Do We Need An IRB/IEC Revolution?
By Kamila Novak, KAN Consulting
Let’s start with the basics and look at the definitions of Institutional Review Board (IRB) and Independent Ethics Committee (IEC). In the current Good Clinical Practice guideline, ICH E6 (R2)1, we find two definitions — although industry has been using the terms interchangeably, seeing both bodies as one and the same thing. As we can see, the GCP definitions are very much alike.
What Is An IRB/IEC?
According to GCP guidelines, an IEC is “an independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favourable opinion on the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.” (GCP R2 Glossary 1.27)
Similarly, an IRB is “an independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.” (GCP R2 Glossary 1.31)
The third revision of the GCP guideline, ICH R6(R3)2, expected to be released by the end of 2023 or early in 2024, includes one definition, indicating alignment with industry thinking that IRB and IEC are the same bodies with the same role.
“Institutional Review Board (IRB)/Independent Ethics Committee (IEC): An independent body (a review board or a committee, institutional, regional, national or supranational) constituted of medical professionals and non-medical members whose responsibility it is to ensure the protection of the rights, safety and well-being of human participants involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing favourable opinion on the trial protocol, the suitability of the investigator(s), the facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial participants. The legal status, composition, function, operations and regulatory requirements pertaining to IRBs/IECs may differ among countries but should allow the IRB/IEC to act in agreement with GCP as described in this guideline.” (GCP R3 Glossary)
A Peek At IRBs/IECs Around The Globe
Indeed, as GCP foresees, IRBs/IECs look different in different countries and regions.
Often, we can find local, site-specific IRBs/IECs and a regulatory authority as the main bodies approving clinical trials. In some countries, such as Romania and most countries in sub-Saharan Africa, there is one National Ethics Committee (NEC), and in others, such as Tunisia, there are a couple of regional ethics committees but no local IRBs. In Kenya, Tanzania, Burkina Faso, Gabon, and Mozambique, institutions can establish a local IRB if they wish to do so. Many of them do, going beyond compliance as they recognize the benefit of having an ethics review body closely associated and familiar with them.
In the European Union, but not only there, many countries have implemented a system that includes local IRBs/IECs, regional or national ethics committees, and regulatory authorities. The local and regional or national ethics committees have distinctive responsibilities in trial approvals. Typically, the regional or national ones focus on reviewing essential documents, while the local ones take a close look at the adequacy of the site and investigators’ and their study team members’ qualifications, as well as clinical trial agreements and budgets.
While regulatory authority approval is required in most countries, it is not a rule. For example, IRBs are very strong in Lebanon, and the country’s Ministry of Health (MoH) is involved in issuing import licenses for investigational products. Everything else goes to the MoH as a simple notification. These IRBs audit every study conducted in their institutions on an annual basis apart from continuing review and decisions whether the study can continue or not. In the U.S., the FDA approves the protocol as the first step, and all other reviews are in the hands of IRBs, whether local or centralized.
In most countries, IRB members work voluntarily, and IRBs may or may not request submission fees. Interestingly, in the U.S., some IRBs act as vendors, may operate as for-profit organizations, and can be owned, bought, and sold by investors. We will get back to this a bit later.
As for accreditations or other authorizations to operate, they vary by country as well. For example, local IRBs must be accredited or approved by the regulatory authority or another governmental body in Jordan, Egypt, and Georgia; members’ resumes and written procedures are reviewed as part of the accreditation process. The accreditation can be suspended or revoked if the regulatory authority finds deficiencies in the IRB work.
Outside the U.S., IRBs are never considered vendors. They are not selected or approved by study sponsors, not owned by any entity, not audited by sponsors’ auditors, not contracted by sponsors, and do not communicate with sponsors directly. All communication goes through the investigator. A sponsor’s representative may be invited to the IRB or NEC meeting to answer questions about the study, but this is used less and less, with communication shifting heavily toward formal correspondence.
What Should All IRBs/IECs Have In Common?
If I were an IRB member, I would consider it a service to study participants and the public, a mission with commitment and accountability. Despite all organizational differences, we should expect IRBs/IECs to have certain attributes in common, such as:
- High standards of ethics. They are ethics committees after all, are they not? Every member of an IRB should be duly and periodically trained in research ethics, evaluate ethical aspects of studies, be able to put himself or herself in the shoes of study participants, and imagine their journey in study. Is it too burdensome?
- Independence. This is another adjective in the name of this body — independent ethics committee. What does it mean? Are the members and the whole IRB free to make decisions without any undue influence?
- A deep understanding of Good Clinical Practice and compliance with the GCP guideline. Deep understanding means not just what is written but the reasons why it is written, not just the verbiage but the “spirit” of the guideline.
- Transparency. I expect the IRB to have their roster, procedures, meeting schedule, submission requirements, required quorum for valid decisions, and more available, ideally on their website. Many IRBs are completely transparent and make their members’ resumes publicly available as well. Again, I must praise the Lebanese and African ones among those I have direct experience with. In other parts of the world, it depends. I have seen an IRB refusing to disclose their members, reasoning that this secrecy is a protection from attempts to influence them. Perhaps. But this also can serve the opposite purpose: hiding possibly influenced, biased members and those with conflicts of interests. Every coin has two sides. On top of that, it means that compliance with GCP requirements regarding IRB composition cannot be verified.
- Non-biased evaluation and decision-making. Are the IRB members free of bias and conflict of interests? If they are not, do they declare it and abstain from voting? Another prerequisite is having sufficient time to evaluate submitted documents. Is the protocol sound, clear, and feasible to be conducted by their investigator in their institution? Is the informed consent document complete, clear, and user-friendly? Does it explain well the study, its procedures, and reasons for performing them? Is the information presented in such a way that helps the participants to see the key points easily and remember them in the long run? Do study benefits outweigh risks? Are all collected data truly needed? Are the safety, well-being, confidentiality, and privacy of study participants safeguarded in this protocol? These are some of the important questions the IRB members should ask themselves during their evaluation.
Do IRBs/IECs Meet Expectations?
Some do and some do not. I have a problem with the concept of an IRB as a vendor or a for-profit organization. Does the status as a sponsor’s vendor that can be replaced if the sponsor is not happy jeopardize independence? Does a commercial status of the IRB do that? In my opinion, there is at least a risk it may.
If the IRB, typically covering many sites with their approval, is a vendor like a CRO, EDC provider, or courier company, it is selected, audited, qualified, approved, and contracted by the sponsor. Is it likely then that the IRB will raise comments related to the submitted documents, thus delaying the study active phase? Is it likely the IRB will take enough time to review complex protocols? Is it likely that, in extreme cases, they will reject the study? Or is it more likely the IRB will tend to readily approve the study? Is this possibly the reason why highly deficient informed consent documents and confusing protocols get approved?3 When I discussed the topic with a friend who served for years in an academic IRB, she asked me how could IRBs approved those consents. Can there be a difference between local IRBs associated with teaching hospitals and academic institutions on one side and multi-center IRBs contracted by sponsors?
Business interests may stand against the GCP-guided role of the IRB. In fact, the U.S. commercial IRB sector has grown significantly over the past few years, and private equity organizations started buying and selling IRBs as any other asset. In June 2022, Blackstone and Canada Pension Plan Investment Board invested $5 billion in Advarra, a provider of IRB, Institutional Biosafety Committee (IBC), and related services. Genstar Capital and Linden Capital Partners, which acquired Advarra in 2019, are said to keep investing in it. While Genstar had likely received its return on investment and possibly gained profit in three years, Blackstone is expected to keep investing for a longer period than traditional private equity.4, 5 I am not judging this deal, as I know several IRB members from Advarra and highly respect them. I am saying that this indicates that commercial IRBs can be a lucrative business. Not all investors are the same and not all IRBs are the same, but some may prioritize business and financial gain over their GCP-defined role.
All these questions are related to people — their resistance or susceptibility to influence, bias, and conflict of interest, as well as their personal integrity and values.
Can AI Solve The Problem?
So, what if we eliminate this weak human piece in the chain? We have been hearing that machine learning (ML), artificial intelligence (AI), and lately, generative AI (gen-AI) will solve all our problems. Let’s take a closer look.
Recently, I have read a brilliant article, “IRBs Enter The ‘Black Mirror’ Era?” by Parker Nolen.6 He concludes that gen-AI such as ChatGPT can become a voting IRB member when he finds no legislation, regulation, or guideline that prohibits it. I recommend reading it; what may sound like hyperbole today can be the reality we wake up in tomorrow.
Now, let’s play the what-if game. If a gen-AI “persona” is a voting IRB member, why not have the whole IRB be AI? We can train different gen-AI personas to represent different roles and be perfectly GCP-compliant. Since AI personas will have audit trails enabled, we will have perfect documentation. Imagine how effective and efficient this IRB can be. How does that sound? Would it solve our problems? With a sigh of relief, I say no, it would not. Does AI think? No, it does not. Can it innovate or reach the “aha” moment? No, it cannot. Is AI ethical? AI is neutral, neither ethical, nor unethical. Can an AI algorithm be trained to be biased? Yes, it can. If something or everything goes wrong, who will go to jail? The programmer? I do not think so. Then who? Nobody. Our legislation does not have these scenarios in its scope, at least not yet.
What Can We Do?
We get back to us as human beings with the ultimate responsibility to remain human and protect our fellow humans to enter, go through, and complete clinical trials safe and protected, experiencing the patient journey with the minimum burden possible. Being an IRB member is a service, a mission with commitment and accountability.
About The Author:
Kamila Novak, MSc, got her degree in molecular genetics. Since 1995, she has been involved in clinical research in various positions in pharma and CROs. Since 2010, she has been working as an independent consultant focusing on QA &QC being a certified auditor for several ISO standards, risk management, medical writing, and training. She is a member of the Society of Quality Assurance (SQA), the World Medical Device Organization (WMDO), the European Medical Writers’ Association (EMWA), the Drug Information Association (DIA), the Continuing Professional Development (CPD) UK, and other professional societies.
References:
- ICH E6 (R2) Good Clinical Practice Addendum, November 2016
- ICH E6 (R3) Good Clinical Practice, draft for public consultation, May 2023
- Study Participant Consenting – Can We Do A Better Job?, Clinical Leader, Guest Column, 24 Jul 2023, https://www.clinicalleader.com/doc/study-participant-consenting-can-we-do-a-better-job-0001
- Advarra, Leading Provider of Life Sciences R&D Compliance and Technology Solutions, Secures Major Investment from Blackstone and CPP Investments, Advarra Resource Library, 10 Jun 2022,
- Blackstone and CPPIB to make majority investment in Advarra, PE Hub, 13 Jun 2022, https://www.pehub.com/blackstone-and-cppib-to-make-majority-investment-in-advarra/
- IRBs Enter The “Black Mirror” Era?, Parker Nolen, MBA, DPS,