3.1 IRB Structure, Roles, and Responsibilities (21 CFR Part 56)

3.1 IRB Structure, Roles, and Responsibilities (21 CFR Part 56)

The Institutional Review Board (IRB) is an independent administrative body established to protect the rights, safety, and welfare of human subjects recruited to participate under biomedical and behavioral research. Under federal regulations, specifically 21 CFR Part 56 (FDA) and 45 CFR Part 46 (HHS), any clinical investigation involving an FDA-regulated product (drugs, biologics, or medical devices) or receiving federal funding must be reviewed, approved, and monitored by an IRB.

Membership Composition (21 CFR 56.107)

To ensure that research proposals undergo a comprehensive and unbiased review, the Food and Drug Administration (FDA) mandates strict requirements for IRB membership:

• Minimum Size: An IRB must have at least five members with varying backgrounds and expertise. This size allows for diverse viewpoints while remaining small enough to hold efficient discussions.
• Diverse Expertise and Representation: The board must not consist entirely of men or entirely of women, nor can it be composed entirely of members of a single profession. It must represent diverse backgrounds, genders, and racial/cultural groups to reflect the community's attitudes and sensitivity.
• Scientific Member: At least one member must have primary concerns in a scientific area (e.g., a physician, a pharmacist, or a Ph.D. clinical scientist). This member evaluates the scientific validity, protocol design, and safety profiles of the research.
• Non-Scientific Member: At least one member must have primary concerns in a non-scientific area (e.g., an ethicist, an attorney, a member of the clergy, or a teacher). This member represents the lay perspective, focusing on readability of consent documents and ethical implications.
• Non-Affiliated Member: At least one member must be non-affiliated with the institution where the research is conducted. This individual (and their immediate family members) must not have any employment, financial, or administrative ties to the institution. They provide an objective, outside perspective free from institutional politics or financial interests.
• Conflict of Interest (COI): According to 21 CFR 56.107(e), no IRB member may participate in the initial or continuing review of any project in which they have a conflicting interest (e.g., acting as an investigator, having a financial stake in the sponsor, or holding patent rights). The conflicted member may only provide information requested by the IRB (e.g., answering questions about the protocol) and must recuse themselves and leave the room for the discussion and vote. Their departure must be documented in the minutes, and they cannot be counted toward the meeting quorum for that specific vote.
• Specialist Consultants: When reviewing protocols involving highly specialized topics or vulnerable populations (e.g., gene therapy or pediatric oncology), the IRB may invite expert consultants to assist. However, these consultants cannot vote or count toward a quorum.

Meeting Quorum and Voting Dynamics (21 CFR 56.108)

For an IRB to conduct official business and vote on research protocols, a quorum must be present:

• Definition of Quorum: A quorum is defined as a majority of the voting members of the IRB (e.g., if the IRB has 9 members, the quorum is 5).
• The Non-Scientist Rule: Crucially, the quorum must include at least one member whose primary concerns are in non-scientific areas (the non-scientist). If a meeting has a numerical majority but no non-scientist is present, the meeting cannot proceed with official votes.
• Maintenance of Quorum: If a member leaves the room due to a conflict of interest, or leaves the meeting early, and their departure reduces the number of present members below the majority, the quorum is lost. The IRB cannot take any official votes or actions until another eligible member arrives to restore the quorum.
• Voting Standards: Approvals, modifications, or disapprovals of protocols require a majority vote of the members present at a convened meeting where a quorum is maintained.

Levels of IRB Review (21 CFR 56.110)

IRBs categorize reviews into three distinct pathways based on the level of risk to subjects:

Full Board Review (Convened Meeting)

This is the default review level for clinical investigations that present more than minimal risk. It is required for almost all phase I, II, and III clinical trials. The entire board reviews the protocol, investigator's brochure, consent forms, and recruitment materials.

Expedited Review (21 CFR 56.110)

An IRB may use an expedited review procedure for research that involves no more than minimal risk and fits into specific, federally published categories (e.g., collection of blood samples by venipuncture, noninvasive collection of biological specimens, or minor modifications to previously approved protocols).

• 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.
• Reviewer Authority: The review is conducted by the IRB chair or an experienced member designated by the chair. The reviewer may exercise all authorities of the IRB (such as approving or requiring modifications), except they may not disapprove the research. Disapproval can only occur through a vote at a convened meeting of the full board.
• Notification: The IRB must have a mechanism to inform all members of studies approved under the expedited process.

Exempt Review (21 CFR 56.104)

Under FDA regulations, very few research categories are exempt from IRB review. The most common exception is the emergency use of a test article (which requires reporting to the IRB within 5 working days, but bypasses prior review). Another category is taste and food quality evaluations. Most clinical investigations of investigational drugs, biologics, or medical devices cannot be exempted.

Criteria for IRB Approval of Research (21 CFR 56.111)

To approve a clinical trial, the IRB must determine and document that the following criteria are met:

1. Risks to subjects are minimized: By using procedures that are consistent with sound research design and do not unnecessarily expose subjects to risk, and by using procedures already being performed on subjects for diagnostic or treatment purposes.
2. Risks are reasonable in relation to anticipated benefits: The IRB must weigh the risks against the potential benefits to the subjects (if any) and the importance of the knowledge expected to result. The IRB must not consider long-range effects of applying the knowledge (e.g., public policy) as research risks.
3. Selection of subjects is equitable: The IRB must assess the recruitment methods and inclusion/exclusion criteria to ensure that the burdens and benefits of research are distributed fairly. It must pay special attention to vulnerable populations (e.g., economically disadvantaged or institutionalized subjects) to prevent exploitation.
4. Informed consent will be sought: Consent must be sought from each prospective subject or their Legally Authorized Representative (LAR).
5. Informed consent will be documented: Written documentation of consent must be obtained unless a waiver of documentation is approved.
6. Safety monitoring: The research plan must include adequate provisions for monitoring the data collected to ensure the safety of subjects (e.g., establishing a Data and Safety Monitoring Board [DSMB]).
7. Privacy and confidentiality: There must be adequate provisions to protect the privacy of subjects and maintain the confidentiality of their data.
8. Vulnerable subjects: When some or all subjects are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, pregnant women, cognitively impaired adults), the IRB must ensure that additional safeguards are in place.

Record-Keeping and Documentation Requirements (21 CFR 56.115)

IRBs must maintain comprehensive records of their activities to demonstrate regulatory compliance:

• Meeting Minutes: The minutes must be highly detailed and record the attendance of each meeting (including the scientific, non-scientific, and non-affiliated status of members present). They must document actions taken by the IRB, the vote count on these actions (including the number of members voting for, against, and abstaining), the basis for requiring changes in or disapproving research, and a written summary of the discussion of controversial issues and their resolution.
• Protocol Records: IRBs must retain copies of all research proposals reviewed, scientific evaluations, approved consent documents, progress reports, safety reports, and records of continuing review.
• Rosters and Guidelines: The IRB must maintain a roster of members, including their degrees, representative capacity, affiliation, and scientific/non-scientific status, as well as the written operating procedures of the IRB.
• Retention Period: All IRB records must be retained for at least 3 years after completion of the research.
• FDA Inspections and Sanctions: If an FDA inspection reveals that an IRB is out of compliance with 21 CFR Part 56, the FDA may issue warnings, refuse to approve new studies, restrict study accruals, or disqualify the IRB, halting all clinical trials under its purview.