Conducting Research at Carle: Institutional and IRB Policies

Kyle L. Galbraith, PhDSeptember 28, 2012

1. Provide an overview of Carle Research and IRB policies governing human subjects research conducted at Carle.

2. Point you in the right direction if/when you need more information.

Presentation Objectives

• Policies designed to show how Carle commits itself to complying with federal regulations, engaging in ethical research.

• Two policy tiers: Research Policies, IRB Policies

• Other institutional policies may be applicable to your research

• Policies from other institutions may also be applicable

• Available online: http://www.carleconnect.com/Research/Policies.aspx

Carle IRB and Research Policies

Conducting Research

So you have a brilliant idea…

1. Is it research?

2. Is it human subjects research?

Research Policy 111 (Definition of Human Subjects Research)

“Human Subjects” + “Research” as defined by HHS and/or FDA:

Human Subject (HHS): A living individual about whom an investigator (whether professional or student) conducting research obtains: (1) data through intervention or interaction with the individual; or (2) identifiable private information.

Research: A systematic investigation, inquiry, or analysis designed to develop or contribute to generalizable knowledge that will primarily benefit those beyond the study participants. Research includes activities that aim to test a hypothesis, discover or collate facts, principles, or effects, reach new conclusions, or reexamine information by the critical study of a subject or course of scientific inquiry…[as well as] basic and applied product development.

What Next?

Does your project meet the definition of human subjects research?

If yes, go to the IRB. Go directly to the IRB. Do not pass GO, Do not collect $200.

If no, your “great idea” does not require IRB review and approval.

Research Policy 106 (Designation of Institutional Review Board)

Prior to initiation, all human subjects research must be reviewed and approved by the Carle IRB or an approved designated IRB when:

a. Carle is conducting or supporting the research, ORb. The research is conducted by or under the direction of any

employee or agent of Carle, ORc. The research involves the use of Carle’s non-public information

to identify or contact human subjects, ORd. The activities of Carle employees/agents meet the OHRP criteria

for “engaged in research.” VERY broadly, this means:i. Identifiable private information about subjects is collected

for research;ii. Data is collected via interaction/intervention; ORiii. Informed consent is obtained.

Research Policy 102 (Education Requirements for Researchers)

Research Policy 102—All Investigators and Key Research Personnel are required to fulfill initial and continuing educational requirements.

“Investigators and Key Research Personnel” include:1. Principal Investigator (PI) and any Co-Investigator;2. All individuals responsible for the design or conduct

of the study, including personnel from subcontractor institutions, consultants, and fellowship applicants and training grant trainees.

The Carle IRB will not approve research projects until this education requirement has been fulfilled.

Research Policy 102 (Education Requirements for Researchers)

Initial Education: Biomedical human subject protection, HIPAA in research, and conflicts of interest

Options for completing initial education:

1. Registering as a CFH affiliate with CITI (www.citiprogram.org) and completing required modules plus one elective.

2. UIUC Human Subjects module and quiz plus NIH Human Subject Protection Training plus “HIPAA and Human Subjects Research” CITI module (as a CFH affiliate).

3. UIUC Human Subjects module and quiz plus CITI modules required by the UIUC IRB plus “HIPAA and Human Subjects Research” CITI module (as a CFH affiliate).

Research Policy 102 (Education Requirements for Researchers)

Initial Education Options cont’d:

4. NIH Human Subject Protection training completed after March 1, 2008 plus 5 (five) CITI modules:a. Social and Behavioral Research for Biomedical Researchersb. FDA-regulated Researchc. HIPAA and Human Subjects Researchd. Conflicts of Interest Involving Human Subjectse. One CITI elective

Continuing Education: CITI Refresher and 1 hour of Local Policy Education

Research Policy 103 (Conflicts of Interest in Research)

• Potential Conflicts are now reported annually and within thirty (30) days after a new conflict arises.

• Required of ALL investigators and key research personnel engaged in research at Carle (as well as spouses and dependent children).

• Report via Research Financial Interest Disclosure Statement

• Reviewed by Research Integrity Officer, VP of Research, and Institutional Official.

• Conflicts of Interest do not necessarily mean research is impermissible.

Research Policy 103 (Conflicts of Interest)

Conflict of Interest: Any situation that would make it difficult for the institution or individual(s) to fairly fulfill the mission, vision, and values of the Institution.

Examples may include:• Receipt or promise of any item of value, including:

– Promises of future employment;– Consulting agreement payments;– Honoraria;– Other items of value.

• Equity interests in a Sponsor, or in an affiliate of a Sponsor, etc. greater than $5,000.

Research Policy 103 (Conflicts of Interest)

Investigators with Public Health Service (PHS) funding:

-Required to complete Conflict of Interest training at least every four (4) years prior to engaging in PHS-funded research and immediately when:

1. Carle’s Conflict of Interest Policy changes in a manner that affects investigator requirements;

2. An investigator is new to the Institutions; or

3. An investigator is not in compliance with the Conflict of Interest Policy or management plan.

Contact Rebecca Morgan-Boyd (rebecca.morgan-boyd@carle.com) with questions about this requirement.

So What Do I Need?

1. Your “great idea” meets the definition of human subjects research;

2. You know your project needs IRB approval;3. Your house is in order (Investigators and

research personnel have been identified and appropriately educated; any conflicts of interest have been declared):

So what do I need to send to the Carle IRB?

Carle IRB Policy 301 (Research Submission Requirements)

Documents required at initial submission:

• Initial Review Application

• Research Protocol

• Investigator Agreement (Appendix A)

• IRB Registration Form

• Informed Consent document, if applicable

• HIPAA documents, if applicable

• Recruitment Materials, if applicable

• Questionnaires and Assessment Instruments

• Data Collection Forms or a clear delineation of data

points to be collected

• Federal Grant application, if applicable

Carle IRB Policy 301 (Research Submission Requirements)

Continuing Review Submission Requirements:• Continuing Review Application (including DSMB/DMC

findings, progress report, significant new findings)

• Up-to-date protocol, including any approved amendments

• IRB Registration Form

• Any actively used documents (consent forms, recruitment materials, data collection forms, etc.)

Carle IRB Policy 401 (Expedited Review)

Expedited Review does NOT necessarily mean “faster”

review!• Studies must meet criteria for expedited review as

described in 45 CFR 46.110 and, if applicable, 21 CFR 56.110.

• Determined to be “no more than minimal risk.”

• Per IRB Policy 401, “minimal risk” is defined 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.”

IRB Policy 402 (Initial Review – Criteria for IRB Approval)

How does the IRB review my project?

Criteria for Initial Carle IRB Approval:

• Risks to Subjects are Minimized

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

• Selection of Subjects is Equitable

• Unless waived by the IRB, 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 appropriate local, state and federal regulations. Informed consent will be appropriately documented.

IRB Policy 402 (Initial Review – Criteria for IRB Approval)

Criteria for Initial Carle IRB Approval cont’d:

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

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

• When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence or for subjects found at international sites, additional safeguards have been included in the study and in the IRB review process, to protect the rights and welfare of these subjects.

• Studies are reviewed at periods appropriate to the degree of risk research subject are exposed to due to their participation in the study, but at least annually.

IRB Policy 403 (Modifications to Previously Approved Research)

What if I want to make changes to my project?

No study modifications can be implemented without prior Carle IRB approval.

Any proposed modifications, amendments, revisions, changes or additions in procedures, alterations of risk compared to the currently approved protocol, or changes in subject population, must be reviewed and approved by the Carle IRB prior to continuation of the research. Prior approval by the Carle IRB is required except when necessary to eliminate apparent immediate hazards to the subject (21 CFR 56.108(a)(4) and 45 CFR 46.103 (b)(4)(iii)).

IRB Policy 403 (Modifications to Previously Approved Research)

Examples of modifications requiring IRB approval include (but are not limited to) changes in:

a) Study personnel;b) Advertising materials (flyers, radio spots, etc.);c) Research procedures;d) Subject populations (e.g., inclusion or exclusion criteria);e) Location where research will be conducted;f) Consent form (including translations);g) Recruitment procedures;h) Study design or methods; ori) Alterations of risk compared to the currently approved

protocol.

IRB Policy 404 (Continuing Review)

If my project is approved once, isn’t it always approved?

All studies must be reviewed at least annually as long as data is collected or analyzed. Frequency of review is based on:

• Investigator Experience• Risk Level of Study• Vulnerability of Study Participants• Number and Type of Serious Adverse Events (SAEs)• Number and Type of Unexpected Adverse Events• Number and Type of Unanticipated Problems• Reports of concerns regarding the study of the Investigator• Protocol Changes• Other Significant New Information

There is no grace period for extending the conduct of research beyond the expiration date of Carle IRB approval.

IRB Policy 413 (“Exempt” Status Review of a Research Study)

Are there any studies that don’t need to undergo continuing review?

Remember, the “exempt” determination is made by the IRB Chair or his/her designee—not the PI!

• “Exempt” studies must first be reviewed by the Carle IRB.

• Exempt determination based on regulations in 45 CFR 46.101(b)

• Application for Exempt Determination must be submitted along with study protocol:

http://www.carleconnect.com/Research/Forms.aspx

IRB Policy 408 (Verification from Sources other than PI)

Where else might the IRB get information?

The Carle IRB may require independent verification of information from sources other than the PI based on routine audits or any legitimate concern that may include (but not limited to) the following:

a) Studies being conducted by Key Research Personnel who have previously failed to materially comply with regulations and Carle IRB policies, including non-responsiveness to requests for information;

b) Studies for which the Key Research Personnel’s conduct was suspect in light of information provided during continuing review or audit;

c) Complaints from any IRB of record or research subjects that appear not to be adequately addressed by the Key Research Personnel;

IRB Policy 408 (Verification from Sources other than PI)

Cont’d

d) Studies in which an IRB of record discovers previously undisclosed information that should have been reported to the IRB of record;

e) Studies in which the Key Research Personnel has disclosed or failed to disclose significant conflict(s) of interest; or

f) Studies that exhibit high-risk profiles such as unexpected frequencies or severity of reported serious adverse events, high participant dropout rates or involving an unusual level or types of risks to subjects.

IRB Policy 405 (Project Closure or Transfer)

So now my project is complete and my paper is in JAMA…what next?

Studies may be closed with the Carle IRB when all research activities have been completed or the oversight has been transferred to an external IRB of record.

-Require the submission of a “Project Closure Form” via IRBNet to describe the reason(s) for project closure.

-Reviewed administratively by the HSP office on behalf of the Carle IRB.

IRB Policy 409 (Clinical Investigations Involving Drugs, Devices, Biological Products)

What if my project involves drugs or devices?

• Subject to FDA regulations (21 CFR 50, 56)

• Investigational New Drug (IND) applications must be filed when testing new drugs, new drug formulations, or new clinical indications for a drug.

• Investigational Device Exemption (IDE) applications must be approved by the FDA prior to a clinical investigation with a device

• Humanitarian Use Devices (HUD) covered under Carle IRB Policy 411

IRB Policy 414 (Facilitated Review of NCI CIRB Protocols)

Phase III Adult Trials sponsored by the National Cancer Institute

• Facilitated Review: Shared responsibility

• NCI CIRB serves as IRB of oversight; Carle IRB reviews trials for local context information.

• Review of local SAEs/UPs

• No “continuing review” by Carle IRB

• Amendments reviewed by Carle only when they impact local context issues.

IRB Policy 501 (Vulnerable Populations)

Can my project involve (insert vulnerable population)?

Vulnerable populations are afforded extra protections when participating in research (45 CFR 46).

Potentially vulnerable populations include:

• Prisoners (Subpart C)• Children (Subpart D)• Pregnant women and fetuses (Subpart B)• Cognitively impaired subjects• Other vulnerable groups (employees, students, terminally ill)

IRB Policy 701 (General Requirements and Documentation of Informed Consent)

What do I need to tell subjects before they start my study?

“Informed Consent” is an ongoing process, not a one-time event.

Required Elements of Informed Consent:

1. A statement that the study involves research, an explanation of the purposes of the research, the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental. Where applicable, any ancillary studies should be noted and distinguished from the primary study.

2. A description of any reasonably foreseeable risks or discomforts to the subject.

3. A description of any benefits to the subject or to others that may reasonably be expected from the research.

IRB Policy 701 (General Requirements and Documentation of Informed Consent)

Required Elements of Informed Consent cont’d:

4. A disclosure of appropriate alternative procedures or courses of treatment, if any, which might be advantageous to the subject.

5. A statement describing the extent to which, if any, confidentiality of records identifying the subject will be maintained and that notes the possibility that the FDA and other regulatory agencies may inspect the records.

6. For research involving more than minimal risk, an explanation as to whether any compensation is provided and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, whether compensation for injury treatment will be provided, or where further information may be obtained.

IRB Policy 701 (General Requirements and Documentation of Informed Consent)

Required Elements of Informed Consent cont’d:

7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject.

8. 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.

9. Any compensation payable to study participants shall be clearly described in the informed consent, and shall not be so excessive as to be coercive.

10. Additional elements may be necessary, depending upon the nature of the study (see IRB Policy 701 for specifics).

IRB Policy 701 (General Requirements and Documentation of Informed Consent)

All consent to participate in research conducted at CFH must be documented, unless the Carle IRB waives documentation.

Documentation of Informed Consent:

• Embodies the elements of informed consent described in 21 CFR 50.25 and 45 CFR 46.116(a).

• “Short form” written consent document may be used with the approval of Carle IRB.

• Translation services available when necessary• Oral consent may be given, as long as certain criteria are met

and as long as the Carle IRB has approved the use of oral consent.

IRB Policy 702 (Waiver of Informed Consent or Waiver of Documentation of Informed Consent)

Is a signed informed consent document always needed? I’m just doing a retrospective chart review!

A Waiver of Informed Consent, a Waiver of certain elements of Informed Consent, or Waiver of Documentation of Informed Consent may be granted by the Carle IRB in certain cases:

• Must meet the criteria set forth in 45 CFR 46.116(c) or (d), and (if applicable) 21 CFR 50.23 and 24 (waiver of informed consent).

• 45 CFR 46.116(c) and 117(c) (alteration of elements of consent).

Examples:

• Research in Emergency Settings• Research could not be practically undertaken without a waiver• Minimal risk studies where the principal risk would be potential harm

resulting from breach of confidentiality.

Any of these waivers must be approved by the Carle IRB!

IRB Policy 801 (Unanticipated Problems and Other Events Requiring Prompt Reporting)

Uh oh…something went wrong…

Unanticipated Problems, Protocol Changes to eliminate apparent immediate hazards, and reports of Noncompliance must be reported to the IRB in a timely fashion.

The Carle IRB reviews all such reports and have the authority to ask for follow-up reports, suspend or terminate research, or require modifications to previously approved research in light of reported events.

IRB Policy 801 (Unanticipated Problems and Other Events Requiring Prompt Reporting)

Definitions:Serious Adverse Event – Any untoward medical occurrence that:

1.Results in death,

2.Is life-threatening (places the subject at immediate risk of death from the event as it occurred),

3.Results in inpatient hospitalization or prolongation of existing hospitalization,

4.Results in a persistent or significant disability/incapacity, or

5.Results in a congenital anomaly/birth defect.

Adverse Event – Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research.

IRB Policy 801 (Unanticipated Problems and Other Events Requiring Prompt Reporting)

Unanticipated Problem –According to the guidance document OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome that meets all of the following criteria:

1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied; and

2. Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and

3. Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

IRB Policy 801 (Unanticipated Problems and Other Events Requiring Prompt Reporting)

Reporting Timelines:

Within five (5) working days of becoming aware of the following:

Any serious adverse event, as defined above, determined by the Principal Investigator to constitute an Unanticipated Problem.

Changes to the protocol and conduct of the research made without IRB approval to eliminate apparent immediate harm to subjects.

Any departure from the protocol (violation or deviation) that causes harm to subjects or others, places them at increased risk of harm, impacts the scientific integrity, and/or has the potential to recur or represent possible serious or continuing noncompliance with the applicable federal regulations, guidance or IRB policies.

IRB Policy 801 (Unanticipated Problems and Other Events Requiring Prompt Reporting)

Within ten (10) working days of becoming aware of the following:

1.Any event determined by the Prinicipal Investigator to constitute an Unanticipated Problem but does not meet the definition of a “serious adverse event.”

2.Breach of confidentiality;

3.Incarceration of a subject in a protocol not approved to enroll prisoners.

4. Information indicating an unexpected change to the risks or potential benefits of the research such as a publication, interim analysis, safety monitoring report, or updated investigator’s brochure.

IRB Policy 801 (Unanticipated Problems and Other Events Requiring Prompt Reporting)

Within ten (10) working days of becoming aware of the following:

5. Reports from a clinical study monitoring body [such as a sponsor, coordinating center, or Data Safety Monitoring Board (DSMB)/Data Monitoring Committee (DMC] of external adverse events that the monitoring body or investigator have determined to constitute Unanticipated Problems.

6. Changes in FDA labeling or withdrawal from marketing of a drug, biologic, or device used in the research.

7. Subject complaints that indicate that there may be an Unanticipated Problem.

8. Administrative holds by an investigator or sponsor.

IRB Policy 801 (Unanticipated Problems and Other Events Requiring Prompt Reporting)

Within ten (10) working days of becoming aware of the following:

9. Observed or apparent serious noncompliance with protocol requirements or IRB policies.

10. Any additional reporting requirements specified by the IRB as a condition of approval.

Where Do I Find Carle IRB Policies?

Internal Link: http://cweb/Research/Policies.htm

External Link: http://www.carleconnect.com/Research/Policies.aspx

Who Do I Contact with Questions?

Questions about:

Research in general: research@carle.com; 326-4508

IRB: irb@carle.com; 326-4509

Conflicts of Interest / Compliance: rebecca.morgan-boyd@carle.com; 278-8612

Research Website: http://www.carleconnect.com/Research.aspx

Questions/Comments

Thank you! Any questions?