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IRB

INSTITUTIONAL REVIEW BOARD

HUMAN SUBJECTS PROTECTION PROGRAM

STANDARD OPERATING PROCEDURES

REVISED: 2015

University of South Alabama

Table of Contents Page #

INTRODUCTION ................................................................................................................................ 1

CONTACT INFORMATION .................................................................................................................. 2

PRINCIPLES, ROLES AND RESPONSIBILITIES

1.0 Regulatory and Ethical Mandate ............................................................................................................... 3 1.1 The Nuremberg Code ..................................................................................................................... 3

1.2 The Declaration of Helsinki .............................................................................................................. 3 1.3 The Belmont Report ........................................................................................................................ 3 1.4 Department of Health and Human Services (DHHS) Regulations .............................................. 4 1.5 Federal Policy (Common Rule) for the Protection of Human Subjects. Food and Drug

Administration (FDA) Regulations at 21 CFR 50 and 56 ............................................................... 4 1.6 Federalwide Assurance ................................................................................................................... 4

2.0 IRB Mission and Authority .............................................................................................................................. 5

2.1 IRB Purpose ....................................................................................................................................... 5 2.2 Definition of Human Subjects Research ....................................................................................... 6 2.3.1 Research .............................................................................................................................. 7 2.3 Agreements to provide IRB review of research conducted by unaffiliated investigators ...... 7

2.4 Human Research Activities Performed at Other Institutions ....................................................... 7 2.4.1 Requirements for Approval of Research at Non-USA Facilities ..................................... 7 2.4.2 IRB Approval of Research to be Done at a Non- USA Institution .................................. 8

IRB ORGANIZATION AND ADMINISTRATION

3.0 IRB membership ............................................................................................................................................ 8

3.1 Chairperson responsibilities ............................................................................................................ 9 3.2 Vice-Chair(s) responsibilities ............................................................................................................ 9 3.3 Committee member appointment .............................................................................................. 9 3.4 Non-voting members ...................................................................................................................... 9 3.5 Termination of appointment ........................................................................................................ 10 3.6 Confidentiality agreement ........................................................................................................... 10 3.7 Orientation and training of IRB members .................................................................................... 10 3.8 Member conflict of interest .......................................................................................................... 10 3.9 Investigator conflict of interest ..................................................................................................... 10

3.0.1 Duties of IRB Members ................................................................................................................. 10 4.0 IRB Administrative Support ........................................................................................................................ 11

4.1 Education and training of staff .................................................................................................... 11 4.2 Investigator and Key Research Personnel Training .................................................................... 12

5.0 IRB Record keeping and Reporting ......................................................................................................... 12

5.1 Documentation and Retention of IRB documents ................................................................... 13

IRB Standard Operating Procedures 2014

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5.2 Access to IRB records ................................................................................................................... 13 5.4 IRBNet Database ........................................................................................................................... 13

6.0 Meeting Materials and Documentation .................................................................................................. 13 6.1 Meeting minutes .......................................................................................................................... 14 6.2 Review by convened IRB ............................................................................................................. 15 6.2.1 IRB review procedures ...................................................................................................... 15 6.2.2 IRB meeting materials ............................................................................................. 16 6.3 IRB Actions/Project Status ............................................................................................................ 17 6.3.1 Approved .......................................................................................................................... 17 6.3.2 Modifications required .................................................................................. 17

6.3.3 Information Required ....................................................................................................... 17 6.3.4 Pending follow-up of receipt and review of serious adverse event .......................... 17 6.3.5 Deferral .............................................................................................................................. 18 6.3.6 Disapproval ....................................................................................................................... 18

6.3.7 Suspension and termination of research study by IRB ................................................. 18 6.3.8 Closed - Expired ................................................................................................................ 18 6.3.9 Closed – Project Completion .......................................................................................... 18 6.3.10 Closed ............................................................................................................................... 19

6.4 Notification of IRB actions ............................................................................................................ 19 6.5 Appeal of IRB decisions ................................................................................................................ 19

IRB RESEARCH EVALUATIONS, PROCEDURES, CRITERIA AND ACTIONS

7.0 Determination of Type of Review ............................................................................................................. 19

8.0 Expedited Review of Research ................................................................................................................ 19 8.1 Types of research eligible for expedited review ....................................................................... 20 8.2 IRB review materials ...................................................................................................................... 22 9.0 Exemption from Continuing Review ...................................................................................... 22 9.1 Types of research eligible for exempt continuing review ........................................................ 23 9.2 Modifications to exempt studies ................................................................................................. 23

10.0 Modifications to Previously Approved Projects ...................................................................................... 24

11.0 Continuing Review of Approved Applications ...................................................................................... 25 11.1 Criteria for requiring review more often than annually ............................................................ 25

11.2 Reminders/Notices ........................................................................................................................ 25 11.3 Lapsed studies ............................................................................................................................... 25 12.0 Study Closure or Completion .................................................................................................................... 26 12.1 Voluntary completion by investigators ....................................................................................... 26


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12.2 Termination of a study by the IRB ................................................................................................ 26 12.3 Expiration of approval period ...................................................................................................... 26

13.0 Adverse Events and Unanticipated Problems in Research .................................................................. 27 13.1 Definitions ....................................................................................................................................... 27

13.2 Special requirements for research involving gene therapy studies ................................ 28 13.3 Internal vs External Reporting Requirements ............................................................... 28 13.4 IRB responsibilities following receipt of SAE/follow-up report ................................................... 29

14.0 Safety Alerts, IND Safety Reports, MED Watch Reports ............................................................................ 29

15.0 Protocol Violations and Deviations ......................................................................................................... 30 15.1 Definitions ....................................................................................................................................... 30 15.2 Reporting procedures .................................................................................................................. 30 15.3 Review by IRB committee ............................................................................................................ 31 15.4 Actions that may be taken during or after the investigation of non-compliance ............... 31 15.5 Continuity of care of research participants when study is suspended ................................... 32 15.6 Final outcome ............................................................................................................................... 32

16.0 IRB Protocol Audits ............................................................................................................. 32

17.0 Recruitment and Advertisement Methods ............................................................................................. 33 17.1 Recruitment methods ................................................................................................................... 34

17.2 Recruitment incentives ................................................................................................................. 34 17.3 Promotional materials .................................................................................................................... 35 17.4 External investigators and recruitment of student population ................................................. 35

18.0 Informed Consent ...................................................................................................................................... 36 18.1 Basic elements of informed consent ........................................................................................... 36 18.2 Additional elements of informed consent ................................................................................. 37

18.3 Exceptions to informed consent requirements .......................................................................... 38 18.4 Research related injury ................................................................................................................. 39 18.5 Audio/video recordings ............................................................................................................... 40 18.6 Consent for mail and telephone surveys .................................................................................. 40 18.7 Short form consent procedures .................................................................................................... 40 18.8 Waiver of written consent ............................................................................................................ 41 18.9 Consent form templates .............................................................................................................. 42 18.10 Assent by minors ............................................................................................................................ 42 18.11 Parental permission ....................................................................................................................... 43 18.12 Surrogate consent for subjects who are decisionally impaired .............................................. 44 18.13 Obtaining consent from non-English speaking subjects ........................................................... 44

18.13.1 Translation and informed consent .............................................................................................. 45 18.14 Consent for use of stored samples and genetic ........................................................................ 45


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18.15 Revised Informed Consent and Reconsenting ......................................................................... 46 18.16 Stamped Copies of Consent Forms ............................................................................ 46 18.17 Record retention of informed consent documents ................................................................. 47

19.0 HIPAA and IRB Review ............................................................................................................................... 47

19.1 HIPAA authorization and informed consent .............................................................................. 47 19.2 HIPAA Security ............................................................................................................................... 48 20.0 Behavioral and Social Science Research ................................................................................................ 48

20.1 Types of risk found with Social/Behavioral research ................................................................. 49 20.2 Research involving deception or withholding of information ................................................. 50

20.3 Oral histories .................................................................................................................................... 51 21.0 Review of Research Using Data and Specimens .................................................................................... 51

21.1 Prospective use of existing materials .......................................................................................... 51 21.2 Retrospective use of existing materials ...................................................................................... 52 21.3 Research using data or tissue banks .......................................................................................... 52

CONSIDERATIONS FOR FDA-REGULATED PRODUCTS

22.0 Research involving an investigational drug/device ............................................................................... 53

22.1 Determination of need for an IND .............................................................................................. 54 22.2 Determination of significant vs non-significant for non-exempt medical devices ............... 55 22.3 Controlling distribution and disposition of devices .................................................................... 55 22.4 Submitting applications ................................................................................................................. 56 22.5 Submitting reports ......................................................................................................................... 56

23.0 Device studies in pediatric populations .................................................................................................. 56 24.0 Emergency Use of an Investigation Drug or Biologic ............................................................................. 57 25.0 Exceptions from informed consent requirements for emergency research ........................................ 58 26.0 Emergency use of unapproved medical devices ................................................................................ 58

26.1 Requirements for emergency use ............................................................................................... 59 26.2 After-use procedures .................................................................................................................... 59

27.0 Reporting the use of a test article to the IRB .......................................................................................... 60 28.0 Treatment use of an investigational drug/device ................................................................................. 60

28.1 Single patient (non-emergency use) ........................................................................... 60 28.2 Humanitarian use device .............................................................................................................. 61

29.0 Biologics ....................................................................................................................................................... 61


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SPECIAL POPULATIONS

30.0 Definitions ..................................................................................................................................................... 62 31.0 Elements to consider in research involving vulnerable subjects ........................................................... 63 32.0 Decisionally impaired subjects ................................................................................................................. 63 33.0 Surrogate permission with subjects judged incompetent to consent ................................................. 63 34.0 Research involving pregnant women, human fetuses and neonates ................................................ 64 34.1 Neonates ........................................................................................................................................ 64 34.2 Placenta, fetal material ............................................................................................................... 67 34.3 Neonates of uncertain viability ................................................................................................... 67 34.4 Nonviable neonates ..................................................................................................................... 67 34.5 Viable neonate .............................................................................................................................. 68 35.0 Research involving prisoners ..................................................................................................................... 68 35.1 Issues to address in reviewing prisoner research ....................................................................... 68 35.2 Categories of research in which prisoners may participate .................................................... 69 35.3 Required findings .......................................................................................................................... 69 35.4 Certification of prisoner research ................................................................................................. 70 36.0 Research involving minors ......................................................................................................................... 71 36.1 Research in school settings .......................................................................................................... 71 36.2 Categories of research involving minors that may be approved by the IRB ........................ 71 36.3 IRB review of research involving minors ...................................................................................... 72 36.4 Students and Employees ............................................................................................................. 72 APPENDICES: Appendix A: The Belmont Report ...................................................................................................................... 74 Appendix B: Unaffiliated Investigator Agreement .......................................................................................... 83 Appendix C: Confidentiality Agreement ........................................................................................................... 85 Appendix D: Requirements for Humanitarian Use Device .............................................................................. 86

INTRODUCTION

Intended Audience and Distribution

The purpose of the Institutional Review Board (IRB) Standard Operating Procedures (SOP) is to provide direction to members of the IRB and the IRB staff in carrying out duties assigned to the IRB, and to provide a “best practices” reference guide. This SOP comprehensively summarizes existing policy as well as the regulatory expectations found in the Common Rule (45 CFR 46) and the Food and Drug Administration (21 CFR 50 and 56). The SOPs provide valuable guidance, in conjunction with the Investigator’s Handbook, to principal investigators, research professional and administrative staff, and others conducting or involved in research.

Maintaining a Current SOP

These SOPs are considered to be a “living document” that will be updated or reviewed annually or more often as changes in statutes, regulation, guidance, practice or policy occur. The SOP is the primary location for compiling, organizing, integrating, and pointing to the rules, policies, practices, and guidance encompassing the University’s Human Subjects Protection Program. At least once every three years the Offices of the IRB and Research Compliance and Assurance initiate a comprehensive review of the SOPs. Revisions may be made at any time, however, as required by changes in law, ethical standards, institutional policy, quality assurance activities, or other considerations. Non-substantive revisions (e.g., to correct typographical errors, update links, or incorporate summaries of new or revised laws or regulations governing the IRB) may be made upon approval of the Office of Research Compliance and Assurance with written notice to the IRB.

The Office of Research Compliance and Assurance would appreciate receiving your questions, comments, and suggestions for improving this first version by e-mail to [email protected]


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CONTACT INFORMATION AND LINKS

OFFICE OF RESEARCH COMPLIANCE AND ASSURANCE Dusty Layton, Director [email protected] 251-460-6625 Website: http://www.southalabama.edu/researchcompliance/index.html IRB OFFICE: SuzAnne Robbins IRB Compliance Specialist 251-460-6308 [email protected] Human Subjects website: http://www.southalabama.edu/com/research/humansubjects.shtml INSTITUTIONAL OFFICIAL: Lynne Chronister VP for Research and Economic Development 251-460-6333 [email protected] INSTITUTIONAL REVIEW BOARD CHAIR: Dr. Ronald J. Russell Chair, IRB [email protected] 251-445-9615 USEFUL LINKS: DHHS Office of Human Research Protections (OHRP): www.hhs.gov/ohrp/about/ OHRP guidance documents: http://www/hhs.gov/ohrp/policy/index.html OHRP compliance references : http://www.hhs.gov/ohrp/compliance/ Food and Drug Administration (FDA): www.fda.gov/ FDA guidance documents: www.fda.gov/opacom/morechoices/industry/guidedc.htm FDA compliance references : www.fda.ora/compliance_ref/


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PRINCIPLES, ROLES AND RESPONSIBILITIES

1.0 Regulatory and Ethical Mandates

The mission of the USA Human Subjects Protection Program is to ensure that:

1. the rights and welfare of human subjects are paramount in the research process;

2. the highest standards of ethical conduct are employed in all human subjects research activities;

3. research investigators are properly trained in the ethical and regulatory aspects of research with human subjects;

4. research investigators inform human subject participants fully of procedures to be followed, and the risks and benefits of participating in research; and

5. research using human subjects at USA conforms with all applicable local, state and federal laws and regulations and the officially adopted policies of the University.

The regulation of human subjects research by the U.S. Department of Health and Human Services is codified in 45 CFR 46. Because Subpart A of 45 CFR 46 has been adopted for human subjects research 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. This research should be guided by the ethical principles adopted in the Belmont Report and, additionally, should conform to the guidance documents described below:

1.1 The Nuremberg Code

The modern history of human subject protections begins with the discovery after World War II of numerous atrocities committed by Nazi doctors in war-related human research experiments. The Nuremberg Military Tribunal developed ten principles as a means of judging their “research” practices, known as The Nuremberg Code. The significance of the Code is that it addressed the necessity of requiring the voluntary consent of the human subject and that any individual “who initiates, directs, or engages in the experiment” must bear personal responsibility for ensuring the quality of consent. Additionally, the Nuremburg Code, more than other counterparts listed here, is a recitation of participants’ legal rights, and has been used as a basis for decisions made in adjudicating the cases involving human research.

1.2 The Declaration of Helsinki

Similar principles to The Nuremberg Code have been articulated and expanded in later codes, such as the World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects (1964, revised 1975, 1983, 1989, 1996, 2000, 2013), which call for prior approval and ongoing monitoring of research by independent ethical review committees.

1.3 The Belmont Report

Revelations in the early 1970s about the 40-year United States Public Health Service Study of Untreated Syphilis in the Negro Male at Tuskegee and other ethically questionable research resulted in the 1974 legislation calling for regulations to protect human subjects and for a national commission to examine


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ethical issues related to human subject research (i.e., the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research). The Commission’s final report, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, defines the ethical principles and guidelines for the protection of human subjects. Perhaps the most important contribution of The Belmont Report is its explanation of three basic ethical principles:

• Respect for persons (applied by obtaining informed consent, consideration of privacy, confidentiality, and additional protections for vulnerable populations);

• Beneficence (applied by weighing risks and benefits); and • Justice (applied by the equitable selection of subjects).

The Belmont Report is attached to this document as Appendix A.

1.4 Department of Health and Human Services (DHHS) Regulations

Federal regulations require specific protections for human subjects. In May of 1974, the Department of Health, Education, and Welfare (later renamed DHHS) codified its basic human subject protection regulations at 45 CFR 46, Subpart A. Revised in 1981, 1991, 1996 and 2005, the DHHS regulations presently include additional protections for fetuses, pregnant women, and human in vitro fertilization (Subpart B), prisoners (Subpart C), and children (Subpart D). The DHHS regulations are enforced by the Office for Human Research Protections (OHRP).

1.5 Federal Policy (Common Rule) for the Protection of Human Subjects. Food and Drug Administration (FDA) Regulations at 21 CFR 50 and 56

When DHHS revised its regulations in 1981, the FDA codified almost identical informed consent regulations at 21 CFR 50 and IRB regulations at 21 CFR 56. Additional FDA regulations that are relevant to the protection of human subjects are:

(1) Investigational New Drug Applications (IND) (21 CFR 312) (2) Radioactive Drugs (21 CFR 361) (3) Biological Products (21 CFR 600) (4) Investigational Device Exemptions (IDE) (21 CFR 812) (5) Additional Safeguards for Children (21 CFR 50, Subpart D).

1.6 Federalwide Assurance

The Common Rule requires that every institution engaged in federally supported human research file an “Assurance” of protection for human subjects. The University of South Alabama conducts human use research under the terms specified in its Federalwide Assurance (FWA), the legally-binding agreement to ensure that all human subjects research complies with the requirements of the governing Federal Department or Agency head and its policies. All human subjects research activities, regardless of funding source, will be guided by the ethical principles in the Belmont Report and all other appropriate ethical standards recognized by Federal Departments and Agencies which have adopted the Federal Policy for the Protection of Human Subjects. All research studies will comply with subparts of DHHS regulations as codified in Title 45 CFR Part 4 and its Subparts A, B, C, and D. The Office of Research Compliance and Assurance will submit the FWA and all updates to the federal Office of Human Research Protections at least every three years. The Common Rule Terms of Assurance are listed on the OHRP website. USA conducts human research under FWA #00001602.


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2.0 IRB Mission and Authority

The Institutional Review Board (IRB) has the authority to ensure that all human subjects research conducted at the University of South Alabama complies with regulations of the Department of Health and Human Services (DHHS) “45 CFR 46”, applicable Alabama state statues and regulations, the principles of the Belmont Report and the Federalwide Assurance {FWA 00001602} of the University of South Alabama.

The Human Subjects Protection Program serves their purpose by:

1. Administratively supporting the University’s IRB

2. Reviewing all research involving human subject’s research before it is initiated

3. Working to protect the rights and welfare of human subjects by fostering and advancing the ethical and professional conduct of persons engaged in research

4. Providing education to researchers and staff

5. Conducting periodic reviews of research involving human subjects, and

6 Serving as the institutional HIPAA Privacy Board

All human subjects research activities must be reviewed, prospectively approved and subject to continuing oversight (at least annually) by the IRB to ensure the safety and welfare of participants, pursuant to the regulation provided in 45 CFR 46. The IRB conducts review and approval for all human subjects research activities conducted under its jurisdiction. This jurisdiction includes research conducted or directed:

• By USA faculty, staff, students, affiliates or outside researchers and occurs on the property of the University of South Alabama regardless of funding sources

• By an outside researcher involving USA faculty, staff, students, or affiliates.

The VP for Research and Economic Development is the Institutional Official for the institution for IRB purposes through the Federalwide Assurance Agreement.

2.1 IRB Purpose

The IRB is responsible for the review and prior approval processes of research activities involving the use of human subjects by engaging in deliberations to adequately provide a comprehensive review of the proposed research activity, assess the risks and benefits to the subjects, ensure the research is conducted ethically in an ongoing manner, and maintain communications with research personnel.

Duties of members including reviewing IRB application materials in advance of convened meetings and being prepared to discuss issues related to human subjects protection, serving as primary reviewer or secondary reviewer when assigned, and having an understanding of the specific requirements of human subjects regulations. Duties include:

1. Conduct initial and continuing review of research involving human subjects at intervals appropriate to the degree of risk, but at least once a year and report IRB findings and actions to the investigator and the institution.


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2. Determine which projects require review more often than annually and which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review.

3. Review proposed changes in research activities to insure that changes in approved research, during the period for which IRB approval has been given, has not been initiated without IRB review and approval.

4. Require or waive documentation of informed consent. 5. Follow procedures to insure that the IRB and Office for Human Research Protections (OHRP) of

the Department of Health and Human Services (DHHS) receive reports of unanticipated problems involving risks to subjects and others.

6. Monitor additional safeguards when vulnerable subjects (minors, mentally incompetent, prisoners, economically and educationally disadvantaged, pregnant females) are involved in the research in order to protect against coercion or undue influence.

7. Conduct its review of research, except when an approved exempt review procedure is used, at convened meetings at which a quorum of the members of the IRB are present.

8. Conduct reviews of all adverse event reports 9. Approve research only with the concurrence of a quorum of those members in attendance. 10. Report to the institution and OHRP any continuing or serious matters of non-compliance by

investigators with the requirements and determination by the IRB. 11. Have authority to suspend or terminate approval of research that is not in compliance with the

IRB’s determinations or has been associated with unexpected serious harm or risks to subjects.

2.2 Definition of Human Subjects Research

In order to ensure the rights, welfare, and protection of all subjects, all human subjects research, and all other activities, which in part involve human subject research, regardless of sponsorship, must be reviewed and approved by the IRB prior to initiation. This includes all interventions and interactions with human subjects for research, including advertising, recruitment and/or screening of potential subjects.

Human subjects research is any research or clinical investigation that involves human subjects.

Note: The DHHS definition of human subjects will generally apply to all human research conducted by investigators at the University of South Alabama unless the research involves a test article. Those investigations involving a test article will also be subject to FDA definitions.

DHHS regulations define a human subject as a living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual; or (2) identifiable private information.

Intervention includes both physical procedures by which data are gathered (e.g., venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.

Interaction includes communication or interpersonal contact between investigator and subject or legal representative in the case of minors or other vulnerable populations.

Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and 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 record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.


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FDA regulations define human subject as an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient.

2.2.1 Research

DHHS regulations define research as a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.

A systematic investigation is an activity that involves a prospective plan that incorporates data collection, either quantitative or qualitative, and data analysis to answer a question.

FDA regulations define a clinical investigation as any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the FDA, or is not subject to requirements for prior submission to the FDA under the Federal Food, Drug, and Cosmetic Act, but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit.

A test article means any drug (including a 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 Federal Food, Drug, and Cosmetic Act.

2.3 Agreements to Provide IRB Review of Research Conducted by Unaffiliated Investigators

USA may be asked to provide IRB review for investigators who are unaffiliated with the University of South Alabama. Circumstances in which this arrangement might be considered would typically involve a study based at USA in which the unaffiliated investigator is collaborating in the study. It will generally not be considered appropriate to extend IRB oversight to research by unaffiliated investigators in which USA is not otherwise engaged.

All requests for USA to serve as the IRB of record for an unaffiliated investigator should be referred to the Institutional Official. This referral should include an “Unaffiliated Investigator Agreement” based on the USA approved template attached as Appendix B, together with a recommendation from the USA IRB with responsibility for that given study and/or group of investigators. Usually, this agreement will apply to a single research project. Copies of the agreement will be provided to the unaffiliated investigator and maintained in the Offices of the IRB and Research Compliance and Assurance.

2.4 Human Research Activities Performed at Other Institutions

All research activities performed by, or under the direction of, USA personnel or which use University resources or facilities, must comply with applicable USA policies and procedures, regardless of funding and whether performed in USA facilities or at offsite locations.

2.4.1 Requirements for Approval of Research at Non-USA Facilities

Any human subjects research conducted in whole or in part outside of USA facilities must be reviewed and approved by USA IRB prior to initiation if it satisfies any of the following criteria.

• It is conducted by or under the direction of USA personnel in connection with his or her USA responsibilities.


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• It uses USA property, facilities, or resources to support or carry out the research. • The name of the University of South Alabama is used in applying for funds (intra or extramural). • The name of the University of South Alabama is used in explanations and/or representations to

subjects. • The investigator plans to use his/her University of South Alabama association in any publication

or public presentation resulting from the research. • Non-public information from USA will be used to identify or contact human research subjects or

prospective subjects.

2.4.2 IRB Approval of Research to be Done at a Non- USA Institution The researcher will need to obtain approval from the Non-USA IRB in addition to the USA IRB for any research done at a Non- USA Institution unless a cooperative review agreement has been executed in advance of the study.

IRB ORGANIZATION AND ADMINISTRATION

3.0 IRB Membership

• At least five members of sufficiently diverse backgrounds, including consideration of racial and cultural backgrounds of members and sensitivity to issues such as community attitudes;

• Persons who are able to ascertain the acceptability of research applications in terms of institutional commitments, applicable law, and professional standards;

• Members of both sexes; • At least one member whose primary area of expertise is with handicapped and/or retarded children; • At least two members whose primary concerns are in behavioral disciplines; • At least one member whose primary concerns are in non-scientific areas; • Members representing more than one profession; • A member who is not affiliated or related to a person who is affiliated with the institution; • Persons who are primarily concerned with the welfare of vulnerable subjects (minors, prisoners,

terminally ill, etc.); • When needed, individuals with competence in special areas to assist in the review of complex issues; • Participants in the initial or continuing review of projects who do not have a conflicting interest; • The standards described above represent minimum requirements which the USA IRB typically exceeds.

In many instances, an IRB will have 15 or more members with varied expertise and speciliaization in order to meet the research review requirements. IRB membership is recorded on a roster that is submitted to the Office of Human Research Protections (OHRP) and is filed in the IRB office.

3.0.1 Duties of IRB Members

Duties of members include reviewing human subject application materials in advance of meetings and being prepared to discuss issues related to human subjects protections, serving as primary reviewer when requested by the chair, and having an understanding of the specific requirements of human subjects regulations. Duties include:

• Protecting rights and welfare of human subjects • Determining risks are minimized • Ensuring that investigators:

o use of procedures are consistent with sound research design and that do not expose subjects to risks


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o when appropriate, use procedures already being performed on the subjects for diagnostic or treatment purposes, and

o ensuring that the investigator follows a procedure for properly documenting informed consent

• Determining that risks to subjects are reasonable in relation to anticipated benefits to subjects • Determining that selection of subjects is equitable. In making this assessment, the following should

be considered: o purpose of the research and setting in which the research is conducted o IRB members should be cogniz2ant of special problems of research involving vulnerable

populations • Determining if informed consent is sufficient and includes all mandated elements, if not, request

clarifications and changes in consent document • Determining that the research plan includes adequate provisions for ensuring the safety of subjects • Determining if adequate protections are afforded to protect the privacy of subjects and maintain

confidentiality of data • If applicable, documenting requirements for wavier of informed consent have been met • Ensuring additional safeguards are in place to protect rights and welfare of subjects that are more

likely to be vulnerable to coercion or undue influence, such as students, children, prisoners, educationally and economically disadvantaged, etc.

3.1 Chairperson Responsibilities

• Chairs convene meetings • Call special meetings when necessary • Make decisions in emergency situations to protect subjects and remain in compliance with regulations • Confirms primary/secondary reviewer assignments made by IRB staff as requested • Conducts review of all protocols discussed at convened meetings • Conducts expedited review of biomedical research studies • Reviews policies and procedures on an ongoing basis • Serves as an advisor/educator in the institution’s research community

3.2 Vice-Chair(s) Responsibilities

• Performs duties of the chair in his/her absence • Assists chairperson, IRB staff as need

3.3 Committee Member Appointment

Committee members are nominated by a Committee on Committees with input from the Director, Office of Research Compliance. Prospective members may also be identified by the IRB chair and staff who review the nature and demands of the IRB. IRB members are appointed for three year terms which are renewable. If a member resigns prior to the end of their term, a person may be appointed to complete the original term.

3.4 Non-voting Members

Non-voting members from among the academic or administrative staff of the University are appointed to aid the IRB in conducting its duties. These members may take part in all meetings of the IRB, participate in discussions and make recommendations, but they may not vote on the decisions. Non-voting members are not included in determining or establishing a quorum at the meetings. IRB meeting minutes reflect the presence of non-voting members.


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3.5 Termination of Appointment:

Appointment to the IRB may be terminated before the expiration of the three-year term. The Institutional Official may remove an IRB member if he/she, in consultation with the IRB chair or other parties, determines that the member fails to perform his or her duties as a member.

3.6 Confidentiality Agreement:

Upon appointment to the IRB or attendance at an IRB meeting, members (voting or otherwise), consultants, guests, etc., will sign a confidentiality agreement attached as Appendix C.

3.7 Orientation and Training of IRB Members:

Following appointment of new members, the Offices of the IRB and Research Compliance and Assurance conducts an orientation session to include topics such as: research compliance, processing of protocols, meeting process and expectations of an IRB member. Additionally, a new member will receive a binder of reference materials and a IRB member handbook (including these SOPs). All members complete the online educational module entitled “Protecting Human Subject Research Participants” provided by the NIH Office of Extramural Research or comparable training. Members are provided with continuing education opportunities within the institution, and receive continuing education materials at regularly held IRB meetings.

3.8 Member Conflict of Interest:

No IRB or consultant may participate in the IRB initial or continuing review of any project in which he/she has a conflict of interest, except to provide information requested by the IRB. Examples of such conflicts of interest could include: a member of the IRB who serves as an investigator or sub-investigator on research under review by the IRB, or a member who holds a financial conflict of interest in a sponsor or product under study. In cases where the assigned initial reviewer has a conflict of interest, the review must declare that conflict of interest and the protocol will be re-assigned to another reviewer. The IRB member will indicate a conflict of interest in IRBNet (i.e., recusal or abstention) and is recorded in the minutes as a recusal.

3.9 Invest igator Conf l ic t o f In teres t

It is University policy that individuals conducting human subjects research have a paramount responsibility to ensure that any conflicting interests of the researchers do not compromise the welfare and rights of those human subjects. Identification of possible conflicts of interest is an important step to protect human participants and maintain the integrity of the IRB process. The University requires submission of an annual conflict of interest disclosure form by all faculty members and Employees in an administrative position at or above a director level, as well as disclosure throughout the year of changes that may either: (a) give rise to a potential conflict of interest; or (b) eliminate a potential conflict previously disclosed. In addition the IRB application includes questions that probe for potential conflict of interest in relation to the specific study.

Investigators, Co-Investigators and any study personnel are required to disclose Financial Conflicts of Interest or other interests that are, or may be perceived to be related to the study on the application for initial IRB review and approval. If there is a potential or perceived conflict related to the study, the Investigator is asked if the conflict has been disclosed and/or managed. Conflict of Interest disclosure forms are reviewed by the department chair/supervisor and forwarded to the Office of Research Compliance and Assurance. If warranted, the IRB will verify that a management plan has been executed. A management plan template for human subjects research may be used for documenting


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and identifying appropriate actions to eliminate, reduce or resolve financial conflicts of interest or conflicts of commitment. These matters may be referred to the University Conflict of Interest Committee and the reporting employee shall be notified of the referral. In instances where a conflict of interest involving human subjects research is allowed, it is essential that research subjects and other interested parties be informed of the conflict of interest. If an investigator is participating in a multi-center trial and has been allowed to conduct human subjects research while possessing a financial interest, that fact should be made known to the Investigator or sponsor by the coordinating center. Notification of research subjects falls within the purview of the applicable IRB, which will determine whether and how the conflict of interest should be disclosed to the relevant human research subjects. This may include a description in the consent form of the conflict of interest.

4.0 IRB Administrative Support

The IRB staff supports the function of the IRB infrastructure and all activities engaged in human subjects research at the direction and under the supervision of the Director of the Office of Research Compliance and Assurance (ORCA). The Director, ORCA is responsible for directing and overseeing all IRB support functions and operations; training, supervising and evaluating IRB staff; and developing and implementing procedures to facilitate efficient document flow and maintenance of all IRB records. The IRB administrative staff:

• Maintain up-to-date knowledge of policies/procedures and regulations regarding human subjects research and IRB operations.

• Perform administrative duties to assure systematic flow of work through the IRB. • Prepare and distribute review materials to members and consultants. • Maintain files • Prepare and distribute minutes • Send out notification of IRB decisions, requests for additional information and correspondence to

investigators in a timely manner. • Assist in the conduct of educational workshops

IRB forms are used to ensure that polices are integrated into the day to day research and review operations. This enables execution of functions in which the IRB can manage, review, track and notify in a consistent manner.

4.1 Education and Training of Staff:

Staff members will initially receive the same orientation as IRB members with an introductory lecture and orientation to IRB and office procedures. Further training is provided by working in close interaction with other staff members. Staff members should be provided with continuing education opportunities and resources should be made available for them to attend regional or national human subject protection meetings, as deemed appropriate by the Director of the Office of Research Compliance and Assurance in consultation with the Institutional Official. Credentials as a Certified IRB Professional (CIP) will be encouraged for IRB staff. A variety of resource materials (i.e., newsletters, textbooks, meeting materials, etc.) are available.

The administrative staff will make every effort to ensure prompt and through review of all submissions to ensure the safety and welfare of research subjects. In addition, it is the responsibility of the IRB chair, Director, ORCA and administrative staff for educating the members of its research community in order to establish and maintain a culture of compliance with regulations and institutional policies relevant to human subject protections.


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4.2 Investigator and Key Research Personnel Training

Investigators and research personnel must complete human subjects research training as a condition of the University’s Federalwide Assurance of Compliance. In addition to human subjects training, all investigator(s) and key research personnel within USA’s HIPAA covered entity must complete USA’s HIPAA in Research tutorial. Completion of training is a condition for IRB approval. The Human Subjects Protection Program has ongoing educational programs for both IRB members, investigators and study staff. Examples of educational opportunities that are offered include:

• Clinical research coordinators/nurses forum • In-service educational presentations scheduled as a component of convened IRB meetings • Workshops tailored and presented for specific research/departments • IRB 101 for Students which includes class presentation to students conducting research as part of their

class assignment

5.0 Record keeping and Reporting:

The Common Rule and, when applicable, Food and Drug Administration (FDA) regulations require written policies and procedures to govern the operations and direct the activities of the IRB. Record keeping and documentation requirements for IRB operations are as follows:

Generally, IRB records shall include:

(1) Written standard operating procedures (2) IRB membership rosters (3) Training records (4) IRB correspondence (5) IRB research application (protocol) files (6) Research (protocol) tracking system (7) Documentation of exemptions, exceptions or waiver of informed consent (8) Documentation of expedited reviews (9) Documentation of convened IRB meetings – minutes (10) Documentation of review for adverse events (11) Documentation of review for protocol deviations/violations (12) Documentation of review by another institution’s IRB when appropriate (13) Documentation of cooperative review agreements, e.g., Memoranda of Understanding (MOUs)

for multi-site research, or as otherwise appropriate (14) Federal Wide Assurances (FWA)

The study-specific records as outlined above relating to research that is conducted shall be retained for at least 3 years after completion of the research.

For studies that the IRB has exempted from continuing review, study-specific records shall be retained for at least three years after the exemption is granted. Annually, the IRB will make an inquiry with the investigator regarding the current status of the project until the investigator reports that the study is complete.

Authorized persons shall be able to access records for inspection and copying at reasonable times and in a reasonable manner. Investigators may be required to follow different record retention policies depending on study sponsorship.


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5.1 Documentation and Retention of IRB Documents

At a minimum, retention of records is required by 45 CFR 46 for a period or three years after a research project is completed. USA retains the following documents in accordance with this requirement.

Records will be retained longer if required by applicable FDA or DHHS regulations or by the study sponsor.

(1) Copies of all research protocols reviewed, evaluations, approved consent documents, applications for initial approval, continuing review, amendments, advertisements, adverse events reports and protocol deviations and any other correspondence from investigators related to the research study.

(2) Minutes of convened IRB meetings. (3) Copies of audit reports (4) Training of IRB members, staff, investigators and key research personnel (5) Correspondence with government officials concerning unanticipated problems (6) Correspondence with government officials that could reasonably be expected to affect the

status of USA’s FWA.

5.2 Access to IRB Records

Ordinarily, access to IRB records is limited to the IO, the IRB chairperson, IRB members, IRB staff, Office of Research Compliance and authorized USA representatives, and officials of Federal and state regulatory agencies, including the Office for Human Research Protections (OHRP), and, if applicable, the Food and Drug Administration (FDA). Investigators shall be provided reasonable access to files related to their research. All other access to IRB records is limited to those who have legitimate need for them, as determined by the IRB Chairperson, the Director, Research Compliance, University Counsel and the Institutional Official.

5.3 IRBNet Online Management System

The IRB utilizes IRBNet, an online management system for submission, review, and approval of human subjects research studies. IRB members use the IRB Review Form to document review of assigned research studies and is uploaded IRBNet. Additionally, adverse events, protocol deviations, and PI conflicts of interest are electronically tracked.

IRBNet resources, including login instructions, creating new project submissions, etc., can be found on the IRBNet resource webpage at: http://www.southalabama.edu/researchcompliance/irbnet.html

MEETING MATERIALS AND DOCUMENTATION

6.0 Meeting Agenda

The meeting agenda outlines human subject research activities subject to review by a convened meeting of board members under the jurisdiction of the IRB. Submission of a research protocol will satisfy all of the procedural requirements necessary for the comprehensive review of all of the relevant materials prior to the convened meeting. Additionally, the agenda provides a listing of any discussion


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items relevant to the operations of the human subject protection program .

The IRB Compliance Specialist prepares the meeting agenda. Additionally, relevant materials for review is distributed via IRBNet to all board members a week in advance of the scheduled meeting.

The agenda shall include the following items:

• Date of meeting • Approval of minutes from previous meeting • Adverse Events • Protocol Deviations • Closed/expired protocols • Protocol Reviews (noted for informational purposes)

o Closed protocols o Exempt protocols o Expedited protocols

• New Protocol Reviews o New Submissions o Amendments o Continuing Reviews

• Information/Education • Research Compliance • Old/New Business

6.1 Meeting Minutes

The minutes of IRB meetings shall be compiled by the IRB Compliance Specialist, following the IRB meeting minutes template. The following specific information shall be recorded in the meeting minutes:

(1) Attendance recorded by name (2) Approval of previous minutes (3) Adverse Events action (4) Protocol Deviations (5) List of closed/expired protocols (6) List of approved exempt and expedited approved protocols and specific citation for the category

of expedited review. (7) Actions taken by the IRB on initial, amendments, and continuing review applications. If applicable,

specific measures taken to protect vulnerable populations and request for waiver of informed consent. • Votes on these actions • Basis for requiring changes in or disapproving research • Summary of controverted issues • Required IRB findings and determinations

(8) Information/Education (9) Old/New Business


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The minutes shall record when a member either enters/leaves the convened meeting as evidence of proper quorum.

The minutes shall records when a member either enters or leaves the convened meeting

The minutes shall record any presence of conflict of interest or abstention

6.2 Review by convened IRB (Full Board Review)

Any study involving greater than minimal risk requires a review by the convened IRB. A few examples of studies that involve greater than minimal risk:

• Studies involving vulnerable populations including pregnant women, prisoners, mentally incompetent patients, and minors.

• Any clinical interventional study that randomly assigns human subjects to alternative experimental or placebo groups

• Studies involving sensitive information connected to personal identifiers

The IRB meets at least once a month on a regularly scheduled day, normally the second Tuesday of each month. Scheduled meetings may be cancelled by the IRB Compliance Specialist due to the inability to secure a quorum for attendance, or other reasons as may arise that make a scheduled meeting unnecessary or otherwise inappropriate. The IRB Office maintains an electronic IRB address book used to notify members of meetings and other pertinent IRB information.

One week prior to the convened meeting, all members of the IRB shall be provided with detailed initial review materials describing the research to facilitate discussion of the protocol adequately and determine the appropriate action during the convened meeting. The materials available in IRBNet are listed in section 6.2.2 below. All members of the IRB are expected to familiarize themselves with meeting materials in order to contribute to the IRB’s deliberations.

6.2.1 IRB Review Procedures

Primary/Secondary Reviewers

Both the primary and secondary reviewer for a given research protocol should make an evaluation of the protocol before the convened IRB meets and should present the protocol during the meeting. A primary/secondary reviewer system is used for review of initial protocols which two members are assigned to lead the review and present the protocol for discussion at the convened meeting. Primary/secondary reviewers are assigned in advance of the meeting by the IRB chair or staff. This review/presentation should include an overview of the project and the identification of major issues arising in the project.

Other reviewers

All IRB members receive the IRB agenda, previous month’s minutes for approval, appropriate IRB application(s), informed consent (or request to waiver informed consent) and surveys/questionnaires. Relevant materials are to be provided for all types of IRB review including initial review, continuing review and amendments for review at the convened meeting.


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6.2.2 IRB Meeting Materials

• IRB protocol • IRB application(s) • Consent document(s) or request for waiver of consent as permitted by 45 CFR 46.116(d) • Appropriate special population checklist, if applicable • Related grant applications or progress reports • Subject surveys/questionnaires • Supporting documentation from sponsors • Advertisements or other information provided to research subjects • Drug related information such as Investigator Brochures or package inserts • Any other information known to be relevant to the determination of safety, risks and benefit

to the research study • Subject recruitment materials, flyers, advertisements

Minutes of previous meeting

All members receive a copy of the minutes from the previous meeting of the IRB. The chair leads the meeting of the convened IRB. This includes calling the meeting to order, leading the IRB through the agenda, and calling for motions and votes. The chair ensures that all members have an opportunity to express their opinions and concerns on the research under review.

Voting

In order for research to be approved, it shall receive the approval of a majority of the members present at the meeting provided a quorum exists. The voting process proceeds as follows: The chair may entertain a motion (which usually comes from a primary reviewer) and a second that the IRB take a certain action regarding a given protocol. The actions the IRB may take are outlined in section 6.3. After a motion has been made and seconded, there should be an opportunity for discussion before a vote is taken. Those members present for the vote should be recorded as either voting for, opposed or abstained.

Recusal of members with a conflict of interest

When an IRB member has a conflict of interest that requires him/her to recuse himself/herself from discussion of and voting on a particular protocol, that member may not participate in the discussion unless asked to address questions raised by other members. If the member’s recusal causes a loss of quorum, the vote should be postponed to another meeting. For this reason, IRB members should notify the chair prior to the meeting if they have a conflict of interest related to a specific protocol slated for review at the meeting, and every effort should be made to ensure adequate members in attendance.

Attendance by investigators

Investigators may be invited to attend the portion of the IRB meeting at which their protocol is discussed. The investigator may answer questions raised by the IRB. The investigator should not be present for the final deliberation and vote on his or her protocol.


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Attendance by guests

The IRB may permit guests to attend a meeting, for example, in order for them to learn about the IRB process. Members should be alerted to the presence of guests and their reason for attending. Guests should sign the confidentiality agreement prior to the start of their attendance at the meeting.

Teleconference/videoconferencing

In some cases, teleconferencing and/or videoconferencing may be necessary in order to have a quorum for a meeting, or to ensure that a protocol is reviewed by someone with a proper level of expertise. When the IRB makes use of this technology, all other normal meeting requirements apply. Additionally, whenever teleconferencing and/or videoconferencing is used, special care must be taken to ensure the security of the data transmissions so that the privacy of researchers and IRB members is protected.

6.3 IRB Actions/Project Status

The IRB administrative staff shall provide written notification of its determinations to investigators.

IRB actions, upon review of research, include the following:

6.3.1 Approved

In the case of an approval with no changes, the research may begin once the investigator receives written documentation of IRB approval.

Unless otherwise specified, the approval period for research approved without changes is one year from the date of the meeting at which approval was granted.

6.3.2 Modifications Required

The IRB may determine that a study may be approved with minor changes or clarifications. Minor changes are those changes that do not involve potential for increased risk or decreased benefit to the human subjects. For minor changes, the IRB administrative staff ensures that the investigator makes the appropriate changes to the research protocol. The research may proceed after the required changes are verified and the investigator receives IRB letter of approval.

6.3.3 Information Required

The primary reviewer and/or secondary reviewer is responsible for reviewing the changes to ensure that the changes are adequately addressed. The IRB protocol receives final approval when all required changes have been submitted and approved by the reviewer(s).

Unless otherwise specified, the approval period for research for which minor changes were stipulated is one year from the date of the last convened meeting at which the protocol was reviewed.


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6.3.4 Pending follow-up of receipt and review of serious adverse event

All outstanding serious adverse event(s) pending review and/or response from the investigator during review of a renewal or amendment submission at the convened meeting will not be granted approval until the adverse event(s) is resolved.

6.3.5 Deferral

Deferral is used to describe the situation in which the IRB determines that substantive changes must be made before approval may be granted. The investigators response, including any amended materials, must be reviewed at the next convened IRB meeting.

Subject to IRB discretion, a proposal may be withdrawn if the investigator does not respond to a deferral within a reasonable amount of time. If the investigator wishes to conduct a study that has been withdrawn, he/she must submit a new application, addressing concerns from the prior IRB review.

Unless otherwise specified, the approval period for research protocols that are deferred is one year from the date of the last convened meeting at which approval was granted or minor changes were stipulated.

6.3.6 Disapproval

If the IRB determines that the research cannot be conducted at USA or by employees or agents of the University or otherwise under the auspices of the University, the project, as proposed, is disapproved and may not go forward. Disapproval usually indicates that a proposal requires major changes not likely to be feasible without a complete reassessment of the protocol by the investigator and/or sponsor.

6.3.7 Suspension and Termination of Research Study by IRB

The chair of the IRB or the convened IRB may suspend a study at any time if it is determined that the study requires further review or evaluation. This determination may be made due to an adverse event, noncompliance or other danger to human subjects. Once a study has been suspended, the convened IRB should review the study and either require changes to the protocol, allow the study to restart, or terminate the study.

Though the chair may suspend a study, only the convened IRB can make the decision to terminate a study. When a study is suspended or terminated, the IRB notifies the Institutional Official. If the suspended or terminated study is externally funded, the IRB will notify the Office of Sponsored Programs. The Institutional Official is responsible for all required reports to federal agencies.

6.3.8 Closed – Expired

IRBNet automatically generates an notice of expiration if a study is not closed or renewed by the date of expiration.

6.8.9 Closed – Project Complete

Upon receipt of a IRB closure form the IRB Office administratively closes the research project. The researcher will not be permitted to have any further interaction with subjects or their data in ways that would require ongoing IRB approval. If the investigator whish to enroll new subjects for the study or


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engage in human subjects research he/she must reactivate the protocol with the IRB Office. The researcher may close a study when he/she is no longer accruing subjects, using research interventions on existing subjects, collection data (including follow-up data), or performing any other tasks identified as part of the IRB approved research study. However, a researcher may continue to analyze aggregate de-identifed data sets beyond study closure.

6.8.10 Closed

Project closure that is not affiliated with project completion or expiration.

6.4 Notification of IRB Actions

Investigators received automated notifications via IRBNet of the IRBs decision and any changes required. Summaries of actions taken are provided to the Institutional Official in the form of meeting minutes. Final approval is not granted until all required changes have been made and submitted for review and approval. The IRB attempts to retain approval periods constant from year to year throughout the life of each project. Therefore, when materials are submitted far enough in advance that the IRB performs the continuing review within 30 days before the current approval period expires, the IRB retains the original anniversary date as the date for the new approval period to begin. That is, the clock need not be reset if review occurs within thirty days of the original anniversary date. This notification process applies to all levels of review. The IRB Chair does not sign approval letters generated in IRBNet. Federal regulations do not specify the procedure the IRBs must use regarding signatures of IRB approval letters. USA IRB does not require signature of approval letters by the Chair.

6.5 Appeal of IRB Decisions

Investigators may appeal IRB requirements for specific changes in the protocol and/or consent document(s). At the discretion of the chair, the investigator may make such an appeal in writing to the IRB. At the IRB’s discretion, the investigator may be invited to the IRB meeting at which his or her appeal will be considered.

If the IRB decides to disapprove a research activity, it shall include in its written notification a statement of the reasons for its decision, and give the investigator an opportunity to respond in person and/or in writing. An appeal of a disapproved research project must be reviewed at a convened meeting.

Other university officials may, in certain cases, decide that a research study may not be conducted despite IRB approval. One example could be a circumstance in which a certain project or area of research is deemed to be inappropriate or underfunded. In the case of a decision by the IRB to disapprove, suspend, or terminate a project, only the Institutional Official may request that the IRB reevaluate a project because of procedural questions related to the IRB review. However, the IRB decision to disapprove, suspend, or terminate a project may not be reversed by the any officer or agency of the University of South Alabama, state government or federal government

IRB RESEARCH EVALUATIONS, PROCEDURES, CRITERIA AND ACTIONS


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7.0 Determination of Type of Review

The IRB chair or administrative staff screens applications and makes determinations as to whether a project constitutes human subjects research and, if so, the type of review required (full board review, expedited review, or exempt). All applications are assigned to full board review if greater than minimal risk. Minimal risk is defined in §46.102(i) as 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. All projects involving the use of investigational drugs, devices, or biologics for which an IND/IDE are required receive full board review.

Reviewers complete the IRB Review Form to document their review and upload the reviewer document in IRBNet.

8.0 Expedited Review of Research

Under expedited review procedures, the review may be carried out by the IRB chair, Vice-chair or designated IRB member utilizing the appropriate IRB evaluation form. In reviewing the research, the reviewer may exercise all of the authorities of the IRB except that the reviewer may not disapprove the research. A research activity may be disapproved only after review at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary affiliation is in nonscientific areas.

Federal regulations limit the use of expedited review procedures to specific research categories published in the Federal Register. Use of expedited review by the IRB must be restricted to those applications that fulfill one of the nine categories listed below in section 8.1.

a. Minimal risk: Research activities that (i) present no more than minimal risk to human subjects and (ii) involve only procedures listed in one or more of the specific nine categories below.

b. The expedited review procedure may not be used where identification of the participants and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subject's 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. Additionally, the expedited review procedures may not be used for government classified research involving human subjects.

8.1 Types of Research Eligible for Expedited Review

The following nine expeditable categories pertain to both initial and continuing IRB review:

Category 1 Research on drugs for which an investigational new drug application(21 CFR 312) is not required or research on medical devices for which a) an investigational device exemption application (21 CFR 812) is not required or b) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.


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Category 2 Collection of blood samples by finger stick, heel stick, ear stick or venipuncture as follows: (a) from healthy, nonpregnant adults, who weigh at least 110 pounds. For these subjects, amounts drawn may not exceed 550 ml in an 8-week period and no more than 2 times per week; or (b) 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/kg in an 8-week period and collection may not occur more frequently than 2 times per week.

Category 3 Prospective collection of biological specimens for research purposes by noninvasive means. Examples: (a) hair and nail clippings in a nondisfiguring manner; (b) deciduous teeth at the time of exfoliation or if routine patient care indicates a need for extraction; (c) permanent teeth if routine patient care indicates a need for extraction; (d) excreta and external secretions (including sweat); (e) 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; (f) placenta removed at delivery; (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; (h) 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; (i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; (j) sputum collected after saline mist nebulization.

Category 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: (a) 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; (b) weighing or testing sensory acuity; (c) magnetic resonance imaging; (d) electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography; (e) moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.

Category 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).

Category 6 Collection of data from voice, video, digital, or image recordings made for research purposes.

Category 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.

Category 8 Continuing review of research previously approved by the convened IRB (a)


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where the research is permanently closed to the enrollment of new subjects, and all subjects have completed all research-related interventions, and the research remains active only for long-term follow-up of subjects; or (b) where no subjects have been enrolled and no additional risks have been identified; or (c) where the remaining research activities are limited to data analysis and report writing.

Category 9 Continuing review of research, not conducted under an investigational new drug application or an investigational device exemption where Category 2 through Category 7 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.

The reviewer must make certain determinations to approve applications. In conducting the expedited review, the designated reviewer(s) must review materials in sufficient detail to make the following determinations required under federal regulations:

• 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 subjects for diagnostic or treatment purposes.

• Risks to subjects are reasonable in relation to anticipated benefits if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.

• Selection of Subjects is Equitable In making this assessment the reviewer(s) 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 disable persons or educationally disadvantaged persons.

• 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 federal regulation and institutional polices.

• Informed consent will be appropriately documented, in accordance with, and to the extent required by federal regulation and institutional polices

• If applicable, approve justification and document criteria is met for waiver of obtaining informed consent or waiver for obtaining signed informed consent

• When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects

• When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.

• Vulnerable Subjects. Additionally, when some or all of the subjects are likely to be vulnerable to coercion or undue influence, the IRB reviewers must determine that additional safeguards have been included in the study to protect the rights and welfare of these subjects.

Research approved previously by expedited review is considered eligible for expedited review at the time of its regular continuing review if during the course of the study, the risks of the study have not increased. Projects that were initially reviewed by the convened IRB continue to receive the same type of review unless the IRB determines that the study meets the criteria for expedited review as described in Category 8 or 9.

8.2 IRB Review Materials

When the IRB administrative staff has determined that a protocol is qualified for expedited review as set forth in DHHS/FDA regulations, a qualified reviewer shall be chosen from the membership of the IRB to complete the expedited review. One reviewer shall be assigned to each expedited review.


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The following materials are provided to the reviewer for expedited review applications:

• IRB application(s); • Sponsor Protocol, if applicable; • Investigator Brochure, if applicable; • Informed consent document and/or script as appropriate; • If applicable, request for waiver of informed consent • Appropriate special population checklist, if applicable • Copies of surveys, questionnaires or videotapes; • Approval letter from external site where research is conducted outside USA entity; • Relevant grant application, if applicable; • Advertising materials, including email solicitations

9.0 Exemption from Continuing IRB Review

Research activities involving human participants that are exempt from the requirement that they receive IRB full or expedited review are identified in 45 CFR 46.101(b)(1)-(6). Only the IRB may determine which activities qualify for an exemption. The Investigators do not have the authority to make an independent determination of research involving human participants or changes in ongoing research. The IRB administrative staff will review the Request for Exemption Application and determine if the project meets one of the six activities listed below. The determination that a research activity is eligible for exempt review must be documented on the Request for Exemption Application. An investigator may not initiate research involving human subjects that the investigator believes is exempt until the investigator has received formal written concurrence of this exempt determination from the IRB. Changes to exempted studies must be reviewed by the IRB just as amendments to studies receiving expedited or convened IRB review. In some instances, changes to an exempted study may render it no longer exempt.

9.1 Types of Research Eligible for Exempt Continuing Review

The following six categories of activities qualify for exempt review:

Category 1 Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (i) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods; or

Category 2 Research not involving children that is limited to the use of educational tests, survey procedures, interview procedures or observations of public behavior unless information obtained is recorded in such a manner that human subjects can be identified, directly or 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. This exemption does not apply to research involving children except for research involving observations of public behavior when the investigator does not participate in the activities being observed, or interact directly with the children. All other exemptions apply to research involving children. [45 CFR 46 101(b)(2) as modified by Subpart D 45 CFR 46.401 (b)]


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Category 3 Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under Category 2 of this section, if: (i) The human subjects are elected or appointed public officials or candidates for public office; or (ii) federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.

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.

Category 5 Research and demonstration projects conducted by or subject to approval of a federal agency and designed to study, evaluate or otherwise examine some aspect of (i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs.

Category 6 Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are 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 or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

9.2 Modifications of Exempt Studies

While no continuing review is required for exempt research, any proposed or anticipated changes in the study must be submitted to the IRB for review and approval. Certain changes may disqualify the research from receiving further administrative/exempt status.

If information comes to the attention of the IRB suggesting that there are factors increasing the sensitivity and/or potential risk to human subjects in research that otherwise would appear to qualify for exemption under the criteria listed above, the IRB may, in its sole judgment, deem the protocol to be subject to expedited or convened IRB review.

10.0 Modifications to Previously Approved Projects

A modification is a change in an approved research protocol. IRB review and approval is required before investigators can modify research protocols, except when necessary to eliminate apparent immediate hazards to the subjects. Any proposed change to a previously approved project must be submitted as an amendment to that project and may be reviewed by the expedited review procedure or by the convened IRB, depending on the IRB’s assessment of associated risk. Minor changes in previously approved research may be approved by expedited review. Minor changes are those that do not significantly alter the risks/benefits relationship or other study elements.

Modifications that might increase the risk to human subjects in a study or otherwise represent a substantive change should be reviewed by the convened IRB. If an amendment requires convened IRB review, at least one primary reviewer is assigned and the amendment is reviewed by the entire IRB, as described for initial or continuing review.


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Modifications that have the potential to affect the subject’s willingness to continue participation will be re-consented. This determination is made during the IRB review process and communicated by the IRB to the study site via the modification approval letter.

11.0 Continuing Review of Approved Applications

Periodic review of research activities is necessary to determine whether the risk/benefit ratio has changed, whether there are unanticipated findings involving risks to participants, and whether any new information regarding the risks and benefits should be provided to participants. The IRB shall have authority to observe or have a third party observe the consent process and the research. All research protocols (except protocols determined by the IRB to qualify for administrative review) must be periodically reviewed, including research for which data analysis is the only on-going research activity.

11.1 Criteria for Requiring Review More Often Than Annually

Intervals for continuing review, in the absence of problems, are often set to a default of one year. However, the IRB may determine that more frequent intervals are appropriate. The IRB shall consider the following factors in determining the criteria for studies requiring more frequent review:

• Nature, probability and magnitude of anticipated risks to subjects; • Likely medical or psychological condition of the proposed subjects; • Overall qualifications of the investigator and other members of the research team; • Specific experience of the investigator and other members of the research team in

conducting similar research; • Nature and frequency of adverse events observed in similar research at this and other

facilities; • Vulnerability of the population being studied (this should be understood to include

unfamiliarity with the language used on consent forms and other printed matter intended for subjects in the study);

• Other factors the IRB deems relevant.

In specifying an approval period of less than one year, the IRB may define the period with either a time interval or a research milestone, e.g. number of subjects enrolled. The minutes should clearly reflect any determination requiring a review more frequently than annually.

11.2 Reminders/Notices:

When a research project is due for continuing review, an automated email notification is generated via IRBNet and provided to the investigator (and, when applicable the Faculty Advisor for student research) 60 and 30 days before the date of continuing review. If an application for renewal is not received from the investigator by the expiration date, then an IRBNet generates an expiration notice and is automatically emailed to the investigator. Copies of all reminders and expiration notices are kept in the IRB protocol file.

11.3 Lapsed Studies:

A lapsed study is one for which the approval period has expired prior to the renewal of approval by the IRB. If the investigator fails to submit the materials for continuing review within one month following the expiration date, then the lapsed study will be classified as an administrative closure. Notification is forwarded to the investigator ordering that all study-related measures must immediately cease except those necessary for welfare of the human subjects.


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12.0 When can project be submitted to the IRB for study Closure

Research studies can be deemed complete for a number of reasons, each requiring a different degree of IRB involvement. More often, however, the investigator or sponsor will close the study and the IRBs role will be more passive, receiving study completion documents and archiving the records for the study.

12.1 Voluntary Completion by Investigators

By submitting a Final Closure report, the researcher confirms that the study is finished and that researchers have no further interaction with subjects or their data. Once the IRB receives and accepts the Final Closure report form, the researcher is no longer required to submit for continuing review for renewal. If the investigator wishes to enroll new subjects for the study, or otherwise engage human subjects in research, he/she must reactivate the protocol with the IRB. Therefore, an investigator should only close a study when he/she is no longer enrolling new subjects, using research interventions on existing subjects, collecting data (including follow-up data), or performing any other tasks that were identified as part of the approved study. A study will not invariably be considered completed when it is closed to accrual, as research-related procedures may still be continuing. The IRB, in consultation with the investigator, may consider closing a study when active data analysis and publication pursuant to the approved study have ceased, even if the investigator retains records that may identify individual subjects. Additional research projects using data acquired in the approved study may constitute new human subjects research studies requiring to separate IRB review.

12.2 Termination of a Study by the IRB

In cases of serious adverse events or unanticipated problems, cases of researcher noncompliance, or in cases of protocol violations, the IRB may suspend a study to ensure subject safety. Upon investigation of the problem prompting suspension of the study, the convened IRB may decide that a study should be terminated. Following the vote of the IRB to terminate a study and the evaluation of any appeals made by the investigator, the study will be classified as closed. Though the chair may suspend a study, pending IRB review, only the convened IRB may vote to terminate a study.

12.3 Expiration of Approval Period

Once the approval period for a given study has expired prior to the renewal of approval by the IRB, it is considered a lapsed study and all research-related procedures must cease, except where doing so would jeopardize the welfare of the human subjects. The IRB generates a notice of expiration letter and electronically sends to the investigator and study coordinator, if applicable, indicating that continuation of research studies is a violation of federal regulations, however if the subjects would be harmed by halting the activities permission must be obtained by the IRB chair to continue research study related activities. If the Investigator fails to submit the materials for continuing review within one month following the expiration date, then the lapsed study will be classified as inactive. If the investigator submits the materials for continuing review within one month following the expiration date, the IRB will conduct continuing review and reactivate the protocol. This reactivation establishes a new approval period that is not retroactive to the prior date of expiration. If the investigator desires to continue a study that has lapsed for more than one month, then the investigator must submit a new application for re-review by the IRB, and must receive IRB approval before resuming research under the protocol.


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13.0 Adverse Events and Unanticipated Problems in Research

Investigators are responsible for prompt reporting to the IRB of "any unanticipated problems involving risks to participants or others…" (45CFR46.103.b (5)). The IRB maintains responsibility for initial assessment of the risk/ benefit ratio in a research activity involving human participants. During the course of the project, investigators are required to promptly inform the IRB of any unanticipated negative effect or undesirable experience that is possibly, probably or definitely related to study procedure(s).

Adverse events are not necessarily physical in nature; attention must be paid to psychological harm (such as depression, thoughts of suicide, etc), threats to privacy or participant safety. An event is considered serious and must be reported when the participant experiences an unusually strong response, recurring problems, and/or death.

13.1 Definitions:

Adverse Event

The University's policies on adverse events are based on Food and Drug Administration regulations. According to the FDA, a "serious adverse drug experience" with respect to human clinical experience includes "any experience that suggests a significant hazard, contraindication, side effect, or precaution," including "any experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose."

Unexpected Adverse Event

An "unexpected adverse experience" is any adverse experience whose nature, severity, and frequency of risk are not described in the information provided for IRB review or in the consent form. However, for purposes of University policy, reportable “unexpected” events are as follows: 1) all adverse events that are both serious and unexpected (even if not-drug related); 2) unexpected adverse events that are mild/moderate and may be related to the study drug (in the PI’s opinion); and unexpected adverse events that are clearly unrelated to the study drug do not have to be reported.

Unanticipated Problems

Unanticipated problems in a study, which might affect subject risk benefit analysis, confidentiality, or subjects’ willingness to continue in a project are to be reported to the IRB. The IRB will consider the effect of the problem on the study and on the subjects already enrolled. In some instances, revisiting the consent process with previously enrolled subjects may be necessary. If the problem prompts a change in the study, the consent process and documentation may require alteration for future study subjects. The investigator should use his/her own judgment when determining if an event is considered reportable beyond the scope of this policy. If there is a question, investigators are encouraged to err on the side of “over-reporting” or contact the IRB Office at 460-6308 or Office of Research Compliance and Assurance at 460-6625 for guidance.

Serious Adverse Event

A serious adverse event is defined as an adverse experience that results in any of the following


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outcomes:

a. death; b. a life-threatening adverse experience; c. inpatient hospitalization or prolongation of existing hospitalization; d. a persistent or significant disability such to disrupt a person’s ability to conduct normal life

functions; e. a congenital anomaly/birth defect; f. causes cancer; g. significant overdose or protocol error; or h. certain medical events that may not result in death, be life-threatening, or require

hospitalization, may also be considered a serious adverse event when appropriate medical or surgical intervention is necessary to prevent one of the outcomes listed above.

All serious adverse events that are unexpectedly associated with the study procedures must be reported to the sponsor and the IRB immediately but no later than 7 working days upon learning of the event using the USA Adverse Event Report Form. All deaths, whether or not they are directly related to study procedures, must be reported. For the purpose of this policy, death is never expected. In addition, any unexpected hospitalization of a research subject must be reported, even if the hospitalization is unrelated to the study medication

13.2 Special Requirements for Research Involving the Gene Therapy Studies

Investigators who have received approval from FDA to initiate a human gene transfer protocol must submit a written report of serious adverse events that are unexpected and associated with the use of the gene transfer product to the NIH Office of Biotechnology Activities (NIH/OBA), the Institutional Biosafety Committee, the IRB, and the FDA or study sponsor within 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.

13.3 Internal vs External Reporting Requirements

Internal adverse event is an adverse event affecting a research subject who is at a USA study site. For internal events, the USA IRB requires all serious adverse events and all unexpected adverse events to be reported to the IRB office within the time table outlined below. Furthermore, any problems involving the conduct of the study or subject participation at an USA study site, including problems with the recruitment and/or consent processes, require reporting. Adverse events judged to be the result of progressive disease need not be reported.

An external adverse event is an adverse event in a subject that is not at an USA study site. All investigational drug and device studies that are industry-sponsored, the study sponsor typically provides information regarding non-USA adverse events to the investigator. Therefore, the definition of an external adverse event is defined according to the sponsor’s federal reporting requirements, pursuant to 21 CFR 312.32 and 21 CFR 812.150. Study sponsors are required to notify investigators regarding adverse events related to the study drug occurring at other study sites (external events). Notification of these events are provided by the sponsor in an IND Safety Report or a MedWatch Report. These safety reports which describe adverse events from different study sites should be forwarded to the IRB along with a cover memorandum from the investigator or study coordinator outlining the pertinent information.


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Adverse Event Reporting TYPE OF EVENT Report to IRB Mild or Moderate and unexpected – on-site (if related, possibly related, probably not related)

14 working days

Serious and unexpected – on-site 7 working days Serious and unexpected – external site 10 working days after receipt

from sponsor Serious and expected – on-site 14 working days Life-threatening – on-site (if related, possible related, probably not related)

7 working days

Death – on-site 3 working days from notification

Death – external site

This timeframe is considered the maximal time for reporting a death.

10 working days after receipt from sponsor

Title 45 and Title 21 of the Code of Federal Regulations, the USA IRB requires that a report be submitted in writing for all unanticipated events.

13.4 IRB responsibilities following receipt of SAE/Follow-up Report

An Adverse Events Subcommittee of the IRB will review all adverse event reports and/or incident reports in order to re-evaluate the risks/benefits of the study and/or the appropriateness of the recruitment/consent process to determine if any changes should be made in the protocol or consent form.. If the investigator has already modified the protocol or consent form in response to these events, the appropriateness of these changes is also reviewed. The Adverse Events Subcommittee may recommend additional review by the full IRB. The IRB office will provide acknowledgement of receipt of this information and request additional information if follow-up or clarification is needed. The full committee has the right to request additional information from the investigator, note the occurrence of the adverse event but take no action, ask the investigator to modify the protocol or the informed consent or suspend or terminate the project.

The IRB is responsible for continuing review of all human subject research. This is done through the annual renewal process required for any ongoing study. Thus, all reported adverse events should also be described in detail in the Annual Renewal Report Form when a renewal application is submitted for the study, so that the IRB may consider renewal of the protocol in light of such information.

If the FDA or DHHS is involved, and if the problem is of sufficient magnitude, the appropriate agency officials will be informed.

14.0 Safety Alerts, IND Safety Reports, MED Watch Reports

During the course of a study, the IRB may receive IND Safety Reports, MedWatch Reports, Data Safety Monitoring Board (DSMB), problems involving risks to the subject or others or other adverse event reports from the Sponsor. The IRB acknowledges such reports as the study progresses and the investigator responsibilities are to ensure that the risk/benefit relationship of the research remains acceptable. The investigators are accountable for determining the impact on continuation of the


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research, whether the informed consent requires revision, and whether subjects who are already enrolled in the study need to be re-consented.

Investigators are required to submit the following reports per study sponsor requirements:

• Safety Updates* • IND Safety Reports • MedWatch Reports • SAE Reports for the study from other sites • DSM B repor t s * • Sponsor annual or interim reports*

* These documents are submitted for review at the time of continuing review for the protocol.

All other external reports are submitted to the IRB with a stamp on each report to include the following information: study number, chance of occurrence at study site and signed/dated by the Investigator.

If applicable, the IRB will inform investigators of their review and any required modifications in the consent or reporting requirements.

15.0 Protocol Violations and Deviations

The IRB has the responsibility to oversee the conduct of research that it approves. Consistent with this responsibility, the IRB may audit research studies at USA or studies in which faculty and/or staff of USA is engaged in research outside the institution. The Director, Office of Research Compliance and Assurance is responsible for conducting periodic and for-cause audits. As a result of an IRB audit, or in the course of routine IRB business, incidents of noncompliance by investigators with federal regulations or USA IRB policies may be identified. When these situations occur they are brought to the attention of the IRB. The incidents of non-compliance are then reviewed and managed in one of several ways depending on the severity of the non-compliance and the determination as to the willfulness of the investigator. For each incident of non-compliance that is identified a plan of correction is documented. Further audit may be required.

15.1 Defintions:

Non-compliance

Failure to comply with applicable Federal Regulations or USA IRB policies/guidelines

Serious non-compliance

An action or omission taken by an investigator or key research personnel that any other reasonable investigator would have foreseen as compromising the rights and/or welfare of the subject. Examples include, but not limited to:

• Failure to adhere to federal regulations governing use of human subjects in research;

- failure to obtain IRB approval prior to initiation of research activities - failure to notify the IRB of changes in approved procedures


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- failure to obtain and/or document informed consent - IRB approval expires due to failure to renew - Failure to notify the IRB of changes in the scope/intent of the study

• Failure to adhere to institutional policies where subject’s welfare has been adversely affected.

Continuing non-compliance

A pattern of repeated actions/omissions taken by an investigator or key research personnel that indicates a lack of ability and/or willingness to comply with federal regulations or USA IRB policies/guidelines.

15.2 Reporting Procedures:

Investigators are required to report protocol deviations to the IRB. Protocol deviations should be reported at the time of continuing review or sooner, as determined by the level of risk to the subject. Minimal risk protocol deviations are administratively reviewed, while greater than minimal risks deviations are brought to the full convened board for review.

15.3 Review by the IRB Committee (Serious or Continuing):

All incidences of non-compliance determined to be serious or continuing will be presented to the IRB. At a convened meeting, the IRB Chair and/or Director of Research Compliance and Assurance will present the issue(s) to the IRB. IRB members will receive audit reports and communication from the investigator. Members attending the meeting will review documents and determine whether:

• There is no issue of serious and/or continuing non-compliance • There is serious and/or continuing non-compliance • More information is needed and determination is deferred to future meeting pending receipt of

additional information

If the investigator offers a timely and satisfactory explanation for the concern and a plan to eliminate future incidents of such noncompliance and the IRB accepts, the IRB may elect to terminate the noncompliance investigation process and report that the noncompliance issues were met with no further action.

If the corrective action plan calls for any changes to the previously approved research and the changes involves more than minor modifications, the modification must be reviewed by the convened IRB. Minor changes will be reviewed by expedited review.

If the Investigator does not provide adequate information or corrective action plan, the IRB may ask the investigator to meet with the chair or attend an IRB meeting to discuss the issue(s).

DHHS regulations at 45 CFR 46.103(a) and (b)(5) require unanticipated problems involving risks to subjects, serious or continuing noncompliance, or suspension/termination of IRB approval conducted under an approved assurance be reported to OHRP.

15.4 Actions That May Be Taken During or After the Investigation of Non-Compliance:

• No action • Suspension: suspend enrollment and/or all research procedures for the specific research study in


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question • Termination of the research • Require a response from the investigator with a plan of corrective action • Initiate audits of all or some part of the investigator’s active protocols • Modification of the research protocol • Modification of the information disclosed during the consent process • Additional information provided to past participants • Modification of the annual review schedule • Acquire additional information pending final outcome • Requirements that current participants re-consent to participate (if applicable) • Monitoring of the research and/or consent process

15.5 Continuity of Care of Research Participants when study is suspended:

After the IRB has decided to suspend/terminate a research project, the IRB may make recommendations to investigators regarding ongoing care and treatment of human subjects who had been participating in research. The IRB shall take into consideration, the risk to the subjects from withdrawal of any investigational drug or device or social or behavioral interventions can be continued by another qualified physician or social/behavioral scientists and need further supervision of the participant(s).

15.6 Final Outcome:

If a finding of research noncompliance has been made, the IRB chair, or in the case of serious or continuing noncompliance, the IRB shall decide which corrective action(s) should be taken.

Corrective actions may include any of the following:

• suspension or termination of the investigator’s research protocol(s); • required training with respect to human subjects research and the regulatory requirements for the

conduct of such research; • imposition of changes in such research protocol(s) to further protect Human Subjects; • a monitoring plan • imposition of restrictions as a condition for the continuation of research by the investigator

16.0 IRB Protocol Audits

The ORCA is responsible for compliance activities including routine and for-cause audits of IRB approved protocols to ensure compliance with the protocol, federal and state regulations, and policies protecting human subjects research. On-site audits are conducted as part of the Human Subjects Protection continuing compliance oversight in accordance with federal regulations. The purpose of the audit procedure is to ensure protection of the human subjects participating in research. The information gathered during the audit is for the IRB to use to monitor the implementation of approved protocols, identify areas that need improvement, correction or targeted education, and to gather information for ways to improve the audit tool or the audit process. This process is viewed as an essential function to maintain a high state of regulatory compliance within the institution. The following information provides a detailed review of these procedures.

1. This standard operating procedure applies to all personnel involved in the implementation and


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coordination of research involving human subjects. The auditing function is a core component of the human subjects protection program and is performed on a proactive and for-cause basis.

2. ORCA shall contact the principal investigator and the study coordinator, if applicable, in writing

to schedule a date and time for the on-site audit. Depending on the number of subjects enrolled, a random sample of the subjects’ research records will be audited.

3. An audit questionnaire will be used as a tool in conducting the audit. All regulatory

documentation and the entire study record are subject to review. A typical audit includes, but is not limited to, review of regulatory information, protocol adherence, informed consent documentation, IRB correspondence, adverse events, inclusion/exclusion criteria, drug accountability, FDA 1572, financial disclosure statements, case report forms and source documentation.

4. Upon completion of each review, a written audit report is prepared. The report will be presented

by the ORCA at a scheduled monthly IRB meeting for review and discussion. The IRB may recommend additional oversight if major deficiencies are observed.

5. Post-audit procedures include a follow-up letter and copy of the written audit report forwarded

to the investigator and study coordinator, if applicable. If the audit identifies significant problems or concerns, the principal investigator will be asked to respond in writing by a specified date to acknowledge and address these issues. The report may include corrective actions which are tracked to assure that investigator responds appropriately.

6. Based on the scope and severity of identified problems, the following corrective actions may be

warranted by the IRB:

- Acknowledgment of the problems, no sanctions required. However, additional information is provided to the investigator(s) to avoid further infractions;

- A temporary halt to new subject accrual, until an identified infraction is corrected, but

continued follow-up for subjects already enrolled is allowed;

- Immediate suspension of the research project;

- Reporting of IRB infraction(s) and actions to the appropriate academic department chair, dean, and regulatory agencies such as the FDA, the Office of Human Research Protections, Office of Research Integrity and/or the funding agency.

7. Upon completion of the audit process, all audit reports are logged into the IRB database system

and officially complete.

8. The ORCA will provide consultation and education to investigators and study coordinators who conduct human subject research when warranted. By identifying noncompliance or potential noncompliance, advising, and consulting with investigators and key personnel, ORCA insures that the research operations involving human subjects minimize risks and meet University and regulatory agency standards

9. If suspected or alleged noncompliance (e.g., breach in IRB policy) is reported to the IRB office or

ORCA, a for-cause audit may be initiated. A for-cause audit is scheduled immediately, but otherwise is conducted and reported as described for routine audits.

17.0 Recruitment and Advertisement Methods


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The IRB is charged with protecting the safety and welfare of human participants through providing a review of the proposed research methodology, including recruitment and advertisement methods. The IRB must prospectively review all aspects of recruitment as planned or envisioned by the Investigator, along with all the information that the participant will see in the process of deciding whether to participate in the research. IRBs and investigators should be aware that advertising for subjects is often the first step in the informed consent process. When advertising is to be used, IRBs must review the information contained in the advertisement, as well as the mode of its communication, to determine whether the procedure for recruiting subjects affords adequate protection and is not misleading to subjects.

Any advertisement to recruit subjects should state clearly that the project is human subjects research and may include:

• the name and contact information of the investigator; • the purpose of the research, and, in summary form, the eligibility criteria that

will be used to admit subjects into the study; • a straightforward and truthful description of the incentives to the subject for participation in the

study (e.g., payment); • the location of the research and the person to contact for further information; • an indication that the advertisement and the study described therein have been reviewed by

the appropriate IRB. (IRB date stamp for flyers)

If a study involves investigational drugs or devices, no claims should be made, either explicitly or implicitly, that the drug/device is safe or effective for the purposes under investigation, or that the drug or device is in any way equivalent or superior to any other drug or device. The IRB should evaluate the proposed method of recruitment as it would be applied to students, employees or trainees to make sure that recruitment materials are not presented in a manner that could suggest that their decision regarding research participation could have an effect on their relationship with instructors, mentors or employers.

17.1 Recruitment methods

• Verbal recruitment (via telephone or in-person): investigators must provide the IRB with a oral script of the verbal recruitment process.

• Electronic recruitment (via email, web sites, or listservs): investigators must provide the IRB with a version of the email script or web site view detailing the recruitment process and how consent will be obtained. The IRB recommends that researchers follow procedures as outlined in the USA guidance document entitled “Conducting Computer and Internet-Based Research Involving Human Subjects”.

• Recruitment by mail: Investigators must provide the IRB with materials that would be used for the mailing campaign

• Recruitment by advertisements: Investigators must provide the IRB with the intended proposed advertisements, flyers, and ads used in the recruitment process. All newspaper advertisements should adhere to USA’s Office of Public Relations template.

17.2 Recruitment Incentives

Investigators often use incentives to enhance research participation to include various methods by offering gift certificates, vouchers, monetary compensation or class “extra credit”. The IRB will consider whether paid participants in research are recruited fairly, informed adequately and paid appropriately.

When using funds obtained from University accounts, investigators must account for monies disbursed


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during the course of a project. This is a necessary component of financial auditing. However, this accounting must be done in a way that participant confidentiality is not compromised. Using any type of identifier will void confidentiality protection mechanisms and possibly contradict what the participant was informed about in the consent document. Each expense should be tracked by participant ID, the amount paid and when payment occurred and retained in the protocol file.

Investigators must provide the IRB with a full description of how extra-credit incentives will be used. As with monetary incentives, a student may decline to participate in the research, but obtain extra-credit by alternate assignment methods. The student who chooses to participate in the research will be informed of the specific requirements to obtain extra-credit for participating in research, without misleading, coercive, or deceiving information. All students must be ensured they will not be penalized or their grade will not be adversely affected by their decision to not participate in the research.

17.3 Promotional materials

As stated in FDA's Information Sheet Guidance on "Recruiting Study Subjects," FDA requires that an Institutional Review Board (IRB) review and have authority to approve, require modifications in, or disapprove all research activities covered by the IRB regulations [21 CFR 56.109(a)]. An IRB is required to ensure that appropriate safeguards exist to protect the rights and welfare of research subjects [21 CFR 56.107(a) and 56.111]. In fulfilling these responsibilities, an IRB is expected to review all the research documents and activities that bear directly on the rights and welfare of the subjects of proposed research. The protocol, the consent document and (for studies conducted under the Investigational New Drug (IND) regulations) the investigator's brochure are examples of documents that the IRB should review. The IRB should also review the methods and material that investigators propose to use to recruit subjects.

The current IRB procedure is to "acknowledge" these materials (rather than facilitating a formal review and signed approval letter). However, the IRB does review and approve materials used in media advertising to recruit study subjects. If advertising materials used to recruit potential subjects (i.e., newspaper ads, radio script, television) are submitted AFTER initial approval, an amendment request must be completed to facilitate review and approval. Additionally, all newspaper ads must be approved for appropriate layout/design through Paul Taylor, Office of Public Relations.

It is the responsibility of the IRB to provide information based on its written standard operating procedures, and not to deviate to serve specific requests by of study sponsors. It is time intensive to provide study sponsors specific written documentation. The IRB needs to be consistent in following its written procedures for handling this type of request for review of promotional or study guidance materials.

17.4 External Investigators and Recruitment of Student Population

Investigators from external institutions periodically seek to recruit USA students to participate in a research study on campus. For any USA faculty or administrator receiving an inquiry about participation of USA students, the following steps should proceed to facilitate appropriate review of such requests:

• Obtain IRB approval from the investigator’s home institution, accompanied by the proposal and active recruitment method that will be used on USA’s campus

• Departmental or administrative official must support the study and active on-campus recruiting • USA faculty or administrator submits information collected from the external institution to the USA IRB

Office


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• USA IRB will evaluate the proposal • USA IRB may consider the external investigator’s home institution IRB review sufficient and grant

permission, request USA IRB approval or deny on-campus recruitment.

18.0 Informed Consent

The IRB recognizes that informed consent is a process to ensure that subjects are prospectively informed to sufficiently make a voluntary decision regarding research participation. Thereby, the IRB ensures all participants are informed about and voluntarily consent to research participation. Any individual invited to participate in a research study should be given a description of the study that is clear and complete enough for the individual to judge whether she or he wants to participate. The informed consent process should be designed to provide potential subjects with readily understandable information in an amount and timing appropriate to the level of risk in participating. As an IRB approved best practice, the teach back method will be used to assess that the subject has at least a basic understanding of what the research involves imparted above the standard of care. A consent certification template is used to facilitate this process. The utilization of this practice will be documented in the IRB Biomedical Research application within the informed consent section.

Consent documents must be written in language understandable to the participants or their authorized representatives. For the typical participant population, use of language at a 6th-8th grade level of schooling is recommended. The informed consent is a process; the face-to-face discussion the most important part. The consent form is only a documentation of that process.

The subject’s consent must follow and not precede receipt of this information unless the IRB approves a waiver or alteration of informed consent (as in some behavioral research that would be compromised by full disclosure in advance). Consent must be obtained from each subject who is legally, mentally, and physically able to provide it unless waived by the IRB. Consent should be in writing unless the IRB finds that written documentation of informed consent may be waived. Consent forms and other informational documents should be written in simple language to be easily understood by persons with no technical background in the field.

No informed consent, whether oral or written, may include any exculpatory language through which the subject or the subject’s authorized representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence.

The standard expectation is that all subjects will sign a document containing all the elements of informed consent, as specified in the federal regulations and noted below. Some or all of the elements of consent, including signatures, may be waived under certain circumstances.

Categories of consent may include: consent with documentation, consent without written documentation or oral consent. The informed consent document MUST include the following basic elements:

18.1 Basic Elements of Informed Consent:

Unless the IRB approves exceptions, the following information must be provided to the subject when seeking informed consent:


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a) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures that are experimental;

b) description of any reasonably foreseeable risks or discomforts to the subject;

c) A description of any benefits to the subject or to others that may be reasonably expected from the research;

d) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject;

e) A statement describing the extent, if any, to which confidentiality of the records identifying the subject will be maintained;

f) For research involving more than minimal risk, an explanation about compensation and/or medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained;

g) An explanation of whom to contact for answers to pertinent questions about the research and research subject’s rights, and whom to contact in the event of a research related injury to the subject, if relevant. Typically, questions concerning a research project should be referred to the PI for that project, whereas questions concerning the rights of human subjects should be referred to the IRB.

h) A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

18.2 Additional Elements of Informed Consent

For some studies, one or more of the following elements or information may be appropriate and required by the IRB:

a) 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) that are currently unforeseeable;

b) Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent;

c) Any additional costs to the subject that may result from participation in the research;

d) The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject (particularly when potentially therapeutic experimental interventions are being administered and unscheduled cessation of the intervention may pose health risks to subjects);

e) A statement that significant new findings developed during the course of the research that may relate to the subject’s willingness to continue participation will be provided to the


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subject;

f) The approximate number of subjects involved in the study.

g) When seeking informed consent for applicable clinical trials, as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be provided to each clinical trial subject in informed consent documents and processes. This will notify the clinical trial subject that clinical trial information has been or will be submitted for inclusion in the clinical trial registry databank under paragraph (j) of section 402 of the Public Health Service Act. The statement is: "A description of this clinical trial will be available onhttp://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time."

18.3 Exceptions to Informed Consent Requirements

The IRB may approve a consent procedure that does not include, or that alters, some or all of the elements of informed consent set forth above, or waive the requirement to obtain informed consent provided the IRB finds and documents that:

During the course of the consent process, investigators must:

a) Provide a copy of the consent form to the participant and/or legal representative;

b) Keep a copy of the consent form for the approved protocol file c) Seek consent only if the potential participant has the mental and legal capacity to give consent; if not, consent must be obtained by a legal

representative;

d) Obtain parental permission for minor participants; e) Provide sufficient opportunity to the potential participant or legal representative

to consider whether or not to participate; f) Ensure that the possibility of coercion or undue influence is absent; g) Enhance each participant’s comprehension of the information; and h) Utilize a consent form appropriate to the age level.

Investigator(s) may propose a short form written consent document, stating that the elements of informed consent required by 45 CFR 46.116 will be presented “orally” to the participant or the participant's legally authorized representative. To do so, investigators must ensure the following:

a) That a witness be present during the oral consent delivery process. b) Provide the IRB with a written summary of what is to be said to the participant or

the legal representative. c) Inform the participant or legal representative that he or she only has to sign the short form

itself. d) Ensure the witness shall sign both 1) the short form; and 2) a copy of the summary; e) Ensure the person actually obtaining consent shall sign a copy of the summary f) Provide the participant or legal representative a copy of the summary, in addition to a

copy of the short form.

Investigator(s) may request that the IRB waive certain requirements of the informed consent process


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if:

a) The research involves no more than minimal risk to the participants, and waiver will not increase the risk; AND

b) The waiver or alteration will not adversely affect the rights and welfare of the participants; AND

c) The research could not practicably be carried out without the waiver or

alteration (there is no reasonable alternative, without the waiver); AND

d) The participant will be given the opportunity to be debriefed immediately after

participation.

For research using protected health information, see also section 19.0 for additional criteria for waiver or modification of HIPAA requirement for written authorization.

Investigator(s) may request that the IRB waive parental or guardian permission if:

a) the regular conditions for waiver of consent are met (45 CFR 46.116(c) or 46.117(d)); or

b) the study focuses on a condition for which parental or guardian permission is not a reasonable requirement to protect the children and an appropriate mechanisms is substituted, e.g. is of such private and sensitive nature that it is not reasonable to require permission; or

c) a subject population for which parental or guardian permission is not a reasonable requirement to protect the children and an appropriate mechanism is substituted (e.g., abused or neglected children, 45 CFR 46.408)

18.4 Research related injury

The following three options in bold is IRB approved template language for research related injury for studies greater than minimal risk. If industry sponsored, pick the option that best matches the proposed contract language.

a. Sponsor pays for injury

If you are injured by being in this study treatment is available. The sponsor will pay for any necessary medical costs related to the treatment of your injury. If you are injured, there is no money set aside for lost wages, discomfort, disability, etc. You do not give up your legal rights by signing this form. If you think you have a research related injury, please call your study doctor.

Instruction:

a. If limiting treatment sites, the investigator must state specifically where the treatment will be provided.

b. If the sponsor attaches conditions state them, e.g., if the subject has followed all the instructions of the investigator, or if the investigator has followed all the procedures in the research study.


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b. Sponsor pays what insurance does not pay for injury

If you are injured by being in this study, treatment is available. Your insurance will be billed for the cost of treatment. The sponsor will pay for any necessary medical costs related to the treatment of your injury due to your taking part in the study and not paid by your insurance or any other payor. If you are injured, there is no money set aside for lost wages, discomfort, disability, etc. You do not give up your legal rights by signing this form. If you think you have a research related injury, please call your study doctor.

Instruction:

a. If limiting treatment sites, the investigator must state specifically where the treatment will be provided.

b. If the sponsor attaches conditions state them, e.g., if the subject has followed all the instructions of the investigator, or if the investigator has followed all the procedures in the research study, or will pay for whatever your insurance will not cover.

c. Sponsor does not pay for injury

If you are injured by being in this study treatment is available. The study site and/or your study doctor have not set aside money to pay for treatment of any injury. You and/or your insurance will be billed for the treatment of these injuries. Before you agree to take part in this research study you should find out whether your insurance will cover an injury in this kind of research. You should talk to the study doctor or staff about this. If you are injured, there is no money set aside for lost wages, discomfort, disability, etc. You do not give up your legal rights by signing this form. If you think you have a research related injury, please call your study doctor.

18.5 Audio/Video Recordings

Subjects must be informed that the study will involve the use of audio and/or video recordings. In addition, subjects should be informed whether or not these recordings are required to participate in the study (if recording is optional, provide a space at the end of the consent document where subjects initial to consent specifically for the audio and/or video recording).

Confidentiality should be addressed accordingly. The proposed use, management and storage of these recordings should be well defined in the consent document. Examples include: how will the study ensure the security of recordings, who will be transcribing the recordings, who will have access to the recordings, and when will the tapes be erased/destroyed.

18.6 Consent for Mail and Telephone Surveys

The consent process for mail surveys can be handled in more than one way. The Investigator may send the subject a letter requesting participation; the letter is accompanied by a conventional consent form which the individual signs and returns with his/her survey. If the study is to be anonymous, the consent form is separated from the survey immediately upon opening the package. In the second way, the Investigator provides on the cover page of the survey the information generally found in the consent form; also included there is a statement that by answering the questions and returning the survey, the subject is providing and documenting his/her consent.


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For telephone surveys, the interviewer reads from a “script” written on the survey document. The script contains a brief description of the study and includes the relevant elements of informed consent in narrative form. The interviewer solicits any questions the potential subject may have and answers them. The interviewer directly asks the person if he/she agrees to participate in the survey. Lastly, the Investigator documents on a data sheet: 1) that the script was read, 2) the individual was offered the opportunity to ask questions, and 3) the individual agreed or declined to participate in the study. The script must be submitted to the IRB for review and approval prior to its use in the study.

18.7 Short Form Consent Procedures

There may be circumstances when a subject is unable to read the full consent document (e.g., when the subject is illiterate or does not speak the language in which the consent document is written). In the latter circumstance, the IRB expects that a translation of the full form will be provided. However, there may be times when there is no opportunity to prepare a long form in advance; in such cases, a short form may be used.

A short form is a written consent document stating that the required elements of informed consent have been presented orally to the subject or the subject's legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the authorized representative. Only the short form itself is to be signed by the subject or the representative. However, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative, in addition to a copy of the short form.

18.8 Waiver of Informed Consent

Investigators must complete the Request for Waiver of Consent form available in IRBNet forms/templates and submit for IRB review and approval.

Waiver of Signed Consent

The IRB may waive the requirement for the investigator to obtain a signed consent form in cases where circumstances warrant such a waiver. Such a waiver is allowable if:

• The consent document is the only link between the subject and the research and the principal risk of harm would come from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern; or [45 CFR 46.117 (c)(1)]

• The research presents no more than a minimal risk of harm to the subjects and involves no procedures for which written consent is normally required outside of the research context. [45 CFR 46.117 (c)(2)]

In lieu of a signed consent form the IRB may require the investigator to provide subjects with a written statement regarding the research in the form of an information or fact sheet. This statement should contain, at a minimum:

• A statement verifying that the project involves research; • A description of the level of involvement and amount of time expected from subjects; • A description of the study; • A description of the risks and benefits to subjects; • A statement describing the subject’s rights;


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• A description of the compensation to be provided to subjects; • Contact information for both the investigator and the IRB.

Examples of circumstances in which a waiver of written consent may be granted include situations where the researcher plans to use an abbreviated consent form, as in recruiting passersby for a brief, minimal risk, procedure. Similarly, a waiver may be granted to allow researchers to obtain oral consent for a survey of passersby or a telephone survey.

Finally, a waiver may also be granted if researchers wish subjects to imply their consent by returning a survey via the mail or the internet. This last approach is especially useful in preserving the anonymity of the subjects surveyed. In situations when anonymity of subjects is an important concern, investigators should ensure that this anonymity is preserved in the process of compensating subjects for their participation (e.g., obtaining social security numbers for check requests, etc.).

Waiver of Requirement for Informed Consent

An 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:

(1) The research involves no more than minimal risk to the subjects; (2) The waiver or alteration will not adversely affect the rights and welfare of the subjects; (3) The research could not practicably be carried out without the waiver or alteration; and (4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

ALL FOUR (4) OF THE ABOVE REQUIREMENTS AS OUTLINED IN 45 CFR 46.116(d) MUST BE MET AND DOCUMENTED BY THE IRB. Example: The subject has entered the Emergency Room due to a trauma. They are unable to consent and there is no Legally Authorized Representative present

18.9 Consent Form Templates

The IRB provides consent form template(s) that may be used for all written consent form documents. This consent template contains all of the basic elements described above. For clarity and to assure timely processing by the IRB, the consent form should follow the guidelines described above.

The consent form should be written at a level understandable to all potential participants and it must contain all information that would reasonably inform the subject’s willingness to participate. In order to facilitate this requirement, the IRB will provide templates that reflect appropriate language for various subject populations. The consent form should be written in second person with “you” or “your child” consistently used to refer to the subject in all statements.

The title of the project as listed on the consent form should be the same as the title listed on the application form, though the IRB may suggest or require modifications in the title under certain circumstances (e.g., in case the title would alert subjects to deception in the study or when the title may be too explicit regarding subject criteria as in a study of dysfunctional parents).

The date on which the consent form was prepared or modified should be indicated on the form so that revised forms can be easily distinguished from prior versions.

18.10 Assent by Minors


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Except under specific circumstances, assent to participate in a study must be obtained from minors (i.e., in Alabama, subjects aged 18 and under) who are capable of providing assent. The IRB shall determine that adequate provisions are made for soliciting the assent of the minor (this includes providing age specific language to the prospective subjects), when in the judgment of the IRB the children are capable of providing assent. In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all minors to be involved in research under a particular protocol, or for each child individually, as the IRB deems appropriate. If the IRB determines that the capability of some or all of the minors 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 minors (such as in a study with therapeutic potential), and is available only in the context of the research, the assent of the child is not a necessary condition for proceeding with the research. The USA IRB guidelines with respect to obtaining consent from parents or legal guardians and assent from minors is specified below:

1. In most cases, parental consent must be obtained if the research involves minors under the age of

19. The requirement for parental consent may be inappropriate in some cases such as research on child abuse.

2. Minors 6 years of age or younger, verbal or written assent is typically not required. Consent is based

on the permission of the parent(s)/guardian(s) and no assent is required. A brief verbal explanation of the research procedure should be explained to the child.

3. Minors 7 years or older should be involved in the decision to participate in a research projects unless:

a) the subject is not capable or mentally/emotionally, of being consulted, b) the IRB specifically waives the requirement.

4. It is highly encouraged that a separate written assent form be used for children age 7 -12 years old

to document assent. In general, it should briefly explain in basic terms: o they are being asked to participate in a research study; o the purpose of the study; o an estimate of how much time is involved in participating; o what will happen to them if they agree to participate (e.g., ‘draw some blood’); o foreseeable risks/discomfort and any benefits they may experience; o they should ask their parents and doctor/researcher any questions they have about

participation; o participation is voluntary and they can withdraw at any time

5. Typically, adolescents 13-18 years old (minors) should be fully informed about a study and give assent to their own participation in the research. In the instance, both the adolescent and the parents(s)/guardian(s) sign the form, with a signature line for the adolescent first. The signature line for parental consent/permission should follow.

6. Assent expires when a child becomes an adult. At that time the subject must sign the IRB approved

adult consent for the research study.

Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement under circumstances in which consent may be waived in accord with 45 CFR 46.116.

18.11 Parental Permission

Unless otherwise provided by state law, or unless this requirement is waived by the IRB pursuant to 45


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CFR 46.408(c), the permission of the parent or legal guardian is required in order for minors to participate in research. Where research is covered by 45 CFR 46.406 and 46.407, permission is to be obtained from both parents unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.

Per 45 CFR 46.408(c), in addition to the normal waiver requirements, the IRB may waive the parental permission requirement if it determines that a research protocol designed for conditions or a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects. This waiver might apply to studies involving neglected or abused children, or older adolescents presenting in medical situations wherein a parental consent requirement might deter the child from seeking needed care (e.g., seeking care at an STD clinic). If parental permission is waived, the IRB must be sure that an appropriate mechanism for protecting the children is substituted. The choice of an appropriate mechanism would depend on the nature and purpose of activities in the protocol, the risk and benefit to the subject, and their age, maturity, status, and condition.

18.12 Surrogate Consent for Subjects Who Are Decisionally Impaired

There is an important distinction between the legal meaning of the term “incompetent” and our broader use of the term “decisionally impaired.”

• “Incompetence” is a finding of a court of law that results in the appointment of a legally authorized representative for the individual judged incompetent by the court.

• Decisionally impaired persons are those who have a diminished capacity for autonomous decision making due to a psychiatric, organic, developmental or other disorder that affects cognitive or emotional functions. Some adult individuals who appear to be decisionally impaired may not have been declared legally incompetent. For these individuals, there may not be a representative authorized under state law to consent to the individual’s participation in research unless the individual had previously, while of sound mind, executed a power of attorney broad enough to include consent for the individual’s research participation.

• Seek the guidance of University counsel if there are questions about legal authorization for surrogate consent in specific situations.

18.13 Obtaining Consent from Non-English Speaking Subjects

The federal regulations for the protection of human subjects require that informed consent information be presented in “language understandable to the subject” and, in most situations, that informed consent be documented in writing (45 CFR 46.116 and 46.117). Where informed consent is documented in accordance with 46.117(b)(1), the written consent document should embody, in language understandable to the subject, all the elements necessary for legally effective informed consent. Subjects who do not speak English should be presented with a consent document written in a language understandable to them. Federal officials (DHHS Office of Human Research Protections) strongly encourage the use of this procedure whenever possible.

Alternatively, 46.117(b)(2) permits oral presentation of informed consent information in conjunction with a short form written consent document (stating that the elements of consent have been presented orally) and a written summary of what is presented orally. A witness to the oral presentation is required, and the subject must be given copies of the short form document and the summary. However, when


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performing research using non-English speaking subjects, the use of short form consent documents should only be used when unexpected circumstances arise and there is not sufficient time to prepare a full consent form translation. The short form should not be used as a convenient way to circumvent translation of the full consent form. Additionally, when the subject population of any research study is expected to include a significant number of subjects who are not fluent in English but are fluent in any single language other than English, the IRB requires a full translation of the English version of the study’s approved consent document (i.e, a long form consent document).

While the use of non-English speaking subjects presents a unique set of challenges for the researcher, care must be taken not to exclude non-English speaking subjects from research that may have potential benefits to this group of indiviudals.

18.13.1 Translation and Informed Consent

Attention should be paid to both oral interpretation and written translation in the informed consent process.

Oral interpretation should be performed by a qualified individual who is not a family member of the prospective subject. The individual performing the interpretation should be available for ongoing communication between subjects and investigators.

Written translation of informed consent documents should be performed by a qualified individual. Though there is no standard definition of what constitutes a “qualified individual,” the investigator should demonstrate due diligence in obtaining an adequate translation of the informed consent documents from an individual whose qualifications would appear adequate to a reasonable person. Back translations to English may be one method for validating the accuracy of the translation. Acceptable translators include the following, although all may not be appropriate for all types of research:

• An individual who is bilingual and fluent in both English and the language of the Non-English speaking subjects, for minimal risk studies

• A commercial entity that provides translations as a service to the public • An external sponsor such as NIH, NSF, or private industry • For Spanish translations, any translator.

For research that is greater than minimal risk, the translated document may be back-translated into English by another individual who is also bilingual and fluent in both languages. If the research is a minor increment over minimal risk, the IRB may waive the requirement of the back translation into English.

18.14 Consent for Use of Stored Samples and Genetic Testing

In general, all anticipated uses of collected samples of human tissues, body fluids, or biological products should be carefully delineated in the consent form. The University of South Alabama IRB biological specimen language and/genetic testing must be used. The study sponsor language should not be used in place of the USA IRB approved language. Do not duplicate if using multiple consent documents.

If genetic testing is to be done on the collected sample, the consent form should disclose the specific genetic information to be obtained, whether the information may be of value to the subject, whether and how that information will be disclosed or made available to the human subject and, if so, whether genetic counseling will be available at the subject’s option.


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If specimens are to be collected and stored for as yet unspecified purposes (genetic testing or otherwise), this should be addressed in the consent form or in an addendum. The IRB provides templates addressing these issues located in IRBNet forms/templates. An addendum to the consent may be used when specimen storage is secondary to the main purpose of the study.

The consent form and process for maintaining human specimens in a repository for future research uses must inform the subjects explicitly about the unspecified possible future use of the specimens and related personal information. The consent process must include the following:

• How the sample will be stored and possibly used in future research studies.

• A description of any personal information about the specimen source will be maintained (this may or may not include identifiers).

• If no personal identifiers will be used for labeling the stored samples, i.e., if it is impossible for the sample to be linked with the subject, the consent form should so state.

• If personal identifiers are to be used that will allow future matching of the subject to the collected sample, the consent form should describe how they will be used, how privacy and confidentiality will be protected, whether and under what circumstances identifying information would be disclosed.

• Future research using the samples will be reviewed by the IRB prior to additional use of the samples

• Whether and how researchers may contact individuals whose specimens are in the repository

• A statement about any potential commercialization and that there are no plans for subjects to share in financial proceeds that may accrue from products derived from the specimens.

• Whether and under what circumstance and how any results from research studies using the specimens would be communicated to or available to the human subjects, if, for example, the information gathered also applied to family members.

• If specimens are individually identifiable, how the specimens and associated data may be withdrawn from the repository. If the specimens are not individually identifiable, a statement that they may not be withdrawn for that reason.

18.15 Revised Informed Consent and Reconsenting

As informed consent is an ongoing process, if, during the course of the trial, the protocol has been modified in such a way that changes are made to the informed consent, subjects who have already given their informed consent may be required by the IRB to be reconsented using the updated form with the changes bolded. All participants currently enrolled in the study must sign the bolded copy of the updated informed consent form to acknowledge the changes. The subject may be reconsented at the next patient contact unless otherwise stated by the IRB or study sponsor.

For potential subjects who are not yet enrolled in the study, the revised informed consent replaces all previous versions for the informed consent and is used in its clean format. Informed Consent is obtained as described above.


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18.16 Stamped Copies of Consent Forms

All approved consent forms will bear the IRB approval stamp which includes the current approval period. The IRB requires that copies signed by participants include a stamp of approval.

18.17 Record Retention of Informed Consent Forms

As with all protocol related materials, a copy of the approved consent documents should be retained by the IRB for a minimum of three (3) years following closure of the study.

19.0 HIPAA and IRB Review

HIPAA stands for the “Health Insurance Portability & Accountability Act of 1996” (Public Law 104-191). In essence, the Rule specifies the actions required to protect the security and privacy of personally identifiable health care information and establishes the conditions for its use and disclosure. In the course of conducting research, researchers may obtain, create, use, and/or disclose individually identifiable health information. Under the Privacy Rule, covered entities are permitted to use and disclose protected health information (PHI) for research provided an individual gives written authorization to use or disclose PHI unless such authorization is waived or excepted by an IRBs or Privacy Board. The use of decedent’s information is protected by the Rule but authorization is not required.

The USA IRB will conduct the following HIPAA review and approval responsibilities within the larger context of its responsibilities such as:

• Review and approval of all authorization documents • Review and approval of all waivers of authorization, included limited waivers of authorization for

access, use and/or disclosure of PHI for University research purpose.

The Privacy Rule does not replace or modify the human research protection regulations found in 45 CFR 46. The Privacy Rule exceeds privacy provisions found in 45 CFR 46 as it extends to decedents, applies to all research, regardless of funding or activity and extends the definition of “identifiable information”.

As defined by the regulations, examples of identifiable health or protected health information include names, telephone numbers, fax numbers, electronic mail addresses, social security numbers, Internet protocol (IP) address numbers, finger and voice prints and full face photographic images and any comparable images.

The HIPAA Privacy Rule only applies if investigators use, receive and/or disclose protected health Information (PHI) from a covered entity in the course of doing research with human participants or human participant data. USA’s activities include both HIPAA covered and non-covered functions; the University is considered a “hybrid” HIPAA entity covering the USA Health System (i.e., USA Hospitals, USA Physician’s Group, Speech Pathology and Audiology, Psychology Clinic, Mitchell Cancer Institute, Center for Strategic Health Innovations and Center for Healthy Communities). Investigators who are not employed or are involved with research falling under the jurisdiction of the University’s hybrid entity are not covered by HIPAA; therefore, HIPAA regulations do not apply. However, confidentiality of data collected must be maintained.


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Review of medical records and ePHI: Designation is made in IRBNet for projects involving retrospective chart review and tagged (PHI – Medical Records) and / or projects involving electronic personal health information, which includes the development and completion of the Research Database

Registration Form which will be tagged (ePHI – dBase)

These two designations / tags are shared with Linda Hudson and Thad Phillips for their review. (USAMC Privacy and Security Officers) An automated email is generated and routed through IRBNet as a notification that reviewer access has been granted. The email will contain a deadline request for the date of completion. If the review has not been completed within the requested timeframe, a second email notification will be generated to ensure timely review.

19.1 HIPAA Authorization and Informed Consent

The authorization document must include all elements defined in the HIPAA regulations as described in the USA HIPAA in Research Compliance Plan. The full compliance plan is available on the Office of Research Compliance and Assurance website at: http://www.southalabama.edu/com/research/hipaa.shtml Researchers must generally obtain authorization for the use of PHI from the human subjects who’s PHI will be included in the study. The HIPAA authorization is incorporated into the informed consent within the confidentiality section. The USA IRB provides an authorization template that complies with HIPAA requirements. The researcher must customize the authorization template for the specific study he/she intends to perform. The USA IRB approved HIPAA Authorization template is located in IRBNet, Forms/ Templates.

The following differences in procedures for signing an authorization are outlined below:

Adults: A competent individual 19 years of age and older, should always sign the authorization to use or disclose his/her PHI. (the general ability to understand the concept of releasing his/her medical information).

Minors: Any parent or legal guardian may sign an authorization for a minor child in his/her legal custody. HIPAA does not require that an assent document specifically for research participation include any version of a HIPAA authorization.

19.2 HIPAA Security

The IRB application collects information on the maintenance of electronic identifiable health information (e-PHI) for each indiviudal study. If e-PHI is maintained, a separate application for the establishment of a research database or repository is submitted by the study site for review and approval. There are several key components that are evaluated during the review process to include the following, 1) workstation use for sending, receiving, storing, or accessing e-PHI information; 2) workstation security; 3) transmission security and implementing measures to protect the security of EPHI when transmitted electronically from one point to another; and 4) development of a contingency plan for the establishment of procedures for the “continuation of business” if the main system goes down.


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Additionally, a risk analysis is conducted to evaluate safeguards and vulnerabilities to the confidentiality, integrity and availability of e-PHI. The Office of Research Compliance and Assurance utilizes a survey instrument for collection of the information. Additionally, periodic physical/technical security inspections are conducted by USA’s HIPAA Security Officer.

20.0 Behavioral and Social Science Research

Behavioral and Social Sciences research often involves surveys, observational studies, personal interviews, or experimental designs involving exposure to some type of stimulus or intervention.

Social and Psychological Harms

When evaluating behavioral and social science research, the IRB carefully examines the research to determine the probability of risk of harm to subjects.

• The IRB considers the potential for participants to experience stress, anxiety, guilt, or trauma that can result in genuine psychological harm.

• The IRB also considers the risks of criminal or civil liability or other risks that can result in serious social harms, such as damage to financial standing, employability, insurability, or reputation; stigmatization; and damage to social or family relationships.

• If information is being collected on living individuals other than the primary “target” subjects the IRB considers the risk of harm to those “non-target” individuals, as well.

To mitigate such risks, the IRB reviews the proposal for appropriate preventive protections and debriefings, adequate disclosure of risks in the informed consent information, and mechanisms to protect the confidentiality and privacy of persons participating in or affected by the research.

Privacy and Confidentiality Concerns

The use of confidential information is an essential element of much social and behavioral and educational research.

• It is important to ensure that the methods used to identify potential research subjects or to gather information about subjects do not invade the privacy of the individuals. In general, identifiable information may not be obtained from private (non-public) records without IRB approval and the informed consent of the participant. This is the case even for activities intended to identify potential participants who will later be approached to participate in research. However, there are circumstances that are exempt from the regulations, and circumstances in which the IRB may approve a waiver of the usual informed consent requirements.

• It is also important to ensure that adequate measures are taken to protect individually identifiable private information once it has been collected to prevent a breach of confidentiality that could lead to a loss of privacy and potentially harm participants.

When information linked to individuals will be recorded as part of the research design, the IRB ensures that adequate precautions are taken to safeguard the confidentiality of the information. The more sensitive the data being collected, the more important it is for the researcher and the IRB to be familiar with techniques for protecting confidentiality. The 45 CFR 16.116(a)(5) regulations and the Common Rule require that subjects be informed of the extent to which confidentiality of research records will be maintained.


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The IRB may require that an investigator obtain a Department of Health and Human Services (DHHS) Certificate of Confidentiality (CoC). The CoC protects against the involuntary release of sensitive information about individual participants for use in Federal, state, or local civil, criminal, administrative, legislative, or other legal proceedings.

20.1 Types of Risk found with Social/Behavioral Research

A. Breach of confidentiality

B. Violation of privacy

C. Validation of inappropriate or undesirable behaviors of participants

D. Presentation of results in a way that does not respect the participants’ interests

E. Possible harm to individuals not directly involved in the research, but about whom data are obtained indirectly (secondary participants), or who belong to the class or group from which participants were selected

F. Harm to participants’ dignity, self-image, or innocence as a result of indiscreet or age-inappropriate questions in an interview or questionnaire that results in embarrassment, harassment, or stigmatization

G. Harm to a participant because of exposure to potential for criminal or civil liability and/or damage to financial standing or employability

20.2 Research Involving Deception or Withholding of Information.

Where deception is involved, the IRB needs to be satisfied that the deception is necessary and that, when appropriate, the participants shall be debriefed. (Debriefing may be inappropriate, for example, when the debriefing itself would present an unreasonable risk of harm without a corresponding benefit.) The IRB will also make sure that the proposed subject population is suitable. The regulations make no provision for the use of deception in research that poses greater than minimal risks to participants. The IRB considers the following issues when reviewing research that involves deception:

A. The scientific value and validity of the research.

B. The ability to obtain the information without the use of deception.

C. Whether the deception used will influence the participants’ willingness to participate.

D. The possibility of harm to the participant and a plan for debriefing which must be conducted as soon as possible after the conclusion of the study. Participants should be given the opportunity to withdraw their participation from the study after debriefing by requesting that any data collected from them be deleted and/or destroyed.

E. The possibility that the deception may cause invasions of privacy.

This information is requested in the IRB application form.

The employment of deception by an investigator(s) for the purpose of securing subject participation and/or to prevent potentially biased reporting of data/information by the subject is permissible provided all of the following conditions exist:


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• Deception is necessary due to the lack of alternative procedures for data collection not

involving deception; • The deceptive procedures will not place subjects at significant financial, physical, legal,

psychological, or social risk; • The data collection/experiment will be followed by careful debriefing sessions whereby the

subjects are fully informed of the nature and purpose of the deception; and • The procedures for deception must meet the guidelines established by the discipline of the

investigator through its professional code of ethics.

20.3 DebriefingIn order for the IRB to adequately review the research, investigators should justify, in detail, in the protocol, the reasons for deceiving or withholding information from subjects, including an explanation of: (a) the necessity for deceiving subjects; (b) how potential benefits of the research justify the use of deception; and (c) how the investigators will conduct the debriefing. In addition, investigators should include a debriefing script or statement that indicates the information subjects will receive regarding their participation in the research. The IRB in collaboration with the investigator will determine whether subjects should be debriefed either after unwittingly participating in the research or after knowingly participating in research that involved deception. The IRB may require debriefing when it contributes to the subject’s welfare, i.e., when it corrects painful or stressful misperceptions, or when it reduces pain, stress, or anxiety concerning the subject’s performance. For example, if a subject is lead to believe through participation in deception research that she/he has committed a crime or has a disease, a debriefing session may correct the induced stress, pain, and/or anxiety.

20.4 Oral Histories

Oral history interviewing projects generally do not involve the type of research as defined by DHHS regulations and therefore are excluded from IRB oversight. However, if the project does not fall within the guidelines below it does require IRB review and routine application submission procedures apply. For purposes of this SOP, projects fulfilling the following criteria are considered to be an oral history project and do not require IRB review:

(a) Oral history projects involve interviews that are explicitly intended for preservation as a historical document. (b) Projects involving oral history interviews that are not designed to contribute to generalizable knowledge as the 45 CFR part 46 regulations describe. The project does not seek underlying principles or laws of nature that have predictive value nor can it be applied to other circumstances for the purposes of controlling outcomes. (c) Projects involving oral history narrators that are not anonymous individuals selected as part of a random sample for the purposes of a survey. Individuals are selected due to their unique relationship to the topic and the questions are gradually developed and open-ended. (d) Projects involving oral history interviews where the historian (PI) follows the Oral History Associations Principles and Standards and Evaluation Guidelines as part of his or her work. (e) Oral history projects involve interviews in which those being interviewed fully understand the purposes, potential uses and their freedom not to answer questions. In most cases, the narrators


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are required to sign a release that addresses copyright and terms of access and reproduction (for interviews deposited in a library or archives), identification of narrators, and disposition of tapes

21.0 Review of Research Using Data and Specimens

Many studies combine characteristics of behavioural and social research with characteristics of biomedical research. There are many interdisciplinary combinations of behavioral and medical research. They often use or create tissue, specimen, or data repositories (banks).

21.1 Prospective Use of Existing Materials

Prospective studies are designed to observe outcomes or events (e.g., diseases, behavioral outcomes, or physiological responses) that occur subsequent to identifying the targeted group of participants, proposing the study, and initiating the research.

o Prospective studies using materials (data, documents, records or specimens) that will “exist” in the future because they will be collected for some purpose unrelated to the research (e.g., routine clinical care) do not qualify for exemption under regulations at 45 CFR 46.101(b)(4) and the Common Rule because the materials in these studies are not in existence at the time the study is proposed and initiated.

o However, the IRB may utilize expedited procedures (under expedited category #5,) to review research that proposes to use materials (i.e., data, documents, records, or specimens) that will be collected in the future (i.e., after the research has been proposed and initiated) for non-research purposes (e.g., clinical observations, medical treatment, or diagnosis occurring in a non-research context).

21.2 Retrospective Use of Existing Materials

Retrospective studies involve research conducted by reviewing materials (data, documents, records, or specimens) collected in the past (e.g., medical records, school records, or employment records) and existing at the time the research is proposed and initiated.

o Such research may be exempt under regulations at 45 CFR 46.101(b)(4) if the information is publicly available or if the information is recorded in such a manner that participants cannot be identified, either directly or through identifiers linked to the participants.

o If not exempt, the IRB may review such research utilizing expedited procedures, provided that the research involves no more than minimal risk to participants

o However, retrospective studies using existing materials occasionally entail significant, greater than minimal risks and require review by the convened IRB (e.g., where the research reveals previously undisclosed illegal drug use and the expedited review had concerns about invasion of participants’ privacy and/or the adequacy of confidentiality protections proposed by the investigators).


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21.3 Research Using Data or Tissue Banks

Human data repositories collect, store, and distribute Identifiable information about individual persons for research purposes. Human tissue repositories collect, store, and distribute identifiable human tissue materials for research purposes.

Tissue and Data Bank activities involve three components: (a) the collectors of data or tissue samples; (b) the bank/repository storage and data management center; and (c) the recipient investigators. Under a repository arrangement, the IRB formally oversees all elements of repository activity, setting the conditions for collection, secure storage, maintenance, and appropriate sharing of the data and/or tissues with external investigators. Specifically, the IRB determines the parameters for sharing data and/or tissues (which are identifiable within the repository) including whether additional informed consent of subjects is required. Typically, these parameters involve formal, written agreements stipulating conditions as follows:

o The repository shall not release any identifiers to the investigator. o The investigator shall not attempt to recreate identifiers, identify participants, or contact

participants. o The investigator shall use the data only for the purposes and research specified. o The investigator shall comply with any conditions determined by the repository IRB to be

appropriate for the protection of participants.

RESEARCH USING FDA-REGULATED PRODUCTS

22.0 Research involving an Investigational Drug or Device

The information below applies to Investigators and to Investigators who may also be sponsors holding an Investigational New Drug (IND) or Investigational Device Exemption (IDE) for the test article under study:

• When the principal intent of the investigational use of a test article is to develop information about the product’s safety or efficacy, an IND or IDE may be required. If an IND or an IDE is required, it is the investigator’s responsibility to submit the appropriate application to the FDA, obtain the necessary documentation, and provide this documentation to the IRB as a part of the approval process.

o An IND may not be necessary if all of the conditions stated in 21 CFR 312.2(b)(1) have been met. If the Investigator does not already have an IND, IRB approval will remain pending until receipt of an IND. If there is a debate regarding the need for an IND, the IRB will require that the Investigator contact the Food and Drug Administration (FDA) to obtain written documentation that an IND is not necessary.

o The IRB will review protocols involving investigational devices to determine if the device is a “Significant-Risk device” (SR) or a “Non-Significant Risk”(NSR) device. If the IRB determines that the research involves a SR device, an IDE is necessary. If the PI does not already have an IDE, the Investigator will be notified that IRB approval is pending receipt of an IDE.

• Protocols involving an Investigational Drug (IND) or Investigational Device (IDE) require consideration and satisfaction of the pertinent FDA and the DHHS regulations (21 CFR 50, 21 CFR 56, 21 CFR 312, 21 CFR 812, and 45 CFR 46). When the USA Investigator is acting as the sponsor of research involving an investigational drug, the IRB requires that the Investigator submit documentation that the proposed drug preparation has been reviewed and


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compliance with Current Good Manufacturing Practices has been confirmed. In addition, the IRB requires that the Investigator review the reporting and record-keeping responsibilities as stated in 21 CFR 312 and 21 CFR 314 (for investigational drugs) or 21 CFR 812 and 21 CFR 814 (for investigational devices).

• The Investigator is responsible for assuring the IRB that investigational drugs and devices are stored in a secure and safe manner and that the storage and safety requirements are consistent with FDA, sponsor, and affiliated research institutions’ storage requirements for drugs or devices of the type under study. Whenever possible, the storage of drugs and biologics should be under the supervision of a registered pharmacist and stored in the pharmacy in a limited access, locked area. Devices should be stored according to manufacturer’s specifications and maintained in a limited access area. Access to the test devices must be limited only to those authorized to use the devices.

• The protocol for the study should outline the security and storage plan for the test article(s) indicating that the plan meets the sponsor’s storage and security requirements. The plan should include whether or not control will be through a hospital pharmacy and under the supervision of a registered pharmacist or held in a proper and secure storage area by the investigator. The protocol should detail how the test article is used in human subjects, indicate who may have access to the test article(s) and outline the accountability plan for the test article(s) to ensure that there is no unapproved access to or use of the test article(s).

• Protocols involving an IND or IDE will undergo initial and continuing review at a convened meeting that includes at least one physician or pharmacist unless the protocol meets the criteria for expedited review (i.e., all treatment components complete, in follow-up only, data analysis only).

• Consent for studies involving an IND and/or IDE will be obtained. Although FDA regulations allow waiver of consent if research meets the criteria specified in 21 CFR 50.23 or 21 CFR 50.24 and DHHS regulations allow a waiver of consent if research meets the criteria specified in 45 CFR 46 “Waiver of Informed Consent Requirements in Certain Emergency Research,” consent is required for all non-emergency research that falls under FDA regulations or involves experimental treatment, tests, or drugs. In addition, the consent form will identify the test article as investigational and will inform participants that the FDA may inspect research records.

• The Investigator who is a sponsor will provide the IRB with all documentation provided by the FDA indicating whether or not that sponsor has complied with FDA regulations dealing with sponsor responsibilities.

22.2 Determination of Need for an IND

Studies that involve FDA-regulated products that are submitted without a valid IND number will be reviewed with respect to determining the need for an IND, based on the investigator’s response to questions contained in the IRB application form.

If the IRB determines that the study is exempt from an IND and approves the study, the study may begin without submission of an IND application to FDA. If the IRB determines that an IND is needed, the investigator/sponsor must submit an IND application to the FDA and provide documentation of the outcome of the FDA determination (IND number) to the IRB before the IRB approves the study.

The IRB may consider a study using a drug product that is lawfully marketed in the United States to be exempt from the requirements for obtaining an IND if all the following apply:

1. 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


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the labeling for the drug; 2. 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;

3. The investigation does not involve a route of administration or dosage level or use in a patient population (e.g., children, prisoners, pregnant women and fetuses) or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;

4. The investigation is conducted in compliance with the requirements for institutional review and with the requirements for informed consent; and

5. The investigation is conducted in compliance with the requirements with regard to promotion and charging for investigational drugs in 21 CFR 3 12.7.63

A clinical investigation involving an in vitro diagnostic biological product that is a blood grouping serum, reagent red blood cells, or anti-human globulin is exempt from the requirements for an IND if (a) it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure and (b) it is shipped in compliance with 21 CFR 312.160.

A drug intended solely for tests in vitro is exempt from the requirements of an IND if it is shipped in accordance with 21 CFR 312.160.

A clinical investigation involving use of a placebo is exempt from the requirements of an IND if the investigation does not otherwise require submission of an IND.

22.2 Determination of Significant Risk (SR) vs. Non-significant Risk (NSR) for Non-Exempt Medical Devices

For determination of the need for an IDE, the convened IRB will address the applicability of FDA regulations under 21 CFR 812.2 and, if necessary, make a significant risk determination. The Investigational Device Exemption (IDE) regulations [21 CFR part 812] describe two types of device studies, "significant risk" (SR) and "nonsignificant risk" (NSR). For both SR and NSR device studies, IRB approval prior to conducting clinical trials and continuing review by the IRB are required. In addition, informed consent must be obtained for either type of study [21 CFR part 50].

• A Significant Risk (SR) device study is one that presents a potential for serious risk to the health, safety, or welfare of a subject and

o is intended as an implant; or o is used in supporting or sustaining human life; or o is for use of substantial importance in diagnosing, curing, mitigating or treating disease, or

otherwise prevents impairment of human health; or o otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

A Non-significant Risk (NSR) device investigation is one that does not meet the definition for a SR study.

The risk determination is based on the proposed use of a device in an investigation, and not on the device alone. In deciding if a study poses an SR, the IRB considers the nature of the harm that may result from 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 is


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considered SR. Also, if the subject must undergo a procedure as part of the investigational study, e.g., a surgical procedure, the IRB considers the potential harm that could be caused by the procedure in addition to the potential harm caused by the device.

FDA has the ultimate decision in determining if a device study is SR or NSR.

If an investigator or a sponsor proposes the initiation of a claimed NSR investigation to an IRB, and if the IRB agrees that the device study is NSR and approves the study, the investigation may begin at that institution immediately, without submission of an IDE application to FDA.

To help in the determination of the risk status of the device, an investigator is asked to include the sponsor’s (including the investigator on investigator-initiated studies) assessment of whether or not a device study presents a significant or non-significant risk. The investigator must provide the IRB with a description of the device, reports of prior investigations with the device, the proposed investigational plan, a description of subject selection criteria, and monitoring procedures. The investigator must inform the IRB whether other IRBs have reviewed the proposed study and what determination was made. The investigator must inform the IRB of the FDA’s assessment of the device's risk if such an assessment has been made. The IRB may also consult with FDA for its opinion.

22.3 Controlling Distribution and Disposition of Devices

Although investigators are responsible for ensuring that investigational devices are made available only to persons who are legally authorized to receive them (see 21 CFR 812.110(c)), sponsors also bear responsibility for taking proper measures to ensure that devices are not diverted outside of legally authorized channels. Sponsors may ship investigational devices only to qualified investigators participating in the clinical investigation (§ 812.43(b)). Sponsors must also maintain complete, current, and accurate records pertaining to the shipment and disposition of the investigational device (§ 812.140(b)). Records of shipment shall include the name and address of the consignee, type and quantity of device, date of shipment, and batch number or code mark. Records of disposition shall describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of disposal.

To further ensure compliance with these requirements, sponsors should take appropriate measures to instruct investigators regarding their responsibilities with respect to recordkeeping and device disposition. The specific recordkeeping requirements for investigators are set forth at § 8 12.140(a). Upon completion or termination of a clinical investigation (or the investigator's part of an investigation), or at the sponsor's request, an investigator is required to return to the sponsor any remaining supply of the device or otherwise to dispose of the device as the sponsor directs (§ 812.110(c)).

22.4 Supplemental Applications

Supplemental applications are required to be submitted to, and approved by, FDA in the following situations:

1. Changes in the investigational plan: FDA approval is required for any change that may affect the scientific soundness of the investigation or the rights, safety or welfare of the subjects. IRB approval is also required for changes that may affect the rights, safety or welfare of the subjects. The change in the investigational plan may not be implemented until FDA approval (and IRB approval, if required) is obtained.


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2. Addition of new institutions/facilities: IRB approval is also required for new institutions. The investigation at the new institution(s) may not begin until both FDA and IRB approval(s) are obtained, and certification of IRB approval is submitted to FDA.

22.5 Submitting Reports

A sponsor shall prepare and submit the following complete, accurate, and timely reports. 1. Unanticipated adverse device effects (with evaluation) to FDA, all IRBs, and investigators within 5

working days after notification by the investigator. Subsequent reports on the effect may be required by FDA.

2. Withdrawal of IRB approval 3. Withdrawal of FDA approval 4. Current 6 month investigator list 5. Annual progress report 6. Recall and device disposition (within 30 working days after the request was made) 7. Final report 8. Use of device without obtaining patient informed consent 9. Significant risk determinations by the IRB when proposed to be nonsignificant risk 10. Other reports requested by the IRB or FDA

23.0 Device Studies in Pediatric Populations

Because the pediatric population represents a particularly vulnerable group, specific measures are needed to protect the safety of pediatric study subjects. Adult devices may be inappropriate for use in pediatric subjects for a variety of reasons, or may require specific design changes and/or specific labeling to accommodate their use in pediatric subjects. We recommend that you consider the following when developing devices or plan a clinical trial for devices intended for pediatric subjects:

• h e i g h t • w e i g h t • growth and development • disease or condition • hormonal inf luences • anatomical and physiological differences from the adult population • activity and maturity level • immune status

24.0 Emergency Use of an Investigation Drug or Biologic

The FDA human subjects regulations allow for an investigational drug/device to be used in emergency situations without prior IRB approval. Emergency use is defined as a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval for the use. These are typically situations in which the intent is not to conduct research but to act in the best interest of an individual patient. Nonetheless, the FDA requires IRB involvement. The health care provider is still required to obtain informed consent under these circumstances. The emergency use must be reported to the IRB in writing within 5 working days.

The written report submitted to the IRB chair must include a cover letter explaining the medical condition, reason for use, and date administered as well as a copy of the signed informed consent document. The health care provider must also include any manufacturer information available on the


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product (e.g., drug brochure). Once the health care provider has provided written notice, the IRB chair or his/her designee responds in writing that the information has been received. This acknowledgement of the IRB receipt does not constitute IRB approval.

Written informed consent must be obtained prior to administration or use unless the emergency situation makes it not feasible to obtain informed consent prior to using the test article. Exemption from the informed consent requirement is granted only when: (1) a life-threatening situation necessitates use of the test material; (2) the subject is unable to provide effective consent; (3) there is insufficient time in which to obtain consent from the subject's legal representative; and (4) there is no available alternative method of approved or generally recognized therapy of equal or greater likelihood of saving the subject's life.

The health care provider must document the infeasibility of obtaining consent as follows: The health care provider and a physician who is not participating in the clinical investigation must certify in writing the existence of all four conditions listed above before use of the test article. If in the health care provider's opinion, immediate use of the test article is necessary to save the life of the subject and there is insufficient time to obtain the independent determination before using the test article, the health care provider is to make his or her own written determinations, then obtain the written review and independent evaluation of a physician who is not participating in the clinical investigation. The documentation of the infeasibility of obtaining informed consent must be submitted to the IRB within five working days after the use of the test material. The IRB will respond to this report with an appropriate letter.

Although this procedure is designed to permit only a single emergency use of a test material for the treatment of one patient by one physician within the University, it is not intended to limit the authority of a physician to provide emergency care in a life-threatening situation. Should a situation arise that would require the emergency use of the test material for a second patient, by either the same or a second physician, subsequent emergency use should not be withheld for the purpose of gaining IRB approval. If it appears probable that similar emergencies will require subsequent use of the test material at the University, the health care provider should submit a protocol for future use of the article. The protocol must be prospectively reviewed and approved by the IRB before future use of the test material.

The use of a test material in a prospective investigation designed to be conducted under emergency conditions (e.g., emergency room or intensive care research) does not qualify for the emergency use exemption. 56.104 21 CFR 56.

25.0 Exceptions from informed consent requirements for emergency research

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 in the patient/subject’s medical record all of the following [21 CFR 50.23(a)]:

• The subject is confronted by a life-threatening situation necessitating the use of the test material.

• 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.


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If, in the investigator's opinion, immediate use of the test material 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 material, 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 material [21 CFR 50.23(c)].

The IRB will review the submitted documents and will indicate the regulatory basis for the emergency use and that its use was appropriate. Data obtained from such emergency use may not be published or otherwise used for research purposes. Submission of a research protocol by the investigator is required if future use of the test material is anticipated.

26.0 Emergency Use of Unapproved Medical Devices

An 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 5 10(k) of the FD&C Act are also considered unapproved devices which require an IDE.

The Food and Drug Administration (FDA) recognizes that emergencies arise where an unapproved device may offer the only possible life-saving alternative, 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. Using its enforcement discretion, FDA has not objected if a physician chooses to use an unapproved device in such an emergency, provided that the physician later justifies in writing to FDA that an emergency actually existed.

26.1 Requirements for Emergency Use

Each of the following conditions must exist to justify emergency use:

a. the patient is in a life-threatening condition that needs immediate treatment; b. no generally acceptable alternative for treating the patient is available; and c. because of the immediate need to use the device, there is no time to use existing

procedures to get FDA approval for the use.

FDA expects the physician to determine whether these criteria have been met, to assess the potential for benefits from the unapproved use of the device, and to have substantial reason to believe that benefits will exist. The physician may not conclude that an "emergency" exists in advance of the time when treatment may be needed based solely on the expectation that IDE approval procedures may require more time than is available. Physicians should be aware that FDA expects them to exercise reasonable foresight with respect to potential emergencies and to make appropriate arrangements under the IDE procedures far enough in advance to avoid creating a situation in which such arrangements are impracticable.


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FDA would expect the physician to follow as many subject protection procedures as possible. These include:

• obtaining an independent assessment in writing, documented in the patient/subject’s medical record by an uninvolved physician;

• obtaining informed consent from the patient or a legal representative; • notifying institutional officials as specified by institutional policies; • notifying the Institutional Review Board (IRB); and • obtaining authorization from the IDE holder, if an approved IDE for the

device exists.

26.2 After-Use Procedures

After an unapproved device is used in an emergency, the physician should:

• report to the IRB within five days [21 CFR 56.104(c)] and otherwise comply with provisions of the IRB regulations [21 CFR part 56];

• evaluate the likelihood of a similar need for the device occurring again, and if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IDE for the device's subsequent use; and

• if an IDE for the use does exist, notify the sponsor of the emergency use, or if an IDE does not exist, notify FDA of the emergency use and provide FDA with a written summary of the conditions constituting the emergency, subject protection measures, and results.

Subsequent emergency use of the device may not occur unless the physician or another person obtains approval of an IDE for the device and its use. If an IDE application for subsequent use has been filed with FDA and FDA disapproves the IDE application, the device may not be used even if the circumstances constituting an emergency exist. Developers of devices that could be used in emergencies should anticipate the likelihood of emergency use and should obtain an approved IDE for such uses.

27.0 Reporting the Use of a Test Material (Drug, Biologic or Device) to the IRB

The investigator’s written report is presented at the next appropriate IRB meeting. When an IRB receives a report by an investigator of an emergency use, the IRB examines the case to assure that the emergency use was justified and that the emergency use complied with FDA regulations. Using FDA guidance, the IRB will determine if the emergency use was justified and document the IRB’s decision in the minutes of the meeting.

The written report submitted to the IRB must include a cover letter explaining the medical condition, reason for use, and date administered as well as a copy of the signed Informed Consent Document. The investigator must also include any manufacturer information available on the product from the manufacturer (e.g., drug brochure).

Once the investigator has provided written notice, the use is assigned a IRB tracking number, and the chair or his/her designee responds in writing that the information has been received.


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Although this procedure is designed to permit only a single emergency use of a test article for the treatment of one patient by one physician within the University or affiliated institutions, it is not intended to limit the authority of a physician to provide emergency care in a life-threatening situation. Should a situation arise that would require the emergency use of the test article for a second patient, either by the same or a second physician, for the same test article, subsequent emergency use should not be withheld for the purpose of gaining IRB approval. If it appears probable that similar emergencies will require subsequent use of the test article at the University or affiliated institutions, every effort should be made either to sign on to the sponsor's protocol or to develop a protocol for future use of the article at the institution. Either of these protocols would need to be prospectively reviewed and approved by the IRB for future use of the test article.

28.0 Treatment Use of an Investigational Drug or Device

The IRB reviews the use of investigational drugs/devices if the investigator provides evidence that a treatment IND or IDE has been obtained or as single patient use (below). In all cases, treatment use of an investigational drug or device requires prospective IRB approval as well as subject informed consent.

28.1 Single Patient (Non-emergency Use)

In non-emergency situations, physicians may obtain investigational drugs for use outside of a controlled clinical trial for a single patient. This is often referred to as “compassionate use.” Usually, the patient is in a desperate situation and unresponsive to other therapies, or no approved or generally recognized treatment is available. There may be little evidence that the proposed therapy is useful, but it is thought to be plausible on theoretical grounds or anecdotal evidence. Access to investigational drugs for use by a single, identified patient may be gained either through the sponsor under a treatment protocol, or through the FDA, by first obtaining the drug from the sponsor and then submitting a treatment IND to the FDA requesting authorization to use the investigational drug for treatment.

IRB approval is also required prior to administration of the investigational drug. The approval is granted for the treatment of a single patient. When an investigator desires to obtain single patient use approval, the investigator submits an application and the study is assigned a University IRB identification number and sent through the new application procedure. The treatment use may occur only after IRB approval is obtained. Subsequent treatment use requires FDA approval for a treatment IND or IDE.

Every single patient use must be reviewed and approved by the IRB as well as the FDA, and all requirements for informed consent must be met. Although the FDA may waive local IRB review for a Single Patient Use, the University IRB Policy does not permit such waivers and will not allow a Single Patient Use without the prior review and approval of the IRB.

28.2 Humanitarian Use Device (HUD)

Humanitarian use of investigational devices is prospectively reviewed by the IRB. The investigator is required to submit a new application for review. Included in the application must be evidence that the investigator/sponsor has obtained a Humanitarian Device Exemption (HDE) from the FDA. These projects are subject to the same new and continuing review requirements as research projects as outlined in this document. The use of such devices is


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approved only for the purposes noted in the FDA approval letter. See Appendix D for additional information on Requirements for Humanitarian Use Device.

29.0 Biologics

IRBs have certain responsibilities when reviewing protocols that include the use of biologics. If biologics are administered as part of a research protocol, their IND status should be specified. Vaccine trials fall under the IND regulations. However, they differ from drugs in that: (a) they are not used to diagnose or cure disease in afflicted individuals, but to prevent a disease in a healthy human; and, (2) they are used to protect people with a high statistical risk for contracting a particular disease. Information concerning the dosage, route of administration, previous use, and safety and efficacy data need to be evaluated along with the phase of testing.

In the review of a protocol involving biologics, the IRB will consider the following:

a. Protocol: Has appropriate FDA clearance and IND approval been obtained? Is there evidence that the vaccine has been tested in animal trials and in the laboratory? What is the severity of the disease to be avoided? Does this protocol require NIH RAC and Biosafety Committee Review?

b. Benefits: What is the direct benefit to the individual subject? Possibility of immunity? To society as a whole?

c. Risks: What is the likelihood that subjects will be exposed to the infectious disease? What is the likelihood that the subject will suffer adverse consequences should he / she contract the disease? What are the adverse events and known complications of the vaccine therapy? In relation to the infectious disease? Is there any chance of allergic or anaphylactic reaction?

d. Recruitment: Will adult and pediatric subjects be vaccinated? Are any subgroups particularly susceptible to side effects i.e. elderly, young, immunocompromised? How will subjects be recruited? Is this a Phase I trial where low risk subjects will be vaccinated? Will there be a control group?

e. Monitoring: What provisions has the sponsor made for monitoring the trial? Is there a DSMB? Does the protocol provide adequate plans to monitor all subjects for immune status and adverse reactions, respond to problems, and disseminate results?

SPECIAL POPULATIONS

It is the policy of the University of South Alabama IRB to review, approve, and provide guidance on the ethical and regulatory considerations when special populations are involved in human subjects research. Special protections are essential to guide research involving vulnerable persons. FDA regulations and the Common Rule require IRBs to give special consideration to protecting the welfare of vulnerable subjects. At the same time, there are also requirements that members of specific populations be permitted or encouraged to become human research subjects to ensure that specific populations are adequately represented in research and have access to potential benefits of such research. The IRB is required to ensure that it has adequate board representation or the input of appropriate external consultants to consider specific kinds of research involving these special populations.


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30.0 Definitions:

Assent: An individual’s affirmative agreement to participate in research obtained in conjunction with permission from the individual’s parents or legally authorized representative. Mere failure to object should not, absent affirmative agreement, be construed as assent. Children/Minors: According to Federal regulations, children are “persons who have not attained the legal age for consent to treatments or procedures involved in the research. In Alabama, individuals are adults and of legal age (released from parental authority), when one attains the age of 19 years. Minors are those individuals who have not attained the age of nineteen years.

Dissent: An individual’s negative expressions, verbal and/or non-verbal, that they object to participation in the research or research activities.

Legally Authorized Representative: An individual, judicial, or other body authorized under applicable law to grant permission on behalf of a prospective participant for their participation in research activities.

Greater than Minimal Risk: The probability and magnitude of harm or discomfort anticipated in the research are greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Minimal risk: 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. An example of minimal risk is the risk of drawing a small amount of blood from a healthy individual for research purposes (because the risk of doing so is no greater than the risk of doing so as part of a routine physical examination).

31.0 Elements to Consider in Research Involving Special Populations

• The methods of recruitment, selection and the inclusion/exclusion criteria should be considered by the IRB, as should informed consent, the confidentiality of data, and the willingness of the subjects to volunteer.

• Group characteristics such as economic, social, physical and environmental conditions should be considered to ensure that the research includes appropriate safeguards for the protection of vulnerable subjects.

• Applicable state or local laws that bear on the decision-making abilities of potentially vulnerable populations.

• Research studies involving potentially vulnerable subject groups should have adequate procedures in place for assessing and ensuring subjects’ capacity, understanding and informed consent or assent. In some cases, researchers should be expected to enhance understanding for potentially vulnerable subjects.

• Whether or not additional safeguards are necessary to protect vulnerable subjects, such safeguards could include IRB monitoring of the consent process or the creation of a waiting period between contact and enrollment to allow for family questions.

32.0 Decisionally Impaired Subjects

Decisionally impaired persons are those who have a diminished capacity for autonomous decision making due to a psychiatric, organic, developmental or other disorder that affects cognitive or emotional functions. Other individuals who may be considered decisionally impaired, with limited decision-making ability, or individuals under the influence of or dependent on drugs or alcohol, those


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suffering from degenerative diseases affecting the brain, terminally ill patients, and persons with severely disabling physical handicaps. There are no regulations specific to research involving cognitively impaired persons.

The National Bioethics Advisory Commission (NBAC) has issued 21 recommendations for IRBs, the research community, and Federal regulators to consider regarding the decision-making capacity of particularly vulnerable participants. The complete report, “Research Involving Persons with Mental Disorders That May Affect Decision Making Capacity” (December 1998), can be found on-line at http://bioethics.gov/capacity/TOC.htm.

33.0 Surrogate Permission with Subjects Judged Incompetent to Consent

Where consistent with state law, the IRB recognizes as legally authorized representatives:

• Court appointed guardians. • Next of kin in the following order: spouse, adult child, parent, and adult sibling.

Surrogate consent may be used only when the prospective participant is incompetent as determined by a medical or psychological authority, as appropriate, who is not otherwise associated with the study, after appropriate mental or medical evaluation, and there is little or no likelihood that the participant will regain competence within a reasonable period of time, or as established by legal determination. This definition of incompetence is not limited to the legal definition but also may also be a clinical judgment that a person lacks the capacity to understand the circumstances of participating in research and to make an autonomous decision to take part.

Aside from issues of who may give legal permission for research participation of individuals who are decisionally impaired, there are many issues the IRB must consider in deciding whether to approve the possible participation of decisionally impaired persons in the research study.

IRBs should take special care to consider issues such as (1) whether decisionally impaired persons may be suitable subjects for this project; (2) whether, if the study is of more than a minor increase over minimal risk, the study holds out the prospect of direct benefit to the individual in a risk-benefit ratio at least as favorable to the subject as that presented by available alternative approaches; (3) whether the informed consent process can be structured to be appropriate and effective within the limits of the individual’s decisional capacity; (4) if surrogate consent will be used, whether assent will also be required; and (5) whether there are any circumstances under which a surrogate decision maker may enroll a decisional impaired individual in the study over the individual’s objection or resistance.

34.0 Research Involving Pregnant Women, Human Fetuses and Neonates

IRBs must consider that research involving women of childbearing potential might involve pregnant women (and viable fetuses), and should evaluate research protocols and risks, inclusion and exclusion criteria, and informed consent procedures, with this in mind.

The following HHS regulations must be applied before an IRB approves research that will deliberately include pregnant women:

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


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(a) Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses; (45 CFR 46.204(a))

(b) 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 which cannot be obtained by any other means; (45 CFR 46.204(b))

(c) Any risk is the least possible for achieving the objectives of the research; (45 CFR 46.204(c))

(d) 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 of subpart A of this part; (45 CFR 46.204(d))

(e) 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 accord with the informed consent provisions of subpart A of this part, except that 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))

(f) Each individual providing consent under paragraph (d) or (e) of this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate; (45 CFR 46.204(f))

(g) For children as defined in §46.402(a) who are pregnant, assent and permission are obtained in accord with the provisions of subpart D of this part; (45 CFR 46.204(g))

(h) No inducements, monetary or otherwise, will be offered to terminate a pregnancy; (45 CFR 46.204(g))

(i) 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))

and

(j) Individuals engaged in the research will have no part in determining the viability of a neonate (45 CFR 46.204(j))

Consent Decision Chart for Pregnant Women and Fetuses


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Direct benefit to mother only

Direct benefit to mother and fetus

Direct benefit to fetus only

No direct benefit or societal benefits only

Risk is more than minimal

Mother's consent Mother's consent Mother and father's consent

NOT APPROVABLE BY IRB

Risk is no more than minimal

Mother's consent Mother's consent Mother and father's consent

Mother's consent

34.1 Neonates

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

A neonate is defined as a newborn child. The following HHS regulations apply to research involving neonates:

(a) Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions are met:

1. 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)).

2. Each individual providing consent under paragraph (b)(2) or (c)(5) of this section is fully informed regarding the reasonably foreseeable impact of the research on the neonate (45 CFR 46.205(a)(2))

3. Individuals engaged in the research will have no part in determining the viability of a neonate (45 CFR 46.205(a)(3))

4. The requirements of paragraph (b) or (c) of this section have been met as applicable (45 CFR 46.205(a)(4)).

(b) Neonates of uncertain viability. Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by this subpart unless the following additional conditions are met:

1. The IRB determines that:

i. 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

ii. The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research; and


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2. 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 subpart A of this part, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest.

(c) 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:

1. Vital functions of the neonate will not be artificially maintained;

2. The research will not terminate the heartbeat or respiration of the neonate;

3. There will be no added risk to the neonate resulting from the research;

4. The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and

5. The legally effective informed consent of both parents of the neonate is obtained in accord with subpart A of this part, except that the waiver and alteration provisions of §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 (c)(5), 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 (c)(5).

(d) 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 this part.

34.2 The Placenta, the Dead Fetus, or Fetal Material

The following HHS regulations apply to research involving the placenta, dead fetuses, or fetal material:

(a) Research involving, after delivery, the placenta; the dead fetus; macerated fetal material; or cells, tissue, or organs excised from a dead fetus, shall be conducted only in accord with any applicable Federal, State, or local laws and regulations regarding such activities.

(b) If information associated with material described in paragraph (a) of this section is recorded for research purposes in a manner that living individuals can be identified, directly or through identifiers linked to those individuals, those individuals are research subjects and all pertinent subparts of this part are applicable.


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34.3 Neonates of Uncertain Viability

Until it has been ascertained whether or not 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))

• 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 28.0: Informed Consent, 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))

34.3 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 28.0: 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))

34.4 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.

35.0 Research Involving Prisoners

Federal regulations define a “prisoner” as 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


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individuals detained pending arraignment, trial, or sentencing. [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).

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 DHHS 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 DHHS Secretary (through OHRP) must determine that the proposed research falls within the categories of research permissible under 45 CFR 46.306(a)(2).

35.1 Issues to Address in Reviewing Prisoner Research

There are special requirements for the IRB involved with review of projects that involve prisoners. The Board must have a member that is either a prisoner or a prisoner representative with an appropriate background and expertise.

Any project that involves prisoners will be reviewed and presented (either primary or secondary) by the IRB’s prisoner representative during the full board meeting. This applies to submissions related to projects that involve prisoners, including initial, periodic review, revision, deviation/violation, and adverse event submissions. If prisoners are proposed as part of the inclusion criteria in a new project application, a Investigator Checklist for Studies Involving Prisoners must be submitted with the new project application. The checklist ensures that the appropriate review is completed for this population and provides regulatory documentation in fulfilling Subpart C requirements.

35.2 Categories of Research in Which Prisoners May Participate

The IRB must find that the research is permissible in one of the following categories:

(A) 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;

(B) 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;

(C) research 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 addition, and sexual assaults) provided that the study may proceed only after the Secretary has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of his intent to approve such research;

(D) research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases, in which


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those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the intent to approve such research.

Categories A and B are considered minimal risk. Minimal Risk is defined as risks normally encountered in the daily lives of non-incarcerated healthy persons, not risks encountered in the daily lives of prisoners.

Categories C and D may require OHRP to have the research reviewed by appropriate experts and may require a notice of intent to approve the research published in the Federal Register.

35.3 Required Findings

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:

(1) the research under review represents one of the categories of research permissible under 45 CFR 46.306(a)(2); (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; (3) the risks involved in the research are commensurate with risks that would be accepted by nonprisoner volunteers; (4) 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; (5) the information is presented in language that is understandable to the subject population; (6) 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 (7) 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.

35.4 Certification of prisoner research

Institutions that conduct HHS-supported research involving prisoners as human subjects must take several steps to certify that the research is permissible according to federal regulations. The Office of Research Compliance will send a brief certification letter to OHRP that simply includes the


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certification statement required in 45 CFR 46.305(a) and a statement indicating that the IRB chose one of the four permissible categories of research in 45 CFR 46.306(a)(2). Inclusion of the following information is recommended to expedite the prisoner certification process:

• In addition to the prisoner certification, researchers should submit the protocol application (which includes the protocol and any IRB submission materials, including consent forms) and the grant application(s) (and any grant award updates).

• Prisoner research certification letter, including:

o OHRP Assurance Number o IRB Number for Designated IRB o Site(s) where research involving prisoners will be conducted o If prisoner research site is engaged in research, provide OHRP Assurance Number o DHHS Grant Award Number o DHHS Funding Agency Name o Funding Agency Grants/Program Officer Name and Phone # o Title of DHHS Grant o Title of Protocol - if the same as the title of the grant, please indicate as such Version Date of Consent Document to be used with “prisoners” o Date(s) of IRB Meeting(s) in which protocol was considered including a brief chronology of:

1. Date of initial IRB review 2. Date of Subpart C reviews 3. Type of IRB review 4. Whether or not this is a special IRB review for prisoner issues

o Principal Investigator(s)

36.0 Research Involving Minors

The federal regulations provide for additional protections for children as research subjects as defined in Subpart D. In most circumstances Subpart D requires parental permission. IRBs reviewing research involving minors as subjects must consider the benefits, risks, and discomforts inherent in the proposed research and assess their justification in light of the expected benefits to the child-subject or to society as a whole. In calculating the degree of risk and benefit, the IRB should weigh the circumstances of the subjects under study, the magnitude of risks that may accrue from the research procedures, and the potential benefits the research may provide to the subjects or class of subjects. An IRB member or a consultant to the IRB with appropriate background and experience should be involved in the review of any protocol involving minors.

Procedures that usually present no more than minimal risk to a healthy child include: urinalyses, obtaining small blood samples, EEGs, allergy scratch tests, minor changes in diet or daily routine, and/or the use of standard psychological or educational tests. The IRB must also consider the extent to which research procedures would be a burden regardless of whether the child is accustomed to the proposed procedures. The assessment of risk and burden should also be informed by an understanding of the anticipated physical health, emotional maturity and other internal and external factors of the proposed population of minors.

36.1 Research in School Settings

With respect to non-health care related research involving minors in an educational setting, studies


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should be carefully examined to determine both the level of risk and the potential benefit for the subjects. The risks involved in social science research are rarely physical; however, minors may be susceptible to emotional and psychological risks as well as risks to their social standing. In addition to these considerations, the informed consent process for children within an educational setting is often quite complex. As part of its review, the IRB would generally expect to see evidence that researchers have obtained permission from the school district, the school site (e.g., principal or headmaster), and the classroom teacher (when applicable). In addition, provisions should be made for obtaining the permission of parents of each participating child and the assent of the child subject.

36.2 Categories of Research Involving Minors That May Be Approved by IRBs

• Research not involving greater than minimal risk. [45 CFR 46.404] • Research involving greater than minimal risk, but presenting the prospect of direct

benefit to an individual subject. Research in this category is approvable provided: (a) the risk is justified by the anticipated benefit to the subject; and (b) the relationship of risk to benefit is at least as favorable as any available alternative approach. [45 CFR 46.405]

• Research involving greater than minimal risk with no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition. Research in this category is approvable provided: (a) the risk represents a minor increase over minimal risk; (b) 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 settings; and (c) the intervention or procedure is likely to yield generalizable knowledge about the subject's disorder or condition that is of vital importance for the understanding or amelioration of the subject's disorder or condition. [45 CFR 46.406]

• Research that is not otherwise approvable, but which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. Research that is not approvable under 45 CFR 46.404, 46.405, or 46.406 may be conducted or funded by DHHS provided that the IRB, and the Secretary, after consultation with a panel of experts, finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a significant problem affecting the health and welfare of children. The panel of experts must also find that the research will be conducted in accordance with sound ethical principles. [45 CFR 46.407]

36.3 IRB Review of Research Involving Minors

The IRB protocol application should provide sufficient detail in the research plan so that the IRB can make the determinations as outlined in Subpart D of the regulations. In addition, applications submitted to the IRB involving minors should include the application supplement entitled “Investigator Checklist for Research Involving Children”. The checklist is to be utilized by the IRB in determining if proposed research studies fulfills all the requirements of the federal regulations as outlined in 45 CFR 46 Subpart D and/or 21 CFR Parts 50 and 56 for inclusion of minors as research subjects. The IRB must concur with the Investigator’s assessment. Otherwise, the IRB notifies the Investigator with modifications before approval is granted. In all cases, the IRB must determine that adequate provisions have been made for soliciting permission from parents or guardian, and soliciting the assent of each child when the IRB deems the children are capable of assent.


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36.4 Students and Employees

Students

Students and employees of USA are considered vulnerable to undue influence. Such individuals may feel pressure to participate in a research study, especially if the requesting investigator is their supervisor, classroom instructor or someone who may be in a position to influence their career. Investigators must exercise caution to avoid even the appearance of pressuring such individuals in enrollment. When students participate in research studies for class credit they should be provided alternative methods of obtaining credit that do not include participation in the study. It is the responsibility of the investigator to determine that those alternative methods exists. Wherever possible, students should be provided with a choice of research opportunities, including those not supervised by the investigator. Alternative choices should be comparable in both time and effort of anticipated study participation.

Researchers need to be cautious when they seek students in a class to participate in research at the same time. Unintended coercion must be avoided by ensuring voluntary participation, no one knows who is and is not participating, and a time/effort equivalent alternative for those who wish not to participate as outlined above. Course grades should not be based on research participation.

Employees

University employees, such as faculty, office staff, lab technicians, and postdoctoral fellows, are similar to students in that they are vulnerable to perceived, even if not intended, pressures to appear cooperative and supportive of their supervisor’s work. Accordingly, many of the same procedures described above to reduce the likelihood of coercion in recruiting student volunteers apply equally to university employees.


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Appendix A

The Belmont Report Ethical Principles and Guidelines for the protection of human subjects of research

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979

AGENCY: Department of Health, Education, and Welfare.

ACTION: Notice of Report for Public Comment.

SUMMARY: On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the charges to the Commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider: (i) the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, (ii) the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, (iii) appropriate guidelines for the selection of human subjects for participation in such research and (iv) the nature and definition of informed consent in various research settings.

The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. It is the outgrowth of an intensive four-day period of discussions that were held in February 1976 at the Smithsonian Institution's Belmont Conference Center supplemented by the monthly


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deliberations of the Commission that were held over a period of nearly four years. It is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. By publishing the Report in the Federal Register, and providing reprints upon request, the Secretary intends that it may be made readily available to scientists, members of Institutional Review Boards, and Federal employees. The two-volume Appendix, containing the lengthy reports of experts and specialists who assisted the Commission in fulfilling this part of its charge, is available as DHEW Publication No. (OS) 78-0013 and No. (OS) 78-0014, for sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.

Unlike most other reports of the Commission, the Belmont Report does not make specific recommendations for administrative action by the Secretary of Health, Education, and Welfare. Rather, the Commission recommended that the Belmont Report be adopted in its entirety, as a statement of the Department's policy. The Department requests public comment on this recommendation.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Members of the Commission Kenneth John Ryan, M.D., Chairman, Chief of Staff, Boston Hospital for Women. Joseph V. Brady, Ph.D., Professor of Behavioral Biology, Johns Hopkins University. Robert E. Cooke, M.D., President, Medical College of Pennsylvania. Dorothy I. Height, President, National Council of Negro Women, Inc. Albert R. Jonsen, Ph.D., Associate Professor of Bioethics, University of California at San Francisco. Patricia King, J.D., Associate Professor of Law, Georgetown University Law Center. Karen Lebacqz, Ph.D., Associate Professor of Christian Ethics, Pacific School of Religion. * David Louisell, J.D., Professor of Law, University of California at Berkeley. Donald W. Seldin, M.D., Professor and Chairman, Department of Internal Medicine, University of Texas at Dallas. Eliot Stellar, Ph.D., Provost of the University and Professor of Physiological Psychology, University of Pennsylvania. * Robert H. Turtle, LL.B., Attorney, VomBaur, Coburn, Simmons & Turtle, Washington, D.C * Deceased.

Table of Contents

1. Ethical Principles and Guidelines for Research Involving Human Subjects 2. Boundaries Between Practice and Research 3. Basic Ethical Principles

1. Respect for Persons 2. Beneficence 3. Justice

4. Applications 1. Informed Consent 2. Assessment of Risk and Benefits 3. Selection of Subjects


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Ethical Principles & Guidelines for Research Involving Human Subjects

Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. Public attention was drawn to these questions by reported abuses of human subjects in biomedical experiments, especially during the Second World War. During the Nuremberg War Crime Trials, the Nuremberg code was drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. This code became the prototype of many later codes(1) intended to assure that research involving human subjects would be carried out in an ethical manner.

The codes consist of rules, some general, others specific, that guide the investigators or the reviewers of research in their work. Such rules often are inadequate to cover complex situations; at times they come into conflict, and they are frequently difficult to interpret or apply. Broader ethical principles will provide a basis on which specific rules may be formulated, criticized and interpreted.

Three principles, or general prescriptive judgments, that are relevant to research involving human subjects are identified in this statement. Other principles may also be relevant. These three are comprehensive, however, and are stated at a level of generalization that should assist scientists, subjects, reviewers and interested citizens to understand the ethical issues inherent in research involving human subjects. These principles cannot always be applied so as to resolve beyond dispute particular ethical problems. The objective is to provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects.

This statement consists of a distinction between research and practice, a discussion of the three basic ethical principles, and remarks about the application of these principles.

Part A: Boundaries Between Practice & Research

A. Boundaries Between Practice and Research

It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other, in order to know what activities ought to undergo review for the protection of human subjects of research. The distinction between research and practice is blurred partly because both often occur together (as in research designed to evaluate a therapy) and partly because notable departures from standard practice are often called ”experimental” when the terms ”experimental” and ”research” are not carefully defined.

For the most part, the term ”practice” refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individuals. (2) By contrast, the term ”research' designates an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective.

When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is ”experimental,” in the sense of new, untested or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project. (3)


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Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.

Part B: Basic Ethical Principles

B. Basic Ethical Principles

The expression ”basic ethical principles” refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions. Three basic principles, among those generally accepted in our cultural tradition, are particularly relevant to the ethics of research involving human subjects: the principles of respect of persons, beneficence and justice.

1. Respect for Persons. -- Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.

An autonomous person is an individual capable of deliberation about personal goals and of acting under the direction of such deliberation. To respect autonomy is to give weight to autonomous persons' considered opinions and choices while refraining from obstructing their actions unless they are clearly detrimental to others. To show lack of respect for an autonomous agent is to repudiate that person's considered judgments, to deny an individual the freedom to act on those considered judgments, or to withhold information necessary to make a considered judgment, when there are no compelling reasons to do so.

However, not every human being is capable of self-determination. The capacity for self-determination matures during an individual's life, and some individuals lose this capacity wholly or in part because of illness, mental disability, or circumstances that severely restrict liberty. Respect for the immature and the incapacitated may require protecting them as they mature or while they are incapacitated.

Some persons are in need of extensive protection, even to the point of excluding them from activities which may harm them; other persons require little protection beyond making sure they undertake activities freely and with awareness of possible adverse consequence. The extent of protection afforded should depend upon the risk of harm and the likelihood of benefit. The judgment that any individual lacks autonomy should be periodically reevaluated and will vary in different situations.

In most cases of research involving human subjects, respect for persons demands that subjects enter into the research voluntarily and with adequate information. In some situations, however, application of the principle is not obvious. The involvement of prisoners as subjects of research provides an instructive example. On the one hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for research. On the other hand, under prison conditions they may be subtly coerced or unduly influenced to engage in research activities for which they would not otherwise volunteer. Respect for persons would then dictate that prisoners be protected. Whether to allow prisoners to ”volunteer” or to ”protect” them presents a dilemma. Respecting persons, in most hard cases, is often a matter of balancing competing claims urged by the principle of respect itself.

2. Beneficence. -- Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being. Such treatment falls under the principle of beneficence. The term ”beneficence” is often understood to cover acts of kindness or charity that


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go beyond strict obligation. In this document, beneficence is understood in a stronger sense, as an obligation. Two general rules have been formulated as complementary expressions of beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms.

The Hippocratic maxim ”do no harm” has long been a fundamental principle of medical ethics. Claude Bernard extended it to the realm of research, saying that one should not injure one person regardless of the benefits that might come to others. However, even avoiding harm requires learning what is harmful; and, in the process of obtaining this information, persons may be exposed to risk of harm. Further, the Hippocratic Oath requires physicians to benefit their patients ”according to their best judgment.” Learning what will in fact benefit may require exposing persons to risk. The problem posed by these imperatives is to decide when it is justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks.

The obligations of beneficence affect both individual investigators and society at large, because they extend both to particular research projects and to the entire enterprise of research. In the case of particular projects, investigators and members of their institutions are obliged to give forethought to the maximization of benefits and the reduction of risk that might occur from the research investigation. In the case of scientific research in general, members of the larger society are obliged to recognize the longer term benefits and risks that may result from the improvement of knowledge and from the development of novel medical, psychotherapeutic, and social procedures.

The principle of beneficence often occupies a well-defined justifying role in many areas of research involving human subjects. An example is found in research involving children. Effective ways of treating childhood diseases and fostering healthy development are benefits that serve to justify research involving children -- even when individual research subjects are not direct beneficiaries. Research also makes it possible to avoid the harm that may result from the application of previously accepted routine practices that on closer investigation turn out to be dangerous. But the role of the principle of beneficence is not always so unambiguous. A difficult ethical problem remains, for example, about research that presents more than minimal risk without immediate prospect of direct benefit to the children involved. Some have argued that such research is inadmissible, while others have pointed out that this limit would rule out much research promising great benefit to children in the future. Here again, as with all hard cases, the different claims covered by the principle of beneficence may come into conflict and force difficult choices.

3. Justice. -- Who ought to receive the benefits of research and bear its burdens? This is a question of justice, in the sense of ”fairness in distribution” or ”what is deserved.” An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be treated equally. However, this statement requires explication. Who is equal and who is unequal? What considerations justify departure from equal distribution? Almost all commentators allow that distinctions based on experience, age, deprivation, competence, merit and position do sometimes constitute criteria justifying differential treatment for certain purposes. It is necessary, then, to explain in what respects people should be treated equally. There are several widely accepted formulations of just ways to distribute burdens and benefits. Each formulation mentions some relevant property on the basis of which burdens and benefits should be distributed. These formulations are (1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.

Questions of justice have long been associated with social practices such as punishment, taxation and political representation. Until recently these questions have not generally been associated with scientific research. However, they are foreshadowed even in the earliest reflections on the ethics of research involving human subjects. For example, during the 19th and early 20th centuries the burdens of serving as research subjects fell largely upon poor ward patients, while the benefits of improved medical care flowed primarily to private patients. Subsequently, the exploitation of unwilling prisoners as research subjects in Nazi concentration camps


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was condemned as a particularly flagrant injustice. In this country, in the 1940's, the Tuskegee syphilis study used disadvantaged, rural black men to study the untreated course of a disease that is by no means confined to that population. These subjects were deprived of demonstrably effective treatment in order not to interrupt the project, long after such treatment became generally available.

Against this historical background, it can be seen how conceptions of justice are relevant to research involving human subjects. For example, the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. Finally, whenever research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research.

Part C: Applications

C. Applications

Applications of the general principles to the conduct of research leads to consideration of the following requirements: informed consent, risk/benefit assessment, and the selection of subjects of research.

1. Informed Consent. -- Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them. This opportunity is provided when adequate standards for informed consent are satisfied.

While the importance of informed consent is unquestioned, controversy prevails over the nature and possibility of an informed consent. Nonetheless, there is widespread agreement that the consent process can be analyzed as containing three elements: information, comprehension and voluntariness.

Information. Most codes of research establish specific items for disclosure intended to assure that subjects are given sufficient information. These items generally include: the research procedure, their purposes, risks and anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research. Additional items have been proposed, including how subjects are selected, the person responsible for the research, etc.

However, a simple listing of items does not answer the question of what the standard should be for judging how much and what sort of information should be provided. One standard frequently invoked in medical practice, namely the information commonly provided by practitioners in the field or in the locale, is inadequate since research takes place precisely when a common understanding does not exist. Another standard, currently popular in malpractice law, requires the practitioner to reveal the information that reasonable persons would wish to know in order to make a decision regarding their care. This, too, seems insufficient since the research subject, being in essence a volunteer, may wish to know considerably more about risks gratuitously undertaken than do patients who deliver themselves into the hand of a clinician for needed care. It may be that a standard of ”the reasonable volunteer” should be proposed: the extent and nature of information should be such that persons, knowing that the procedure is neither necessary for their care nor perhaps fully understood, can decide whether they wish to participate in the furthering of knowledge. Even when some direct benefit to them is anticipated, the subjects should understand clearly the range of risk and the voluntary nature of participation.


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A special problem of consent arises where informing subjects of some pertinent aspect of the research is likely to impair the validity of the research. In many cases, it is sufficient to indicate to subjects that they are being invited to participate in research of which some features will not be revealed until the research is concluded. In all cases of research involving incomplete disclosure, such research is justified only if it is clear that (1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them. Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and truthful answers should always be given to direct questions about the research. Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator.

Comprehension. The manner and context in which information is conveyed is as important as the information itself. For example, presenting information in a disorganized and rapid fashion, allowing too little time for consideration or curtailing opportunities for questioning, all may adversely affect a subject's ability to make an informed choice.

Because the subject's ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject's capacities. Investigators are responsible for ascertaining that the subject has comprehended the information. While there is always an obligation to ascertain that the information about risk to subjects is complete and adequately comprehended, when the risks are more serious, that obligation increases. On occasion, it may be suitable to give some oral or written tests of comprehension.

Special provision may need to be made when comprehension is severely limited -- for example, by conditions of immaturity or mental disability. Each class of subjects that one might consider as incompetent (e.g., infants and young children, mentally disable patients, the terminally ill and the comatose) should be considered on its own terms. Even for these persons, however, respect requires giving them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections of these subjects to involvement should be honored, unless the research entails providing them a therapy unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes and by the use of third parties to protect them from harm.

The third parties chosen should be those who are most likely to understand the incompetent subject's situation and to act in that person's best interest. The person authorized to act on behalf of the subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the subject from the research, if such action appears in the subject's best interest.

Voluntariness. An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of informed consent requires conditions free of coercion and undue influence. Coercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance. Undue influence, by contrast, occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance. Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.

Unjustifiable pressures usually occur when persons in positions of authority or commanding influence -- especially where possible sanctions are involved -- urge a course of action for a subject. A continuum of such influencing factors exists, however, and it is impossible to state precisely where justifiable persuasion ends and undue influence begins. But undue influence would include actions such as manipulating a person's choice through the controlling influence of a close relative and threatening to withdraw health services to which an individual would otherwise be entitled.


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2. Assessment of Risks and Benefits. -- The assessment of risks and benefits requires a careful arrayal of relevant data, including, in some cases, alternative ways of obtaining the benefits sought in the research. Thus, the assessment presents both an opportunity and a responsibility to gather systematic and comprehensive information about proposed research. For the investigator, it is a means to examine whether the proposed research is properly designed. For a review committee, it is a method for determining whether the risks that will be presented to subjects are justified. For prospective subjects, the assessment will assist the determination whether or not to participate.

The Nature and Scope of Risks and Benefits. The requirement that research be justified on the basis of a favorable risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that informed consent be obtained is derived primarily from the principle of respect for persons. The term ”risk” refers to a possibility that harm may occur. However, when expressions such as ”small risk” or ”high risk” are used, they usually refer (often ambiguously) both to the chance (probability) of experiencing a harm and the severity (magnitude) of the envisioned harm.

The term ”benefit” is used in the research context to refer to something of positive value related to health or welfare. Unlike, ”risk,” ”benefit” is not a term that expresses probabilities. Risk is properly contrasted to probability of benefits, and benefits are properly contrasted with harms rather than risks of harm. Accordingly, so-called risk/benefit assessments are concerned with the probabilities and magnitudes of possible harm and anticipated benefits. Many kinds of possible harms and benefits need to be taken into account. There are, for example, risks of psychological harm, physical harm, legal harm, social harm and economic harm and the corresponding benefits. While the most likely types of harms to research subjects are those of psychological or physical pain or injury, other possible kinds should not be overlooked.

Risks and benefits of research may affect the individual subjects, the families of the individual subjects, and society at large (or special groups of subjects in society). Previous codes and Federal regulations have required that risks to subjects be outweighed by the sum of both the anticipated benefit to the subject, if any, and the anticipated benefit to society in the form of knowledge to be gained from the research. In balancing these different elements, the risks and benefits affecting the immediate research subject will normally carry special weight. On the other hand, interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects' rights have been protected. Beneficence thus requires that we protect against risk of harm to subjects and also that we be concerned about the loss of the substantial benefits that might be gained from research.

The Systematic Assessment of Risks and Benefits. It is commonly said that benefits and risks must be ”balanced” and shown to be ”in a favorable ratio.” The metaphorical character of these terms draws attention to the difficulty of making precise judgments. Only on rare occasions will quantitative techniques be available for the scrutiny of research protocols. However, the idea of systematic, nonarbitrary analysis of risks and benefits should be emulated insofar as possible. This ideal requires those making decisions about the justifiability of research to be thorough in the accumulation and assessment of information about all aspects of the research, and to consider alternatives systematically. This procedure renders the assessment of research more rigorous and precise, while making communication between review board members and investigators less subject to misinterpretation, misinformation and conflicting judgments. Thus, there should first be a determination of the validity of the presuppositions of the research; then the nature, probability and magnitude of risk should be distinguished with as much clarity as possible. The method of ascertaining risks should be explicit, especially where there is no alternative to the use of such vague categories as small or slight risk. It should also be determined whether an investigator's estimates of the probability of harm or benefits are reasonable, as judged by known facts or other available studies.

Finally, assessment of the justifiability of research should reflect at least the following considerations: (i) Brutal or inhumane treatment of human subjects is never morally justified. (ii) Risks should be reduced to those necessary to achieve the research objective. It should be determined whether it is in fact necessary to use human


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subjects at all. Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures. (iii) When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject -- or, in some rare cases, to the manifest voluntariness of the participation). (iv) When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits. (v) Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process.

3. Selection of Subjects. -- Just as the principle of respect for persons finds expression in the requirements for consent, and the principle of beneficence in risk/benefit assessment, the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the selection of research subjects.

Justice is relevant to the selection of subjects of research at two levels: the social and the individual. Individual justice in the selection of subjects would require that researchers exhibit fairness: thus, they should not offer potentially beneficial research only to some patients who are in their favor or select only ”undesirable” persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons. Thus, it can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions.

Injustice may appear in the selection of subjects, even if individual subjects are selected fairly by investigators and treated fairly in the course of research. Thus injustice arises from social, racial, sexual and cultural biases institutionalized in society. Thus, even if individual researchers are treating their research subjects fairly, and even if IRBs are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects.

Some populations, especially institutionalized ones, are already burdened in many ways by their infirmities and environments. When research is proposed that involves risks and does not include a therapeutic component, other less burdened classes of persons should be called upon first to accept these risks of research, except where the research is directly related to the specific conditions of the class involved. Also, even though public funds for research may often flow in the same directions as public funds for health care, it seems unfair that populations dependent on public health care constitute a pool of preferred research subjects if more advantaged populations are likely to be the recipients of the benefits.

One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.

(1) Since 1945, various codes for the proper and responsible conduct of human experimentation in medical research have been adopted by different organizations. The best known of these codes are the Nuremberg Code of 1947, the Helsinki Declaration of 1964 (revised in 1975), and the 1971 Guidelines (codified into Federal Regulations in 1974) issued by the U.S. Department of Health, Education, and Welfare Codes for the conduct of


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social and behavioral research have also been adopted, the best known being that of the American Psychological Association, published in 1973.

(2) Although practice usually involves interventions designed solely to enhance the well-being of a particular individual, interventions are sometimes applied to one individual for the enhancement of the well-being of another (e.g., blood donation, skin grafts, organ transplants) or an intervention may have the dual purpose of enhancing the well-being of a particular individual, and, at the same time, providing some benefit to others (e.g., vaccination, which protects both the person who is vaccinated and society generally). The fact that some forms of practice have elements other than immediate benefit to the individual receiving an intervention, however, should not confuse the general distinction between research and practice. Even when a procedure applied in practice may benefit some other person, it remains an intervention designed to enhance the well-being of a particular individual or groups of individuals; thus, it is practice and need not be reviewed as research.

(3) Because the problems related to social experimentation may differ substantially from those of biomedical and behavioral research, the Commission specifically declines to make any policy determination regarding such research at this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.


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APPENDIX B

Unaffiliated Investigator Agreement

Name of Institution with the Federalwide Assurance (FWA): Applicable FWA #: Unaffiliated Investigator’s Name: Specify Research Covered by This Agreement:

(1) The above-named Unaffiliated Investigator has reviewed: 1) The Belmont Report: Ethical Principles and

Guidelines for the Protection of Human Subjects of Research (or other internationally recognized equivalent; see B1 of FWA Terms for institutions outside the United States); 2) the U.S. Department of Health and Human Services (DHHS) regulations for the protection of human subjects at 45 CFR 46 (or other internationally recognized equivalent, see B3 of FWA Terms for institutions outside the United States); 3) the Federalwide Assurance (FWA) referenced above; and 4) the relevant institutional policies and procedures for the protection of human subjects.

(2) The Unaffiliated Investigator understands and hereby accepts the responsibility to comply with the

standards and requirements stipulated in the above documents and to protect the rights and welfare of human subjects involved in research conducted under this Agreement.

(3) The Unaffiliated Investigator will comply with all other National, State, or local laws or regulations that may

provide additional protection for human subjects. (4) The Unaffiliated Investigator will abide by all determinations of the IRB designated under the above

Assurance and will accept the final authority and decisions of the IRB, including but not limited to directives to terminate participation in designated research activities.

(5) The Unaffiliated Investigator will complete any educational training required by the Institution and/or the

IRB prior to initiating research covered under this Agreement. (6) The Unaffiliated Investigator will report promptly to the IRB any proposed changes in the research

conducted under this Agreement. The investigator will not initiate changes in the research without prior IRB review and approval, except where necessary to eliminate apparent immediate hazards to subjects.

(7) The Unaffiliated Investigator will report immediately to the IRB any unanticipated problems involving risks to

subjects or others in research covered under this Agreement. (8) The Unaffiliated Investigator will obtain, document, and maintain records of informed consent from each

subject or the subject’s legally authorized representative as required under DHHS and FDA regulations (or other international or national equivalent) and stipulated by the IRB.

(9) The Unaffiliated Investigator acknowledges and agrees to cooperate in the IRB responsibility for initial and

continuing review, record keeping, reporting, and certification. The Unaffiliated Investigator will provide all information requested by the IRB in a timely fashion.


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(10) In conducting research involving FDA-regulated products, the Unaffiliated Investigator will comply with all

applicable FDA regulations and fulfill all investigator responsibilities (or investigator-sponsor responsibilities,

where appropriate), including those described at 21 CFR 312 and 812.

(11) The Unaffiliated Investigator will not enroll subjects in research under this Agreement prior to its review and approval by the IRB.

(12) Emergency medical care may be delivered without IRB review and approval to the extent permitted under

applicable Federal regulations and State law. However, data and information obtained as a result of emergency medical care may not be included as part of federally-supported or –conducted research.

(13) This Agreement does not preclude the Unaffiliated Investigator from taking part in research not covered by

the Agreement.

(14) The Unaffiliated Investigator acknowledges that he/she is primarily responsible for safeguarding the rights and welfare of each research subject, and that the subject’s rights and welfare must take precedence over the goals and requirements of the research.

Investigator Signature: Date: Name: Degree(s): (Last) (First) (Middle Initial) Address: (City) (State/Province) (Zip/Country) Phone #: FAX #: Email: FWA Institutional Official (or Designee): Date: Name: Degree(s): (Last) (First) (Middle Initial) Address: (City) (State/Province) (Zip/Country) Phone #: FAX #: Email:


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APPENDIX C

CONFIDENTIALITY AGREEMENT

University of South Alabama

Institutional Review Board

I, _________________________________, will be participating in the review of proposed human subject research (i.e., convened meeting or expedited review) on behalf of or with the University of South Alabama’s Institutional Review Board. Regardless of my role, I understand and agree that the information and documentation to which I will be exposed during and related to my participation with the Institutional Review Board is confidential.

I further acknowledge and agree that I will not, without appropriate authorization, access information that the IRB considers privileged or confidential, release such privileged or confidential information to anyone outside of the review process within or without the University, or use such information for unauthorized purposes.

I understand that I am authorized to discuss for educational and/or professional purposes only the general aspects of the review process but may not include specific information regarding any of the research proposals made to or discussed by the Institutional Review Board. I also agree that I will not copy or otherwise take any documentation or written information from the Institutional Review Board without express permission from the IRB Office.

Regardless of my association with the Institutional Review Board, I further understand and agree that this confidentiality agreement continues after the end of my affiliation with the University.

Signature: _____________________________________

Date: __________________

Affiliation: IRB Member Guest: (faculty investigator) Guest: (student)


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APPENDIX D

REQUIRMENTS FOR HUMANITARIAN USE DEVICE

1. Definition of Humanitarian Use Device - The definition of a HUD is a device that is intended to benefit

patients in the treatment and diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the United States per year.

2. Physician Responsibilities for the Use of a HUD

A physician may utilize a HUD when agreeing to the following:

• The HUD will be utilized for treatment, diagnosis, or research in accordance with the labeling of the device, intended purpose, and in the designated population for which the FDA approved its use;

• The patient must be informed that the HUD is a device authorized under Federal law for use; however, the effectiveness of the device for a specific indication has not been demonstrated; and

• The informed consent of the patient or the patient’s legally authorized representative will be obtained when the use of the HUD involves research or when required by the IRB. The UCI IRB generally requires that treating physicians obtain informed consent.

3. The IRB’s Role in HUD Review and Approval

Pursuant to 21 CFR 814.124(a), the FDA requires IRB review and approval before a HUD is used, as well as continuing review of the use of the HUD. The IRB must ensure that the proposed use is within the FDA-approved indication and that the use of the device does not exceed the scope of the FDA’s approval. The use of a HUD does not constitute research unless the physician or health care provider intends to collect data from its use.

4. Initial IRB Approval. The HUD and its proposed use must be submitted to the IRB for review and approval

by a convened IRB committee. Thirty-five copies of the following materials should be provided for review:

• The HUD manufacturer’s product labeling, clinical brochure and/or other pertinent

manufacturer information materials • The FDA HDE approval letter • Written statement from the principal investigator specifying how (ie, for what clinical

indication(s), where and by whom the HUD will be used within the clinical setting. The clinical indication should be limited to what is specified in the FDA-approved product labeling.

5. Clinical Consent Form

All invasive clinical procedures require written informed consent. Therefore, there should be a consent form addressing the proposed clinical use of the HUD. Because the HUD is approved for clinical use, terms such as “research” should be avoided in the consent document. Although the FDA regulations do not require a consent form, it is up to the institution to determine whether one should be used. Historically, the University’s IRB has requested that consent be obtained and that the proposed consent form be reviewed by the IRB. Please submit a copy with your IRB application or provide justification for waiver of consent. The consent form should be modeled after other clinical consent forms for invasive procedures. A HUD informed consent template has been developed for your use.


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6. Continuing Review

• Federal regulations require that an annual review be submitted to the IRB. The annual review can be reviewed in an expedited manner. A renewal report should be submitted to the IRB to include the total number of patients who have received the device in the previous year, a copy of the current FDA approved product labeling for the HUD, a copy of the current IRB approved consent document.

7. Reporting Adverse Events to the IRB

• Investigators are required to submit adverse events as they would on a research study using the

IRB Adverse Event Report form.

8. Off-Label Use of a HUD in Emergency or Compassionate Situation

• In special instances an HUD can be used on an emergent basis. If an HUD is used under emergency circumstance, it can not be used again until a complete IRB application has been submitted and approved. Emergency use is defined as necessary to save the life or protect the well-being of a given patient. Under these circumsantances, the physician should, on a case by case basis:

a. Before the device is used, if at all possible, notify the IRB Chair or Vice Chair of the

planned “off-label” use of the HUD. The IRB Chair or Vice-Chair will provide an independent assessment as to whether the proposed use constitutes an emergency or compassionate situation.

b. Obtain clinical informed consent for the “off-label” use of the HUD.

c. FDA approval for “off-label” use of the HUD should be obtained by the device

manufacturer (HDE holder) prior to the device for the emergency/compassionate use procedure. Please remember that use of an HUD in an off-label manner is a violation of federal laws. The IRB has been mandated to monitor HUD uses so that off-label uses are reported to the FDA.

d. 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 then submit this report as an amendment to the HDE.

9. Compassionate Use of a HUD in a Non-Emergency Sitatution

The IRB may approve compassionate use of a HUD if the physician determines that there is no emergency, but there is no alternative device for the patient’s condition. The physician who wishes to use the HUD should provide the HDE holder with the following:

a. a description of the patient’s condition and the circumstances necessitating treatment with the device

b. a discussion of why alternative therapies are unsatisfactory, and c. information to address patient protection measures.


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APPLICABLE REGULATIONS AND GUIDELINES

FDA, Humanitarian Device Exemption (HDE) Regulation: Questions and Answers; Final Guidance for Industry, July 12, 2001 21 CFR 814, Premarket Approval of Medical Devices 21 CFR 814, Subpart H, Humanitarian Use Devices Humanitarian Use Devices, A brief guide for clinicians, investigators, and IRB members, Dale E. Hammerschmidt, M.D., University of Minnesota, October, 2001 (http://www.research.umn.edu/irb/members/education/HUDs.pdf)