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The Declaration of Helsinki was first developed in 1964 as a set of ethical principles for physicians regarding human experimentation. It’s been revised 10 times since then, most recently earlier this year. The Office of Global Policy and Strategy recently spoke to FDA Chief Medical Officer Dr. Hilary Marston and Ann Meeker-O’Connell, director of the FDA’s Office of Clinical Policy, about the latest revision and the FDA’s role in the revision process.
Q: What is the Declaration of Helsinki, and who is responsible for it?
Dr. Marston: The Declaration describes principles that underlie ethical clinical research. It was created by the World Medical Association because physicians were engaging in research but needed to have some guidance about ways to conduct the research in a way that still respected the rights of their patients. Over time, the Declaration has evolved as clinical practice has evolved, most tangibly because doctors aren't the only ones doing clinical research now; it is health care providers. But there are a number of other ways that the Declaration has evolved as well.
Meeker-O’Connell: In many ways the Declaration has served as a foundational ethical resource for those conducting medical research. And one of the things that is particularly valuable about its structure is that it is very principles-based. Hopefully, and ideally, these are enduring principles that stand the test of time, even as it's evolved.
Q: When was the Declaration first established? Was it addressing problems that were recognized at the time?
Meeker-O’Connell: It was adopted in 1964 after a period of reflection about some of the things that had occurred during the Second World War and after, when the international medical community really wanted to lay a global foundation for ethical research.
Q: What were the major topics incorporated into the Declaration?
Meeker-O’Connell: Over time the Declaration has evolved, but some of its core concepts include respect for participants and protecting the rights, welfare and safety of participants, the concept of informed consent, and of having an independent ethical review. So, in many ways there are some of the core foundational aspects that you see reflected in our own human subject protection regulations.
Q: By my count the Declaration has been revised 10 times. Some of the revisions have been minor. When did the latest revision begin? What prompted it, and how did the process work?
Dr. Marston: The World Medical Association wanted to make sure that every part of the world had a voice in reshaping the Declaration. And so it began with a series of regional consultations hosted by one of the regional medical associations focusing on a thematic topic. For example, they had a thematic meeting about vulnerable populations in Germany, and another about placebo control in Brazil. There were a number of issues that they realized were going to have a lot of discussion in the revision, so they wanted to get in-depth consultations about those.
Q: What was the FDA’s role in the revision process?
Dr. Marston: We were brought in quite early in the process after the first consultation to offer regulatory perspective. We have regulations that govern our regulated research in terms of human subject research protection that serve a complementary role to the ethical guidelines stated in the Declaration. The regulatory responsibilities and ethical principles underlying medical research are certainly complementary, but they're not identical. So, the WMA wanted to ensure that they were getting the regulatory perspective as they were updating the Declaration.
Q: This was about a 30-month process. So, you must have been involved in many meetings around the world. What key priorities and themes did you focus on when you were in this process?
Dr. Marston: What we focused on was representing FDA and HHS equities to the best of our ability in these consultations. We knew that the American Medical Association was at the writing table — the U.S. government was not. So, we focused on specific issues that we really wanted to weigh in on, rather than trying to suggest edits on absolutely everything in the document.
An example of that was the topic of vulnerable populations where we really felt that the Declaration as previously written had made researchers pretty hesitant to enroll vulnerable populations in clinical trials. This has left the clinical community in a position where they didn't always have the evidence they needed to safely treat these populations. So, what we tried to do was talk to the group about ways that research involving vulnerable populations could have safeguards in place to ensure that their rights are respected, but that they aren’t inappropriately excluded from participating in research.
 Dr. Hilary Marston, FDA Chief Medical Officer, and Ann Meeker-O’Connell, Director of the FDA’s Office of Clinical Policy.
Q: What is a vulnerable population? And give me an example of how these populations could be protected in research.
Dr. Marston: So, for example, kids, right? We have specific regulations that provide additional safeguards for clinical investigations involving children, as well as draft guidance on this — on the ethical conduct of clinical trials in children. Further, ICH [International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use] guidance recommends that IRBs [Institutional Review Board] reviewing this research have expertise in pediatric issues — either through their members or by consulting experts. When you're looking at clinical investigations involving kids, the IRB generally needs to make sure that there is a prospect of direct benefit to that child, or, if there isn't a prospect of direct benefit, that there's no more than a minor increase above minimal risk to that child.
Meeker-O’Connell: I think it's interesting that the Declaration uses the terms vulnerable and vulnerability but doesn't actually define what that means. I think if we look at our FDA human subject protection regulations, they talk about participants that are likely to be vulnerable to coercion or undue influence. For example, there might be a power differential. Our regulations currently outline examples of different groups who IRBs are supposed to look at, in the context of the research, to make sure there are appropriate protections to guard against undue influence or coercion.
It's also an area that is evolving. In September of 2022 we published a proposed rule to revise our regulations on human subject protections which, as written, included pregnant people in the description of groups who are considered vulnerable. Our proposed rule would remove that reference to pregnant people among other changes. So, one of the things that strikes me as we think about the Declaration is that it's also evolving to look at the unintended consequences of some of the statements it makes. That is, instead of just excluding groups or individuals who have vulnerabilities from research, can we look at how could we provide supports to include them.
Q: I wanted to ask about some of the other major revisions beginning with research, integrity, and scientifically sound and rigorous design. Was this a new emphasis, and what was our take on that?
Meeker-O’Connell: As in in many different communities and groups, this concept of research waste and lessons learned from the pandemic loomed large as the WMA writing committee was making its deliberations. The Declaration has long held that design should be informed by scientific information and shouldn't just be drafted up at somebody's kitchen table — it should be supported by compelling evidence. But this idea that design should be rigorous was introduced, in large part, because of the concern that there was, both in research during the COVID pandemic and in clinical research generally, research waste where trials were designed that actually have limitations that mean that they will never yield reliable evidence. Some of the discussions that we had were around making that statement, but really clarifying that the person who holds the pen, the sponsor or researcher who's designing the trial, really has that ultimate responsibility for the design being appropriate.
Dr. Marston: I think that's very well said. There was a lot of discussion about the responsibility of the researcher to the participants. If you were launching a study that didn't have any prospect of deriving scientifically valid evidence, then that is somewhat of a breach of trust. The question really becomes whose responsibility is it to make sure that at least, a priori, you have that prospect of getting a reliable result. And as Ann said, it is ultimately the sponsor’s responsibility, and in terms of oversight of that, there are a number of different players that have a role in reviewing trial design.
In the end, the key thing is to make sure that the individuals that are looking at the design and assessing if it's scientifically robust, have the clinical, statistical, and methodological expertise to assess that particular design. For example, we’ve seen a number of universities or funders that have independent scientific review of their protocols.
Meeker-O’Connell: There's a tendency to gravitate toward placing the entire responsibility for scientific soundness on the Institutional Review Board, when they may not have the scientific, statistical, or methodological expertise. And I think there was some clear feedback from the research and institutional community that this is something that is probably beyond the composition of ethics committees given the array of innovative designs that require specific subject matter expertise. We heard from members of the institutional community that IRBs should be asking if there has been an independent scientific review, which may support their consideration of whether risks to participants have been minimized and are reasonable in light of the anticipated benefits and knowledge expected to be gained from the research.
Q: Very interesting. This is somewhat related because you mentioned COVID, but there is a new paragraph about ethical principles during public health emergencies.
Meeker-O’Connell: That was one that was added recognizing that in an emergent situation, like with COVID, there's a need to guard against overlooking or sidestepping long-standing ethical principles. Hilary mentioned our regulations and guidance, and this is an area where FDA has guidance related to major disruptions in clinical trials due to disasters or public health emergencies. This guidance describes approaches to help sponsors and others protect the safety of participants and maintain compliance with GCP [Good Clinical Practice], including ethical aspects, during these challenging situations.
Q: There was a section on biobanks, but that was revised and taken further to include personal data stored after trials. What was that, why was it important, and how did the FDA weigh in on that?
Meeker-O’Connell: That started out in the first version as a statement that could have been interpreted very broadly as applying to any databank containing health data. We had a lot of discussions on that because, again thinking of FDA equities, we have a real interest in promoting and supporting the use of things like real world evidence to provide insights on the safety and efficacy of products. The final revision ended up more focused on the secondary use of data and biospecimens collected from research participants. So, in that sense, it started broad and was somewhat refined. This is another area addressed in the 2022 proposed rule. We proposed adding an additional element of informed consent that would make participants aware of whether and how their data or biospecimens collected might be shared or used for future research.
One area where I think we still have concerns on this issue in the Declaration of Helsinki is an incorporation by reference to the Declaration of Taipei, which is a broad document, broader than just research. It has been acknowledged by the World Medical Association to be outdated, and it is unlike the Declaration, which is a very principles-based document. The Declaration of Taipei is a very procedural, operational document that says IRBs will do this, you’ll have governance —very much a rules-based approach that seems to conflict with the spirit of the Declaration.
So that was an area where I think we commented vigorously, with the understanding that the rationale for including it was recognition that there is a much broader use of data in data-driven research with artificial intelligence that they were looking to be vocal on. We just think that the manner in which they tried to do it, by incorporating a noted outdated document in the time of vast technological change, was probably not the ideal strategy.
Q: Well, there's always the next revision.
Meeker-O’Connell: Oh, they have actually signaled that they will be updating the Declaration of Taipei. We hope to be involved quite early in those discussions.
Q: Help me put the Declaration into context with other documents that deal with medical research ethics, such as the FDA’s own GCP requirements.
Meeker-O’Connell: That is a great question, because I think there's sometimes confusion about the role of the Declaration, particularly with FDA-regulated clinical investigations. As a regulatory authority, we operate within a statutory framework; we issue regulations that are binding and we issue guidance to provide our recommendations related to those regulations. The Declaration is a consensus guideline from the World Medical Association, an external party that, again, represents the opinion of a group of experts in the medical community, informed by comments globally, but it is not legally binding for the research that FDA regulates. So, I think our GCP requirements and the Declaration have distinct purposes but share a joint commitment to protecting those who participate in research.
Q: Before I ask my last question, what stood out to you from the regional meetings you attended?
Dr. Marston: That’s a great question. The placebo meeting in Brazil was certainly one of the spicier meetings. The Declaration previously had a statement that a new research intervention should always be tested against the best proven intervention(s) and that using a placebo control was only acceptable where there is no proven intervention or when it is necessary in other narrow circumstances. That was often interpreted as stating that an intervention should always be compared against top standard of care. It was interesting to have a consultation in Brazil, where we had a lot of members of the Global South at the table who were concerned about not getting access to standard of care. There was also discussion about what standard of care would mean in different settings — whether that was really a single thing around the world, but also whether standard of care is necessarily knowable because there are so many cases where we don't know what the optimal therapy is.
Also, there was discussion about the importance of placebo control not just when there's no effective alternative, but also when, say an alternative is particularly toxic and really not well tolerated by patients. That was a good first meeting for us to come to, because I think there had been a false perception that the FDA had an adversarial view on the Declaration of Helsinki. And really what we were able to explain was that we have different audiences. They’re speaking directly to clinicians who are engaged in research, and we are speaking to a broader group, including regulated industry, so some differences fall out from that, but we are aligned with the general principles of the Declaration of Helsinki. Ann, anything to add to that or do you want to speak about community engagement?
Meeker-O’Connell: The meeting that I attended in South Africa really focused on the community. We often tend to think of clinical trials as involving individual participants. The perspective there was looking at engaging the community in discussions about research, ensuring those community attitudes are represented and thinking about vulnerability in a way that does not stigmatize groups but rather as something that is fluid, that people can be situationally vulnerable.
The thing that really stuck out to me, though, that kind of was woven throughout the two days, was the concept of Ubuntu – as I am, so are we, or I am because of us. So, just this idea that you can't necessarily separate an individual from the community, which I think you see reflected in the Declaration and its focus on engaging not just the individuals who may participate in the trial, but the communities surrounding them in decisions about research priorities and research design.
Another meeting led to a focus on encouraging the involvement of populations who have been underserved by the research community and really engaging with them. And I think these are consistent with FDA’s efforts to address enrollment of representative populations in the trials conducted with the medical products that we regulate to help ensure that the trial population really reflect the populations that might use them if they were approved.
Q: There were eight regional and topical meetings. Did we go to all of them?
Dr. Marston: We went to all but the first one in Tel Aviv, because we hadn't been invited yet, and the one in the Vatican, which I believe was a second meeting on vulnerable populations, and its specific focus was less central to FDA equities.
Q: You said there was a topical meeting on placebo. What were the other topical meetings?
Dr. Marston: Each one had a topic, so each of the regional consultations had a unifying topic. So, for example, the Japan meeting was around health emergencies. And they had a researcher from Hiroshima who was able to talk about the impact on future generations and research on radiation injury and subsequent cancers.
Q: It strikes me that having a global document like this is especially helpful today when you might have clinical sites all over the world. Is it helpful to have a global document with that in mind?
Meeker-O’Connell: It's a two-part answer. Yes, it's useful to have global documents that provide a unifying perspective. I think for certain research that FDA oversees, the ICH guidance documents help provide that global unifying perspective. Taking my FDA hat off and recognizing not all medical research involves the types of products we regulate, I think a global document is also valuable when social and behavioral research is done or when there is research on interventions based on something other than the products we regulate, but I view the work that WMA has done with the Declaration as distinct from, but very complementary to, the work that we do with international forums we participate in as a regulator.
Q: OK. And finally, having gone through this process, does the FDA need to make any changes to its own GCP requirements or any of its policies?
Meeker-O’Connell: Short answer is we have our regulatory framework and guidance. The Declaration of Helsinki is a valuable resource, but it doesn’t have any kind of direct impact on our authorities. I think what is of value is to look at what we learned and think whether there are things that we might take a deeper look at.
Q: Answer that question. What have you learned, and where might you take a deeper look?
Meeker-O’Connell: I think of it not in terms of regulatory policy, but how would we leverage what we heard in how we talk about vulnerabilities. A lot of the discussion during this process was about protecting through research, not from research, and so as we continue developing guidance related to our regulations, it means taking a lens to make sure that we aren’t unintentionally inhibiting the inclusion of vulnerable participants where appropriate.
Dr. Marston: I think the topics that they picked were kind of the hot topics in this area right now. And these are areas that we’re already engaging in and hopefully in some ways really leading on as an agency. For example, the issue of control groups. We put out a draft guidance on the design and conduct of externally controlled trials. We also put out our rare disease guidance, which touches on some of those issues in providing recommendations on conducting efficient and successful drug development programs for drugs and biologics intended to treat rare diseases or issues around vulnerable populations. I mentioned the draft guidance on ethical conduct of pediatric trials.
We’re also working on updating the pregnancy guidance and all of the work around expanding the clinical research tent. There is a whole suite of guidances on these issues, and most recently the draft guidance on integrating randomized controlled trials into routine clinical practice and the final guidance on decentralized clinical trials. So, these are issues that FDA is already working on. What was great was being able to speak to experts from around the world who work on these issues, some of whom were regulators, but some of whom were not. This allowed us to hear those different perspectives.
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