, and the subject must receive a copy of their

signed authorization.

Effective January 1, 2005, authorizations must be combined with the informed consent document.

De-identification

Certain research projects can be accomplished through the use of de-identified data.

The Privacy Rule provides two methods to de-identify data. Under the first method, all of the following

18 elements specified in the Privacy Rule as identifiers are removed.

1 Names.

2 All geographic subdivisions smaller than a state, including street address, city, county,

precinct, ZIP Code, and their equivalent geographical codes, except for the initial three digits

of a ZIP Code if, according to the current publicly available data from the Bureau of the

Census:

1. The geographic unit formed by combining all ZIP Codes with the same

three initial digits contains more than 20,000 people.

2. The initial three digits of a ZIP Code for all such geographic units

containing 20,000 or fewer people are changed to 000.

3 All elements of dates (except year) for dates directly related to an individual, including birth

date, admission date, discharge date, date of death; and all ages over 89 and all elements of

dates (including year) indicative of such age, except that such ages and elements may be

aggregated into a single category of age 90 or older.

4 Telephone numbers.

5 Facsimile numbers.

6 Electronic mail addresses.

7 Social security numbers.

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8 Medical record numbers.

9 Health plan beneficiary numbers.

10 Account numbers.

11 Certificate/license numbers.

12 Vehicle identifiers and serial numbers, including license plate numbers.

13 Device identifiers and serial numbers.

14 Web universal resource locators (URLs).

15 Internet protocol (IP) address numbers.

16 Biometric identifiers, including fingerprints and voiceprints.

17 Full-face photographic images and any comparable images.

18 Any other unique identifying number, characteristic, or code, unless otherwise permitted by

the Privacy Rule for re-identification.

The second way is to have a qualified statistician determine, using generally accepted statistical and

scientific principles and methods, that the risk is very small that the information could be used, alone

or in combination with other reasonably available information, by the anticipated recipient to identify

the subject of the information. The qualified statistician must document the methods and results of

the analysis that justify such a determination. This documentation must be kept for at least 6 years

from the date of its creation or the date when it was last in effect, whichever is later.

Waiver of Individual Authorization For some types of research, it is impracticable for researchers to obtain written Authorization

from research participants, or to use either de-identified data or a limited data set. To address these

situations, the Privacy Rule allows the IRB to approve a waiver or an alteration of the Authorization

requirement in whole or in part for the research uses and disclosures of PHI. A complete waiver occurs

when the IRB determines that no Authorization will be required for a covered entity to use and

disclose PHI for a particular research project. A partial waiver of Authorization occurs when the IRB

determines that an Authorization is not required for all PHI uses and disclosures for research

purposes, such as disclosing PHI for research recruitment purposes. The IRB may also approve a

request that removes some PHI, but not all, or alters the requirements for an Authorization (an

alteration) such as screening information.

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In order to approve a waiver or an alteration of the Authorization requirements the IRB must

document that the following criteria are satisfied.

The use or disclosure of protected health information involves no more than a minimal risk to the

privacy of individuals based on, at least, the presence of the following elements;

An adequate plan to protect the identifiers from improper use and disclosure;

An adequate plan to destroy the identifier at the earliest opportunity consistent with conduct

of the research, unless there is a health or research justification for retaining the identifiers or

such retention is otherwise required by law; and

Adequate written assurances that the protected health information will not be reused or

disclosed to any other person or entity, except as required by law, for authorized oversight of

the research study, or for other research for which the use or disclosure of protected health

information would be permitted by the Privacy Rule;

(A) The research could not practicably be conducted without the alteration or waiver;

AND

(B) The research could not practicably be conducted without access to and use of the protected health

information.

In planning a project that employs a waiver of authorization, researchers should consider their

responsibility to comply with the minimum necessary standard of the Privacy Rule. Only the minimum

amount of protected health information should be used and disclosed, as necessary to accomplish the

goals of the research. For example, date of birth should not be recorded if age will suffice.

The Privacy Rule requires that when PHI is accessed through a waiver of authorization, the

researcher’s access must be included in the patient’s accounting of disclosures. For example, accessing

PHI in a patient’s medical record under a waiver of authorization requires an accounting of the

disclosure. (see Accounting for Disclosures, below).

Waiver of authorization for research studies that qualify for review through Expedited Procedures may

be carried out by the IRB Chair or one or more IRB members designated by the Chair, otherwise the

waiver of authorization must be made by the full convened IRB.

Limited Data Set When only certain identifiers are needed it may be possible for a researcher to use a limited data set. .

A limited data set excludes the following direct identifiers:

1 Names;

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2 Street address/Postal address information, other than town or city, State, and zip code;*

3 Telephone and fax numbers;

4 Electronic mail addresses;

5 Social security numbers;

6 Medical record numbers, health plan beneficiary numbers or other account numbers;

7 Certificate/license numbers;

8 Vehicle identifiers and serial numbers, including license plate numbers

9 Device identifiers and serial numbers;

10 Web universal resource locators (URLs) or Internet protocol (IP) address numbers;

11 Biometric identifiers, including finger and voice prints; and

12 Full face photographic images and any comparable images.

Unlike de-identified data, the limited data set may include:

Addresses other than street name or street address or post office boxes. The five-digit zip code or

any other geographic subdivisions, such as State, county, city, precinct and their equivalent geocodes

may be included.

All elements of dates, such as date of birth, date of admission, date of discharge, and procedure

dates.

Unique identifiers if certain requirements are met. The Privacy Rule permits a covered entity to

assign to, and retain with, the health information a code or other means of record identification if that

code is not derived from or related to the information about the individual and could not be

translated to identify the individual. The covered entity may not use or disclose the code or other

means of record identification for any other purpose and may not disclose its method of re-identifying

the information. For example, a randomly assigned code that permits re-identification through a

secured key to that code would not make the information to which it is assigned PHI, because a

random code would not be derived from or related to information about the individual and because

the key to that code is secure.

A limited data set is considered to be PHI under the Privacy Rule.

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Disclosing a Limited Data Set Prior to disclosing the limited data set, the researcher must provide a Data Use Agreement. A

template WFUBMC Date Use Agreement has been developed by the Institutional Legal Counsel and

can be found on the IRB website under the HIPAA link. You must retain a copy of the Data Use

Agreement with the study documents and provide the recipient of the limited data set with a copy.

The data use agreement must contain the following elements:

The permitted uses and disclosures by the recipient

The approved users and recipients of the data

Agreement by the recipient not to re-identify the data or contact the individuals

Assurances that the recipient will use appropriate safeguards to prevent use or disclosure of the

limited data set other than as permitted by the data use agreement

Agreement that the researcher will report to the covered entity any uses or disclosures of the

limited data set which were not specifically allowed

Agreement to require that any agents and subcontractors adhere to the same safeguards

Receiving a Limited Data Set from outside the institution When receiving a limited data set from an entity outside WFUBMC, the researcher must request a

Data Use Agreement. If a covered entity is the recipient of a limited data set and does not have a data

use agreement in place, the covered entity has violated the Privacy Rule.

The IRB Director, IRB Associate Director, or Institutional Legal Counsel must review and approve all

Limited Data Use Agreements.

While the Privacy Rule dictates the identifiers that must be removed in a limited data set, the

minimum necessary standard of the regulation remains in effect for any other health information.

Researchers are responsible for requesting only the information that is necessary to accomplish the

research purpose. For example, if age expressed in years, months, or days will suffice, date of birth

should not be requested.

Reviews that are Preparatory to Research The Privacy Rule allows researchers to review PHI in medical records or elsewhere to prepare a

research protocol, or for similar purposes preparatory to research. This review allows the researcher

to determine, for example, whether a sufficient number or type of records exists to conduct the

research. Importantly, the covered entity does not permit the researcher to remove any PHI from the

covered entity. This includes data obtained within the covered entity being placed on a lap top

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computer that can be carried outside the covered entity if that lap top or other device is personally

owned by the researcher. If the lap top or portable device is owned by the institution, it can be taken

off campus and still be part of the covered entity. This means that researchers may review PHI as

preparatory to research but may not record any PHI unless it meets the requirement for de-identified

data, the requirements for a Limited Use Data Set, or the IRB has waived the requirements for

authorization.

In order to conduct a review preparatory to research, the researcher must provide the covered entity

that maintains the PHI documentation that:

The use or disclosure is sought solely to review PHI as necessary to prepare the research protocol

or other similar preparatory purposes.

No PHI will be removed from the covered entity during the review.

The PHI the researcher seeks to use or access is necessary for the research purposes.

The Privacy Rule requires that when PHI such as a medical record is accessed for activities preparatory

to research, the researcher’s access must be included in the patient’s accounting of disclosures (see

Accounting for Disclosures, below).

Research Recruitment under HIPAA The requirements of the Privacy Rule impact the way in which potential subjects are identified and

recruited for studies. According to the rule, health care providers involved in the treatment of an

individual are allowed to talk with their patient about enrolling in a research study. This discussion

would not require an authorization.

However, if the health care provider shares the patient’s information with a researcher who is not

involved in the patient’s care, some form of privacy permission must be in place, either through

written authorization from the patient or a waiver of authorization for the recruitment activity. The

written permission or the waiver allows the researcher to view the patient’s protected health

information in order to make a determination about study eligibility.

Investigators can identify potential subjects for their research through the preparatory to research

provision. However, if the researcher wishes to contact that individual, a waiver of authorization must

be granted by the Institutional Review Board.

Once a potential subject has been identified, research teams should follow appropriate ethical

standards about contacting the patient. Preferably, the initial contact should come from someone

who is known to the patient as having legitimate knowledge of their health status, based on an

established clinical relationship.

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Allowable Recruitment Practices

1. Health care providers who are conducting a study may talk with their own patients about the option

of study enrollment.

2. Health care providers may use their own knowledge of the patient’s condition and their knowledge

about a colleague’s study to inform their patients about a study. At that point, two possibilities exist:

a. The provider gives the researcher’s contact information to the patient, and the patient initiates the

contact.

b. The patient signs an authorization so that the provider can give the patient’s name to the researcher.

3. Health care providers may release their patient records to a researcher, if the researcher obtains a

waiver of authorization from the IRB. Then the researcher can review the chart, determine eligibility,

and work with the provider on contacting potential subjects.

4. The researcher posts IRB-approved flyers or advertisements, and eligible patients directly contact the

researcher.

Research on Decedents Research on decedents is not subject to human subject regulations; however, it is subject to the

HIPAA Privacy Rule. In order to access PHI, such as medical records, on decedents, the researcher

must provide the holder of the PHI with assurances that:

The information being sought is solely for research on decedents

The information being sought is necessary for research purposes

The holder of the PHI has a right to require documentation of the death of the individuals. HIPAA

regulations require that when a medical record is accessed for research on decedents, the

researcher’s access must be included in the patient’s accounting of disclosures (seeAccounting for

Disclosures, below).

The IRB’s Role Related to the Privacy Rule The Privacy Rule establishes the authority of the IRB to consider, and act upon, requests for a partial

or complete waiver or alteration of the Privacy Rule's Authorization requirement for uses and

disclosures of PHI for research. Wake Forest University Health Sciences and North Carolina Baptist

Hospital rely on the Wake Forest University Health Sciences IRB (IRB) to act upon requests to waive or

alter the Authorization requirements.

When acting upon a request to waive or alter the Authorization requirement, the IRB will follow the

procedural requirements of the HHS Protection of Human Subjects Regulations and/or, if applicable,

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FDA regulations, including using either the normal review procedures (review by the convened IRB) or

the expedited review procedures.

For research studies that qualify for review through Expedited Procedures under the procedural

requirements of the HHS Protection of Human Subjects Regulations and/or, if applicable, FDA

regulations, a request to approve a waiver or alteration of the Authorization requirements may be

carried out by the IRB Chair or one or more IRB members designated by the Chair. The IRB will advise

all its members of such requests for waivers or alterations of the Authorization requirement by

including the approval of the waiver in the IRB minutes. If the head of the Federal department or

agency (or his/her designee) regulating the research has restricted, suspended, terminated, or chosen

not to authorize an institution or IRB to use expedited review procedures, the IRB cannot grant

waivers or alterations of the Authorization requirement on an expedited basis.

A request to waive or alter the Authorization requirements for a research study that does not qualify

for review through Expedited Procedures must be considered at a convened meeting of the IRB.

When considering a request for a partial or complete waiver or alteration of Authorization the IRB will

document that the following criteria have been met:

The PHI use or disclosure involves no more than minimal risk to the privacy of individuals based

on at least the presence of

1. An adequate plan presented to the IRB to protect PHI identifiers from improper use and disclosure;

2. An adequate plan to destroy those identifiers at the earliest opportunity, consistent with the research,

absent a health or research justification for retaining the identifiers or if retention is otherwise

required by law; and

3. Adequate written assurances that the PHI will not be reused or disclosed to any other person or entity

except

a. As required by law

b. For authorized oversight of the research study, or

c. For other research for which the use or disclosure of the PHI is permitted by the Privacy Rule.

The research could not practicably be conducted without the requested waiver or alteration.

The research could not practicably be conducted without access to and use of the PHI.

Following approval of a request to waive or alter the Authorization requirements the IRB will provide

the investigator documentation of the approval that includes:

The identity of the approving IRB

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The date on which the waiver or alteration was approved

A statement that the IRB has determined that all the specified criteria for a waiver or an alteration

were met (see Waivers or Alterations of the Authorization Requirements)

A brief description of the PHI for which use or access has been determined by the IRB to be

necessary in connection with the specific research activity

A statement that the waiver or alteration was reviewed and approved under either normal or

expedited review procedures (see IRB Approval Proceedings)

The required signature of the IRB chair or the chair's designee

Under the Privacy Rule, an Authorization may be combined with the informed consent document for

research. If the informed consent document is combined with an Authorization meeting the Privacy

Rule's requirements, 45 CFR part 46 and/or 21 CFR parts 50 and 56 require IRB review of the

combined document.

Effective January 1, 2005, the institution is requiring that all HIPAA Authorization language be

combined in the informed consent form for all new studies and those undergoing continuing review.

A modification to a previously approved research protocol, which only involves the addition of an

Authorization for the use or disclosure of PHI to the IRB-approved informed consent, may be reviewed

by the IRB through an expedited review procedure, since this type of modification may be considered

to be no more than a minor change to research.

Other Research Related Topics

Research Databases and Repositories

The creation of a research database or repository, and the use or disclosure of PHI from a database or

repository for research purposes, may each be considered a research activity under the Privacy Rule.

When using existing databases and repositories, it may be impractical to obtain written authorization

to use the PHI. In this case, the IRB can waive the requirement for written authorization if the criteria

outlined in this document are met.

The Privacy Rule specifies three ways in which protected health information can be compiled for a

research database or repository:

Individual, written authorization is obtained from the subject of the information

Waiver of the individual authorization requirement is obtained from an IRB or privacy board

The PHI is obtained from a covered entity in a limited data set and accompanied by a data use

agreement

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Prospective collection or data or tissue samples for a research repository requires IRB approval and

will generally also require informed consent and a privacy authorization. Researchers should note that

if approval is granted for the general purpose of constructing and maintaining the repository, then

subsequent studies of the material also will require IRB review. Depending on the nature of the

subsequent study, the IRB will determine whether consent/privacy authorization is required or if the

consent/privacy authorization requirement is waived.

“Minimum Necessary” Provision and Role-Based Access When conducting research apart from an individual privacy authorization, HIPAA requires that

researchers request and maintain only the minimum necessary protected health information to

accomplish the research purpose. The holder of the medical record may reasonably rely on the

researcher’s representation that the information being requested is indeed the minimum necessary.

The HIPAA principle of role-based access complements the standard of minimum necessary.

Researchers are responsible for designating personnel who need access to study files that contain

identifiable data. Access should be commensurate with the role on the research project.

Transition Requirements for Ongoing Research

Under HIPAA’s transition provisions, researchers are allowed to use study-specific protected health

information that is obtained either before or after April 14, 2003, provided that the subject’s written

informed consent or an IRB waiver of consent occurred prior to that date. The grandfathering

provision only applies to studies where all participants were recruited and signed an informed consent

form prior to April 14, 2003.

For ongoing studies employing written consent, prior to study participation, new subjects enrolled on

or after April14, 2003 must sign a HIPAA Authorization in addition to the informed consent document

or an informed consent that contains the Authorization requirements. Additionally, all subjects who

are re-consented for any reason on or after April 14, 2003 also

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must sign a HIPAA authorization or an informed consent that contains the Authorization

requirements.

Accounting for Research Disclosures Federal regulations allow an individual the right to receive an accounting of disclosures of protected

health information made by a covered entity in the six years prior to the date on which the

accounting is requested. The accounting process was established so that they could learn about how

their information was disclosed in cases where written permission was not required. Disclosures of

PHI from an individual, such as from their medical record, that are made under a waiver of

authorization, for activities preparatory to research, or for studies on decedents must be included in

the accounting process. The holder of the PHI is responsible for having a process that meets the

accounting for disclosure provisions in the Privacy Rule. The Principal Investigator in the research

study is responsible for assisting the holder of the PHI in fulfilling their accounting duties and is

therefore required to account for such disclosures.

An example of when researchers must account for disclosures is when performing a retrospective

chart review. This type of research typically includes a waiver of authorization to access and use PHI.

Researchers must account for such disclosures.

The accounting for each disclosure must include the following:

The date of the disclosure.

The name of the entity or person who received the protected health information and, if known,

the address of such entity or person.

A brief description of the protected health information disclosed.

A brief statement of the purpose of the disclosure that reasonably informs the individual of the

basis for the disclosure or, in lieu of such statement, a copy of a written request for a disclosure.

An accounting of disclosures should be kept on file by the Principal Investigator for a minimum of six

years.

Additional Uses and Disclosures of Protected Health Information A covered entity can use and disclose PHI without an authorization under the following

circumstances:

To the extent that the use or disclosure is required by law. For example, a covered entity may

disclose, without authorization, information to a cancer registry if the disclosure is required by law.

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Disclosure of PHI to a public health entity that is authorized by law to collect or receive

information for purposes of preventing or controlling disease, injury, or disability. For example, a

covered entity can report, without written authorization, information regarding an individual’s HIV or

Hepatitis status.

Information can be disclosed to the FDA when the information involves an FDA-regulated product

or activity. For example, while participating on a clinical trial where the FDA has jurisdiction, serious or

unexpected adverse events can be reported without written authorization.

Disclosure of PHI to oversight agencies, such as the Office of Human Research Protections (OHRP)

for activities authorized by law that are necessary for the oversight of government- related programs

is allowed without written authorization.

Certificates of Confidentiality Investigators working with vulnerable populations or collecting sensitive information may obtain a

certificate of confidentiality to protect the study participants. A certificate of confidentiality protects

participants from compelled disclosure of identifying information about subjects enrolled in sensitive

biomedical, behavioral, clinical or other research. Certificates of Confidentiality are issued by the

National Institutes of Health (NIH) and other HHS agencies to protect identifiable research information

from forced or compelled disclosure. They allow the investigator and others who have access to

research records to refuse to disclose identifying information on research participants in civil, criminal,

administrative, legislative, or other proceedings, whether federal, state, or local. Certificates of

Confidentiality may be granted for studies collecting information that, if disclosed, could have adverse

consequences for subjects, such as damage to their financial standing, employability, insurability, or

reputation. By protecting researchers and institutions from being compelled to disclose information

that would identify research subjects, Certificates of Confidentiality help to minimize risks to subjects

by adding an additional level of protection for maintaining confidentiality of private information. IRB

approval of the research is required prior to obtaining a Certificate of Confidentiality.

Resources

Resources are available to assist you in learning more about how the HIPAA Privacy Rule affects

research. The following is a list of such resources:

Office of Civil Rights - http://www.hhs.gov/ocr/hipaa

US Dept. of Health & Human Services and the National Institute for Health Website -

http://privacyruleandresearch.nih.gov

o Education materials include the following guidance documents:

http://www.hhs.gov/ocr/hipaa

http://privacyruleandresearch.nih.gov/

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o Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule

o Research Repositories, Databases and the HIPAA Privacy Rule

o Clinical Research and the HIPAA Privacy Rule

o HIPAA Authorization for Research

References:

45 CFR 160.103

45 CFR 164.508

45 CFR 164.502(d)

45 CFR 164.512(i)(2)

45 CFR 164.514(e)

45 CFR 164.512(i)(1)(ii)

45 CFR 164.512(i)(1)(iii)

45 CFR 164.512(i)(2)

45 CFR 164.528

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20.0 Medical Devices

Regulatory Background The Food, Drug and Cosmetic Act, as amended by the Medical Device Amendments of 1976, regulate the

development, testing, approval and marketing of medical devices. A medical device is defined as an

instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or

related article, including any component, part, or accessory, which is

(1) Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or

prevention of disease, in man or other animals; or

(2) Intended to affect the structure or any function of the body of man or other animals, and which does not

achieve its primary intended purposes through chemical action within or on the body of man or other

animals and which is not dependent upon being metabolized for the achievement of its primary intended

purposes.

A medical device is also defined, in part, as any health care product that does not achieve its primary

intended purposes by chemical action or by being metabolized. Medical devices include, among other

things, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and

orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro

diagnosis (IVD) of disease and other medical conditions such as pregnancy.

An investigational device is a medical device which is the subject of a research study designed to evaluate

the effectiveness and/or safety of the device. The research use of any medical device in human subjects

must comply with the federal regulations for the protection of human research subjects and institutional

policies and procedures, regardless of whether or not the device is investigational.

For studies that require an FDA submission involving significant risk devices, investigators will be expected

to provide direct documentation from the FDA that either an IDE application has been approved or that

an IDE application has been submitted and greater than 30 days have passed without additional comment

from the FDA. This supporting documentation will be reviewed by the IRB staff and by IRB members

assigned to a study as reviewers to ensure its validity.

Determining which devices pose Significant or Non-significant Risk The Investigational Device Exemption (IDE) regulations [21 CFR part 812] describe two types of device

studies:

1. Significant risk (SR) and

2. Non-significant risk (NSR)

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Significant Risk Devices A Significant Risk device study is defined [21 CFR 812.3(m)] as a study of a device that presents a potential

for serious risk to the health, safety, or welfare of a subject and

1. Is intended as an implant; or

2. Is used in supporting or sustaining human life; or

3. Is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents

impairment of human health; or

4. Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

Non-significant Risk Devices A Non-significant Risk device investigation is one that does not meet the definition for a significant risk

study. NSR device studies, however, should not be confused with the concept of "minimal risk," a term

utilized in the Institutional Review Board (IRB) regulations [21 CFR part 56] to identify certain studies that

may be approved through an "expedited review" procedure.

For both SR and NSR device studies, IRB approval prior to conducting clinical trials and continuing review

by the IRB is required. In addition, informed consent must be obtained for either type of study [21 CFR

Part 50].

The determination that a device presents a SR or NSR is initially made by the sponsor. Studies that the

sponsor determines to be SR must meet the full IDE requirements [21CFFR812]. These studies are first

submitted to the FDA for review and approval of the IDE application, and then to the IRB. The primary

reviewers assigned to the study will verify the validity of an IDE number.

Devices determined to be NSR need to meet only the abbreviated IDE requirements [21CFR812.2(b)]. In

cases where the sponsor makes an initial determination that a device is NSR, an IDE number may not be

submitted with the original application. For these studies the IRB makes a determination whether it

considers the device to be SR or NSR. The primary reviewers of a study will determine, upon their review,

whether the sponsor or investigator determination of risk for a device is appropriate. If the IRB

determines that the device is SR, then the primary reviewers will request that a full IDE application must

be submitted to the FDA and written approval obtained from the FDA before starting the research study.

If the IRB determines the device to be NSR and approves the study, the study may then proceed in

accordance with the abbreviated IDE regulations, without the need for further FDA review and approval.

The FDA may review a study at any time and has the ultimate decision in determining if a device is SR or

NSR. An IDE number may not be required if the device falls under one of the following IDE exemption

categories:

• A device, other than a transitional device, in commercial distribution immediately before May 28,

1976, when used or investigated in accordance with the indications in labeling in effect at that time.

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• A device, other than a transitional device, introduced into commercial distribution on or after

May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial

distribution immediately before May 28, 1976, and that is used or investigated in accordance with the

indications in the labeling FDA reviewed under subpart E of part 807 in determining substantial

equivalence.

• A diagnostic device, if the sponsor complies with applicable requirements in 21 CFR 809.10(c) and

if the testing:

1. Is noninvasive

2. Does not require an invasive sampling procedure that presents significant risk

3. Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically

established diagnostic product or procedure

4. A device undergoing consumer preference testing, testing of a modification, or testing of a

combination or two or more devices in commercial distribution, if the testing is not for the

purpose of determining safety or effectiveness and does not put subjects at risk.

5. A custom device as defined in 21 CFR 812.3(b), unless the device is being used to determine

safety or effectiveness for commercial distribution.

6. Whether research studies have the resources necessary to protect subjects

7. Adequate time for the investigators to conduct and complete the research.

The risk determination should be based on the proposed use of the device in the research study and not

on the device alone. In deciding if the proposed use of a device poses a SR the IRB will consider the nature

of the harm that may result from the use of the device. Studies where the potential harm to subjects

could be life-threatening, could result in permanent impairment of a body function or permanent damage

to body structure, or could necessitate medical or surgical intervention to preclude permanent

impairment of a body function or permanent damage to body structure should be considered SR. Also if

the subject must undergo a procedure as part of the investigation the IRB will consider the potential harm

that could be caused by the procedure in addition to the potential harm caused by the device.

Once the SR/NSR decision has been reached, the IRB should consider whether the study should be

approved or not. The criteria for deciding if SR and NSR studies should be approved are the same as for

any other FDA regulated study [21 CFR 56.111]. The IRB should assure that risks to subjects are minimized

and are reasonable in relation to anticipated benefits and knowledge to be gained, subject selection is

equitable, informed consent materials and procedures are adequate, and provisions for monitoring the

study and protecting the privacy of subjects are acceptable. To assure that the risks to the subject are

reasonable in relation to the anticipated benefits, the risks and benefits of the investigation should be

compared to the risks and benefits of alternative devices or procedures. This differs from the judgment

about whether a study poses a SR or NSR which is based solely upon the seriousness of the harm that

may result from the use of the device. Minutes of IRB meetings must document the rationale for SR/NSR

and subsequent approval or disapproval decisions for the clinical investigation.

FDA considers studies of all significant risk devices to present more than minimal risk; thus, full IRB review

for all studies involving significant risk devices is necessary. Generally, IRB review at a convened meeting

is also required when reviewing NSR studies. Some NSR studies, however, may qualify as minimal risk [21

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CFR 56.102(i)] and the IRB may choose to review those studies under its expedited review procedures [21

CFR 56.110].

Responsibilities of the Investigator The IRB will use its best abilities, the information in the regulations and guidelines, and the risk evaluation

provided by the applicant to decide whether a device is SR or NSR. To help the IRB in determining the risk

status of a device the investigator and/or sponsor will provide the IRB the following:

Reports of prior research studies conducted with the device

The proposed research protocol or plan

A description of the subject selection criteria

A description of the monitoring procedures

A description of the device

What risk determination (SR or NSR) was made by the sponsor and explanation of how the sponsor

reached this determination

Whether other IRBs have reviewed the proposed study and what determinations they have made

If the IRB decides the study is Significant Risk IRB Responsibilities: Notify sponsor and investigator of SR decision. After IDE obtained by sponsor,

proceed to review study applying requisite criteria [21 CFR 56.111] Sponsor Responsibilities: Submit IDE

to FDA or, if electing not to proceed with study, notify FDA (CDRH Program Operations Staff 301-594-

1190) of the SR determination; Study may not begin until FDA approves IDE and IRB approves the study.

Sponsor and investigator(s) must comply with IDE regulations [21 CFR part 812], as well as informed

consent and IRB regulations [21 CFR parts 50 and 56].

If the IRB decides the study is Non-significant Risk IRB proceeds to review study applying requisite criteria [21 CFR 56.111] If the study is approved by the

IRB, the sponsor and investigator must comply with "abbreviated IDE requirements" [21 CFR 812.2(b)],

informed consent and IRB regulations [21 CFR parts 50 and 56].

Reporting IRB determinations of Significant and Non-Significant Risk Once the decision of whether a device is SR or NSR, the IRB will then consider whether or not

the study should be approved. The criteria for deciding if a study should be approved will be the same as

for any other study and comply with the required determinations at 56.111 and 46.111. Minutes of the

IRB meeting will document the rationale for a determination of SR or NSR for a device and the

subsequent decision regarding whether or not to approve the study. The investigator will be notified in

writing of the IRB’s determination regarding whether the device is SR or NSR, and whether or not the

study is approved. When the IRB determines that a research study presented for approval as involving an

NSR device actually involves a SR device both the investigator and sponsor will be notified.

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Billing Compliance Issues Notification of approval from Clinical Trials Office is required in addition to IRB approval before a device

can be used. It is the responsibility of the investigator to coordinate billing issues with the departments

referenced above. If subjects will incur costs as a result of the use of the device, this should be clearly

outlined in the informed consent document.

Contingency Payments Wake Forest School of Medicine does not allow payments for research procedures to be covered by the

sponsor contingent on the subject’s inability to pay through other means (i.e. we do not allow sponsors to

make payment for research procedures to be made available only to subjects who are under or uninsured

or otherwise unable to cover the costs themselves or in cases where such costs are billed to a study

subject’s insurance and paid only by a study sponsor only in the event of an insurance denial. All subjects

must receive the same level of cost coverage for research procedures.

Storage and control of Investigational Devices It is the investigator’s and sponsor’s responsibility to maintain appropriate storage and handling of

investigational devices. The protocol analyst and board reviewers assigned to the protocol will assess the

plan to control the investigational devices so that they are used only in approved research protocols and

under the direction of approved investigators.

When following ICH-GCP (E6), researchers must:

Manufacturing, handling, and storage in accordance with applicable good manufacturing practice.

Where allowed or required, the investigator may assign some or all duties for investigational articles

accountability at the trial sites to an appropriate pharmacist or another appropriate individual who is

under the supervision of the investigator.

The investigator, pharmacist, or other designated individual will maintain records of the product’s

delivery to the trial site, the inventory at the site, the use by each participant, and the return to the

sponsor or alternative disposition of unused products. These records will include dates, quantities,

batch/serial numbers assigned to the investigational products and trial participants.

Investigators should maintain records that document adequately that the participants are provided

the doses specified by the protocol and reconcile all investigational products received from the sponsor.

References:

21 USC 321

21 CFR part 812

21 CFR Part 50

21 CFR 56.111

21 CFR 56.102(i)

21 CFR 56.110

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21.0 Humanitarian Use Devices

Regulatory Background An HUD is a device that is intended for the diagnosis or treatment of a disease or condition that affects

fewer than 4,000 individuals in the United States per year.

FDA regulations provide for the submission of a humanitarian device exemption (HDE) application, which

is similar in both form and content to a pre-market approval (PMA) application. However, unlike a PMA

application, an HDE application is not required to contain the results of scientifically valid clinical

investigations demonstrating that the device is effective for its intended purpose. The HDE application

must, however, contain sufficient information for the FDA to determine that the device does not pose an

unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the

risk of injury or illness from its use; taking into account the probable risks and benefits of currently

available devices or alternative forms of treatment. Additionally, the HDE applicant must demonstrate

that no comparable devices are available to treat or diagnose the disease or condition, and that the

device could not otherwise be brought to market unless it is granted HUD status.

The use of a HUD is limited to the indication specified in its product labeling; unlabeled or off- labeled use

of a HUD is not permitted under the HDE regulations. Thus, use of a HUD for an indication that is not

specified in the approval product labeling must comply with the FDA’s and IRB’s provisions for Emergency

Use of Unapproved Medical Devices or be approved through a separate IDE protocol that has been

approved by the FDA and IRB.

An approved HDE authorizes marketing of the HUD for clinical use, however, clinical use of the device is

limited to the indication specified in the product labeling. The labeling for an HUD must state that the

device is a humanitarian use device and that, although the device is authorized for clinical use by Federal

law, the effectiveness of the device for the specific clinical indication for which it is approved has not

been demonstrated.

A HUD may only be used in facilities that have established a local institutional review board (IRB) to

oversee the clinical introduction and use of the device within that institution.

HDE regulation do not require informed consent because an HDE provides for marketing approval, and so

use of the HUD does not constitute research or an investigation which would normally require informed

consent. Although the regulation does not require informed consent, there is nothing in the law or

regulation that preempts a state or institution from requiring prospective informed consent. The IRB

requires that either informed consent be obtained or a description of what information will be provided

to the patient and a statement that the use of the HUD will be noted in the patient’s medical record or on

clinical procedure consent be provided.

The unlabeled or off-labeled use of a HUD is not permitted under the HDE regulations. The use of a HUD

is limited to the indication specified in its product labeling. Use of a HUD for an indication that is NOT

specified in the respective product labeling must comply with the FDA’s and IRB’s provisions for the

Emergency Use of Unapproved Medical Devices or be through a separate IDE protocol that has been

approved by the FDA and IRB.

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Procedures to be followed by the Principal Investigator Although use of a HUD does not constitute research, FDA regulations require IRB review and approval of a

detailed protocol that describes the circumstances and procedures under which the HUD is used, before

the first device is used. Thereafter, each individual use of the HUD does not require prior IRB approval.

Applications for approval of use of an HUD are made through eIRB process. Principle investigators should

submit the following materials for Initial IRB Approval and Continuing Review of a HUD:

1. The HUD manufacturer’s product labeling, clinical brochure, investigator’s brochure and/or other

pertinent manufacturer informational materials.

2. The FDA HDE approval letter

3. A copy of the proposed informed consent or description of what information will be provided to the

patient and a statement that the use of the HUD will be noted in the patient’s medical record or on a

clinical procedure consent

4. A signed memorandum from the responsible physician stating the use of the HUD will be limited to the

indications listed in the FDA approved product labeling specifying where the device will be used (e.g.

operating room, clinic, special procedures room, etc.) listing all approved users by name

NOTE: In addition to IRB approval, approval from Compliance Manager and WFUP Director of Regulatory

& Reimbursement Services is required in addition to IRB approval before a HUD can be used. It is the

responsibility of the investigator to coordinate billing issues with the departments referenced above. If

subjects will incur costs as a result of the use of the device, this should be clearly outlined in the informed

consent document. Approval of the HUD is reported to in the IRB minutes along with all other research

studies submitted to the Board for approval.

Also, be aware that any Conflicts of Interest issues must be addressed in the usual course of IRB review

and approval.

HUD Use in Emergency Settings In accordance with Section 520(m)(4) of the act and section 21 CFR 814.124(a), IRB approval is required

before an HUD is used in a facility, except in emergencies where the physician determines that approval

cannot be obtained in time to prevent serious harm or death to the patient.

In an emergency situation, a HUD may be used off-label; however, the IRB, along with the FDA,

recommends you follow certain patient protection measures before use. Because IRB review and

approval is required before a HUD is used within its approved labeling, FDA believes similar procedures

should apply if you use a HUD outside of its approved labeling. That is, in an emergency situation, a HUD

may be used off-label to save the life or protect the physical well-being of a patient; however, in this

situation, FDA recommends that the physician and HDE holder follow the same emergency use

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procedures that govern the use of unapproved devices. Further details regarding this procedure can be

found in the Emergency Use of Investigational Devices policy.

Before the device is used in the emergency setting, if possible, the physician should obtain

1. The IRB chairperson’s concurrence,

2. Informed consent from the patient or his/her legal representative,

3. An independent assessment by an uninvolved (i.e., not the referring) physician, and

4. Authorization from the HDE holder

After the emergency use occurs, the physician should submit a follow-up report on the patient’s condition

and information regarding the patient protection measures to the HDE holder, who would then submit

this information as a HDE report to the FDA. The physician should also inform the IRB of these events

within 5 days if previous approval was not obtained.

If an HUD is used in an emergency situation, the physician should devise a schedule for monitoring the

patient, taking into account the specific needs of the patient and the limited information available about

the risks and benefits of the device.

21.3.1 HUD Use in Compassionate Situations

The IRB, along with the FDA, allow for the use of a HUD for compassionate use. As in the case of

emergency use, the IRB and the FDA recommend that the physician ensures that patient protection

measures discussed above are addressed before the device is used. In addition, we recommend you first

obtain FDA approval for compassionate use.

A physician who wishes to use a HDE-approved device for compassionate use should provide the HDE

holder with:

1. A description of the patient’s condition and

2. The circumstances necessitating use of the device,

3. A discussion of why alternative therapies or diagnostics are unsatisfactory

4. Information to address the patient protection measures.

The IRB and the FDA also recommend the HDE holder submit the above information in a HDE report for

FDA approval before the use occurs to help ensure adequate patient protection. FDA will review the

information in the most expeditious manner possible and issue a letter to the HDE holder.

If a physician undertakes a compassionate use, he or she should devise a schedule for monitoring the

patient, taking into consideration the specific needs of the patient and the limited information available

regarding the risks and benefits of the device for this unapproved use.

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Procedures to be followed by the IRB The IRB is responsible for initial and annual continuing review of the HUD. For initial review of a protocol

HUD, the FDA requires a full board review. However, the FDA allows expedited review procedures for

continuing review, since the initial review is always by the full board and use of a HUD within its approved

labeling does not constitute research, unless the IRB determines that full board review should be

performed.

Consent

FDA regulations do not require informed consent for use of an HUD, because the HDE provides marketing

approval, and use of the HUD does not constitute research. Nonetheless, nothing in the FDA HUD

regulations preempts a state or institution from requiring prospective informed consent. In this regard,

the IRB requires that the investigators either obtain informed consent, or provide a detailed description

of the rationale, risks, and benefits of the HUD to the patient and note the use of the HUD in the patient’s

medical record or on a clinical procedure consent.

References:

21 CFR 814.124(a)

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22.0 Investigational Drugs

Regulatory Background An Investigational New Drug (IND) Application are exemptions from the law that otherwise requires that

a drug or biologic must be approved before it can be transported across state lines. Generally, one of

these exemptions is required whenever a research study uses a drug or biologic that has not received FDA

marketing approval. An IND may also be required for a drug that does have FDA marketing approval if the

research study proposes a use of the drug that was not included in the existing FDA approval. (See the

FDA Information Sheets on "Off-Label" and Investigational Use of Marketed Drugs, Biologics, and Medical

Devices" for additional requirements.) IND research studies are subject to the same new and continuing

review requirements as for human subjects research in general, but they also require FDA approval for

the proposed research use. No research should begin until a valid IND is in place or an exemption has

been determined. This includes recruiting, obtaining consent, and screening participants for a specific

study that is subject to the IND.

Most IND studies at the institution are research protocols developed and sponsored by the commercial

entity that is developing a drug or device pursuant to FDA regulations and is itself responsible for

obtaining the IND approvals and for fulfilling all other FDA requirements for such a study.

There are some IND studies for which the study protocol has been developed independently by a

university investigator and for which that investigator is responsible for obtaining the IND and for fulfilling

all FDA required filings and other documentation. Investigators should contact the Office of Research for

guidance and support regarding IND studies.

Investigators will provide the IND number as a part of the IRB application; the IRB staff and the primary

reviewers verify that the IND number is valid by assuring consistency across documents (e.g., FDA letters,

sponsor protocol). When research involves the use of a drug other than the use of a marketed drug in the

course of normal medical practice, IRB approval will not be granted until the researcher has either

provided documentation of an IND or meets one of the FDA exemptions from the requirement to have an

IND. Investigators will be expected to provide direct documentation from the FDA that either an IND

application has been approved or that an IND application has been submitted and greater than 30 days

have passed without additional comment from the FDA. The IRB is not required to monitor the

investigator’s performance of required FDA paperwork. However, in reviewing the study, the IRB should

be mindful that in this context, the IRB review should include a determination of whether an IND is

required and may also require more intense IRB scrutiny of the protocol and related risks as well as more

guidance to the investigator regarding the scientific design, subject safety parameters, informed consent

process and other human subjects protection factors. For FDA-regulated research involving and

investigational drug conducted outside of the United States, an IND is not required provided the research

is conducted under the Declaration of Helsinki and Good Clinical Practice guidelines.

For emergency use of an investigational product, see SOP 23.0, Emergency Use of an Investigational or

Unlicensed Test Article.

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For non-emergency situations, prospective IRB approval is required. Single patient use allows a physician

to obtain access to an investigational drug upon receiving approval from the IRB. This approval is granted

for the treatment of a single patient. The treatment use may occur only after IRB approval is obtained.

Compliance with IND regulations When research involves the use of a drug other than the use of a marketed drug in the course of normal

medical practice, the IRB will confirm that:

The drug has an IND; or

The protocol meets one of the FDA exemptions from the requirement to have an IND:

Exemption 1

The drug product is lawfully marketed in the United States.

The investigation is not intended to be reported to FDA as a well-controlled study in support of a new

indication for use nor intended to be used to support any other significant change in the labeling for the

drug.

If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the

investigation is not intended to support a significant change in the advertising for the product.

The investigation does not involve a route of administration or dosage level or use in a patient

population or other factor that significantly increases the risks (or decreases the acceptability of the risks)

associated with the use of the drug product.

The investigation will be conducted in compliance with 21 CFR 50 and 56.

The investigation will be conducted in compliance with the requirements of 21 CFR 312.7.

Exemption 2

A clinical investigation is for an in vitro diagnostic biological product that involves one or more of the

following:

Blood grouping serum.

Reagent red blood cells.

Anti-human globulin.

The diagnostic test is intended to be used in a diagnostic procedure that confirms the diagnosis made by

another, medically established, diagnostic product or procedure.

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The diagnostic test will be shipped in compliance with 21 CFR 312.160.

Exemption 3

A drug intended solely for tests in vitro or in laboratory research animals if shipped in accordance with 21

CFR 312.160.

Exemption 4

A clinical investigation involving use of a placebo if the investigation does not otherwise require

submission of an IND.

Storage and control of Investigational Drugs It is the investigator’s and sponsor’s responsibility to maintain appropriate storage and handling of

investigational drugs. The protocol analyst and primary board reviewer assigned to the protocol will

assess the plan to store the drugs and ensure that the plan is adequate.

When following ICH-GCP guidelines researchers should:

Maintain a description that the manufacturing, handling, and storage is in accordance with

applicable good manufacturing practice.

Maintain records of the product’s deliver to the clinical trial site, the inventory at the site, the use

by each participant, and the return to the sponsor or alternative disposition of unused products.

These records include dates, quantities, batch or serial numbers, and expiration dates (if

applicable), and the unique code numbers assigned to the investigational products and trial

participants.

Maintain records that document adequately that the participants are provided the doses

specified by the protocol and reconcile all investigational products received from the sponsor.

Contingency Payments Wake Forest School of Medicine does not allow payments for research procedures to be covered by the

sponsor contingent on the subject’s inability to pay through other means (i.e. we do not allow sponsors to

make payment for research procedures to be made available only to subjects who are under or uninsured

or otherwise unable to cover the costs themselves or in cases where such costs are billed to a study

subject’s insurance and paid only by a study sponsor only in the event of an insurance denial. All subjects

must receive the same level of cost coverage for research procedures.

References:

21 CFR 50

21 CFR 56

21 CFR 312.7

21 CFR 312.160

ICH-GCP 2.12

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ICH-GCP 2.13

ICH-GCP 4.6.1

ICH-GCP 4.6.2-4.6.4

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23.0 Emergency Use of a test article in Life Threatening Situations

Regulatory Background Federal regulations recognize that, in a life threatening situation where standard treatment is unavailable

and treatment with an investigational product or procedure is thought to be in the best interest of the

subject, the ability to obtain full Institutional Review Board (IRB) approval may not be possible.

The IRB may agree that a situation represents an emergency exemption for the use of an unapproved

drug, device, or procedure without full IRB approval in accordance with Food and Drug Administration

(FDA) and Department of Health and Human Services regulatory standards.

FDA regulations contain a specific provision for this exemption from IRB review. HHS regulations do not

contain such provision but contain a section 46.116(f) that specifies that nothing in the HHS regulations is

intended to limit the authority of a physician to provide emergency care to the extent the physician is

permitted to do so under applicable federal, state and local law.

The emergency use of a test article, other than a medical device, is a clinical investigation, the patient is a

participant, and the FDA may require data from an emergency use to be reported in a marketing

application. DHHS regulations do not permit data obtained from patients to be classified as human

participant research, nor permit the outcome of such care to be included in any report of a research

activity subject to DHHS regulations.

The emergency use provision in the FDA regulations is an exemption from prior review and approval by

the IRB. The exemption, which may not be used unless all of the conditions described in 21 CFR

56.102(d) exist, allows for one emergency use of a test article without prospective IRB review. FDA

regulations require that any subsequent use of the investigational product at the institution have

prospective IRB review and approval. FDA acknowledges, however, that it would be inappropriate to deny

emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time

to convene a meeting to review the issue.

When an unapproved device may offer possible life saving alternative treatment, but an IDE for the

device does not exist, or the proposed use is not approved under an existing IDE, or the physician or

institution is not approved under the IDE, the device may be used in an emergency setting.

IRB policy recommends that the IRB be notified prior to use of an investigational drug in an emergency

situation; however, this is not required. Investigators should submit a written notification to the IRB

Director or Executive Chairmen to confirm that the use of the investigational product complies with FDA

regulations. In addition, this notification should not be construed as IRB approval. Notification is used by

the IRB to initiate tracking to ensure that the investigator files a report within the five day time-frame

required by 21 CFR 56.104(c). The FDA regulations do not provide for expedited IRB approval in

emergency situations. Therefore, "interim," "compassionate," "temporary" or other terms for an

expedited approval process are not authorized.

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Definitions Emergency Use means the use of an investigational drug or biological product with a human subject in a

life-threatening situation in which no standard acceptable treatment is available, and in which there is not

sufficient time to obtain IRB approval.

Test Article means any drug for human use, biological product for human use, medical device for human

use, human food additive, color additive, electronic product, or any other article subject to regulation

under the act or under these sections.

Life-threatening means diseases or conditions where the likelihood of death is high unless the course of

the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the end point

of clinical trial analysis is survival. The criteria for life-threatening do not require the condition to be

immediately life-threatening or to immediately result in death. Rather, the subjects must be in a life-

threatening situation requiring intervention before review at a convened meeting of the IRB is feasible.

Severely debilitating means diseases or conditions that cause major irreversible morbidity. Examples of

severely debilitating conditions include blindness, loss of arm, leg, hand or foot, loss of hearing, paralysis

or stroke.

Medical device is defined, in part, as any health care product that does not achieve its primary intended

purposes by chemical action or by being metabolized. Medical devices include, among other things,

surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins.

Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis (IVD of

disease and other medical conditions such as pregnancy.

Unapproved medical device is defined as a device that is used for a purpose or condition for which the

device requires, but does not have, an approved application for premarket approval under section 515 of

the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 360(e)]. An unapproved device may be used in

human subjects only if it is approved for clinical testing under an approved application for an

Investigational Device Exemption (IDE under section 520(g) of the Act [21 U.S.C 360(j)(g)] and 21 CFR part

812. Medical devices that have not received marketing clearance under section 510(k) of the FD&C Act

are also considered unapproved devices which require an IDE.

Procedures to be followed by the Investigators prior to use: Requirements for Emergency Exemption from Prospective IRB Approval

The FDA permits researchers to use an investigational product in an emergency situation without

prospective IRB approval, provided that all the following criteria are met:

1. The subject is confronted with a life-threatening situation necessitating the use of the test article.

2. No alternative method of approved or generally recognized therapy is available that provides an equal or

greater likelihood of saving the life of the subject.

3. There is not sufficient time to obtain IRB approval.

4. There is not sufficient time to obtain informed consent

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5. When using a medical device, there is no time to obtain an IDE number through the FDA. The FDA and IRB

expect the investigator to determine whether these criteria have been met to assess the potential for

benefits from the unapproved device, and to have substantial reason to believe the benefits will exist.

The investigator may not conclude that an emergency exists in advance of the time when treatment may

be needed based solely on the expectation that IND or IDE approval procedures may require more time

than is available.

In the event that a device is to be used in the circumstances meeting the criteria listed about, the device

developer should notify the Center for Devices and Radiological Health (CDRH), Program Operation Staff

by telephone (301-594-1190) immediately after the shipment is made. Nights and weekends, contact the

Division of Emergency and Epidemiological Operations (202 857-8400).

Note: an unapproved drug or device may not be shipped in anticipation of an emergency.

Informed Consent Considerations

Even for an emergency use, the investigator is required to obtain informed consent of the subject or the

subject's legally authorized representative unless both the investigator and a physician who is not

otherwise participating in the clinical investigation certify in writing all of the following:

The subject is confronted by a life-threatening situation necessitating the use of the test article.

Informed consent cannot be obtained because of an inability to communicate with, or obtain legally

effective consent from, the subject.

Time is not sufficient to obtain consent from the subject's legal representative.

No alternative method of approved or generally recognized therapy is available that provides an

equal or greater likelihood of saving the subject's life.

If the investigator is not able to obtain informed consent prior to using an investigational device due to

circumstances meeting the criteria stated above, the investigator should inform the subject of the

investigational procedures at the first available opportunity, and provide documentation of the

information provided to the subject/LAR to the IRB.

If, in the investigator's opinion, immediate use of the test article is required to preserve the subject's life,

and if time is not sufficient to obtain an independent physician's determination that the four conditions

above apply, the clinical investigator should make the determination and, within 5 working days after the

use of the article, have the determination reviewed and evaluated in writing by a physician who is not

participating in the clinical investigation. The investigator must notify the IRB within 5 working days after

the use of the test article.

Expanded Access to Investigational Test Articles

Investigational products are sometimes used for treatment of conditions either for a single subject or for

a group of subjects who are not eligible for participation in on-going clinical trials but who do not meet

the requirements for Emergency Use of an Investigational Drug or Biologic.

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The procedures that have evolved for an investigational new drug (IND) used for these purposes reflect

the recognition by the Food and Drug Administration (FDA) that, when no satisfactory alternative

treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-

threatening and debilitating illnesses. The following mechanisms expand access to promising therapeutic

agents without compromising the protection afforded to human subjects or the thoroughness and

scientific integrity of product development and marketing approval.

Emergency Use IND

The need for an investigational drug may arise in an emergency situation that does not allow time for

submission of an IND in the usual manner. In such cases, the FDA may authorize shipment of the drug for

a specified use, usually conditioned upon the sponsor filing an appropriate application as soon as

practicable. Requests for such authorization may be made by telephone or other rapid communication

means. Prospective IRB review and approval through the usual IRB process is required unless the criteria

for the Requirements for Emergency Exemption from Prospective IRB Approval as described above are

met. In addition, informed consent is required unless the criteria for the Informed Consent Exception

Requirements are met.

Obtaining an Emergency Use IND

The emergency use of an unapproved investigational drug or biologic requires an IND. If the intended

subject does not meet the criteria of an existing study protocol, or if an approved study protocol does not

exist, the usual procedure is to contact the manufacturer and determine if the drug or biologic can be

made available for the emergency use under the company's IND.

Billing Issues

Notification of approval from NCBH Patient Financial Services Compliance Manager and WFUP Director of

Regulatory & Reimbursement Services is required in addition to IRB approval before the emergency use

of an investigational drug or biologic can be used (see the WFUBMC Policy on Investigational/FDA

Conditionally Approved Medical Devices – PPB-MC-31). It is the responsibility of the investigator to

coordinate billing issues with the departments referenced above. If a subject will incur cost as a result of

the use of the drug or biologic, this should be clearly outlined in the informed consent document.

Procedures to be followed by Investigators after use Reporting to the IRB

Emergency use of an investigational drug or biologic must be reported in writing to the IRB within 5

working days of such use. This report must provide documentation supporting each of the above listed

criteria for Emergency Exemption from Prospective IRB Approval. A copy of the informed consent or

documentation supporting each of the above listed criteria for the Informed Consent Exception

Requirement must be attached. If available, additional supporting information such as a protocol,

investigator’s brochure or published reports of similar use should be included. The IRB will then review

the documentation that is provided and determine whether the circumstances met FDA regulations.

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Emergency use of a test article will be reported to the IRB as information. Data arising from emergency

use may used for research purposes only to the extent allowed by FDA regulations. Any subsequent use

of the test article at the institution is subject to IRB review.

If using a medical device and an IDE for the use does not exist, documentation that the sponsor has been

notified should be provided to the IRB, of if an IDE does not exist, documentation that the FDA has been

notified, should be provided. FDA notification should include a written summary of the conditions

constituting the emergency, subject protection measures, and results.

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Non-emergency indications Treatment IND

The treatment IND is a mechanism for providing eligible subjects with investigational drugs for the non-

emergency treatment of serious and life-threatening illnesses for which there are no satisfactory

alternative treatments. A treatment IND may be granted after sufficient data have been collected to show

that the drug "may be effective" and does not have unreasonable risks. Because data related to safety and

side effects are collected, treatment INDs also serve to expand the body of knowledge about the drug.

There are four requirements that must be met before a treatment IND can be issued:

(1) The drug is intended to treat a serious or immediately life-threatening disease;

(2) There is no satisfactory alternative treatment available;

(3) The drug is already under investigation, or trials have been completed; and

(4) The trial sponsor is actively pursuing marketing approval.

Treatment IND studies require prospective IRB review and approval through the usual IRB process unless

the criteria for the Requirements for Emergency Exemption from Prospective IRB Approval as described

above is met. Informed consent is required unless the criteria for the Informed Consent Exception

Requirements are met.

Parallel Track

The FDA's Parallel Track policy permits wider access to promising new drugs for AIDS/HIV related diseases

under a separate "expanded access" protocol that "parallels" the controlled clinical trials that are essential

to establish the safety and effectiveness of new drugs. It provides an administrative system that expands

the availability of drugs for treating AIDS/HIV. Prospective IRB review and approval through the usual IRB

process is required.

Single Patient Use

Single Patient Use is a process for providing investigational drugs for the non-emergency treatment of

serious and life-threatening illnesses for which there are no satisfactory alternative treatments to a single

subject. Prospective IRB review and approval through the usual IRB process is required.

The following materials are required for IRB review and approval of a Single Patient Use:

1) A signed memorandum from the responsible physician

Include in the subject line “Request for Single Patient Use”

Describe the disease or condition under treatment

Document the lack of alternative treatment

Describe the proposed treatment

DO NOT include the name of the subject receiving treatment in the memorandum

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2) A copy of the proposed protocol

3) A copy of the proposed informed consent

4) Any other supporting information such as an investigator’s brochure

IRB submissions for Single Patient Use will be taken directly to the next convened IRB meeting for review.

Group C Treatment IND

The "Group C" treatment IND was established by agreement between FDA and the National Cancer

Institute (NCI). The Group C program is a means for the distribution of investigational agents to oncologists

for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are

generally Phase 3 study drugs that have shown evidence of relative and reproducible efficacy in a specific

tumor type. They can generally be administered by properly trained physicians without the need for

specialized supportive care facilities. Group C drugs are distributed only by the National Institutes of

Health under NCI protocols. Although treatment is the primary objective and patients treated under Group

C guidelines are not part of a clinical trial, safety and effectiveness data are collected. Prospective IRB

review and approval through the usual IRB process is required

The following materials are required for IRB review and approval of a Group C Treatment IND

submission:

1) A signed memorandum from the responsible physician Include in the subject line “Group C Treatment

IND”

Describe the disease or condition under treatment

Document the lack of a satisfactory alternative treatment

Describe the proposed treatment

DO NOT include the name of the subject receiving treatment in the memorandum

2) A copy of the proposed protocol

3) A copy of the proposed informed consent

4) Any other supporting information such as an investigator’s brochure

5) Documentation from either the FDA or the National Cancer Institute of Group C Treatment

6) IND designation for the proposed treatment

Submissions for Group C Treatment IND Use will be taken directly to the next convened IRB meeting for

review.

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Compassionate Use to Individual Patient Access to Devices

Compassionate Use or Individual Patient Access is the use of a device when a serious, but not life-

threatening, condition exists where no alternative device is available. This does not constitute Emergency

Use of an Unapproved Medical Device. Compassionate Use of Individual Patient Access is governed by the

IDE regulations and FDA approval is required before the device is used. IRB review and approval through

the usual review process is required before the device is used.

Treatment Use of Medical Devices

Treatment Use is intended to facilitate the availability of promising new devices early in the development

process and to obtain additional data on the device’s safety and effectiveness when a serious, but not life-

threatening condition exists where no alternative device is available. Treatment use does not constitute

Emergency Use of an Unapproved Medical Device. Treatment use id governed by the IDE regulations and

FDA approval is required before the device is used. IRB review and approval through the usual review

process is required before the device is used.

References:

21 CFR 56.104(c)

45 CFR 46.116(f)

21 CFR 56.102(d)

21 CFR 312

21 CFR 812

21 CFR 50.23

57 FR 13250

62 FR 48490

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24.0 Protocol Deviations

Definitions Protocol Deviation: Any event, action, or activity associated with the conduct or oversight of a human

subject research study that fails to comply with the approved study protocol or consent; IRB Policies and

procedures; Federal agency regulations; or other applicable regulatory policies governing such research,

regardless of whether or not it causes harm of any kind to research subjects, increases the risk of harm, or

otherwise negatively impacts their safety, rights, welfare, or privacy.

Unanticipated Problem: Any event, action, or activity associated with the conduct or oversight of a human

subject research study - not articulated in the study protocol or consent or expected as a consequence of

the natural history of a disease under study- that causes physical, psychological, economic, or social harm

to a human subject; increases the risk of harm of any kind; or otherwise compromises subject's safety,

rights, welfare, or privacy. Please note that many study deviations are not unanticipated problems (UAPs)

and that not all UAPs are study deviations.

Adverse Event: Any negative outcome or undesirable problem that occurs during the conduct of a study,

whether or not it is associated with the conduct or oversight of a research study.

Serious Adverse Event: An adverse event that results in: 1) death; 2) a life-threatening situation; 3)

hospitalization; 4) disability or permanent damage; 5) congenital anomaly or birth defect;6) the immediate

need for medical or surgical intervention to prevent one of these outcomes. Please note that (serious)

adverse events are not UAPs if they have been enumerated in the protocol and consent or are reasonably

expected as a consequence of the natural history of the disease process under study; neither are they

protocol deviations if the study protocol has been faithfully followed.

Corrective Action Plan: A formal written plan submitted by an investigator in response to a protocol

deviation or UAP which outlines the measures that will be taken to prevent a recurrence of the deviation,

problem, or event in the future and/or reduce future risks to subjects. Examples include revision of the

protocol and/or consent form, re-consenting subjects, additional training of study staff, or notification of

the appropriate government oversight agencies.

Continuing Noncompliance: A pattern of repeated protocol deviations that indicates a deficiency in the

ability or willingness of an investigator/study team to comply with Federal regulations, IRB policies, or

other institutional requirements.

Serious Noncompliance: Any protocol deviation that causes harm of any kind to a research subject;

adversely affects subjects' safety, rights, welfare, or privacy; or compromises the scientific integrity of the

study. Examples of serious noncompliance include, but are not limited to:

1. Conducting non-exempt human subjects research without IRB approval

2. Recruiting subjects, conducting study interventions, or collecting data after IRB approval has expired

3. Enrolling subjects who do not meet study eligibility criteria, thereby placing them at increased risk

4. Failure to obtain informed consent or failure to use current, IRB approved consent forms

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5. Failure to report protocol deviations or unanticipated problems

6. Failure to submit an annual renewal of an active IRB protocol

7. Failure to respond in a timely fashion to concerns communicated by the Human Research Monitoring and

Oversight Specialist or IRB Administration

Regulatory Background All protocol deviations shall be reported to the IRB, the study sponsor, OHRP, FDA or other Agency as

required by federal regulations, the research protocol, grant, or research contract, regardless of the

funding source, and regardless of whether or not they constitute an unanticipated problem or adverse

event.

Investigator Requirements for Reporting Protocol Deviations to the IRB Protocol deviations that do NOT constitute an unanticipated problem should be entered into the study

Protocol Deviation Log and submitted to the IRB at the time of annual continuing review. A Protocol

Deviation Log template is available on the Monitoring and Oversight website

(http://www.wakehealth.edu/IC_Office-of-Research/Human-Research-Oversight.htm) If the IRB

subsequently determines that any of the deviations recorded on the log constitute serious or continuing

non-compliance, an appropriate Corrective Action Plan will be requested.

Any protocol deviations that could constitute an unanticipated problem should be reported to the IRB

within 7 days after it first comes to the attention of any member of the study team. Reports should be

submitted via eIRB using the IRB Safety Event reporting process. All reports should include a complete

description of the event, an explanation as to why it occurred, relevant medical records, and any changes

to the protocol or other corrective actions that have been taken or are proposed in response to the

protocol deviation.

IRB Review of Protocol Deviations All protocol deviations that could constitute an unanticipated problem are initially reviewed by the Human

Research Monitoring and Oversight Specialist (HRMOS), who is also an IRB member. The HRMOS will make

an initial assessment of the degree and manner in which the protocol deviation caused harm or increased

the risk of harm; whether the study protocol had minimized the risks to subjects through sound research

design and/or standard of care procedures; the adequacy of the data safety and monitoring plan to fully

ensure the safety of subjects; and the likelihood that any proposed corrective action plans would prevent

such events in the future.

In making this assessment the HRMOS may request more detailed information from the investigator(s),

the sponsor, the study coordinating center, or DSMB/DMC, and may consult with IRB members or non- IRB

members with special expertise related to the event. If more detailed information is required, the safety

event will be returned to the study team with a list of specific concerns. The principal investigator must

then respond in writing within 30 days of the date that the concerns are communicated. Failure to

respond within 30 days will be deemed to be serious noncompliance.

http://www.wakehealth.edu/IC_Office-of-Research/Human-Research-Oversight.htm

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Determinations and Required Responses If the HRMOS determines that protocol deviation does not constitute an unanticipated problem, violation

of IRB policies and procedures, or other actionable/reportable event, then it will be processed by

expedited procedures and reported to the Board as information at a scheduled meeting. No additional

action on the part of the principle investigator or study team will be required.

If the HRMOS determines that protocol deviation constitutes an unanticipated problem, violation of IRB

policies and procedures, or other actionable/reportable event, then it will be processed as outlined in the

IRB Policy regarding Unanticipated Problems Increasing Risks to Subjects and Others.

If the HRMOS determines that protocol deviation could constitute continuing or serious noncompliance,

then the HRMOS will place the report and any comments, findings, or supporting information on the

agenda for review by the full IRB. If the Board thereafter determines the report represents continuing or

serious noncompliance, it will review the adequacy of any proposed corrective action plans to protect the

safety, rights and welfare of subjects and/or enumerate the elements of an acceptable corrective action

plan and communicates them to the principle investigator and study team. Other actions as set forth in

the IRB policies and procedures for Investigator Non-Compliance may also be invoked.

If the HRMOS finds that the protocol deviation is reportable to external agencies, the HRMOS will advise

the IRB Director, who will be responsible for executing the appropriate regulatory reporting.

If the HRMOS finds that the protocol deviation constitutes a HIPAA violation, a security breach, or possible

research misconduct, these concerns will be forwarded to the appropriate institutional oversight bodies.

References:

45 CFR 46.103(b)(5)

21 CFR 56.108(b)(1)

21 CFR 312.32

21 CFR 312.66

21 CFR 312.64(b)

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25.0 Unanticipated Problems Involving Risks to Subjects or Others/Safety

Event Reporting

Definitions Adverse Event -Undesirable problem which affects a study participant, whether or not it is considered

related to the subject’s participation in the research. The effect may be a result of:

Study interventions, interactions, or procedures

Underlying disease, disorder, or medical condition

Other circumstances completely unrelated to the research study

Serious adverse event - Any adverse event that results in significant harm to or increased risk for the

subject or others. Examples include but are not limited to:

Death

Inpatient hospitalization or prolongation of existing hospitalization Persistent or significant

disability/incapacity

Congenital anomaly/birth defect

Other significant medical events which require medical or surgical intervention to prevent one of

the outcomes listed above, or which, based upon reasonable medical judgment, could jeopardize

the subject’s health or welfare Examples of such significant medical events are:

o Allergic bronchospasm requiring intensive treatment in an emergency room or at home

o Blood dyscrasias or convulsions that do not result in inpatient hospitalization

o Development of drug dependency or drug abuse.

Data Safety Monitoring Board (DSMB)-An independent group of experts who ensure subject safety and

study validity by meeting at defined intervals to monitor the accruing interim data of the study and make

recommendations regarding the continuation of the study

External adverse event- An adverse event that occurs at a study site which is not subject to the authority

of the Wake Forest IRB

Greater Risk- an event, incident, experience, outcome, or substantive change in the research protocol

which increases the likelihood of a serious adverse event or places subjects or others at a greater risk of

harm (physical, psychological, economic, or social) than was previously known or recognized

Internal adverse event- An adverse event that occurs at a study site which is subject to the authority of

the Wake Forest IRB

Related or possible related- Reasonable possibility that the event, incident, experience, or outcome may

have been caused by the procedures or interventions involved in the research

Unanticipated Problem - Any event, incident, experience, or outcome which occurs in a research study

and meet ALL of the following criteria:

Unexpected in nature, frequency, or severity

Related or possibly related to participation in the research

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Place subjects or others at a greater risk of harm than was previously known or recognized

Please note that unanticipated problems should result in a corrective action plan that lists the actions that

will be taken to minimize any risk to subjects or ensures that they are aware of newly confirmed risks.

Unexpected- Not identified by nature, severity, or frequency in the investigator’s brochure, sponsor

protocol, or current IRB approved research protocol or informed consent document, taking into account

the characteristics of the subject population being studied

Unrelated- Any event, incident, experience, or outcome which is determined to be solely caused an

underlying disease, disorder, or condition of the subject; or other circumstances unrelated to the subject's

participation in the research

Regulatory Background Any unanticipated problems involving risks to subjects or others shall be promptly reported to the IRB.

In addition, unanticipated problems shall be reported to the study sponsor, OHRP, FDA or other

Department or Agency as required by federal regulation, the research protocol, or the research contract.

Unanticipated problems, including those which may occur after the participant has completed or has

withdrawn from the study, should be reported until the time of study closure. Reporting to the IRB is

required regardless of the funding source, study sponsor, or whether the event involves an investigational

or marketed drug, biologic or device. Reportable events are not limited to physical injury, but also include

psychological, economic and social harm. Reportable events may arise as a result of the use of drugs,

biological agents, devices, procedures or other interventions, or as a result of the use of questionnaires,

surveys, observations or other interactions with research subjects.

ALL members of the research team share the responsibility for reporting unanticipated problems involving

risk to subjects or others to the IRB and other applicable parties. The Principal Investigator, however, is

ultimately responsible for ensuring the prompt reporting of unanticipated problems involving risk to

subjects or others to the IRB, whether these reports are from a local site or from an external site

conducting the same protocol. The Principal Investigator is also responsible for ensuring that all reported

unanticipated risks to subjects and others are reviewed to determine whether the report represents a

change in the risks and/or benefits to study participants, and whether any changes in the informed

consent, protocol or other study-related documents are required.

Investigator Requirements for Reporting to the IRB The following must be reported to the IRB within 7 calendar days of the investigator or other members of

the study team becoming aware of the event:

1. Unanticipated problems involving risks to subjects or others occurring at a site overseen by the Wake

Forest IRB (internal adverse events) - All unexpected, related (or possibly related), serious adverse events

occurring at a site approved by the Wake Forest IRB are considered unanticipated problems.

2. Unanticipated problems involving risks to subjects or others occurring at another site (not under the

oversight of the IRB) conducting the same protocol being carried out at a site that reports to the IRB

(external adverse events) - IRB recognizes that for multicenter studies, the sponsor is in a better position

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to process and analyze event information for the entire study, and thereby assess whether an event is an

“unanticipated problem.” Accordingly, if a sponsor determines that an event meets the criteria for an

unanticipated problem, then the IRB report should also include a corrective action plan (such as a protocol

or consent change).

The following must be reported to the IRB as soon as possible, but no later than seven days, after the

investigator or other members of the study team becoming aware of the event:

1. Events, incidents, experiences, outcomes, or substantive changes in the research protocol or informed

consent process/document, which increase the risk of the research or otherwise threaten the safety, rights

or welfare of research subjects. Examples include, but are not limited to:

Any breach of confidentiality or privacy

Incarceration of a study subject in a medical study not approved to enroll prisoners

An unexpected natural disaster, such as a flood or tornado, that destroys records or disrupts

scheduling

2. Any changes that were made to the research without prior IRB approval to mitigate an imminent risk of

harm to the subjects

The following should NOT be reported to the IRB:

Any event, incident, experience, or outcome that does not meet all of the criteria for an unanticipated

problem involving risks to subjects or others

External adverse event reports when all subjects at the site have completed study participation, and

the adverse events do not require the notification of previously enrolled subjects.

Unanticipated problems involving risks to subjects or others that occur at another site as part of a

study that has not been approved by the IRB (external events)

When following Department of Defense requirements, any unanticipated problems involving risk to

participants or others for any DoD supported research must promptly (no longer than 30 days) be

reported to the DoD human research protection officer.

Report Content

Reports of unanticipated problems involving risks to subjects or others should include the following

information

The title of the research protocol, IRB project number, and investigator’s names A detailed

description of the event, incident, experience, or outcome;

An explanation of the basis for determining that the event, incident, experience, or outcome

represents an unanticipated problem; and

A description of any changes to the protocol or other corrective actions that have been taken or

are proposed in response to the unanticipated problem

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ICH-GCP Reporting Guidance

When following ICH-GCP guidance, investigators should report to the IRB any new information that may

affect adversely the safety of the subjects or the conduct of the clinical trial. Investigators should also

report any changes which significantly affect the conduct of the clinical trial or increase the risk to

subjects. Some examples of reporting circumstances are listed below:

Report all serious adverse events (SAEs) to the Sponsor except for those SAEs that the protocol or

other document identifies as not needing immediate reporting.

Report adverse events or laboratory abnormalities identified in the protocol as critical to safety

evaluations to the Sponsor according to the reporting requirements and within the time periods specified

by the Sponsor in the protocol.

For reported deaths, the investigator supplies the Sponsor and the IRB with additional requested

information.

Provide written reports to the Sponsor and the IRB on any changes significantly affecting the conduct

of the clinical trial or increasing the risk to subjects.

New information that may affect adversely the safety of the participants of the conduct of the clinical

trial.

Reports should be made through the eIRB reporting process.

IRB Responsibilities for Review and Response All unanticipated problems involving risks to subjects or others that are internal or external reports

occurring in a study that has also been approved by the IRB are initially reviewed by the Human Research

Monitoring and Oversight Specialist (HRMOS) or designee. The HRMOS makes an initial assessment of

whether:

1. The report represents unanticipated problems involving risks to subjects or others;

2. The response proposed by the investigator is appropriate to ensure the safety, rights and welfare of

subjects;

3. Risks to subjects are minimized (i) by using procedures which are consistent with sound research design

and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using

procedures already being performed on the subject for diagnostic or treatment purposes

4. Risks to subjects are reasonable in relation to anticipated benefits, if any, to the subjects, and the

importance of the knowledge that may reasonably be expected to result

5. When appropriate, the research plan makes adequate provision for monitoring the data collected to

ensure the safety of subjects

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When an unanticipated problem involves no more than minimal risk to the participants or others, the

HRMOS will review the report based on the criteria listed above. If the reported event meets criterion 1

above, then the event is an unanticipated problem involving risks to subjects or other, then it must be

reported in accordance with policy under section 25.6. The HRMOS may concur with the management

plan or determine that additional action is needed to protect subjects. This may include, but is not limited

to, notifying subjects of the new information, modifying the consent document, or modifying the protocol.

The HRMOS will also consider criteria 3, 4, and 5 above in making a determination about whether the

management plan is adequate to protect subjects.

In addition to reporting the unanticipated problem to the organizational officials and applicable regulatory

agencies, the IRB at the next convened meeting will also be informed through the IRB minutes. The

HRMOS is an IRB member.

If the event is determined to be more than minimal risk to the participant, the HRMOS may request more

detailed information from the investigator(s), the sponsor, the study coordinating center, or DSMB/DMC.

If more detailed information is needed, the safety event will be returned to the study team with specific

concerns outlined. The principal investigator must respond within 30 days of the date concerns are sent to

the study team. Failure to respond to concerns within 30 days will be considered noncompliance and will

be handled as outlined in the Investigator Non-Compliance policy of IRB. The HRMOS may consult with IRB

members or non-IRB members with special expertise related to the event. If the HRMOS finds the report

represents unanticipated problems involving risks to subjects or others they will place the report and any

comments, findings or supporting information on the agenda for review by the full IRB. When

unanticipated problems involving more than minimal risk to participants or others are reviewed by the full

IRB, information is provided through the eIRB system to the primary reviewer, who will lead discussion of

the event, and also provided through the eIRB system to all other board members. If the IRB determines

the report represents unanticipated problems involving risks to subjects or others the IRB will then

determine whether:

a. The proposed response is appropriate to ensure the safety, rights and welfare of subjects;

b. Risks to subjects are minimized (i) by using procedures which are consistent with sound research design

and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using


c. Risks to subjects are reasonable in relation to anticipated benefits, if any, to the subjects, and the


d. When appropriate, the research plan makes adequate provision for monitoring the data collected to

ensure the safety of subjects. The IRB has the responsibility for the protection of subjects’ safety, rights,

and welfare when reviewing unanticipated problems. IRB actions may include, but are not limited to:

Request for further clarification from the investigator Suspension of the research

Termination of the research

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Notification of current participants when such information may relate to participants’ willingness to

continue to take part in the research.

Additional optional actions may include:

Modification of the protocol.

Modification of the information disclosed during the consent/assent process

Provision of additional information during the consent/assent process

Requiring current participants to re-consent to participation

Modification of the continuing review schedule

Monitoring of the research

Monitoring of the consent process

Referral to other organizational entities.

Acknowledgment/acceptance without further recommendation

IRB Reporting of Unanticipated problems to appropriate institutional officials,

the department or agency head (or designee), and OHRP The Director of the Institutional Review Board and/or Executive Chair of the IRB is responsible for

reporting unanticipated problems to appropriate Institutional Officials, the department or agency head (or

designee), and OHRP. (See policy outlining mandated reporting to external agencies)

Other reporting requirements

The investigator and study team are responsible for meeting other reporting requirements, such as to the

sponsor, other study sites, coordinating center, or data safety monitoring committee that are specified in

the research protocol, contract, grant or other study documents. Please note that the reporting

requirements for IRB may differ from the reporting requirements for the sponsor.

Other Safety Reports Data and Safety Monitoring Board (DSMB) reports

All Data and Safety Monitoring Board (DSMB) reports must be submitted to the IRB within 30 calendar

days of receipt by the investigator or study team. These reports are initially reviewed by the HRMOS, who

may thereafter request additional review by the IRB Executive Chair, the IRB Director, IRB members or

non-IRB members with special expertise related to the event. The HRMOS may request more detailed

information from the investigator(s), the sponsor, the study coordinating center, or DSMB/DMC.

The HRMOS makes an initial assessment of whether:

Any proposed response is appropriate to ensure the safety, rights and welfare of subjects;

Risks to subjects are minimized (i) by using procedures which are consistent with sound research

design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using


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Risks to subjects are reasonable in relation to anticipated benefits, if any, to the subjects, and the


When appropriate, the research plan makes adequate provision for monitoring the data collected to


The HRMOS then places the reports and any clarifying or supporting documentation on the agenda for

review by the full IRB. If the IRB determines the report represents unanticipated problems involving risks

to subjects or others the IRB will then determine whether:

The proposed response is appropriate to ensure the safety, rights and welfare of subjects;

Risks to subjects are minimized (i) by using procedures which are consistent with sound research

design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using


Risks to subjects are reasonable in relation to anticipated benefits, if any, to the subjects, and the


When appropriate, the research plan makes adequate provision for monitoring the data collected to


If DSMB reports are expected but not received prior to the annual continuing review of a study, the

convened IRB should not vote to approve the study without the appropriate updates and information

provided by the DSMB.

Audit/Monitoring Reports

All reports received from external auditors/monitoring visits should be reported to the IRB within 30 days

of receipt. Examples of external auditors/monitors include representatives from the study sponsor, CRO,

or federal agency. The HRMOS will review each audit report to ensure that the safety, rights, and welfare

of subjects are protected. External reports will be assessed and processed in the same manner as DSMB

reports. Reviews conducted by the HRMOS are for the benefit of the investigator and are not reportable to

the IRB. If significant deficiencies are noted during a HRMOS review, then these deficiencies may require

reporting to the IRB as directed by the HRMOS.

FDA 483 report

All FDA 483 reports should be reported to the IRB. The HRMOS will review each report to ensure that the

safety, rights, and welfare of subjects have not been put at higher risk. FDA 483 reports will be assessed

and processed in the same manner as DSMB reports.

Follow-up to a previously submitted safety event

The IRB expects prompt reporting of all safety events. The IRB also understands that investigators may not

have all the relevant information needed within the required 7 day window of initially learning about the

event. If investigators later obtain additional information regarding the relatedness, expectedness, or

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severity of the event, then a follow-up report should be filed. Investigators should provide a summary of

the new information learned and indicate which original event the follow-up report relates to. The HRMOS

will review follow-up event reports in the same manner as the initial submission.

Subject Complaints

Formal complaints may be filed within the eIRB system. When a complaint is filed, the HRMOS reviews

that made the complaint, what was done by the study team in response to the complaint, and what

measures will be taken to prevent similar complaints in the future. After review by the HRMOS, complaints

may be placed on an upcoming meeting agenda for discussion by the IRB or reported as an information

item. Complaints may also be forwarded to the IRB Director or other appropriate institutional officials

based on the nature of the complaint.

Other reports

Updated study safety information or reports that address the risk or potential benefits of the research

should be reported to the IRB. If the reports warrant a change to the research (i.e. informed consent form,

recruitment documents, study status, etc.), then an amendment should be submitted concurrently.

Examples of “other” reports include:

FDA safety alerts

Publication in the literature or other findings

Any information that requires prompt reporting according to the protocol or the study sponsor

Incarceration of a participant in a protocol not approved to enroll prisoners

Breach of confidentiality

Please note that the following reports should always be submitted as amendments, NOT as safety events:

Revised Investigator’s brochure

Study summaries- Summaries of study data by enrollment numbers, drug toxicities, safety events,

etc.

Annual reports25.8 Special Requirements for adverse event reporting for research involving the

transfer of human genes

National Institutes of Health (NIH) guidelines require that any serious adverse event that is unexpected

and associated with the use of the gene transfer product must be reported to the IRB, WFUSM Biosafety

Committee, NIH Office of Biotechnology Activities (OBA), and the FDA or study sponsor within the

specified timeframes as found in Appendix M-1-C-4 in the NIH Guidelines for Research Involving

Recombinant DNA Molecules (NIH Guidelines). Gene therapy investigators must submit annual reports to

OBA as set forth in Appendix M-1-C-3 of the NIH Guidelines.

References:

45 CFR 46.103(b)(5)

21 CFR 56.108(b)(1)

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21 CFR 312.32

21 CFR 312.66

21 CFR 312.64(b)

ICH-GCP 4.10

ICH-GCP 4.11

ICH-GCP 4.12

ICH-GCP 4.13

DoD: Instruction 3216.02 4.b.4

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26.0 Study Suspension or Termination

Definitions A suspension of IRB approved research means that some or all of the research activities must temporarily

cease.

A termination of IRB approval means that all research activity permanently ceases.

Regulatory Background The convened IRB has the authority to suspend or terminate approval of research that is not being

conducted in accordance with the IRB approval, that has been associated with serious or continuing

noncompliance, or that has been associated with harm to the rights and welfare of human subjects. Any

suspension or termination of approval shall include a statement of the reason for the IRB action.

The IRB Chair or designee has the authority to request that the IRB suspend approval, however the final

decision on whether to suspend or terminate a study must come from a convened meeting of the full

board with established quorum. This request may be made when the continuation of the research may

adversely affect the rights and welfare of research subjects or when the IRB needs additional information

to ensure that the rights and welfare of subjects are protected and there is insufficient time to have the

convened IRB review the situation.

The IRB reports the suspension or termination promptly to the investigator and appropriate institutional

official(s). If the research is funded by an extramural agency, federal regulations dictate whether the

funding agency must be informed that IRB approval has been suspended or terminated. Principal

investigators (PIs) are responsible for informing the funding agency of any suspension or termination of

funded research.

Reporting to federal regulatory agencies is not required if the PI voluntarily closes down a study to new

subject accrual or temporarily halts the research procedures. The IRB, IRB Chair, IRB Director, or

administrative officials may recommend voluntary closure to the PI, but the PI makes the decision whether

closure is appropriate. However, if the IRB, IRB Director or IRB Chair requires suspension or termination,

then the incident is reportable under the Reporting to External Agencies SOP.

Procedures to be followed by the IRB Suspension of IRB Approval

A request or motion to suspend an approved protocol may be made by the IRB Chair or Director, however

the convened IRB determines and documents in the minutes the reasons for suspending the research and

any information needed from the PI and/or corrective actions or events that need to take place for the IRB

to consider a withdrawal of the suspension.

When a suspension involves the withdrawal of current subjects from a research protocol, the IRB

considers alternatives that protect subjects currently enrolled to ensure that harm is not incurred from

such withdrawal. Such considerations may include, but are not limited to, possible transfer of subjects to

another investigator, arrangement of clinical care outside the research, continuation of some research

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activities under the supervision of an independent monitor, permitting follow-up of subjects for safety

reasons, or requiring reporting of adverse events or outcomes to the IRB and the sponsor.

If the IRB suspends approval, the IRB Chair or Director documents the reason for suspension and notifies

the PI in writing. Correspondence with the PI may include, but is not limited to, the following:

An explanation of the extent of the suspension in terms of enrollment, recruitment, interventions,

interactions, and data analysis;

The reasons for the suspension, an explanation of the reasons for the decision, and an offer to the

investigator to respond to the convened IRB in writing;

A request for a description of any procedures needed to protect the rights and welfare of current

subjects if the suspension involves currently enrolled subjects;

A description of whether follow-up of subjects for safety reasons is permitted or required.

The IRB determines which institutional officials to notify of the suspension and whether to report the

suspension to an external agency. (See Reporting to External Agencies SOP) Copies of suspension

correspondence may also be sent to other administrative units in accordance that are relevant. These

groups could include, but are not limited to, the Radiation Safety Committee, Cancer Review Committee,

Clinical Research Unit, Biosafety Committee, or Grants and Contracts Administration.

Termination of IRB Approval

The convened IRB determines and documents in the minutes the reasons for terminating the research.

When a termination involves the withdrawal of current subjects from a research protocol, the IRB

considers alternatives that protect subjects currently enrolled to ensure that harm is not incurred from

such withdrawal. Such considerations may include, but are not limited to, possible transfer of subjects to

another investigator, arrangement of clinical care outside the research, continuation of some research

activities under the supervision of an independent monitor, permitting follow-up of subjects for safety

reasons, or requiring reporting of adverse events or outcomes to the IRB and the sponsor.

IRB staff will notify the PI of the termination in writing. The notification may include, but is not limited to,

the following:

An explanation of the extent of the termination in terms of enrollment, recruitment, interventions,

interactions, and data analysis;

The reasons for the termination, an explanation of the reasons for the decision, and an offer to the

investigator to respond to the convened IRB in writing;

A request for a description of any procedures that need to be followed to protect the rights and

welfare of current subjects if the termination involves currently enrolled subjects;

A description of whether follow-up of subjects for safety reasons is permitted or required; An

explanation that any request for appeal of the termination must be made within 30 days from

date of the notification.

The IRB determines which institutional officials to notify of the suspension and whether to report the

suspension to an external agency. (See Reporting to External Agencies SOP) Copies of suspension

correspondence may also be sent to other administrative units in accordance that are relevant. These

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groups could include, but are not limited to, the Radiation Safety Committee, Cancer Review Committee,

Clinical Research Unit, Biosafety Committee, or Grants and Contracts Administration.

Responsibilities of the Principal Investigator The PI is responsible for notifying enrolled subjects of any suspended or terminated research protocol. The

PI should consider the appropriate procedures for withdrawal of enrolled subjects, taking into account

their safety, rights, and welfare.

When following Department of Defense requirements, any suspension or termination of DoD- supported

research is promptly (no longer than 30 days) reported to the DoD human research protection officer.

Reporting of Suspension or Termination See the SOP regarding reporting to external agencies for a detailed description of reporting obligations.

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27.0 Reporting to External Agencies

Regulatory Background Institutional policy requires compliance with all applicable accreditation, local, state, and federal reporting

requirements in the conduct of research involving human subjects. The IRB/OR notifies appropriate

officials when research falls under the purview of a federal regulatory agency and one or more of the

following occurs:

Unanticipated problems involving risks to subjects or others;

Serious or continuing noncompliance with the regulations or requirements of the IRB;

Suspension or termination of IRB approval for research due to noncompliance;

Changes in IRB membership.

Reporting to regulatory federal agencies is not required if the principal investigator (PI) voluntarily closes

down a study to new subject accrual or temporarily halts the research procedures. The IRB, IRB Chair, IRB

Director, or administrative officials may recommend voluntary closure to the PI, but the PI makes the

decision whether closure is appropriate. However, if the IRB or IRB Chair requires suspension or

termination, then the incident may be reportable under this policy.

Procedures to be followed by the IRB

The procedures listed below will be used when reporting unanticipated problems, non-compliance,

suspension or termination of research. Collectively, these items will be subsequently referred to as events.

The Federalwide Assurance (FWA) with OHRP is restricted to research funded by the federal DHHS.

However, the same process for conducting investigations and taking actions by the IRB will apply to all

research regardless of funding source. If an event involves research that is not federally funded, the report

will be sent to the Institutional Official in lieu of OHRP or any of the federal agencies. All other reporting

requirements listed below will remain in effect. The IRB reserves the right to voluntarily report any event

that is not associated with federal funding to OHRP.

After completing an investigation, a report will be drafted promptly. It is the aim of the OR to have a draft

report sent to the appropriate agency within 30 days from the time the event is resolved to the

satisfaction of the IRB. The report will be drafted by the IRB Director in consultation with the IRB Chair, the

HRMOS, the Assistant Dean for Research, and others as needed. All correspondence with any federal

agency will be sent on behalf and with knowledge of the Institutional Official. Following this internal

review process, the report will be signed and sent by the IRB Director.

The report should contain the following elements:

Title of the research protocol

Name of the PI on the protocol

IRB number assigned to the research protocol

Grant award number

Nature of the event

Findings of the investigation

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Action plan to prevent future occurrence

Actions taken by the IRB and/or the University and final resolution

Reasons for the IRB’s actions

Plans for continued review, if warranted

FDA Regulated Research

When research is regulated by the FDA, the IRB requires the PI to report to the sponsor, who should report

to the FDA with a copy to the IRB. If the PI is also the sponsor, then the IRB requires that the PI report to

the FDA. The IRB Director may choose to prepare and send the report of a suspension or termination

directly to the FDA.

DHHS Funded Research

If the DHHS conducts or funds the research, the IRB Director sends the report to the OHRP.

If an agency that is subject to the “Common Rule,” other than the DHHS, conducts or funds the research,

the IRB Director sends the report to the agency as required by the agency and OHRP.

Record Retention

The IRB Director maintains all correspondence relating to the serious or continuing noncompliance. The

IRB Director provides a copy of the federal report(s) and any final IRB actions to the staff, which are

responsible for placing the report(s) in the IRB study file.

Individuals receiving the report

The report will be copied to the following individuals:

Institutional Official

Director of IRB

HRMOS

IRB with oversight for the study in which the event arose

PI

Privacy Officer (If HIPAA related)

Assistant Dean for Research

In addition, copies may be sent, when appropriate, to:

PI’s Department Chair, Dean or Director

Other interested parties, at the discretion of the Institutional Official and Director of the IRB

DoD supported research

Any unanticipated problems involving risks to participants or others, study suspension, or study

termination for any Department of Defense (DoD)-supported research must be promptly (no longer than

30 days) reported to the DoD human research protection officer.

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Any suspension or termination of Department of Defense (DoD)-supported research must be promptly (no

longer than 30 days) reported to the DoD human research protection officer.

Changes in IRB Membership/Registration When a change in IRB membership occurs, OR staff notify OHRP/FDA via their online registration system,

the IRB Director or designee enters the required information regarding the changes in membership and

submits the data to OHRP/FDA within fifteen days of receipt of the Dean’s approval of the membership.

The IRB Director or designee is responsible for revising registration information such as changes in IRB

member contact or Chair contact information within 90 days of the change, changes in the IRB’s decision

to review or discontinue review of types of FDA products or FDA clinical investigations within 30 days, or

the University’s decision to disband an IRB within 30 days of permanent cessation of the IRB’s review of

research.

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28.0 Non-compliance

Definitions Noncompliance is defined as:

Failure of an investigator or study team member to follow institutional policies and relevant

government regulations for the protection of human subjects in research

Failure to submit a protocol describing proposed research project to the IRB for review and

approval prior to commencing such research

Failure of an investigator or study team member to adhere to the terms and requirements of the

IRB approval.

Protocol deviations do not fall within this definition unless they meet the definition of serious or

continuing compliance. Please see the IRB policy on reporting deviations for additional information.

Examples of noncompliance include, but are not limited to:

beginning research before securing IRB approval as outlined above;

misuse or non-use of informed consent documents;

failure to secure IRB approval before introducing any changes in an IRB approved protocol;

failure to submit an annual renewal of an IRB protocol but continuing to collect study data and/or

intervention with subjects after IRB approval expires.

Serious noncompliance is defined as noncompliance that involves the risk of harm to a human subject;

that violates the rights and/or welfare of a human subject under applicable federal regulations; that

involves the failure of an investigator to seek, obtain, and comply with IRB review of a research activities,

or that involves the failure of an investigator to abide by the IRB reporting guidelines for human subject

research. A single instance of noncompliance may be deemed as serious non-compliance upon

consideration of the facts by the IRB.

Continuing noncompliance is defined as a pattern or series of non-compliant events, regardless of

whether it is a consequence of a lack of knowledge on the part of the investigator or a willful lack of

commitment by the investigator and study team to human subjects protection. Continuing noncompliance

if not addressed and rectified, may compromise the integrity of the entire WHUHS Human Subjects

Protection Program.

An allegation of non-compliance is defined as a report by a second party of an incident of non-

compliance, provided in person, in writing, by email or via a phone message. All allegations of non-

compliance will be investigated by the IRB.

Regulatory Background The IRB is responsible for the protection of the rights, safety, and welfare of human subjects participating

in research projects that take place at Wake Forest Baptist Medical Center. This policy applies to all faculty,

staff, students, and any other individuals who are involved in human subjects research as defined in the

IRB Policies For Conducting Human Subjects Research. This policy outlines the process for ensuring prompt

reporting to the IRB, appropriate Institutional Officials, Department or Section heads, and the Office of

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Human Research Protection (OHRP), if applicable, of serious or continuing noncompliance with federal

regulations described in 45 CFR Part 46.

The IRB approves any research that meets the criteria for human subjects research outlined in the federal

regulations (45 CFR Part 46). The Principal Investigator and study team are expected to comply with all

ethical standards for the conduct of human subjects research, institutional policies, state and federal laws

and regulations related to human subjects research, and any conditions placed on the conduct of the

research activity by the IRB. All reports or allegations of non-compliance will be investigated and

addressed by the IRB and/or the Institutional Official.

Notification of Potential Serious or Continuing Noncompliance Upon notification of an allegation of potentially serious or continuing non-compliance, the following will

occur:

Preliminary Determination of Suspension or Non-suspension

The IRB Director, upon consultation and agreement by an IRB Chair, will determine if immediate

suspension of study procedures and/or study enrollment is required for the specific research project in

question, as well as for other research projects conducted by the investigator in question. This initial

decision is based on preliminary review of available information, communication with the principal

investigator(s) involved in alleged noncompliance activities, and the seriousness of the allegations.

The principal investigator(s) involved in the allegations and associated research staff personnel,

appropriate Department or Section Head(s), and Institutional Official (IO) will be are notified in

writing about the actions taken.

Federal regulatory agencies, including the OHRP, will be notified in writing about the action, if

applicable.

Further fact-finding and timely review by a convened IRB or sub-committee of the IRB will

determine the length of any suspension.

Inquiry

1. The IRB Director and IRB Chair will undertake an inquiry of the allegations within 5 working days of the

recognized concern. The purpose of the inquiry is fact-finding, and may involve examination of study

records and discussion with the PI, the research team, other personnel, research participants, witnesses,

the complainant (if not anonymous), and others as appropriate.

2. The IRB Director will document and compile information from the inquiry

3. The IRB Director, along with the IRB Chair, will determine whether the noncompliance is serious or

continuing, which may warrant further investigation by the IRB.

Resolution of Inquiry

1. Noncompliance Not Meeting The Definition of Serious or Continuing If the noncompliance activity is

determined to not be serious or continuing:

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The issue will be resolved by discussions among the IRB Director, IRB Chair(s), Monitoring and

Oversight Unit, the principal investigator(s) involved in noncompliance activities, the Department

or Section Head(s) and the Institutional Official.

The IRB Director will document the outcome of all deliberations and communications in writing.

This report will include any sanctions or corrective actions required on the part of the investigator

and the time frame for such corrective actions to occur.

A copy of this report will be sent to the principal investigator(s) involved in the noncompliance

activities, associated research staff personnel, the Institutional Official and others as deemed

appropriate.

A written response from the principal investigator acknowledging receipt of the report and

describing actions to implement the recommended corrective actions will be required within 10

working days from the date of the corrective report.

The complainant will be provided information regarding the outcome of the investigation, as

deemed appropriate by the IRB Director.

All communication will be documented and filed under restricted access in the office of the IRB

Director.

IRB committees will be kept apprised of non-serious and non-continuing noncompliance actions,

as they arise, including the corrective recommendations and written responses from the principal

investigator. The principle investigator or their designee should keep a log of non-serious, non-

continuing noncompliance events, which should be uploaded for IRB members to review at the

time of continuing review. Events that are reported individually and do not meet the definition of

serious or continuing non-compliance will be reported to the IRB as informational items on a

future agenda.

2. Serious and/or Continuing Noncompliance If the noncompliance activity is determined to be of a serious

or continuing nature that warrants further investigation by the IRB:

The IRB Director, in conjunction with the appropriate IRB Chair(s), the Monitoring and Oversight

Unit, and/or subcommittees of the IRB, will readdresses the possible need for suspension of study

procedures and/or study enrollment for the project in question, as well as for other projects

approved by the IRB for the investigator in question, pending a timely review by a convened

Institutional Review Board.

The principal investigator(s) involved in alleged noncompliance activities will be notified and

provided with an opportunity to discuss the allegations.

If research activity suspension is warranted:

The principal investigator(s) involved in noncompliance activities and associated research staff

personnel, Department or Section Head(s), and the Institutional Official will be notified in writing

about the suspension.

Federal regulatory agencies will be notified, if applicable.

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In cases of externally funded programs, notice will be sent to the sponsor and to the Office of

Sponsored Programs.

If not done previously, a written report summarizing the inquiry findings will be sent to the

principal investigator(s) involved in noncompliance activities and associated research staff

personnel.

The principal investigator(s) involved in noncompliance activities will be required to respond to the

inquiry findings within 2 working days from the date of the written report, unless an extension is

requested in writing and granted by the IRB Director.

An initial meeting with the principal investigator for further fact finding will then be scheduled at

the earliest opportunity.

The IRB Director, with consultation from the IRB Chair(s), will determine if a sub-committee of the

IRB should be formed to further investigate the allegations of serious or continuing non-

compliance.

The IRB sub-committee will review the documented communications and discussions concerning

the noncompliance, will determine if further information is required, and will meet with the

principal investigator involved in noncompliance activities, the complainant (if not anonymous),

and others as needed. Once the IRB sub-committee has completed its investigation, a vote will be

taken as to whether noncompliance has occurred. If noncompliance is found, the sub-committee

of the IRB will outline corrective actions and additional steps necessary to rectify the situation.

The report of the investigation conducted by either the IRB Director or sub-committee of the IRB

will be presented at a convened IRB meeting. Relevant documents pertaining to instances of

serious or continuing non-compliance will be distributed through the eIRB system to all members

of the IRB for review and discussion at a convened meeting. For urgent issues, the IRB Director

may convene an emergency meeting of the IRB.

The IRB has the authority to suspend or terminate IRB approval of protocols that are found to be

noncompliant with institutional policies and procedures, state laws, and/or federal laws or

regulations.

Other sanctions may be imposed by the IRB, including but not limited to, regular compliance

audits, letters of reprimand, additional training, and restrictions on serving as an investigator on

protocols that enroll human participants.

Corrective Actions can include but are not limited to the following:

No action;

Modification of the research protocol;

Modification of the information disclosed during the informed consent process;

Additional information be provided to past participants;

Notification of current participants (required when such information may relate to participant’s

willingness to continue to take part in the research;

Requirement that current participants re-consent to participation

Modification of the continuing review schedule

Monitoring of the research

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Monitoring of the consent process

Suspension of the research

Termination of the research

Restrictions on serving as an investigator on protocols that enroll human participants

Obtaining more information pending final decision, such as requiring an audit;

Referral to other organizational entities (e.g., legal counsel, risk management, compliance); or

Other actions as appropriate for the local context.

Dissemination of Findings All communication will be documented and stored in folders with restricted

access in the IRB Director’s office.

The IRB Director, on behalf of the IRB, will send written notification of the IRB's determinations

and required actions to the principal investigator(s) involved in the allegations and associated

research staff personnel, Department or Section Head(s), and Institutional Officials.

In cases of externally funded programs, notice will be sent to the sponsor and to the Office of

Sponsored Programs when any action includes suspension or termination.

Federal regulatory agencies including OHRP or FDA will be notified, if applicable.

Others will be notified as deemed necessary by the IRB (e.g., the complainant, study participants,

other research sites, etc.).

The maximum time allowed between the recognition of a reportable event and fulfilling reporting

requirements is 30 days, when following DoD regulations.

Research Misconduct

In cases that involve allegations of research misconduct, the IRB Director will notify the Institutional

Official and the Research Integrity Officer for further action. This does not preclude the IRB Chair(s) or any

member of the IRB from independently contacting the Institutional Official about any allegation of

research misconduct. Inquiries or investigations into research misconduct do not preclude IRB review and

actions.

References:

45 CFR 46

DoD Instruction 3216.02 6 para.4.b.(4)

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29.0 IRB Authorization Agreements

Regulatory Background Cooperative research projects are those projects which involve more than one institution. In the conduct

of cooperative research projects, each institution is responsible for safeguarding the rights and welfare of

human subjects and for complying with this policy. With approval of the Institutional Official, or their

designee, an institution participating in a cooperative project may enter a joint review arrangement, rely

upon the review of another qualified IRB, or make similar arrangements for avoiding duplication of effort.

The IRB can enter into an IRB Authorization Agreement with other institutions, a Central IRB, and/or

Independent IRB with whom the institution and faculty collaborate on single or multiple projects.

When collaborating with other institutions, an IRB Authorization Agreement is drafted to identify:

The names of the collaborating institutions and their respective FWA numbers The title of the

project

The Principal Investigator and any Co-Investigators

The study sponsor

The IRB Authorization Agreement establishes a written understanding defining the scope of responsibility

of the respective institutions for the research study in which both institutions are involved. The review,

approval and continuing oversight performed by the Approving Institution’s IRB must satisfy the

requirements of the HHS regulations for the protection of human subjects at 45 CFR 46, as well as the

requirements of federal, state and local laws. For research involving FDA regulated products, the

Approving Institution’s IRB must be in compliance with the requirements defined in 21 CFR Parts 50, 56,

312 and 812 and ICH (International Conference on Harmonization) guidance related to GCPs (Good Clinical

Practices).

To ensure congruency between the grant and protocol document, the IRB must be the IRB of record when

the grant award is to a Faculty member. Additionally, the IRB must be the IRB of record when WFBMC

maintains liability for research related injury.

Responsibilities of the IRB IRB Authorization Agreements will only be established with Institutional Review Boards which are

registered with the Office of Human Research Protections. The IRB Director in consultation with the IRB

Chairs, as needed, determines whether or not the IRB enters into an Authorization Agreement with

another institution. IRB Authorization Agreements are signed by the IRB Director. IRB Authorization

Agreements are kept on file in the IRB office.

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Responsibilities of the Investigator Investigators wishing to collaborate with other institutions must contact the IRB to determine whether or

not an IRB Authorization Agreement is appropriate. The IRB Administrative Office will contact the

collaborating institution to discuss the possibility of entering into the Agreement.

Reference:

45 CFR 46.114

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30.0 Individual Investigator Agreements

Regulatory Background The IRB can enter into an Individual Investigator Agreement with individuals with whom the institution

and faculty collaborate on a single project.

When collaborating with an investigator, an Individual Investigator Agreement is drafted to identify:

The name of the Institution approving the research

The Institution’s FWA number

The title of the project

The Individual Investigator’s Name

The Individual Investigator Agreement establishes a written understanding defining the scope of

responsibility of the investigator for the research study involved. The investigator must review and

understand HHS regulations for the protection of human subjects at 45 CFR 46, as well as the

requirements of federal, state and local laws. For research involving FDA regulated products, the

Investigator must be in compliance with the requirements defined in 21 CFR Parts 50, 56, 312 and 812 and

ICH (International Conference on Harmonization) guidance related to GCPs (Good Clinical Practices).

Responsibilities of the IRB Individual Investigator Agreements are signed by the IRB Director. Individual Investigator Agreements are

reported to the IRB as information on the meeting agendas and documented in the minutes.

Responsibilities of the Investigator Investigators wishing to collaborate with an individual investigator must contact the IRB to determine

whether or not an Individual Investigator Agreement is appropriate. The approval of Individual

Investigators must be approved by the IRB Director or their designee. Individual Investigators must have

proof of Human Subjects Protection Training before an Agreement can be executed. If proof of no such

evidence is provided, then the Individual Investigator will be required to complete the CITI training.

References:

45 CFR 46

21 CFR 50

21 CFR 56

21 CFR 312

21 CFR 812

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31.0 Multi-site studies where Wake Forest is the lead coordinating center

Multi-site studies where Wake Forest is the lead coordinating center This scenario arises when:

Wake Forest is the lead coordinating center responsible for overall study conduct; or

A Wake Forest employee serves as principal investigator for the entire multi-site study, (unless

coordinating function located elsewhere as in some NIH-sponsored groups), or

Wake Forest is the sponsor (initiates contracts with and disburses funds to other sites).

Under these circumstances, the PI has additional responsibilities beyond those for a single site study which

include notifying the IRB of the multi-site nature of the study.

In addition, the PI should notify the Office of Sponsored Programs when the project is externally funded. If

there is a contractual agreement between the organization and the research site(s) the contract should

address the responsibilities described in this addendum.

For such multi-site studies, it is the responsibility of the Wake Forest PI to provide to the Wake Forest IRB

assurance that the study at that site will be conducted in compliance with federal regulations (including 45

CFR 46 and HIPAA), all applicable state and local regulations, and ethical principles governing research

involving human subjects. Each site must have IRB approval for the study whether by the site’s IRB or by

an external IRB before the study can be conducted at that site. For studies that are federally funded it may

be necessary for each site to have its own Federalwide Assurance (FWA) with OHRP, depending on the

nature of its engagement (see OHRP guidance at

http://www.hhs.gov/ohrp/humansubjects/assurance/engage.htm)

In many cases, investigators at an FWA institution will have a local IRB to which they are responsible; if no

such affiliation exists, then the IRB may serve as the IRB of record for that investigator. These agreements

should be negotiated at the time of initial review or as sites are added.

Responsibilities of the Principal Investigator The PI is responsible for collecting and maintaining documentation of IRB approvals at each of the

participating sites. Submission of these approvals to the IRB is required either by amendment or at the

time of continuing review. The submission of related documents (e.g., consent forms for participating

sites) to the IRB is not required, unless requested.

The PI is responsible for developing a Data and Safety Monitoring Plan and for implementing a system for

reporting and reviewing all unanticipated problems (UP) and adverse events (AEs). If the IRB deems formal

oversight by an independent Data and Safety Monitoring Board (DSMB) to be necessary and there is no

external DSMB provided, the IRB may require oversight by the Institutional DSMB.

http://www.hhs.gov/ohrp/humansubjects/assurance/engage.htm

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The investigator is also responsible for the management of information that is relevant to the protection

of subjects such as: unanticipated problems involving risk to subjects or others, interim results, and

protocol modifications.

31.1 Responsibilities of the IRB

The IRB is responsible for reviewing the proposed research plan and activities to be conducted at the

coordinating center. The IRB will review the system of monitoring safety events and may determine that a

DSMB is needed if not presently established. The IRB will also determine if the management of

information that is relevant to the protection of subjects is adequate.

31.2 Conducting DoD supported research

When conducting multi-site research, policies and procedures indicate that a formal agreement between

organizations is required to specify the roles and responsibilities of each party.

References:

SECNAVINST 3900.39D 8f

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32.0 Use of the Copernicus IRB

Purpose An agreement has been executed and regulatory filings completed to allow Copernicus IRB to function as a

reviewing IRB for Wake Forest Baptist Medical Center. This provides the opportunity to have an

independent IRB review of human research studies in situations where review by an independent IRB is

determined appropriate.

Criteria for recommending use of the Copernicus IRB The following are circumstances when a research study may be recommended for review by

Copernicus:

The IRB lacks the requisite expertise to conduct the review of the study Review by the IRB would

create an unresolvable conflict of interest

The institution identifies other compelling reasons for which review of a study by the Copernicus

IRB would be in the best interests of the institution

The Conflict of Interest in Research Committee recommends review by an independent IRB as part

of a management plan for an Investigator, whose research proposals present an individual or

institutional conflict of interest

Investigator identifies an institutional conflict of interest and contacts the IRB

Procedures Individual investigators and study sponsors cannot request or require review of a study by the

Copernicus IRB. The recommendation must come from the IRB and the Conflict of Interest Office.

All studies that are recommended for review by the Copernicus IRB must be recommended by the

IRB and the Conflict of Interest (COI) Office.

IRB and COI Office recommendations will be forwarded to the Dean of the School of Medicine who

will provide formal approval for the review by Copernicus and will determine responsibility for the

cost of the review.

The Dean of the School of Medicine will provide written approval for the use of Copernicus and

forward this information back to the IRB or Conflict of Interest in Research Committee. The IRB

will communicate this information to the Principal Investigator.

The Principal Investigator will be responsible for the submission to the Copernicus IRB, all

subsequent interactions and correspondence with Copernicus, and compliance with all

determinations and requirements made by the Copernicus IRB.

Once approval is obtained from the Copernicus IRB, the approval memo, and approved study

material should be submitted to the Wake Forest IRB for facilitated review.

The principal investigator is also responsible for compliance with all institutional and IRB policies

and procedures related to submission to the Copernicus IRB (i.e. notification of the submission,

notification of any suspension or termination, etc.).

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Responsibility for Copernicus Fees When institutional COI is identified on industry sponsored studies, the cost for Copernicus will

be covered by the study budget.

When the IRB lacks the expertise to conduct the review of the study, Wake Forest will pay the

costs of Copernicus.

On PI initiated studies where there is an identified institutional conflict of interest, the

responsibility for Copernicus costs will be determined by the Dean of the School of Medicine.

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33.0 Procedure for the IRB to serve as the IRB of Record to Sites

External to our Institution

Regulatory Background If external sites are engaged in the research, then by federal regulations, they must be reviewed and

approved by an Institutional Review Board. The following criteria must be met before Wake Forest will

serve as the IRB of record for external sites:

The principal investigator must be a Wake Forest University Health Sciences faculty member.

The protocol must be investigator initiated.

The research protocol could not be conducted without the use of the external site.

Investigators should contact the IRB office to discuss the protocol and role of the external

sites.

This policy does not imply that Wake Forest will be the IRB of record for privately sponsored

research trials conducted either on the medical center campus or externally.

The Wake Forest faculty member is ultimately responsible for conduct and compliance of the study.

This policy outlines the process for establishing and maintaining a Memorandum of Understanding

(MOU) for sites where the Wake Forest Institutional Review Board serves as the IRB of Record for all

research activity at the site external to our institution or for a specific research project.

External Site Investigator Responsibilities A. The external site Investigator will complete the initial Set Up Questionnaire for each site and submit to

the IRB Office for processing.

B. The following documentation will be submitted with the Set Up Questionnaire for each site:

A certificate of insurance for general comprehensive liability and professional liability for Investigators

and staff involved in the conduct of research;

A list of all research staff identifying their role in the study with correct titles and degrees;

Curriculum Vitas or resumes for all external site Investigators and key study personnel involved in the

conduct of the study;

Certificates for all Investigators and key study personnel, verifying successful completion of the CITI or

other Human Subjects Protections Training program;

Names of the local contacts, Institutional Signatory Official, and Human Protections Administrator for

the site requesting the IRB to serve as the IRB of Record;

C. The external site Investigator must provide all necessary information regarding local research context

in accordance with IRB Policy. The information provided should also include the following:

Local contacts for IRB questions;

Local contacts for research participants;

Local subject injury language; and

Local HIPAA authorization language.

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D. The external site Investigator must provide to the IRB and keep current the names, addresses, and

phone numbers of local contact persons who can make decisions regarding IRB issues.

E. All external site Investigators and key study personnel must participate in human research protections

continuing education as stated in IRB Policy and provide documentation to the IRB.

F. A copy of an approved Federalwide Assurance (FWA) must be submitted to the IRB.

G. An original signature on the MOU of the Institutional Official with the authority to sign contracts is

required.

H. The external site Investigator will comply with all oversight activities deemed appropriate by the IRB

Committee, Federal oversight agencies and/or Federal funding agencies at all sites (e.g., monitoring,

auditing).

I. All conflicts of interest between the external site investigators and the study sponsor must be

disclosed to the Wake Forest IRB. An appropriate conflict management plan must be

established/approved prior to completing a memo of understanding.

Wake Forest Investigator Responsibilities

The Wake Forest Investigator will agree to abide by all IRB policies and procedures including

accessing the IRB website to view any revisions and/or updates.

The Wake Forest Investigator will assure adherence to the agreements outlined in the MOU.

The Wake Forest Investigator will fully inform the IRB of all locations in which human subjects

will be recruited into the Research Project.

The Wake Forest Investigator will seek prior review and approval from the IRB Director for all

amendments to the currently approved research activities and/or new studies under the

MOU. The IRB may reasonably require higher insurance limits to provide sufficient coverage

commensurate to the risks involved in the research study which may be increased depending

on the amendment.

The Wake Forest Investigator will comply with all oversight activities deemed appropriate by

the IRB Committee, Federal oversight agencies and/or Federal funding agencies at all sites

(e.g., monitoring, auditing).

The Investigator will provide payment of the following fees determined at the time of the

MOU negotiations (additional fees will be assessed for each additional site):

Initial Set Up Fee of $1000 – Due within thirty (30) days of the effective date of the MOU.

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IRB Review Fee(s) of $2500- Due for each individual human subjects research project

reviewed by the IRB.

Annual Renewal Fee of $1000 - Due at least thirty (30) days prior to the renewal date of

the research project.

The Wake Forest Investigator or Human Protections Administrator at the external site must notify

the IRB immediately if an external site Investigator or key study personnel receives a suspension

or restriction of any duties, clinical or research related. In addition, they must notify the IRB if any

Investigator or key study personnel have received a determination of serious or continuing non-

compliance. Failure to do so may result in cancellation of the MOU.

All IRB-related communication and documents will be submitted by the Wake Forest Investigator

to the IRB, including any electronic submissions.

IRB Administration Responsibilities The Director of the IRB in consultation with the IRB staff will make all final determinations

regarding the IRB’s willingness to serve as the IRB of Record for a performance site “engaged” in

research.

The IRB Committee must review the CVs of the Investigator at Wake Forest and the external site

and key study personnel to determine if they are qualified to conduct the research in relationship

to their specific roles.

The IRB Committee must assess if the external site has the appropriate resources to safely and

ethically conduct the study. Items to be considered include, but are not limited to, the following:

The number and composition of staff;

The facilities, e.g. resources available to handle emergency situations, etc.;

The mechanism of recruitment utilized;

The process of informed consent; and

Past historical experiences.

With the approved MOU, the IRB agrees to:

Maintain and provide a copy of an approved Federalwide Assurance (FWA);

Inform the IRB Staff of the conditions of the MOU; and

Keep the MOU on file in the IRB.

The IRB will report promptly to the Wake Forest Investigators all actions taken by the IRB regarding (a)

any serious or continuing noncompliance by external site Investigators and (b) any suspension for

cause or termination for cause of IRB approval in accordance with the IRB policies and procedures.

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The IRB will verify insurance limits meet minimum requirements and will especially verify any

exclusions or endorsements. If necessary, the IRB may contact Legal Counsel and/or Risk

Management for advice on indemnification language and insurance limits.

If the external sites require inclusion of local context such as local contact names/numbers, subject

injury language, HIPAA authorization language, conflict of interest, etc., the IRB suggests the use of

one informed consent with each site’s utilizing a rider at the end to include the local information that

varies from site to site.

If there are questions that the PI cannot answer, the IRB will contact the local site for additional

information.

The IRB may conduct an audit of the external site depending upon but not limited to the following:

1. The level of risk of the research study;

2. The number of reported unanticipated problems involving risk to participants or others or serious

adverse events (e.g., this could be an inordinate low number of reports in a high risk study);

3. The degree of oversight provided by the coordinating center or other internal study monitoring

program;

4. The involvement of a Data Safety Monitor or Board;

5. An increased number of protocol deviations;

6. Complaints from participants; or

7. Any issues of noncompliance.

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34.0 Facilitated Review

Regulatory Background It is the policy of the IRB that as part of the responsibility for safeguarding the rights and welfare of

human participants, the IRB has the option of participating in cooperative research projects by

entering into joint review arrangements, relying upon the review of another qualified IRB, or making

similar arrangements for avoiding duplication of effort. This policy applies specifically to the

agreement in place between the IRB and the National Cancer Institute Central IRB (NCI CIRB) for adult

oncology research projects and the National Cancer Institute Pediatric Central IRB (NCI PedCIRB) for

pediatric oncology research projects. This policy also applies to any institution which the IRB has

executed a Memo of Understanding or Authorization Agreement that details the reliance

arrangements.

Responsibilities of the IRB Applications proposing the NCI CIRB or the NCI PedsCIRB as the IRB of record must be approved

by the Comprehensive Cancer Center at Wake Forest University School of Medicine prior to

submission to the IRB. Applications undergo a facilitated review at Wake Forest by designated

members of the IRB, the IRB Chairmen, IRB Vice Chairmen, or the IRB Director. The purpose of the

facilitated review is to determine whether there are local concerns that need to be addressed and

whether to accept the CIRB Review of the proposed research project. Amendments and Continuing

Review applications will undergo the same facilitated review process as described above while Safety

Events will be submitted and reviewed under current policy for all active studies at the institution.

The individual performing the facilitated review can propose/approve additions to the protocol or

word substitutions in the informed consent as outlined by the NCI CIRB. Local IRBs have the option to

accept the CIRB approval "as is", accept it with de minimus modifications, or may decide not to accept

the CIRB review and require that the investigator submit the protocol for full Board review.

Upon acceptance of the study, appropriate communication and documentation of the reliance to the

original institution’s IRB will occur.

Responsibilities of the Investigator The IRB Facilitated Review Packet must be submitted to the IRB and the application should name the

outside institution as the IRB of record for the proposed research study. The IRB Facilitated Review

packet should include a copy of the approval memo for the reviewing institution, the approved and

stamped consent form, the approved protocol, and any other relevant documents needed for

adequate review of the study. The IRB reserves the right to ask for additional documentation from the

reviewing IRB when needed.

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35.0 Children Involved in Research

Who is considered a child? The regulations outlined below apply to all research subjects who have “not attained legal age

for consent to treatments or procedures involved in the research, under the applicable law of the

jurisdiction in which the research will be conducted.” In the state of North Carolina, a minor is defined

as a resident under the age of 18 unless he or she is emancipated by the court, in the armed forces, or

legally married.

Definitions Assent - a child's affirmative agreement to participate in research. Mere failure to object, absent

affirmative agreement, should not be construed as assent.

Permission - the agreement of parent(s) or guardian to the participation of their child or ward in

research.

Parent - a child's biological or adoptive parent

Guardian - an individual who is authorized under applicable State or local law to consent on behalf of

a child to general medical care.

Ward of the State - a child who is placed in the legal custody of the State or other agency, Institution,

or entity, consistent with applicable Federal, State, or local law.

Regulatory Background Research involving children requires careful consideration of the additional regulatory provisions

intended to protect children from being enrolled in research which exceeds a high level of risk.

The Children’s Health Act of 2000 requires that research “involving children that is conducted,

supported, or regulated by the Department of Health and Human Services (DHHS) be in compliance

with subpart D.” The IRB is considerate of the National Institute for Health’s (NIH) requirement of the

inclusion of children in research and will assess the inclusion of children in research only when their

participation is necessary to answer the scientific question being evaluated.

The IRB is comprised of members who are knowledgeable about and experienced working with

children. Research involving children can be considered exempt from further IRB review per the

regulations meeting the definition of exempt research. However, the exemption for research

“involving the use of educational tests, survey procedures, interview procedures, or observation of

public behavior” cannot be used for research involving children unless the research is restricted to

“observation of public behavior when investigators do not participate in the activities being

observed.” Research involving children can be expedited in accordance with the regulations for the

expedited review of research.

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IRB Considerations The IRB is concerned specifically with the level of risk to the subject and the prospect of direct benefit

when reviewing research proposals that involve children. The IRB can approve research involving

children only if it falls into one of three categories:

1. Research presenting no more than minimal risk to children;

2. Research involving an intervention or procedure presenting more than minimal risk to children that

offers the prospect of direct benefit or may contribute to the well-being of the individual child; or

3. Research involving an intervention or procedure that presents only a minor increase over minimal risk

yet does not offer any prospect of direct benefit or contribute to the well-being of the child.

Research not involving greater than minimal risk. [45CFR46.404 and 21CFR50.51]

Assent of the child is sought; unless waived by the IRB

Permission of one parent or guardian is sought; unless waived by the IRB

Research involving greater than minimal risk but presenting the prospect of direct benefit to the

individual subjects, or by a monitoring procedure that is likely to contribute to the subject's well-

being [45CFR46.405 and 21CFR50.52] is permissible only if:

The risk is justified by the anticipated benefit to the subjects;

The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that

presented by available alternative approaches; and requires

Assent of child is sought; and

Permission of one parent or guardian is sought

Research involving greater than minimal risk and no prospect of direct benefit to individual

subjects, or by a monitoring procedure which is not likely to contribute to the well- being of the

subject, but likely to yield generalizable knowledge about the subject's disorder or condition

[45CFR46.406 and 21CFR50.53] is permissible only if:

The risk represents a minor increase over minimal risk;

The intervention or procedure presents experiences to subjects that are reasonably

commensurate with those inherent in their actual or expected medical, dental, psychological,

social, or educational situations;

The intervention or procedure is likely to yield generalizable knowledge about the subject's

disorder or condition which is of vital importance for the understanding or amelioration of the

subjects' disorder or condition; and requires

Assent of child is sought; and

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Permission of both parents or guardians is sought - unless one parent is deceased, unknown,

incompetent, or not reasonably available; or only one parent has legal responsibility for the

care and custody of the child. For a parent to not be reasonably available, they must be out of

the country for an extended period of time or a situation similar to this.

You must contact the IRB Director and IRB Chair for prior approval if permission of both parents

cannot be obtained as directed by the IRB.

Research not otherwise approvable which presents an opportunity to understand, prevent, or

alleviate a serious problem affecting the health or welfare of children

This research requires the approval of the Secretary of the Department of Health and Human Services

or The Commissioner of Food and Drugs as applicable to the research. Once an IRB determines that a

protocol does not meet the requirements of 46.404, 46.405, or 46.406 for approval of research, but

does meet the requirements for review under 45CFR46.407(a) the institution or the Institutional

Review Board may request that the Office for Human Research Protections (OHRP), on behalf of the

Secretary, HHS, conduct a 46.407 review.

This research can be conducted if the following requirements are met:

(a) the IRB finds that the research presents a reasonable opportunity to further the understanding,

prevention, or alleviation of a serious problem affecting the health or welfare of children; and

(b) the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science,

medicine, education, ethics, law) and following opportunity for public review and comment, has

determined either:

a. that the research in fact satisfies the conditions of 45CFR45.404; 405 and 406 , as

applicable, or (2) the following:

i. the research presents a reasonable opportunity to further the understanding,

prevention, or alleviation of a serious problem affecting the health or welfare

of children;

ii. the research will be conducted in accordance with sound ethical principles;

iii. adequate provisions are made for soliciting the assent of children and the

permission of their parents or guardians, as set forth in 45CFR46.408

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Requirements for permission by parents or guardians and for assent by

children Adequate provisions must be made for obtaining the permission of parents or guardians and for soliciting

the assent of children, when in the judgment of the IRB, the children are capable of providing assent. In

determining whether children are capable of assenting, the IRB will take into account the ages, maturity,

and psychological state of the children involved. This judgment may be made for all children to be

involved in research under a particular protocol, or for each child, as the IRB deems appropriate. The

determinations that assent is not appropriate for some or all children involved in a study, and thus not

required, will be documented in the meeting minutes. The IRB will document, in the minutes and the

approval letter, for which children the waiver of assent is applicable. The IRB expects assent to be

collected on all research subjects 7 years of age and older unless waived by the IRB.

When a child who was enrolled in research with parental or guardian permission subsequently reaches the

legal age of consent to the procedures involved in ongoing research, the subject’s participation in the

research is no longer regulated by the requirements of 45CFR46.408 regarding parental or guardian

permission and subject assent. Unless the Institutional Review Board (IRB) determines that the

requirements for obtaining informed consent can be waived, the investigators should seek and obtain the

legally effective informed consent, as described in the regulations from the now-adult subject for any

ongoing interactions or interventions with the subjects.

When parental or guardian permission is obtained, it must be documented in accordance with and to the

extent described in the requirements for informed consent. When a child's assent is required, the IRB will

determine whether and how the assent must be documented.

IRB Waiver of Assent and Parental Permission If the IRB determines that the capability of some or all of the children is so limited that they

cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a

prospect of direct benefit that is important to the health or well-being of the children and is available only

in the context of the research, the assent of the children is not a necessary condition for proceeding with

the research.

Even when the IRB determines that the subjects are capable of assenting, the IRB may still waive the

assent requirement under circumstances detailed in the policy on informed consent.

If the IRB determines that a research protocol is designed for conditions or for a subject population for

which parental or guardian permission is not a reasonable requirement to protect the subjects (e.g.,

neglected or abused children), it may waive the consent requirements for parents or guardians, provided

an appropriate mechanism for protecting the children who will participate as subjects in the research is

substituted, and provided further that the waiver is not inconsistent with Federal, State, or local law. The

choice of an appropriate mechanism would depend upon the nature and purpose of the research activities

described in the protocol,

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the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition.

The IRB may waive the requirements for obtaining parental or guardian permission if it makes and

documents the findings under either 45CFR46.116(c) or (d). In addition to the provisions for waiver

contained in 46.116(c) and (d), if the IRB determines that a research protocol is designed to study

conditions in children or a subject population for which parental or guardian permission is not a

reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive

the parental permission requirements provided that an appropriate mechanism is in place to protect the

children, and provided that the waiver is not inconsistent with federal, state, or local law. The choice of an

appropriate substitute mechanism (for example, appointing a child advocate or an assent monitor) for

protecting children participating in research would depend on the nature and purpose of the activities

described in the protocol, the risk and anticipated benefit to the research subjects, and the child’s age,

maturity, status, and condition.

Wards of the State Children who are wards of the state may be included in research that presents minimal risk or studies that

involve greater than minimal risk with no prospect of direct benefit (as outlined in the regulations above)

only if the IRB determines and documents that such research is

Related to their status as wards; or

Conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of

children involved as participants are not wards.

If children who are wards of the state are to be included in research with no prospect of direct benefit, the

IRB shall appoint an advocate for each child who is a ward. It is the responsibility of the principal

investigator to locate someone who can serve as an advocate and who possesses the expertise to be an

advocate; however, the determination of the role of the advocate is determined through an appointment

by the IRB.

Advocates

The advocate must be an individual who has the background and experience to act in, and agrees to act in,

the best interests of the child throughout the duration of the child’s participation in the research. This

includes ensuring that to the extent possible, the child understands what will be required of him or her

during the research, and that if capable, the child provides his or her assent to participate. Acting in the

best interests of the child could include evaluating the ongoing impact of the research study on the child.

The advocate should represent the individual child subject’s interests throughout the child’s participation

in the research. This added protection is intended to ensure that the ward, who is particularly vulnerable,

is not exploited, coerced, or subjected to undue influence or harm in the course of the research. HHS

regulations further require that the advocate not be associated in any way

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(except in the role of advocate or member of the Institutional Review Board (IRB)) with the research,

the investigator(s), or the guardian organization.

The role of the advocate would include the following:

The advocate will serve in addition to any other individual acting on behalf of the child as a

guardian or in loco parentis;

One individual may serve as advocate for more than one child;

The advocate must sign a separate contract with the IRB acknowledging their role as advocate

for the Ward in the specified research project.

If children who are wards are to be included in any research study, the investigator must provide the

IRB with detailed information about the proposed permission/assent process, as well as the identity

and authority of individuals who will provide permission for the Ward subjects. The following

information must be submitted to the IRB with the original application or via an amendment if the

investigator later determines he/she wishes to enroll a ward of the state.

As part of the protocol application process, investigators will be asked if at the time of submission of

the application there is a likely possibility that a protocol could involve children who are Wards of the

State as potential research subjects, and if so, does the investigator plan to recruit Wards. If the

investigator indicates a possibility that a protocol could involve Wards and the investigator wishes to

offer the protocol to Wards, the IRB will make the required regulatory findings.

If there is a possibility that Wards may be included in the research and the risk/benefit classification is

minimal risk or greater than minimal risk with a prospect of direct benefit, the IRB reserves the right to

require reporting to the IRB of the enrollment of such wards and the appointment of an advocate as

necessary. However, enrollment of wards in research that is minimal risk or greater than minimal risk

with a prospect of direct benefit would not require the appointment of an advocate.

If there is a possibility that Wards may be included in the research and the risk/benefit classification is

greater than minimal risk with no prospect of direct benefit the special regulatory provisions for

Wards will be followed. This includes documenting the required findings and the appointment of an

advocate outlined above.

If the investigator does not initially anticipate the inclusion of Wards in the protocol, but

circumstances change or a situation arises where the investigator wishes to include a Ward, a protocol

amendment must be submitted to the IRB so that any required regulatory requirements may be

fulfilled.

Legally Authorized Representatives

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Principal Investigators are responsible for determining any changes in a legally authorized

representative (LAR) for children participating in research. The investigator will inform the IRB which

methods will be used for determining changes in the status of the LAR. This could include but is not

limited to the following:

A. periodically asking the accompanying adult if there has been a change in guardianship;

B. including within the informed consent that the guardian should inform the investigator if here has

been a change in status;

C. other methods that are reasonably designed to ensure prompt notice of such changes, sufficient to

protect the rights of children as human subjects under the circumstances presented in the study.

A change in the LAR status requires obtaining permission from the newly appointed LAR in order for

the child to continue participation in the research.

Investigators are asked at the time of continuing renewal if the study has enrolled vulnerable

populations in the past year which includes and is not limited to children and Wards of the State. If an

investigator answers yes and describes enrollment of Wards of the State, and if this information was

not indicated in the initial application, the IRB will reassess the regulatory determinations for the

research and document findings. The investigator will be subject to the requirements above.

Please note that parents of children in Department of Social Services (DSS) care or custody may, and

most often do, retain the right to consent for their child to participate in medical or psychological

procedures and research. However, depending on the circumstances, DSS and even court consent may

also be required. If the parent(s) has sole legal custody, only parental permission via consent is

necessary for the child to participate in a research study. If DSS has sole or joint legal custody and the

parent(s) consent for their child to participate in a research study, DSS is likely to consent as well

absent special circumstances. DSS may withhold consent in situations where the parent cannot be

located, where a petition to terminate parental rights has been granted, when a child has been

surrendered for adoption, or for reasons specific to a family’s or child’s circumstances and needs. If

DSS withholds consent based solely on the absence of the family, they may seek judicial approval for

the child’s participation; it is unlikely DSS will permit participation based solely on its administrative

consent where a parent who has the right to consent (provide permission) cannot be located.

For situations in which a child enrolled in the research study is placed in the care of DSS, the

investigator is required to notify DSS of the research so they are aware of the participation and any

questions can be addressed. In addition, if a child begins a study under DSS custody without

permission from the parent and the child is later reunited with the parent, parental permission must

be obtained from the parent in order for the child to continue his/her participation in the study.

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Investigators and their staff are encouraged to contact the IRB office should you have any questions or

concerns regarding the enrollment of Wards in research protocols.

All IRB determinations including the need for an advocate will be documented in the minutes of the IRB

meetings.

References:

45 CFR 46 subpart D

21 CFR 50, subpart D

45 CFR 46.107

45 CFR 46.101(b)

45 CFR 46.110-111

45 CFR 46.116

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36.0 Research Involving Pregnant Women, Human Fetuses and Neonates

Regulatory Background In addition to the general requirements for review of research by the IRB, prior research with

animal subjects, and, if feasible, research with non-pregnant persons should form the basis of the

risk/benefit assessment for fetal research. The proposed research should seek information not obtainable

in any other way. If abortion is involved, the investigators may have no part in either the decision to abort

or decisions about the timing or the method to be used; no change in the abortion procedure that would

present more than minimal risk to the fetus or its mother can be introduced for research purposes. No

monetary or other inducements (e.g., free care) may be offered to a woman to induce her to terminate

her pregnancy for research purposes.

Pregnant women may be involved in several categories of research. IRB duties differ in each category, but

the primary objectives are assessing: (1) whether the research holds out the prospect of direct benefit for

the mother's health or for the fetus; and (2) the risks to the woman and to the fetus or infant. These

requirements do not apply when the enrollment of pregnant women is entirely coincidental and bears no

relationship to the research (e.g., a minimal risk survey of 1000 respondents and 1 happens to be

pregnant).

Conditions required for pregnant women or fetuses to be involved in research Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical

studies, including studies on non-pregnant women, have been conducted and provide data for assessing

potential risks to pregnant women and fetuses; (45 CFR 46.204(a))

The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct

benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not

greater than minimal and the purpose of the research is the development of important biomedical

knowledge that cannot be obtained by any other means; (45 CFR 46.204(b))

Any risk is the least possible for achieving the objectives of the research; (45 CFR 46.204(c))

If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct

benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus

when risk to the fetus is not greater than minimal and the purpose of the research is the development of

important biomedical knowledge that cannot be obtained by any other means, her consent is obtained in

accord with the informed consent provisions in 45 CFR 46.204(d).

If the research holds out the prospect of direct benefit solely to the fetus, then the consent of the

pregnant woman and the father is obtained in accordance with the informed consent provisions. The

father's consent need not be obtained if he is unable to consent because of unavailability, incompetence,

or temporary incapacity or the pregnancy resulted from rape or incest; (45 CFR 46.204(e))

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Each individual providing consent under SOP 33.1.4 or 33.1.5 is fully informed regarding the reasonably

foreseeable impact of the research on the fetus or neonate; (45 CFR 46.204(f))

For children as defined in 45 CFR 46.402(a) who are pregnant, assent and permission are obtained in

accord with the provisions of SOP 35.0, Research Involving Children (45 CFR 46.204(g))

No inducements, monetary or otherwise, will be offered to terminate a pregnancy; (45 CFR 46.204(h))

Individuals engaged in the research will have no part in any decisions as to the timing, method, or

procedures used to terminate a pregnancy; (45 CFR 46.204(i))

Individuals engaged in the research will have no part in determining the viability of a neonate. (45 CFR

46.204(j))

Conditions required for neonates of uncertain viability and nonviable neonates

to be involved in research

Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for

assessing potential risks to neonates; (45 CFR 46.205(a)(1))

Each consenting individual under SOP 33.3 and 33.4 is fully informed regarding the reasonably foreseeable

impact of the research on the neonate. (45 CFR 46.205(a)(2))

Individuals engaged in the research will have no part in determining the viability of a neonate. (45 CFR

46.205(a)(3))

The requirements of SOP 16 have been met as applicable. (45 CFR 46.205(a)(4))

Neonates of uncertain viability Until it has been ascertained whether a neonate is viable, a neonate may not be involved in research

covered by this subpart unless the following additional conditions are met:

The IRB determines that:

The research holds out the prospect of enhancing the probability of survival of the neonate to the

point of viability, and any risk is the least possible for achieving that objective, or (45 CFR

46.205(b)(1)(i))

The purpose of the research is the development of important biomedical knowledge that cannot

be obtained by other means and there will be no added risk to the neonate resulting from the

research; and (45 CFR 46.205(b)(1)(ii))

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The legally effective informed consent of either parent of the neonate or, if neither parent is able to

consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed

consent of either parent's legally authorized representative is obtained in accord with the Informed

Consent policy, except that the consent of the father or his legally authorized representative need not be

obtained if the pregnancy resulted from rape or incest. (45 CFR 46.205(b)(2))

Nonviable neonates After delivery a nonviable neonate may not be involved in research covered by this subpart unless all of

the following additional conditions are met:

Vital functions of the neonate will not be artificially maintained; (45 CFR 46.205(c)(1))

The research will not terminate the heartbeat or respiration of the neonate; (45 CFR 46.205(c)(2))

There will be no added risk to the neonate resulting from the research; (45 CFR 46.205(c)(3))

The purpose of the research is the development of important biomedical knowledge that cannot be

obtained by other means; and (45 CFR 46.205(c)(4))

The legally effective informed consent of both parents of the neonate is obtained in accord with SOP 16.0,

Informed Consent, except that the waiver and alteration provisions of 45 CFR 46.116(c) and (d) do not

apply. However, if either parent is unable to consent because of unavailability, incompetence, or

temporary incapacity, the informed consent of one parent of a nonviable neonate will suffice to meet the

requirements of this paragraph, except that the consent of the father need not be obtained if the

pregnancy resulted from rape or incest. The consent of a legally authorized representative of either or

both of the parents of a nonviable neonate will not suffice to meet the requirements of this paragraph.

(45 CFR 46.205(c)(5))

Viable Neonates A neonate, after delivery, that has been determined to be viable may be included in research only to the

extent permitted by and in accord with the requirements of subparts A and D of 45 CFR 46.

References:

45 CFR 46 subpart B

21 CFR 50 subpart B

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37.0 Research Involving Prisoners

Definition of research addressed in this section A prisoner is any individual involuntarily confined or detained in a penal institution. The term is intended

to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals

detained in other facilities by virtue of statutes or commitment procedures that provide alternatives to

criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment,

trial, or sentencing, or under house arrest. [45 CFR 46.303(c)]

The regulations covering research involving prisoners apply not only to research that targets prisoners or

the prison setting, but also to subjects who become incarcerated following their enrollment or subjects for

whom their incarceration is coincidental with their research involvement, (e.g., a prisoner with cancer

enrolled in a treatment-oriented study that involves no other prisoners).

Special considerations for prisoner research When a proposal proposes to enroll prisoners as a study population, the IRB should ascertain whether that

population was chosen simply out of convenience to the investigator. Because the population is relatively

stable and the life is routine, prisons have in the past seemed ideal environments in many ways for the

conduct of certain types of research. Some procedures that would inconvenience free subjects are not a

burden to prisoners. Since prison pay scales are notably lower than those in the free world, the cost of

using prisoners as subjects may be less than using those who are not prisoners. And, unlike the general

civilian population, they are all in one place. However, the nature of incarceration may conflict with the

ethical principle of autonomy.

The primary issue surrounding the participation of prisoners in research is whether prisoners have a real

choice regarding their participation in research, or whether their situation prohibits the exercise of free

choice. A secondary issue is whether confidentiality of participation and of data can be adequately

maintained in the prison. These issues must be evaluated by both the IRB as well as the North Carolina

Department of Correction (DOC), for studies that involve its prisoner population. The PI is responsible for

communicating with the DOC prior to submission of an IRB application.

The circumstances common in prisons create environments in which the offer to participate in research

may give rise to undue influence in favor of participation. The lack of control allowed prisoners and their

desire to obtain the advantages offered to those who agree to participate may impair their ability to weigh

fairly the risks and benefits involved in participation. An example of a situation potentially presenting

undue influence may be one in which research participants are moved to special units where they are

given additional medical care and where the living conditions may be better than those provided to the

general prison population. Other rewards for participation, such as offering parole or a reduction in

sentence, would likewise constitute an undue inducement. Even the opportunity to leave the prison cell

and interact with people from outside the prison may act as an undue inducement to participate in

research.

Another question is whether prisoner-subjects can ethically be paid for participation, and if so, how much?

Where prisoners must earn money to purchase the means by which to maintain their health and personal

hygiene, and one way to earn that money is by participating in research, the potential for undue influence

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also exists. In non-prison settings, paying subjects to participate in research is considered ethically

acceptable, so long as it is equivalent to the time, effort or inconvenience involved. Paying prisoners the

same amount that would be paid to non- prisoners may, however, be seen as unduly influential in a

setting where inmates can earn only a small fraction of that amount for any other "work" activity. On the

other hand, paying prisoners a fraction of what would be paid to non-prisoners can be seen as exploitive.

In addition to problems of undue inducement, the involvement of prisoners in research raises questions of

burden and benefit. Prisoners should neither bear an unfair share of the burdens of participating in

research, nor should they be excluded from its benefits, to the extent that voluntary participation is

possible.

Minimal risk, as defined for studies involving prisoners, is the probability and magnitude of physical or

psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or

psychological examination of healthy persons. In assessing risk to prisoners, the IRB should ensure that the

risks involved in the research are equivalent to risks that would be accepted by non-prisoner volunteers.

[45 CFR 46.303 (d)]

Confidentiality is extremely difficult to maintain in a prison environment. In prisons, people do not move

about freely; the movements of prisoners are carefully tracked. When inmates are moved around (e.g., to

go to a research appointment), everyone will know about it. Prison records, including health care records,

are accessible to persons who in other settings would not have access to such personal information, thus

compromising the security of confidential information.

Generally, research involving prisoners does not qualify for expedited review; however, in the event that

such a research study does qualify for expedited review, a prisoner representative should be one of the

designated reviewers. The exemptions under 45 CFR 46.101 do not apply to research involving prisoners.

Responsibilities of the IRB If the IRB is to review a study involving the enrollment and participation of prisoners, then it must invoke

the prisoner roster to the appropriate board for review. A prisoner representative must be present for the

discussion and vote of all studies involving prisoners. The prisoner representative will serve in an alternate

capacity if no protocols on the agenda involve prisoners, and will not be counted toward quorum unless

needed to review a prisoner application.

For research reviewed by the convened IRB (greater than minimal risk) involving prisoners:

The prisoner representative must be a voting member of the IRB.

The prisoner representative must review research involving prisoners.

The prisoner representative must receive all materials pertaining to the research (same as primary

reviewers

The prisoner representative must be present at a convened meeting when the research involving

prisoners is reviewed. If the prisoner representative is not present, research involving prisoners

cannot be reviewed or approve

The prisoner representative must present his or her review either orally or in writing at the

convened meeting of the IRB when the research involving prisoners is reviewed.

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Minor modifications may be reviewed using the expedited procedures as described below based

on the type of modification

Substantial modifications reviewed by the convened IRBs must use the same procedures for initial

review including the responsibility of the prisoner representative.

Continuing reviews must use the same procedures for initial review including the responsibility of

the prisoner representative.

For research reviewed by expedited procedures (no greater than minimal risk) involving interaction with

prisoners (including obtaining consent from prisoners):

Research involving prisoners involving interaction with prisoners (including obtaining consent

from prisoners) may be reviewed by the expedited procedure, if a determination is made that the

research is minimal risk for the prison population being studied or included.

The prisoner representative must concur with the determination of minimal risk.

The prisoner representative must review the research as a reviewer or consultant. This may be as

the sole reviewer of in addition to another reviewer, or in place of another reviewer as

appropriate.

Review of modification and continuing review must use the same procedures for initial review

using this expedited process including the responsibility of the prisoner representative.

For research reviewed by the expedited procedure that does not involve interaction with prisoners (e.g.

existing data or record review):

Research involving prisoners that does not involve interaction with prisoners may be reviewed by

the expedited procedure, if a determination is made tha the research is minimal risk for the prison

population being studied or included.

The prisoner representative may review the research as a reviewer or consultant if designated by

the IRB chairs, but review by the prisoner representative is not required.

Review of modification and continuing review must use the same procedures for initial review

using this expedited process including the responsibility of the prisoner representative.

For Department of Defense-regulated research involving prisoners, research involving prisoners of war is

prohibited. The IRB must also be aware of the definition of “prisoner of war” for the Department of

Defense component granting the addendum.

When following ICH-GCP guidance, adults are unable to consent; the IRB must determine the following:

A non-therapeutic clinical trial (i.e. a trial in which there is no anticipated direct clinical benefit to

the subject) should be conducted in subjects who personally give consent and who sign and date

the written consent document.

Non-therapeutic clinical trials may be conducted in subjects with consent of a legally acceptable

representative provided the following conditions are fulfilled:

The objectives of the clinical trial cannot be met by means of a trial in subjects who can give

consent personally.

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The foreseeable risks to the subjects are low.

The negative impact on the subject’s well-being is minimized and low.

The clinical trials are not prohibited by law.

The opinion of the IRB is expressly sought on the inclusion of such subjects, and the written

opinion covers this aspect.

Such trials, unless an exception is justified, should be conducted in patients having a disease or

condition for which the investigational product is intended. Subjects in these trials should be

particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

When an IRB is reviewing a protocol in which a prisoner is a subject, the IRB must make, in addition to

other requirements under 45 CFR 46, subpart A, seven additional findings under 45 CFR 46.305(a), as

follows:

the research under review represents one of the categories of research permissible under 45 CFR

46.306(a)(2);

any possible advantages accruing to the prisoner through his or her participation in the research, when

compared to the general living conditions, medical care, quality of food, amenities and opportunity for

earnings in the prison, are not of such a magnitude that his or her ability to weigh the risks of the research

against the value of such advantages in the limited choice environment of the prison is impaired;

the risks involved in the research are equivalent to risks that would be accepted by non- prisoner

volunteers;

procedures for the selection of subjects within the prison are fair to all prisoners and immune from

arbitrary intervention by prison authorities or prisoners. Unless the principal investigator provides to the

IRB justification in writing for following some other procedures, control subjects must be selected

randomly from the group of available prisoners who meet the characteristics needed for that particular

research project;

the information is presented in language that is understandable to the subject population;

adequate assurance exists that parole boards will not take into account a prisoner’s participation in the

research in making decisions regarding parole, and each prisoner is clearly informed in advance that

participation in the research will have no effect on his or her parole; and

where the IRB finds there may be a need for follow-up examination or care of participants after the end of

their participation, adequate provision has been made for such examination or care, taking into account

the varying lengths of individual prisoners’ sentences, and for informing participants of this fact.

For research conducted or supported by HHS to involve prisoners, two actions must occur:

(1) The institution engaged in the research must certify to the Secretary (through OHRP) that the IRB

designated under its assurance of compliance has reviewed and approved the research under 45 CFR

46.305, and (2) The Secretary (through OHRP) must determine that the proposed research falls within the

categories of research permissible under 45 CFR 46.306(a)(2). The categories of permissible research are

the following:

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study of the possible causes, effects, and processes of incarceration, and of criminal behavior,

provided that the study presents no more than minimal risk and no more than inconvenience to

the subjects; (Note that the definition of minimal risk for prisoner research at 45 CFR 46.303(d)

differs from the definition of minimal risk for other research, contained in 45 CFR 46, subpart A, 45

CFR 46.102(i))

study of prisons as institutional structures or of prisoners as incarcerated persons, provided that

the study presents no more than minimal risk and no more than inconvenience to the subjects;

search on conditions particularly affecting prisoners as a class (for example, vaccine trials and

other research on hepatitis which is much more prevalent in prisons than elsewhere; and research

on social and psychological problems such as alcoholism, drug addiction, and sexual assaults)

provided that the study may proceed only after the Secretary (through OHRP) has consulted with

appropriate experts including experts in penology, medicine, and ethics, and published notice, in

the Federal Register, of the Secretary’s intent to approve such research; or

research on practices, both innovative and accepted, that have the intent and reasonable

probability of improving the health or well-being of the subject. In cases in which those studies

require the assignment of prisoners in a manner consistent with protocols approved by the IRB to

control groups that may not benefit from the research, the study may proceed only after the

Secretary (through OHRP) has consulted with appropriate experts including experts in penology,

medicine, and ethics, and published notice, in the Federal Register, of the Secretary’s intent to

approve such research.

an additional fifth category of permissible research is provided by HHS Secretarial waiver for

certain epidemiological research conducted or supported by HHS. The criteria for this category are

that the research must have as its sole purpose (i) to describe the prevalence or incidence of a

disease by identifying all cases, or (ii) to study potential risk factor associations for a disease. The

institution still must review the research under subpart C and certify to OHRP that an

appropriately constituted IRB has reviewed the proposal and made all other required findings

under HHS regulations at 45 CFR 46.305(a) and receive OHRP authorization prior to initiating any

research involving prisoners. All of the other requirements of subpart C apply to research in this

category.

Meeting minutes and the IRB approval letter should indicate which of the four categories of permissible

research involving prisoners in 45 CFR 46.306(a)(2) is applicable to the research (i, ii, iii or iv), for

example:.

The IRB determined that the study meets criteria at 46.306(a)(2)(iv) ―research on practices, both

innovative and accepted, which have the intent and reasonable probability of improving the health or

well-being of the subject.

Additional Consent requirements Prospective Approval: When submitting an IRB Application for involving prisoner subjects (or those likely

to be detained) for prospective IRB review and approval, the PI must describe the prisoner-subject

population planned for, including (i) the types of ‘involuntary confinement, detainment, or incarceration’,

(ii) the names/types of ‘penal institutions or alternative facilities’ with which he or she has established a

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relationship, and (iii) if enrollment is planned through the facility versus the relationship with the facility

established in anticipation of an enrolled subject becoming a prisoner (in the case of the later, it should be

clear that prior experience with research subjects necessitates the inclusion of prisoner-subjects). Please

see the consent template for specific language to be included.

Amended Approval: When a specific research subject becomes incarcerated and the IRB has not

previously approved the research to involve prisoners, all research interactions and interventions with,

and obtaining identifiable private information about, the now-incarcerated prisoner-subject must cease

immediately until the requirements of subpart C have been satisfied (unless it is determined to be in the

best interest of the subject to continue). The Principal Investigator MUST IMMEDIATELY notify the IRB of

this event. The principal investigator is also responsible for amending the consent form and re-consenting

the subject if they wish to continue participation in the study, prior to continuing study interventions or

interactions. Please see the consent template for specific language to be included.

Certification of prisoner research Institutions that conduct DHHS-supported research involving prisoners as human subjects must take

several steps to certify that the research is permissible according to federal regulations. The institution

must certify to OHRP that the IRB has made the seven findings required under 45 CFR 46 305(a), including

the finding that the proposed research represents one of the permissible categories of research under 45

CFR 46 306(a)(2). The institution must send OHRP a certification letter to that effect which should include

the name and address of the institution and specific identification of the research protocol including the

relevant grant number. OHRP also encourages the institution to include the following information in its

prisoner research certification letter:

Title of the Protocol and PI name

Purpose of the study

OHRP Assurance number for Engaged Site

IRB Registration number

Title of DHHS Grant

PI named on DHHS grant

DHHS Grant Award Number

DHHS Funding Agency Name

Funding Agency Grants/Program Officer Name/Phone

Site(s) Where Research Will be Conducted

IRB for Site Where Research Will be Conducted

OHRP Assurance # for Non-Wake Forest Site

Version of Consent Form

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Date of IRB Meeting where IRB approved findings for research to be certified to OHRP, including a

brief chronology that encompasses the date of initial IRB review and date of Subpart C review.

Reason for IRB Review (Choose most applicable from the following; edit as necessary)

o Amendment to non-prison study in which subject(s) has become incarcerated and PI

wishes to continue the subjects(s) participation in the study.

o b Non-prison study with at-risk population (e.g., probationers, substance abusers).

o Non prison study, majority of study population are non-prisoners but PI seeks to enrolls

some prisoners (as defined in 45 CFR 46.303(c))

o Minimal risk DHHS conducted or supported epidemiologic research, majority of study

population are non-prisoners but PI seeks to enroll some prisoners (prisoners are not the

focus of the study) and the sole purpose of the study is either: (1) to describe the

prevalence or incidence of a disease by identifying all cases, or (2) to study potential risk

factor associations for a disease

o Initial Subpart C review of study designed to be conducted in a prison or using prisoners

(as defined in 45 CFR 46.303 (c)) – PI seeks to enroll already incarcerated subjects.

Under its authority at 45 CFR 46.115(b), OHRP requires the institution to also submit to OHRP a copy of

the research proposal so OHRP can determine whether the proposed research involves one of the

categories of research permissible under 45 CFR 46. 306(a)(2) and, if so, which one. Copies of the following

materials should be enclosed for OHRP review when relevant:

IRB application

Consent form(s)

Master Protocol

Copy of grant application

Approval letter from the IRB

Approval from any other IRBs, if relevant to the project’s oversight where prisoners will be studied

FWA information, where applicable for external sites

Minutes from the relevant IRB meeting(s)

References:

45 CFR 46 Subpart C

45 CFR 46.115(b)

45 CFR 46.101

21 CFR 56.111(b)

DoDD 3216.2 para. 4.4.1

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DoDD 3216.2 para. 4.4.2 SECNAVINST 3900.39D, para. 6a(8) SECNAVINST 3900.39D, para. 6a(6)

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38.0 Genome Wide Association Studies

Purpose This policy outlines how investigators at the Wake Forest will submit data and materials as well as retrieve

information from the Genome-Wide Association Studies (GWAS) repository database which is maintained

by the National Institutes for Health (NIH).

GWAS is the study of genetic variation across the entire genome that is designed to associate genetic

variations (SNPs) with traits or with the presence or absence of disease or condition. Whole genome

information, when combined with clinical and other phenotype data, offers the potential for increased

understanding of basic biological processes affecting human health, improvement in the prediction of

disease and patient care, and ultimately the realization of the promise of personalized medicine.

Competing GWAS applications must include a GWAS data sharing plan as part of the research plan (grant

application) or outline why such data sharing is not appropriate.

Definitions Coded means that any identifying information (such as name or social security number) that would enable

the investigator to readily ascertain the identity of the individual to whom the private information or

specimens pertain has been replaced with a number, letter, symbol, or combination thereof (i.e., the

code); and a key to decipher the code exists, enabling linkage of the identifying information to the private

information or specimens.

De-identified, for purposes of this document, means that the identities of data subjects cannot be readily

ascertained or otherwise associated with the data by the repository staff or secondary data users (45 CFR

46.102(f)), the 18 identifiers enumerated at section 164.514(b)(2) of the HIPAA Privacy Rule are removed

and the submitting institution has no actual knowledge that the remaining information could be used

alone or in combination with other information to identify the subject of the data.

Regulatory Background According to the GWAS policy, local institutions are responsible for certifying that plans for the submission

of genotypic and phenotypic data to GWAS meet the expectations of the GWAS policy.

Responsibilities of the IRB The IRB is responsible for reviewing the investigator’s plans for data submission, as well as the adequacy

of the informed consent process and documents through which the data were obtained. Because the

genotype and phenotype information generated about individuals will be substantial and, in some

instances, sensitive (such as data related to the presence or risk of developing particular diseases or

conditions and information regarding family relationships or ancestry), the confidentiality of the data and

the privacy of participants must be protected. The IRB encourages investigators submitting data to the

GWAS repository to obtain a Certificate of Confidentiality from the NIH. Certificates of Confidentiality may

provide an additional safeguard with regard to compelled disclosure in any civil, criminal, administrative,

legislative, or other proceeding, whether at the federal, state, or local level, of information that could be

used to identify individual research participants.

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For studies submitting data and materials to the GWAS repository, the IRB must certify that each of the

following are met:

The data submission is consistent with all applicable laws and regulations as well as institutional

policies;

The appropriate research uses of the data and the uses that are specifically excluded by the

informed consent documents are delineated;

o The identities of research participants will not be disclosed to the NIH GWAS data

repository; and

o An IRB and/or Privacy Board, as applicable, reviewed and verified that:

o The submission of data to the NIH GWAS data repository and subsequent sharing for

research purposes are consistent with the informed consent of study participants from

whom the data were obtained;

o The investigator’s plan for de-identifying datasets is consistent with the standards

outlined in the policy;

o It has considered the risks to individuals, their families, and groups or populations

associated with data submitted to the NIH GWAS data repository; and

o The genotype and phenotype data to be submitted were collected in a manner consistent

with 45 CFR Part 46.

Responsibilities of the Investigator The data submitted for inclusion in the NIH GWAS data repository will be coded and de-identified by the

submitting investigator; however, the investigator may retain the key to the code that would link to

specific individuals. The National Center for Biotechnology Information (NCBI) which houses the GWAS

repository will never receive the code or any other information that would enable the identification of the

individuals who are the source of the data.

In order to minimize risks to study participants, data submitted to the NIH GWAS data repository will be

de-identified and coded using a random, unique code. Data should be de-identified according to the

following criteria:

1. The identities of data subjects cannot be readily ascertained or otherwise associated with the data by the

repository staff or secondary data users

2. The 18 identifiers enumerated at section 45 C.F.R. 164.514(b)(2) (the HIPAA Privacy Rule) are removed;

3. The submitting institution has no actual knowledge that the remaining information could be used alone or

in combination with other information to identify the subject of the data.

Submission of Data Collected Prospectively

To submit data and materials to the GWAS for prospective studies (studies in which informed consent will

be obtained prospectively), investigators must provide the following information to the IRB for

consideration:

A data sharing plan which should include:

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Documentation that data submission is consistent with applicable laws and institutional policy

The appropriate research uses of the data and any specific research exclusions as outlined in

the informed consent document

Confirmation that the materials and data submitted to the GWAS data repository are de-

identified per the HIPAA Privacy Rule regulations and at no time will the link to the identifying

information, nor the actual identifying information, be disclosed to the GWAS data repository.

The informed consent document should include information regarding the data sharing. The

informed consent must be clear that DNA will undergo genome-wide analysis and that genotype

and phenotype will be shared for research purposes with investigators who submit proposals to

the GWAS data repository. (The Informed Consent template contains suggested language for use

in informed consent documents).

Submission of Data Collected Previously

To submit data and materials to the GWAS data repository for retrospective studies (studies in which

informed consent was collected previously as part of a research study), investigators must provide the

following information to the IRB for consideration:

A data sharing plan which should include:

o Documentation that data submission is consistent with applicable laws and institutional

policy

o The appropriate research uses of the data and any specific research exclusions as outlined

in the informed consent document

o Confirmation that the materials and data submitted to the GWAS data repository are de-

identified per the HIPAA Privacy Rule regulations and at no time will the link to the

identifying information, nor the actual identifying information, be disclosed to the GWAS

data repository.

The IRB must review the informed consent documents which were signed by participants to

confirm whether or not the initial consent under which genetic materials were obtained is

consistent with the submission of data to the GWAS data repository and the sharing as outlined in

the GWAS policy.

o The IRB may determine that the original consent is not consistent with submission of data

to the GWAS data repository and may request re-consent of subjects.

o The IRB may determine that the original consent is not consistent with submission of data

to the GWAS data repository and determine that it cannot verify that the criteria outlined

in the GWAS policy have been met for submission of data to the GWAS data repository

and therefore, such submission is not appropriate.

o The IRB cannot waive the requirement for informed consent for the submission of data

and materials to the GWAS data repository.

Investigators Prospective use of Data from the GWAS Repository

Investigators choosing to request data from the GWAS data repository must submit an application to the

IRB for determination that the research meets the qualifications for Not Human Subjects Research (NHSR).

For additional information, please see the IRB policy for Exempt and NHSR.

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Withdrawal of Individual Consent The NIH GWAS data repository has developed policies with regard to removal of individual data records if

consent is withdrawn. Submitting investigators and their institutions may request removal of data on

individual participants from the data repository in the event that a research participant withdraws

consent. However, data that have already been distributed for approved research use will not be able to

be retrieved.

References:

45 CFR 46.102(f)

45 CFR 164.514(b)(2)

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39.0 Charges for IRB Review The Institutional Review Board (IRB) charges for the review of industry supported research protocols. The

fee structure is as follows:

Fees for review will be billed to the sponsor for:

Protocols that are supported by industry (i.e., Industry supplying drug, device, and/or funds).

Please note that funded studies in which the sub-contract is with an organization that receives funding

from industry for support of the research, will be considered by the IRB to be supported by industry

and IRB review charges will apply.

** No distinction is made between Investigator Initiated studies and Sponsor Initiated studies. IRB fees

should be included in the initial budget at the time of submission.

Fee Structure $2500 for initial IRB review by the Full Board

$1200 for initial IRB review under expedited procedures

$750 for continuing review

$350 for substantive amendments (those amendments which require Full Board review)

$1000 for facilitated review

Studies exempt from the regulations and those determined not to be human subject research are

excluded from the fee requirements. There are also no current fees for amendments reviewed under

expedited procedures, study-associated promotional material, or for the review of adverse event reports.

Invoicing Procedures The Clinical Trials Office will invoice for IRB fees on a monthly basis. Three invoice notices will be issued

to the sponsor to request payment (one following execution of the contract, then two more at 30 day

intervals if necessary).

IRB charges are non-refundable. Sponsors are requested to pay review fees directly to the Clinical Trials

Office. However, if a sponsor includes IRB fees in a payment that includes payment for other expenses,

the IRB will request that the department transfer the fee to the IRB account.

No review fees will be collected from the following sponsors

Protocols that are wholly sponsored by Federal government agencies and other sponsors paying

The institution’s full negotiated Federal Research facilities and administrative cost rate in effect at

the time of IRB initial review. Review fees are considered to be included in the negotiated facilities

and administrative cost receipts.

Studies wholly sponsored by intramural funds or non-profit entities (proof of non-profit status

may be required) do not incur review charges.

HRPP/IRB Policies

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In very rare instances, a waiver of IRB review fees may be justified. These circumstances will be

considered on a case-by-case basis by the IRB Director and the Assistant Dean for Research. An example

would be bankruptcy of the sponsor after IRB review, but prior to the receipt of start- up and IRB fees by

the institution.

HRPP/IRB Policies

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40.0 Compensation for Research Participants

Regulatory Background The general requirements for Informed Consent as outlined in 45 CFR 46.116 (OHRP Regulations) and 21

CFR 50.20 (FDA regulations) emphasize that investigators must seek legally effective informed consent

under circumstances that minimize the possibility of coercion or undue influence. Thus, the issue of

compensation for a subject’s participation in research must be considered in evaluating the

appropriateness of the informed consent process and the informed consent document for any given

protocol. In FDA Information Sheets (October 1, 1995), it is stated that:

If subjects are paid for their participation in studies, credit for payment must accrue as the study

progresses and must not be contingent upon completion of the entire study. Payment of a small bonus

as compensation for completion of the study is acceptable, providing that such compensation is not

coercive. The IRB should determine that the amounts paid are reasonable and the amount of any

payment based upon completion should not be so large as to unduly induce subjects to stay in the study

when they would otherwise have withdrawn. Therefore, the amount and schedule of all payments

should be presented to the IRB at the time of initial review and the IRB should determine their

acceptability. The consent document should outline the amount, schedule and conditions of earning

payment.

Compensation for research participation is distinctly different from compensation for injury or

negligence associated with participation in a research study. The institution has the authority to regulate

compensation for injury due to research participation. This policy is outlined in informed consent

documents for studies deemed greater than minimal risk and do not give the appearance of a waiver of

the subject’s legal rights. According to 45 CFR 46.116(a)(6) and 21 CFR 50, the subject must be told

whether any compensation and any medical treatment(s) are available if injury occurs and, if so, what

they are or where further information may be obtained

Compensation for research participation is not required. However, if research subjects are to be

compensated for their participation, the total amount and the schedule of payment(s) (a per visit

amount), if applicable, must be included in the informed consent document. The amount of the

compensation must be "reasonable", i.e. adequate to offset expenses (such as the subject’s/family’s

time and travel) and/or appropriate to serve as a modest compensation to participate.

The amount of compensation should not be proportional to the risks of the study. The amount must not

be so out of proportion to the subject’s efforts that it seems to elicit undue influence. If the study

involves multiple study visits involving procedures or significant time commitments, then payment must

not be contingent upon the subject’s completion of the study. That is, partial payments at intervals

throughout the study are appropriate and compensation should be broken down in a per visit type

schedule.

The following information is guidance for investigators and institutional review board members when

considering whether or not to reimburse study subjects for their participation in research activities at

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Wake Forest University Baptist Medical Center. If investigators feel that they have reasonable

justification for compensating research subjects at levels greater than the amounts outlined in this

guidance, they must provide such justification in writing at the time the protocol is initially submitted to

the IRB. In addition, the IRB can determine that compensation as described in an informed consent form

is inappropriate based on the study description, procedures, risk, etc. and can require adjustment with

appropriate justification to the investigator.

Guidelines for IRB Review of "Reasonable Compensation" The following ranges of compensation are suggested as guidelines for investigators and institutional

review board members:

Studies involving a minimal amount of time and inconvenience:

Up to -$100 per study visit: Study visits involving minimally inconvenient procedures (e.g., blood draws,

urine specimens, vital signs, x-rays, anthropometry) and/or questionnaires. The lower end of the

suggested range would apply to study visits with one or only a few such procedures. The top end of the

range would apply to study visits that involve many procedures and/or take several hours of the

subject’s time.

Actual Transportation Costs Regardless of Study Type:

$10-$50 for transportation to performance sites that is of some distance from the subject’s home.

Compensation for actual travel expenses (or similar costs such as childcare) could be offered in addition

to compensation to participate in the study visits procedures.

Moderately to Extremely Time-consuming Study Procedures:

$50-$250 per study visit involving moderate to extremely time consuming procedures (spinal taps,

arterial catheters, biopsies, administration of drugs), or significant inconvenience (e.g., extensive

pulmonary function testing, esophageal manometry, exercise physiology testing). Compensation in this

range could be offered for each day of inpatient studies, but should not exceed the recommended total

(below).

Total Compensation for Multiple Visits:

$100-$1500 total for a study involving multiple study visits, length and number of time commitments,

and inconvenience of participation.

The IRB will evaluate the appropriateness of the proposed compensation for each protocol as part of its

full board and expedited reviews. If you have any questions or concerns regarding the guidance

document, feel free to contact the IRB office.

References:

45 CFR 46.116

21 CFR 50.20

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41.0 Research Related Injury

Regulatory Background For research studies involving greater than minimal risk, Federal Regulations require that research

subjects must be told whether any compensation and any medical treatment(s) are available if injury

occurs and, if so, what they are, or where further information may be obtained. It is the position of the

IRB that for any research study it approves and determines to be of greater than minimal risk, provisions

must be made for the coverage of reasonable costs for the necessary treatment for illnesses, adverse

events or injuries that results from medications, devices, interventions, procedures, or tests that the

research study subject would not have been exposed to had he or she not volunteered to participate in

the research study.

The IRB recognizes that study related illnesses, adverse events, and injuries do not include those arising

from non-research study related activities, pre-existing medical conditions, underlying disease,

negligence or willful misconduct. In providing coverage for research related illnesses, adverse events, or

injuries it is not acceptable to condition coverage on the research subject first obtaining a denial from

third party insurance companies, government programs or other third parties. In the event that a

research subject’s insurance company, government program or other third party is providing coverage

for research related illnesses, adverse events or injuries the research study sponsor must coordinate

payments under the terms of the research subject’s benefits directly with the benefit provider. The IRB

is not responsible for the coordination of payment between the sponsor and the participant. Based on

the principle of Justice outlined in the Belmont Report, it is not acceptable for such agreements to

include provisions restricting participation in research studies on the basis of medical insurance

coverage status or the subject’s ability to pay. Further, medical care and treatment for research study

related illness, adverse events, or injuries cannot be limited to immediate, acute or emergency care.

Any study related illness, adverse event, or injury that results in a claim for payment for treatment

under the provisions for coverage of research related injury is considered by the IRB to be a serious and

unexpected adverse event. These must be reported to the IRB in accordance with the IRB policy and

procedure on Unanticipated Problem Reporting.

Template Language To assist investigators and sponsors in meeting the expectations of the IRB the following guidance is

provided on appropriate statements to include in the informed consent. To insure the rights and welfare

of research subjects the IRB may alter this guidance or impose additional requirements at its discretion.

For research studies involving no greater than minimal risk

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the

research are not greater in and of themselves than those ordinarily encountered in daily life or during

the performance of routine physical or psychological examinations or tests. For research studies

involving no greater than minimal risk of harm a statement is not required regarding whether any

compensation and any medical treatment(s) are available if injury occurs and, if so, what they are, or

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where further information may be obtained. Either the IRB or the research study sponsor may, however,

require inclusion of such a statement.

For industry sponsored research studies greater than minimal risk

For research studies of greater than minimal risk that are industry sponsored, provisions must be made

for the coverage of reasonable costs for the necessary treatment for illness, adverse events or injuries

that results from medications, devices, interventions, procedures, or tests that the research study

subject would not have been exposed to had he or she not volunteered to participate in the research

study protocol. An industry sponsor is generally a for-profit company or organization as opposed to a

non-profit or not for-profit company or organization. The informed consent for such studies must

contain the following statements, or a statement that the IRB determines to be equivalent. The research

agreement between the University and the Sponsor must contain an obligation for the Sponsor to

provide the same level of medical care as described in the informed consent.

For Industry Sponsored Research Studies Involving Medications, Interventions, Procedures, Tests and

Devices

SPONSOR shall reimburse for reasonable and necessary medical expenses (the “Covered Expenses”)

incurred by research subjects for medical care, including hospitalization, in the treatment of adverse

reactions arising from study drugs, devices, intervention, procedures and tests following their

administration or use in accordance with the protocol, which expenses were not caused by negligence

or misconduct of any person in the employment of Wake Forest University Health Sciences or to your

own failure to follow instructions. The SPONSOR is not responsible for expenses that are due to pre-

existing medical conditions or underlying disease. The research subjects medical or hospital insurance

and other third party payors are not responsible for any of the Covered Expenses.

If injury language has not been negotiated with sponsors at the time of IRB review, a placeholder may be

inserted into the consent form. The IRB will apply a “DRAFT” watermark to the consent. Once the terms

have been finalized, consistent language between the contract and consent form will be inserted via an

amendment. Only at this time the watermark will be removed and participants may be enrolled in the

study.

For NIH or WFUSM Departmentally Sponsored Studies greater than minimal risk

The Wake Forest University School of Medicine maintains limited liability insurance coverage to provide

for the treatment of research related injuries that occur as a result of participation in non-sponsored

research (e.g. NIH or Departmental). Such studies must contain the following statements in the

informed consent.

Should you experience a physical injury or illness as a direct result of your participation in this study,

Wake Forest University School of Medicine maintains limited research insurance coverage for the usual

and customary medical fees for reasonable and necessary treatment of such injuries or illnesses. To the

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extent research insurance coverage is available under this policy the reasonable costs of these necessary

medical services will be paid, up to a maximum of $25,000. Wake Forest University Baptist Medical

Center provides the insurance policy for this coverage.

It provides a maximum of $25,000 coverage for each claim. The Wake Forest University School of

Medicine, and The North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay

for these medical services or to provide any other compensation for such injury or illness. Additional

information may be obtained from the Medical Center’s Director of Risk and Insurance Management, at

(336) 716-3467.

You do not give up any legal rights as a research participant by signing this consent form. For more

information on medical treatment for research related injuries or to report a study related illness,

adverse event, or injury you should call <PI NAME> at <PI PHONE>.

References:

45 CFR 46.102(i)

45 CFR 46.116(a)(6)

21 CFR 50.1(k)

21 CFR 50.25(a)(6)

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42.0 SOP Revisions

General Description The IRB and the OR maintain standard operating procedures to ensure effective functioning of the

human research protection program. The OR documents when procedures are initiated, revised, and

disseminated to staff, IRB members, investigators, and study personnel. Further, it is necessary to

document the procedures for staff training regarding SOPs and maintenance of training records. The

SOPs are available in a searchable format on the IRB website, and the IRB staff can assist with questions

or interpretation of the policies and procedures.

Procedures Procedure for Writing Standard Operating Procedures

The IRB Director, with advice from OR staff, IRB Chairs, IRB members and/or investigators determines

when a new SOP needs to be established. Designated staff are responsible for writing SOPs.

Any staff member may draft an SOP based on his/her specialization. All SOPs are in compliance with

federal, state, and institutional regulations.

Staff consults with the IRB Chairs and/or IRB members on IRB related issues in developing the SOPs.

As appropriate, the OR staff distributes copies of newly drafted SOPs to designated IRB Chairs, IRB

members, and/or OR staff members for review.

If the SOP involves coordination with another University administrative office, the IRB Director, or staff

cooperate with the administrative unit involved in drafting the SOP and route the SOP to the

appropriate individual representing that office for approval and signature.

The staff ensures that each SOP designates the date on which it originally became effective as well as

the most recent revision date, which serves as the currently effective date for the SOP. The most recent

revision date indicates that this version is currently in effect.

Revisions to Standard Operating Procedures

The IRB Director, with advice from OR staff, IRB Chairs, and/or IRB members, determines when to revise

an existing SOP. Any staff member may draft revisions to an SOP based on his/her specialization. All SOP

revisions are in compliance with federal, state, and institutional regulations.

In revising SOPs, staff may consult with IRB Chairs and/or IRB members on IRB related issues.

As appropriate, the copies of newly revised SOPs are circulated to IRB Chairs, IRB members, and/or staff

for review.

If the revised SOP involves coordination with another University administrative office, the SOP is routed

to the appropriate individual representing that office for review, approval, and signature.

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A designated staff person posts the updated SOP to the website and advises staff and/or IRB members

of the revisions.

If an SOP impacts investigators/study personnel, the IRB Director or designee provides this information

to them through the website and disseminates changes through a variety of educational initiatives (e.g.,

list serve announcements, newsletters, presentations).

The IRB Director or designee informs institutional officials of all changes in the SOPs when appropriate.

Review of Standard Operating Procedures

The IRB Director, MOP Coordinator, or designee conducts a periodic review of the continuing suitability

of the SOPs.

Staff may review SOPs at any time for accuracy/applicability. The IRB staff obtains information necessary

to update procedures through monitoring of sources including, but not limited to, the U.S. Food & Drug

Administration website, Department of Health & Human Services, and the Office for Human Research

Protections listserv.

If significant or applicable changes to procedures become necessary, the IRB Director or designee

revises the SOP in question as soon as possible.

Record Keeping

A copy of all current SOPs in both hard copy and electronic files will be maintained. A designated staff

person archives copies of all previous editions of the SOPs.

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43.0 Case Reports A Case Study or Case Report is a description of the clinical characteristics or treatment(s) provided to a

single patient or a small group of patients that share a common condition, that did not involve activities

defined as research in the Code of Federal Regulations (i.e. “systematic investigation, including research

development, testing and evaluation, designed to develop or contribute generalizable knowledge”).

Innovative medical procedures or conventional treatments can be described in a case report provided

that these activities do not involve research. Case reports may include more than one subject or case.

Statistical analysis of the data presented in a case report must be primarily descriptive in nature, i.e.

means, standard deviations and measures of central tendency are acceptable, whereas comparative

statistics such as t-tests and ANOVA are not appropriate for case reports.

Because a case report is developed for medical/educational purposes, the use of protected health

information (PHI) to prepare the manuscript does not require IRB review. However, the use of PHI in

preparing and publishing a case report must comply with HIPAA regulations. A signed authorization

should have been obtained from either the patient (or their legally authorized representative) prior to

receiving clinical care. To protect the identity of the patient(s) involved, according to the HIPAA privacy

rule, none of the following PHI should be included in a case report:

1. Names

2. Address

3. Full Date Elements

4. Telephone numbers

5. Facsimile numbers

6. Electronic mail address

7. Social security numbers

8. Medical record numbers

9. Health plan beneficiary numbers

10. Account numbers

11. Certificate/license numbers

12. Vehicle identifiers and serial numbers

13. Device identifiers and serial numbers

14. Web universal resource locators (URLs)

15. Internet protocol (IP) address numbers

16. Biometric identifiers, including fingerprints and voiceprints

17. Full-face photographic images and comparable images

18. Any other unique identifying number, characteristic, or code, unless otherwise permitted by the privacy

rule for re-identification

When PHI has been collected and analyzed, the authors should take care to convert this information to a

non-identifiable format. For example, date of birth should be converted to age in years, and the dates

of treatment should be numbered and reported numerically. Authors should also avoid identifying

individuals by inference of characteristics.

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EXAMPLE OF A CASE REPORT

A retrospective analysis is conducted of the clinical records of patients seen in the Asthma Clinic who

developed H1N1 influenza between September 1, 2009 and December 31, 2009. The report gives the

mean age of all the patients seen, categorizes the different courses of treatment by age range, and gives

hospitalization rates and length of stay by asthma severity.

PLEASE NOTE:

The following are characteristics of activities that ARE considered research, and thus require review and

approval by the IRB before they are carried out:

There is a plan to collect additional information that would not ordinarily be collected in the

course of standard medical care for the sake of future reporting or publication.

Records collected for the report or publications are kept separate from clinical records (i.e. for

study purposes only).

There is a plan to prospectively randomize or compare treatment to a control group.

There is a protocol or study plan.

Investigational drugs or devices are involved.

The purpose of the activity is to answer a research question, rather than to provide care.

The data are collected prospectively with the intent of future analysis and publication.

The data are collected for deposition in a data repository or database.

The data are extracted and analyzed from a previously collected database.

If there are questions concerning case studies and case reports, please consult with the IRB staff for

more information.

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44.0 Application of ICH-GCP Guidance to the conduct of clinical trials

Purpose The policy describes the requirements, in addition to the Department of Health and Human Services

(DHHS) – Office of Human Research Protections (OHRP) and Food and Drug Administration (FDA)

regulations and Wake Forest University Health Sciences policies and procedures, for clinical trials

involving human subjects to be compliant with Guidance for Industry E6 Good Clinical Practice.

Good Clinical Practice (GCP) guidance is an international “ethical and scientific quality standard” for

designing, conducting, recording, and reporting clinical trials in human subjects that was developed by

the International Conference on Harmonization of Technical Requirements for the Registration of

Pharmaceuticals for Human Use (ICH). The GCP guidance developed by ICH is based on FDA regulations

for the protection of human subjects and defines the roles and responsibilities of Institutional Review

Boards (IRBs), investigators, monitors, and sponsors.

General principles of ICH & GCP include, but are not limited to:

1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the

Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s)

(ICH-GCP 2.1)

2. The available nonclinical and clinical information on an investigational product should be adequate to

support the proposed clinical trial. (ICH-GCP 2.4)

3. The investigator should have available an adequate number of qualified staff and adequate facilities for

the foreseen duration of the trial to conduct the trial properly and safely. (ICH- GCP 4.2.3)

4. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. (ICH-GCP

2.5)

5. Investigational products should be manufactured, handled, and stored in accordance with applicable

good manufacturing practice (GMP). They should be used in according with the approved protocol. (ICH-

GCP 2.12).

Definitions Clinical Trial/Study: Any investigation in human subjects intended to: discover or verify clinical,

pharmacological, and/or other pharmacodynamic effects of an investigational product; identify any

adverse reactions to an investigational product; and/or study absorption, distribution, metabolism, and

excretion of an investigational product to determine its safety and/or efficacy. (ICH-GCP 1.12)

Good Clinical Practice (GCP): A standard established by the International Conference on Harmonization

for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical

trials that provides assurance that the data and reported results are credible and accurate, and that the

rights, integrity, and confidentiality of clinical trial subjects are protected. (ICH-GCP 1.24)

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International Conference on Harmonization of Technical Requirements for the Registration of

Pharmaceuticals for Human Use (ICH): Voluntary, international initiatives to increase coordination of

the requirements for developing and marketing new drugs. The ICH includes representatives from the

pharmaceutical industry and regulatory authorities from the United States, Japan, and the European

Union.

Investigational Product: A pharmaceutical form of an active ingredient or placebo being tested or used

as a reference in a clinical trial, including a product with marketing authorization when used for

assembled (formulated or packaged) in a way different from the approved form, or when used for an

unapproved indication, or when used to gain further information about an approved use. (ICH-GCP 1.33)

Investigator: A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted

by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be

called the principal investigator. (ICH-GCP 1.34)

Legally Authorized Representative: An individual or judicial or other body authorized under acceptable

law to consent, on behalf of a prospective subject, to the subject’s participation in the clinical trial. (ICH-

GCP 1.37)

Sponsor-Investigator: An individual who both initiates and conducts, alone or with others, a clinical

trial, and under whose immediate direction the investigational product is administered to, dispensed to,

or used by a subject. The term does not include any person other than the individual (e.g., it does not

include a corporation or an agency). The obligations of a sponsor-investigator include both those of a

sponsor and those of an investigator. (ICH-GCP 1.54)

IRB Responsibilities The IRB voluntarily apply the ICH-GCP (E6) Guidelines to certain types of human subjects research

conducted under its HRPP. In general, Wake Forest apply ICH-GCP guidelines only to the extent that they

are compatible with FDA and DHHS regulations. When a sponsor requires institutional ICH-GCP

compliance, the IRB will conduct a review in accord with ICH-GCP requirements.

To be approved, clinical trials must satisfy the requirements described in the section 16 of this policy

manual.

Trial protocols/amendments, written informed consent forms and consent forms updates that the

investigator proposes for the use in the trial, subject recruitment procedures, written information to be

provided to the subjects, Investigator’s Brochure, available safety information, information about

payments and compensation available to subjects, the investigator’s curriculum vitae and/or other

documentation evidencing qualifications, and any other documents that the IRB may require for fulfill its

responsibilities, will be provided to the IRB for review. (ICH-GCP 3.1.2)

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Informed Consent Requirements In addition to the required elements of consent disclosure described in section 16 of this policy manual,

the following additional information will be included:

That the monitor(s), the auditor(s), the IRB, and the regulatory authority(ies) will be granted

direct access to the subject’s original medical records for verification of clinical trial procedures

and/or data, without violating the confidentiality of the subject, to the extent permitted by the

applicable laws and regulations and that, by signing a written informed consent form, the

subject of the subject’s legally authorized representative is authorizing such access. (ICH_GCP

4.8.10(n))

The alternative procedure(s) or course(s) of treatment that may be available to the subject, and

their important potential benefits and risks. (ICH-GCP 4.8.10(i))

Prior to beginning the trial, the investigator should have IRB written approval of the written

informed consent form and any other written information to be provided to the subjects. (ICH-

GCP 4.8.1)

Documentation of the informed consent of clinical trial subjects process include:

Prior to a subject’s participation in the trial, the written informed consent form should be signed

and personally dated by the subject or by the subject’s legally authorized representative, and by

the person who conducted the informed consent discussion (ICH-GCP 4.8.8)

If a subject is unable to read or if a legally authorized representative is unable to read, an

impartial witness should be present during the entire informed consent discussion. After the

written informed consent and any other written information to provided to the subjects, is read

and explained to the subject or subject’s legally authorized representative, and after the subject

or the subjects LAR has orally consented to the subject’s participation in the trial and, if capable

to do so, has signed and personally dated the informed consent form, the witness should sign

and personally date the consent form. By signing the consent form, the witness attests that the

information in the consent form and any other written information was accurately explained to,

and apparently understood by, the subject or subject’s LAR, and that the informed consent was

freely given by the subject or subject’s LAR. (ICH-GCP 4.8.9)

When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled

in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or

patients with severe dementia), the subject should be informed about the trial to the extent

compatible with the subject’s understanding and, if capable, the subject should sign and

personally date the written informed consent. (ICH-GCP 4.8.12)

Prior to participation in the trial, the subject or the subject’s LAR should receive a copy of

thesigned and dated written informed consent form and any other written information provided

to the subjects. (ICH-GCP 4.8.11)

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Vulnerable Populations Except as described below a nontherapeutic trial (i.e., a trial in which there is no anticipated direct

clinical benefit to the subject) should be conducted in subjects who personally give consent and who

sign and date the written informed consent form. (ICH-GCP 4.8.13)

Non-therapeutic clinical trials may be conducted in subjects with consent of a LAR provided the

following are fulfilled:

The objectives of the clinical trial cannot be met by means of a trial in subjects who can give consent

personally

The foreseeable risks to the subjects are low

The negative impact on the subject’s well being is minimized and low

The clinical trial is not prohibited by law

The approval/favorable opinion of the IRBs is expressly sought on the inclusion of such subjects and

the written approval/favorable opinion covers this aspect

Such trials, unless an exception is justified, should be conducted in patients having a disease or

condition for which the investigational product is intended. Subjects in these trials should be

particularly closely monitored and should be withdrawn if they appear to be unduly distressed. (ICH-

GCP 4.8.14)

Investigator Qualifications The investigator should be qualified by education, training, and experience to assume responsibility for

the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory

requirements, and should provide evidence of such qualifications through up-to- date curriculum vitae

and/or other relevant documentation requested by the sponsor, the IRB, and/or other regulatory

authority. (ICH-GCP 4.1.1)

The investigator should be thoroughly familiar with the appropriate use of the investigational products,

as described in the protocol, in the current Investigator’s Brochure, in the product information, and in

other information sources provided by the sponsor. (ICH-GCP 4.1.2)

A qualified physician, who Is an investigator or a sub-investigator for the trial, should be responsible for

all trial-related medical decisions. (ICH-GCP 4.3.1)

The investigator should be qualified by education, training, and experience to assume responsibility for

the proper conduct of the trial, should meet all the qualification specified by the applicable regulatory

requirements, and should provide evidence of such qualifications through up-to-date curriculum vitae

and/or other relevant documentation requested by the sponsor, the IRB, and/or the regulatory

authorities. (ICH-GCP 4.1.2)

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The investigator should maintain a list of appropriately qualified persons to whom the investigator has

delegated significant trial-related duties. (ICH-GCP 4.1.5)

Investigator Responsibilities In order to satisfy the ICH-GCP (E6) requirements, Investigators who conduct research involving human

subjects must satisfy the following:

During and following a subject’s participation in a trial, the investigator/institution should ensure that

adequate medical care is provided to a subject for any adverse events, including clinically significant

laboratory values, related to the clinical trial (ICH-GCP 4.3.2).

The investigator informs a subject when medical care is needed for other illnesses of which the

investigator becomes aware (ICH-GCP 4.3.2).

The investigator should follow the trial’s randomization procedures, if any, and should ensure the code

is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly

document and explain to the sponsor any premature unblinding (e.g. accidental unblinding, unblinding

due to a serious adverse event) of the investigational product (ICH-GCP 4.7).

It is recommended that the investigator informs the subject’s primary physician about the subject’s

participation in the trial if the subject has a primary physician and if the subject agrees to the primary

physician being informed (ICH-GCP 4.3.3).

Although a subject is not obligated to give his or her reasons for withdrawing prematurely from a trial,

the investigator should make a reasonable effort to ascertain the reasons, while fully respecting the

subject’s rights (ICH-GCP 4.3.4).

Investigator should promptly report the following to the IRB:

Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial Changes

increasing the risk to subjects and/or affecting significantly the conduct of the trial All adverse

drug reactions (ADRs) that are both serious and unexpected.

New information that may affect adversely the safety of the subjects or the conduct of the trial.

(ICH-GCP 3.3.8)

Where allowed, the investigator may assign some or all duties for investigational product accountability

at the trial sites to an appropriate pharmacist or other appropriate individual who is under the

supervision of the investigator and/or institution (ICH-GCP 4.6.2).

The investigator, pharmacist, or other appropriate individual, who is designated by the investigator

and/or institution, should maintain records of the product’s delivery to the trial site, the inventory of the

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site, the use of each subject, and the return to the sponsor or alternative disposition of unused

products. These records will include dates, quantities, batch/serial numbers, expiration dates (if

applicable), and the unique code numbers assigned to the investigational products and trial subjects.

Investigators should maintain records that document adequately that the subjects were provided the

doses specified by the protocol and reconcile all investigational products received from the sponsor

(ICH-GCP 4.6.3).

The investigator permits monitoring and auditing by the sponsor, and inspection by the appropriate

regulatory authorities (ICH-GCP 4.1.4).

The investigator ensures the accuracy, completeness, legibility, and timeliness of the data reports to the

sponsor (ICH-GCP 4.9.1).

Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety

evaluations should be reported to the sponsor according to the reporting requirements and within the

time periods specified by the sponsor in the protocol (ICH-GCP 4.11.2).

The investigator reports all serious adverse events (SAEs) to the sponsor except those SAEs that the

protocol or other document (e.g., investigator’s brochure) identifies as not needing immediate

reporting. The investigator follows regulatory requirements related to the reporting of unexpected

serious adverse drug reactions to the regulatory authority and the IRB (ICH-GCP 4.10.2).

The investigator should promptly provide written reports to the sponsor, the IRB, and where required by

the applicable regulatory requirements, the institution on any changes significantly affecting the

conduct of the trial and/or increasing the risk to subjects (ICH-GCP 4.10.2).

If the investigator terminates or suspends a trial without prior agreement of the sponsor, the

investigator should inform the institution, where required by the applicable regulatory requirements,

and the investigator/institution should promptly inform the sponsor and the IRB and should provide the

sponsor and the IRB a detailed written explanation of the termination or suspension (ICH-GCP 4.12.1).

If the IRB terminates or suspends its approval /favorable opinion of a trial, the investigator should

inform the institution, where required by the applicable regulatory requirements, and the

investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed

written explanation of the termination or suspension (ICH-GCP 4.12.3).

Upon completion of the trial, the investigator should, where required by the applicable regulatory

requirements, inform the institution, and the investigator/institution should provide the sponsor with all

the required reports, the IRB with a summary of the trial’s outcome, and the regulatory authorities with

any reports they require of the investigator/institution (ICH-GCP 4.13).

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For reported deaths, the investigator should supply the sponsor and the IRB with additional requested

information (e.g. autopsy reports and terminal medical reports) (ICH-GCP 4.11.3).