Ethics Committees and E6(R3): Strengthening Independent Review in a Risk-Based Framework

Introduction:

Every clinical trial must be reviewed and approved by an Ethics Committee (EC) – also known as an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) – to ensure the study is ethical and participants’ rights and welfare are protected. ICH E6(R3) reinforces the critical role of these committees and clarifies their responsibilities, aligning with current practices in many regions. It also introduces the concept that ethics review can be streamlined or shared, and that committees should apply proportionality in oversight just as sponsors and investigators do. In this blog, we explore what E6(R3) means for ethics committees, including changes in review requirements and how ECs can implement a risk-based approach to their evaluations.

The Ethics Committee’s Mandate Under E6(R3)

Ethics committees stand as independent gatekeepers for trials. E6(R3) reaffirms key duties:

• Reviewing the trial protocol and any amendments,
• Reviewing participant-facing materials (informed consent forms, recruitment ads, etc.),
• Ensuring the risk/benefit ratio is acceptable,
• Monitoring the progress of the trial (usually via annual or periodic updates),
• Safeguarding participant rights (like privacy and informed consent).

Some updates and emphases in E6(R3) include:

• Combined Regulatory and Ethics Review: Principle 3 in the new guideline states that regulatory authorities and IRBs/IECs can coordinate or combine reviews where feasible. This is an endorsement of what the EU Clinical Trials Regulation now does – a single submission yields a combined assessment covering both regulatory and ethics aspects. For ethics committees, this means working more closely with regulatory agencies in some contexts. In practical terms, while an EC’s fundamental approach doesn’t change (they still examine the protocol ethically), the process might be integrated: e.g., an ethics committee might get a consolidated feedback including scientific issues from regulators and ethical issues, and might deliberate with regulatory input in mind. The key point is E6(R3) approves this collaboration if it streamlines trial approval without compromising thoroughness.
• Expedited and Ongoing Review: E6(R3) explicitly confirms that IRBs/IECs should conduct continuing review of ongoing trials at appropriate intervals (typically annually, or more often for higher risk studies). This isn’t new, but it’s a reminder that an EC’s job isn’t one-and-done at initial approval. They need to receive progress reports and act on any new information (like new safety data or amendments). The guideline doesn’t dictate frequency, but expects it proportional to risk – a small low-risk observational study might get a lighter-touch annual review, whereas a first-in-human gene therapy trial might merit more frequent oversight. Ethics committees are encouraged to apply judgment on this, focusing resources on riskier trials.
• Review of Assent and Special Materials: E6(R3) adds specifics that ECs should review not just the main consent form, but also assent forms for minors and any other materials given to specific populations (e.g., simplified information for cognitively impaired participants or emergency consent procedures). This ensures that vulnerable populations’ processes get a second set of eyes. For example, if a trial involves adolescents, the EC should see the teen-focused information sheet to ensure it’s appropriate.
• Alternatives to Investigator’s Brochure (IB): If an Investigator’s Brochure isn’t required (for instance, an authorized product in a new use might use the approved Summary of Product Characteristics instead of an IB), E6(R3) confirms the ethics committee should get a relevant alternative document. This is more a note to sponsors to provide it, but it means ECs should expect some document summarizing known safety information even if a formal IB isn’t made.
• Layperson/Non-affiliated Member: The guideline broadens the definition of a non-scientific lay member on the committee – it can be anyone whose background isn’t in medical sciences, not necessarily literally “lay” in common terms. This gives ECs flexibility in composition while retaining the principle that not all members should be clinicians or researchers. The presence of a diverse membership (including community or patient representatives, clergy, ethicists, etc.) is important to provide balanced views. E6(R3) supports continued diversity in EC composition.
• Reimbursement vs. Inducement: Ethics committees often grapple with what constitutes undue influence in terms of participant payment. E6(R3) explicitly notes that reimbursement for reasonable expenses (travel, lodging, etc.) is not considered coercive. This is helpful guidance. It means an EC can allow compensation for costs and even modest compensation for time, as long as it’s not so high as to sway someone to take on serious risk they otherwise wouldn’t. Committees still judge that line, but the guideline reassures them that not all payments are problematic. Many ECs had already adopted this stance; now it’s validated by GCP.

Proportionate Review and Risk Adaptation

A theme across E6(R3) is proportionality – focusing on aspects commensurate with their risk and importance. For ethics committees, this can translate to:

• Tailoring the Depth of Review: While every interventional trial requires full committee review at least initially, some ethics committees have expedited pathways for minimal risk studies or minor amendments. E6(R3) doesn’t explicitly detail expedited procedures, but by embracing proportionate approaches, it implicitly supports them where legally permitted. For instance, if a study amendment only adds a new questionnaire that doesn’t pose added risk, an EC might do an expedited review with just the chair or a subcommittee, rather than convene everyone. In contrast, a major protocol change affecting safety monitoring would get full discussion. The underlying expectation is that ECs will not waste time on trivial changes and can spend more time on trials or changes that meaningfully impact participant welfare.
• Assessing Risk/Benefit Continuously: Ethics committees should adopt a mindset similar to Data Monitoring Committees in some respects – stay alert to emerging risks or benefits. E6(R3) encourages transparency: sponsors should inform ECs of new safety information, and ECs can then re-evaluate if the trial’s risk/benefit balance remains acceptable. For example, if mid-trial results elsewhere show a class of drug has a new severe side effect, the EC might require the consent form to be updated or even pause the trial to get more info. Essentially, ECs are expected to adjust their recommendations as new data emerge (which is why continuing review is critical). A risk-based mindset also means focusing on critical issues during initial review: e.g., does the protocol include adequate safety monitoring for a high-risk therapy? Are stopping rules defined if things go wrong? These points should get significant attention in an EC meeting for a high-risk trial, more so than, say, minor editorial issues in the consent text (not to say those shouldn’t be fixed, but prioritization of discussion time is implied).
• Public Involvement and Diversity: Though primarily sponsor responsibilities, ECs under E6(R3) have an interest in how studies consider participant diversity and engagement. The guideline mentions that sponsors should justify exclusion of certain populations. ECs can and should query a protocol that, for instance, unnecessarily excludes older adults or women without sound reason. This is part of ethical review – is the study fair and equitable in subject selection? By raising such questions, ECs reinforce the principle that trials should strive to be representative or at least not unjustifiably restrictive. Similarly, ECs might appreciate when sponsors include patient input in their protocol design (like simplifying procedures for patient convenience); it shows respect for participants. E6(R3) touches on this ethos of patient-centricity, which ECs naturally champion.

Documentation and Communication from ECs

ICH E6(R3) outlines some specifics that ethics committees should document:

• Clear Opinion/Decision Letters: An EC’s decision on a trial (approval, conditional approval, or disapproval) should be given in writing, with date and any conditions clearly stated. This is standard, but important. E6(R3) ensures that there is a record for sponsors and inspectors of what exactly was approved (including version numbers of documents and any required changes). ECs should timestamp and file these determination letters along with the approved documents.
• Minutes of Meetings: The guideline doesn’t explicitly mention meeting minutes, but GCP practice is that ECs maintain detailed minutes recording attendance, discussions summary, decisions, and any dissenting opinions. Investigators and sponsors generally don’t see minutes, but inspectors may audit an EC and review them. Under E6(R3), minutes would ideally reflect, for instance, the risk-benefit deliberation, any issues flagged and how resolved, and demonstration that quorum and appropriate expertise were present. If a trial had an unusual element (like use of a new technology for consent), the minutes might note that the committee discussed its ethical implications. For ECs, keeping good minutes is part of demonstrating they fulfilled their review duties diligently.
• Continuing Review Records: When an EC reviews annual progress or safety reports, they should have a record of that (the submission, the acknowledgment or re-approval letter, etc.). E6(R3) expects these continuing reviews to happen, so missing records of them could be a compliance gap. Many ECs provide a simple acknowledgment if no issues arise or a renewal approval letter if required by local regulation. Those should be archived.
• Protocol Deviations or Serious Breaches: If investigators report serious non-compliance or deviations to the EC (as required in many regions for ethically relevant breaches), E6(R3) would expect the EC to review those and decide on action (like whether the trial can continue, requires re-consent of participants, etc.). Documentation should show the EC considered the issue and what their directive was. For example, if a site enrolled a participant without consent by mistake, the EC might state that the participant must be informed and that additional training is required, and that recruitment can continue since it was addressed. Keeping this correspondence and decisions is important to show proper oversight.

How ECs Can Apply a Risk-Based Framework

Ethics committees inherently focus on risks and benefits, so they are familiar with risk-based thinking. E6(R3) encourages ECs to formalize some risk-based approaches:

• Allocate Time According to Study Risk: ECs often have a full agenda of items – new protocols, amendments, safety reports, etc. A practical tip is to triage and allocate more time to complex or high-risk trials. For instance, a first-in-human gene therapy trial might warrant reading the entire protocol thoroughly, inviting an outside expert (if needed) for consultation, and deep discussion. A low-risk nutrition survey, while still reviewed, might not need as lengthy a debate. Some ECs use subcommittees to pre-review and highlight issues for the full board, which can help focus discussion on pivotal concerns. E6(R3) supports such efficiency as long as full review standards are met for interventional trials.
• Use Expertise Judiciously: Ensure the EC has or obtains the expertise needed for each review. For example, if reviewing a pediatric oncology trial, have a pediatric specialist or an oncologist consult if those fields are not represented on the EC. Rather than having all experts as permanent members (which can be unwieldy), ECs often invite ad hoc experts. E6(R3) explicitly notes a broader notion of who can be members (e.g., layperson definition), indirectly acknowledging that committees may bring in experts as needed. It’s risk-based because you bring in heavy expertise for complicated trials, but for a simple healthy volunteer trial, the generalist clinical knowledge on the committee might suffice.
• Focus on Participant Experience: Polices around how participants are recruited and retained often carry ethical weight. ECs should evaluate if the trial is minimizing inconvenience and maximizing consideration for participants. For high-risk or burdensome trials, see if the protocol aligns with patient-centric practices (like providing reimbursements, flexibility in scheduling, psychological support if needed, etc.). If not, the EC can recommend enhancements. This is a subtle risk-based approach: trials that pose higher burden should have stronger measures to support participants.
• Safety Monitoring Plans: ECs should pay particular attention to the safety monitoring plan of a study. Higher risk trials should have Data Monitoring Committees (DMCs) or frequent interim analyses; moderate risk trials might rely on investigator/sponsor monitoring. E6(R3) does mention that content about safety and quality management has been expanded. An EC should satisfy itself that a trial has adequate provisions to protect participants as it proceeds (e.g., clear stopping rules or pause criteria for serious events, emergency procedures in place if a participant has an issue at home in a decentralized trial, etc.). If those aren’t sufficient, the EC can condition approval on strengthening them.

Collaborative Oversight: ECs, Sponsors, and Regulators

E6(R3) fosters a vision where ethics committees, sponsors, and regulators each play their part but coordinate for participant safety and trial integrity. For ECs, collaborating means:

• Communicating with sponsors/researchers regularly (requiring periodic reports, being available for advice if a study scenario arises).
• Possibly interacting with regulatory bodies for joint review or inspections. In some countries, regulators audit ethics committees to ensure they comply with GCP and national law; in others, regulators rely on ECs as partners to watch over trials in real-time.
• Embracing transparency: e.g., public registration of trials is mandated and ECs often check that a trial is registered before approving. Some ECs publicly list approved studies. E6(R3) encourages transparency (Principle 9 mentions trial registration and result disclosure). ECs play a role by requiring registration and possibly reviewing summary results (in some regions, sponsors are asked to provide lay summaries of results to ECs).

Conclusion: A Strengthened Ethical Oversight System

ICH E6(R3) essentially validates and strengthens the framework in which ethics committees operate. It doesn’t diminish their authority in any way – in fact, it arguably elevates their role by highlighting ethical design (like focusing on inclusive participant selection and manageable burden) and by integrating ethics review with overall trial quality management.

For IRB/IEC members and administrators, the guideline’s changes underline the importance of:

• Diligent initial review with appropriate expertise,
• Proportionate ongoing oversight,
• Thorough documentation of decisions and rationale,
• Willingness to adapt oversight level to trial risk.

Ethics committees that adopt these practices will be aligned with E6(R3) and, ultimately, will help ensure that clinical trials are not only scientifically sound but also ethically robust and participant-friendly.

In an era of complex trials (e.g., multi-country, adaptive, decentralized), a strong EC that can adeptly handle new challenges is crucial. E6(R3) provides them the latitude to innovate (like accepting remote consent processes, or coordinating reviews internationally) while upholding core principles. The result should be a more efficient ethics review process that does not compromise thoroughness, allowing good trials to start without undue delay, and providing careful check-points for safety and ethics as trials proceed.

From a sponsor or investigator perspective, understanding the EC’s priorities under E6(R3) can help in preparing submissions that meet those expectations: e.g., including clear risk justifications, describing patient involvement, simplifying consents, etc., which can smooth the ethical approval. When sponsors and ECs are on the same page, the outcome is better designed trials and stronger protection for participants. That alignment is exactly what the harmonization effort of E6(R3) hopes to achieve, making the ethical review process a well-integrated part of overall trial quality management rather than a siloed hurdle.

References

• ICH Guideline for Good Clinical Practice E6(R3), Final Step-4 Guideline, Jan 6, 2025. [1]
• “The revamped Good Clinical Practice E6(R3) guideline: Profound changes in principles and practice,” Arun Bhatt, Perspectives in Clinical Research, 2023. [3]
• TransCelerate/ACRO’s E6(R3) Asset Library: tools on trial design, risk management, data governance. [5]

For those interested in gaining our Transcelerate Biopharma-certified courses, please enroll in our ICH GCP E6 R3 courses at https://www.whitehalltraining.com/

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Guidance To Explore

For those wanting to dive deeper into the details:

• ICH E6 (R3) Final Guideline (Step 4, January 6, 2025) – The official reference text.
• FDA Overview of ICH E6 (R3) – A clear outline of the changes and their implications.
• EMA Step 5 Guideline – European regulatory perspective on implementation.
• TransCelerate ICH E6 Asset Library – Practical tools and frameworks to support adoption (TransCelerate).