8.3 IRB/IEC Composition, Functions, Review Types (Full, Expedited, Exempt) & Continuing Review

IRB/IEC Composition, Functions, Review Types (Full, Expedited, Exempt) & Continuing Review

Exam scope note: This section cites national regulations (for example US Code of Federal Regulations provisions) because they shape day-to-day practice. ACRP states the ACRP-CP exam is referenced only to ICH Guidelines and that no country-specific framework is tested. Treat those citations as professional context; the provision examined here is ICH E6(R3) Principle 3 and Annex 1 section 1 (Submission and Communication, Responsibilities, Composition, Procedures, Records).

Quick Reference: Under 21 CFR Part 56, 45 CFR Part 46, and ICH GCP E6 Section 3, the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) is an independent body formally designated to review, approve, and monitor biomedical and behavioral research involving human subjects. The primary mandate of the IRB/IEC is to safeguard the rights, safety, and well-being of all trial subjects, with special attention paid to vulnerable populations. No clinical trial procedures or screening activities may be initiated at an investigative site without prior documented approval from an IRB/IEC.

For the ACRP-CP (ACRP Certified Professional) examination, mastery of IRB composition standards, quorum rules, conflict of interest recusals, review classifications (Exempt vs. Expedited vs. Full Board), Single IRB (sIRB) governance, and continuing review renewal timelines is essential.

---

1. IRB/IEC Composition & Membership Mandates (21 CFR 56.107 & ICH E6(R3) Annex 1 1.3)

Federal regulations establish strict structural requirements for IRB membership to ensure balanced, unbiased, and multidisciplinary ethical review.

┌───────────────────────────────────────────────────────────────────────────┐
│                     MANDATORY IRB MEMBERSHIP RULES                        │
├───────────────────────────────────────────────────────────────────────────┤
│  1. MINIMUM SIZE: At least FIVE (5) voting members.                       │
│  2. SCIENTIFIC DIVERSITY: At least ONE (1) Scientific Member.             │
│  3. NON-SCIENTIFIC DIVERSITY: At least ONE (1) Non-Scientific Member.     │
│  4. COMMUNITY INDEPENDENCE: At least ONE (1) Unaffiliated Member.         │
│  5. DEMOGRAPHIC & PROFESSIONAL BALANCE: Diverse experience, gender, race.  │
│  6. CONFLICT OF INTEREST: Zero conflicted members participating in votes. │
└───────────────────────────────────────────────────────────────────────────┘

Deep-Dive on Required Member Roles:

1. Scientific Member: An individual with primary training and professional experience in medical or scientific areas (e.g., physician, pharmacologist, PhD toxicologist, research scientist) capable of evaluating study design, statistical validity, pharmacology, and clinical risk.
2. Non-Scientific Member: An individual whose primary concerns and background are in non-scientific areas (e.g., bioethicist, attorney, member of the clergy, community advocate, teacher). Their role is to evaluate informed consent language, understandability, ethical balance, and subject protections.
3. Unaffiliated / Community Member: A member who is not otherwise affiliated with the institution (directly or through an immediate family member). This member represents the perspectives of the broader community and local cultural attitudes.

Strict Conflict of Interest (COI) Recusal (21 CFR 56.107(e))

• No IRB member may participate in the initial or continuing review of any project in which the member has a conflicting interest (e.g., serving as the Principal Investigator, Sub-Investigator, study coordinator, or holding a financial interest/equity in the sponsor company).
• Operational Quorum Rule: A conflicted member may be invited to answer questions or provide information to the board, but must leave the meeting room during formal deliberations and voting. The conflicted member cannot be counted toward the quorum for that specific vote.

Ad Hoc Consultants (21 CFR 56.107(f))

An IRB may invite individuals with specialized competence in complex areas (e.g., pediatric rare diseases, artificial intelligence diagnostic software, gene therapy) to assist in the review of complex protocols. Consultants may advise the board, but cannot vote or count toward a quorum.

---

2. Criteria for IRB Approval of Research (21 CFR 56.111 & 45 CFR 46.111)

To grant approval for a clinical trial, the IRB must determine that all of the following statutory criteria are satisfied:

┌───────────────────────────────────────────────────────────────────────────┐
│                     8 CORE STATUTORY APPROVAL CRITERIA                    │
├───────────────────────────────────────────────────────────────────────────┤
│  1. RISKS MINIMIZED: Sound design, no unnecessary exposure to danger.     │
│  2. RISK-BENEFIT RATIO: Risks reasonable in relation to anticipated       │
│     benefits to subjects and importance of knowledge to be gained.        │
│  3. EQUITABLE SUBJECT SELECTION: Fair inclusion without discriminatory    │
│     recruitment practices or improper exploitation of vulnerable groups.  │
│  4. INFORMED CONSENT SOUGHT: Appropriately sought from subject or LAR.     │
│  5. INFORMED CONSENT DOCUMENTED: Compliant written ICF or approved waiver. │
│  6. DATA MONITORING PLAN: Adequate provisions for monitoring data to       │
│     ensure safety (e.g., Data Safety Monitoring Board / DSMB).            │
│  7. PRIVACY & CONFIDENTIALITY: Robust protections for subject privacy     │
│     and security of identifiable health data (HIPAA / GCP).               │
│  8. VULNERABLE POPULATIONS: Additional safeguards for children,           │
│     prisoners, pregnant women, or cognitively impaired individuals.       │
└───────────────────────────────────────────────────────────────────────────┘

---

3. Categories of IRB Review: Exempt, Expedited & Full Board

Federal regulations define three tiers of IRB review based on the inherent risk of the research and the nature of the submission.

┌───────────────────────────────────────────────────────────────────────────┐
│                     EXPEDITED REVIEW: THE "CANNOT DISAPPROVE" RULE        │
├───────────────────────────────────────────────────────────────────────────┤
│  Under 21 CFR 56.110(b):                                                  │
│  An IRB Chair or designated expedited reviewer has full authority to:     │
│  • APPROVE the research protocol or amendment                             │
│  • REQUIRE MODIFICATIONS (to secure approval)                             │
│  HOWEVER: If the reviewer believes the study should be DISAPPROVED,      │
│  the protocol MUST be referred to the FULL CONVENED BOARD for review.    │
│  A single reviewer can NEVER unilaterally issue a disapproval!            │
└───────────────────────────────────────────────────────────────────────────┘

---

4. Single IRB (sIRB) Mandate for Multi-Site Research

Historically, in multi-center clinical trials across the United States, every participating academic medical center and hospital conducted its own independent local IRB review, creating massive administrative redundancy and startup delays.

The Modern sIRB Framework:

• Regulatory Mandate: The Revised Common Rule (45 CFR 46.114) and NIH Policy mandate the use of a Single IRB (sIRB) for all multi-site cooperative research conducted in the United States.
• Reviewing IRB (sIRB / Central IRB): A designated single IRB (commercial IRB such as WCG or Advarra, or a lead academic IRB) that conducts the comprehensive ethical review and serves as the IRB of record for all participating study sites.
• Relying Institutions (Participating Sites): Investigative sites that formally cede review authority to the sIRB via a legal Reliance Agreement (IRB Authorization Agreement / IAA). Relying sites remain responsible for local institutional context (conflict of interest disclosures, radiation safety committee approvals, institutional credentialing, and local HIPAA compliance).

---

5. Continuing Review & Managing Approval Expirations / Lapses

The Continuing Review Mandate (21 CFR 56.109(f))

For all FDA-regulated clinical trials (IND drugs and IDE devices), the IRB must conduct continuing review of ongoing research at intervals appropriate to the degree of risk, but NOT LESS THAN ONCE PER YEAR (365 days).

Regulatory Divergence Note: While the 2018 Revised Common Rule eliminated annual continuing review for certain minimal-risk studies under HHS oversight, the FDA did NOT adopt this change. Under FDA regulations (21 CFR 56.109(f)), annual continuing review remains mandatory for all ongoing FDA-regulated clinical trials.

┌───────────────────────────────────────────────────────────────────────────┐
│               CONSEQUENCES OF AN IRB APPROVAL LAPSE / EXPIRATION          │
├───────────────────────────────────────────────────────────────────────────┤
│  If IRB approval expires (e.g., at midnight on the 365th day):            │
│  1. ALL RESEARCH ACTIVITIES MUST IMMEDIATELY STOP:                         │
│     • No new subjects may be screened or enrolled.                        │
│     • No protocol-mandated interventions or blood draws may occur.        │
│     • No investigational drug/device may be administered.                 │
│  2. CRITICAL SAFETY EXCEPTION:                                            │
│     • If stopping study drug would pose an immediate hazard or jeopardize │
│       the safety/welfare of an actively enrolled subject (e.g., oncology  │
│       chemotherapy, immunosuppressant in transplant), the investigator   │
│       may continue treatment for that specific subject.                   │
│     • The investigator must IMMEDIATELY notify the IRB Chair in writing.  │
└───────────────────────────────────────────────────────────────────────────┘

---

6. Investigator Reporting Obligations to the IRB/IEC

The Principal Investigator is legally obligated to submit prompt reports to the IRB/IEC for specific critical events:

┌───────────────────────────────────────────────────────────────────────────┐
│                     MANDATORY PROMPT REPORTS TO THE IRB                   │
├───────────────────────────────────────────────────────────────────────────┤
│  1. UNANTICIPATED PROBLEMS (UPIRSOs): Events involving risk to subjects   │
│  2. MAJOR PROTOCOL VIOLATIONS / DEVIATIONS: Compromising safety or data   │
│  3. EMERGENCY SAFETY DEVIATIONS: Implemented to eliminate immediate hazard│
│  4. SERIOUS OR CONTINUING NON-COMPLIANCE: Systemic procedural breakdowns  │
│  5. SUSPENSIONS OR TERMINATIONS: By sponsor, FDA, or other entity         │
│  6. STUDY CLOSURE: Final close-out summary and subject disposition report │
└───────────────────────────────────────────────────────────────────────────┘

Defining Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO)

Under 21 CFR 56.108(b)(1) and 45 CFR 46.108(a)(4)(i), an event is classified as an Unanticipated Problem (UP) if it meets ALL THREE of the following criteria:

1. Unexpected: In terms of nature, severity, or frequency, given the research protocol, Investigator's Brochure, and characteristics of the subject population;
2. Related or Possibly Related: There is a reasonable possibility that the incident, experience, or outcome was caused by the procedures involved in the research; AND
3. Suggests Greater Risk: The event indicates that the research places subjects or others at a greater risk of harm (physical, psychological, economic, or legal) than was previously known or recognized.

Note on SAEs vs. UPs: Not all Serious Adverse Events (SAEs) are Unanticipated Problems. An expected SAE (e.g., disease-related progression already listed in the IB) is not a UPIRSO and does not require expedited reporting to the IRB unless mandated by local IRB SOPs.

---

7. Realistic Clinical Scenario & ACRP-CP Critical Analysis

Scenario: The convened IRB of an academic medical center meets to review a Phase II trial testing an investigational CAR-T cell therapy for refractory lymphoma. The IRB roster consists of 7 members: 4 physician-scientists, 1 bioethicist (non-scientist), 1 attorney (non-scientist), and 1 unaffiliated community member (non-scientist).

At the meeting, 5 members are present: 3 physician-scientists, the bioethicist, and the attorney. One of the 3 physician-scientists present is Dr. Sterling, who is the Principal Investigator for the proposed CAR-T trial. During the presentation of the CAR-T protocol, Dr. Sterling answers questions about vector safety. When the IRB Chair calls for final deliberations and the approval vote, Dr. Sterling remains seated in the room and votes in favor of approval. The protocol is approved with a 5-0 vote.

ACRP-CP Critical Evaluation & Regulatory Non-Compliance Breakdown:

1. Conflict of Interest Violation (21 CFR 56.107(e)): Dr. Sterling has an undeniable conflict of interest as the trial PI. While Dr. Sterling could answer questions during the preliminary presentation, Dr. Sterling must be recused from deliberations and voting.
2. Quorum Invalidation:
   • Initial attendees = 5 members (meets overall quorum of majority of 7).
   • When Dr. Sterling recuses, voting members present = 4 members (3 is less than a majority of 7, but 4 is a majority of 7).
   • However, Dr. Sterling voted, making the vote illegal. If Dr. Sterling had left, 4 members remained: 2 physician-scientists, 1 bioethicist, and 1 attorney (satisfying the requirement for a majority of 7 AND having non-scientists present).
3. Inspection Impact: Because a conflicted investigator participated in the vote, the approval is invalid. An FDA Bioresearch Monitoring (BIMO) inspection will issue an observation against the IRB, and the protocol approval must be formally rescinded and re-voted at a properly constituted convened meeting.