By Holly Fernandez Lynch
Today, the Multi-Regional Clinical Trials Center (MRCT) at Harvard University and the Petrie-Flom Center at Harvard Law School are co-hosting a daylong conference on “Post-Trial Responsibilities: Ethics and Implementation.” We’ll be live blogging the conference here at Bill of Health, and video/slides from the conference will be available soon.
The conference was kicked off by Mark Barnes, co-director of MRCT, who pointed to two key statements of ethics that refer to post-trial responsibilities, the Declaration of Helsinki’s Paragraph 34 (DoH) – which Mark referred to as “mysterious,” as it could not in practice mean what it literally says – and the Council for International Organizations of Medical Sciences Guideline 10 (CIOMS).
Mark went on to describe the wide spectrum of issues that may be encapsulated in the simple phrase “post-trial access” – for example, over what period of time is access provided, is it provided for chronic diseases or only transient conditions, is it necessary only till a patient is stabilized or for longer, is it a lifetime commitment, does it apply only to research subjects themselves or broader research communities? How much evidence should we demand of benefit before imposing post-trial responsibilities? Exactly what should be provided – only the study drug, whatever was offered to the control group, other supportive care? Must post-trial access be free of charge? What about improved infrastructure, knowledge, and other benefits as components of post-trial access? Our goal for the day will be to clarify the ways in which the Declaration of Helsinki, the CIOMS guidelines, and other ethical standards and regulatory requirements require additional guidance for practical application to the complex real-life circumstances of clinical trials.
The conference’s first panel – “Setting the Stage” – had the objective of introducing current ethical and regulatory approaches, as well as key controversies. The panel was kicked off by Christine Grady (NIH), who gave a talk on the ethics of post-trial responsibilities, including history, models, agreements, and controversies. Christine explained that compared to the very clear articulation of researchers’ responsibilities before and during a trial, they have very little guidance on what should happen when a trial is over. Indeed, they had no guidance whatsoever until the 1990s, when there was both an upsurge in international collaborative research, and HIV research more specifically. In that context, new efforts cropped up to minimize the possibility of exploitation in international research, including development of the concepts of responsiveness to local needs and reasonable availability of research benefits, as well as capacity building, collaboration, and community engagement.
Christine noted some empirical data suggesting that when participants in an HIV research study, IRB members, and investigators were asked about post-trial access, many respondents indicated that everyone in the world who needed the drug should have access. Of course, the practical reality is much more complicated.
Christine noted some key areas of agreement on post-trial responsibilities. For example, investigators must plan in advance for what will happen when a trial is over, including taking reasonable efforts to help participants access beneficial treatments, describing their plans to review committees and participants, informing participants about study outcomes, and honoring any commitments made.
However, there are also many unsettled areas, most importantly the ethical underpinnings for post-trial responsibilities, which are essential to helping us answer questions about who owes what to whom. Christine noted that research is not the same as health care, and researchers and sponsors are not in a position to provide access in perpetuity. She also noted that several of the usual principles used to support post-trial responsibilities have important shortcomings. For example, it is not clear that providing benefits at the end of a trial is the only way – or even an effective way – to avoid exploitation, especially if subjects understand and consent to participate without such post-trial access. Similarly, although post-trial responsibilities are a way to address background disparities in health care, it is not clear that this is the most appropriate mechanism, especially when focused exclusively on research participants over other community members. In the end, the set of reasons sometimes used to impose post-trial responsibilities is incomplete at best, and there are important and powerful arguments against imposing such obligations.
Next, Jeff Blackmer (University of Ottawa, World Medical Association) discussed his experience with the Declaration of Helsinki. Jeff clarified that the DoH was created to establish the highest possible standards of ethical behavior and care by physicians, and has been revised with relative frequency since its initial appearance in 1964, including several times regarding its position on post-trial access.
DoH first referred to post-trial access in 2000, with a very strong statement:
At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.
This was met with significant backlash, and led to a 2004 note of clarification, which Jeff suggested actually clarified very little:
The WMA hereby reaffirms its position that it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care.
Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.
The most recent version from 2013 is somewhat less stringent than it was in 2000, although still stronger than other available guidelines:
In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.
Jeff emphasized that as a declaration of high level ethical principles, DoH is not intended and cannot address and clarify the many complex details associated with implementing post-trial access, including a key question, which is whether requiring such arrangements will serve as a disincentive to important clinical research in some settings.
Next, Alex John London (Carnegie Mellon) discussed the CIOMS approach to post-trial access. Alex emphasized that the CIOMS guidelines have a special focus on international collaborative research and research in developing countries, and provide substantially more elaboration on ethical responsibilities than DoH. He also recognized the important caveat that ethical guidelines cannot be everything to everyone – they cannot be perfect philosophical statements while also being sufficiently practical and accessible to researchers on the ground.
CIOMS’ Guideline 10 introduces two important concepts for post-trial responsibilities: (1) responsiveness to local health needs, and (2) reasonable availability:
Before undertaking research in a population or community with limited resources, the sponsor and the investigator must make every effort to ensure that:
- the research is responsive to the health needs and the priorities of the population or community in which it is to be carried out; and
- any intervention or product developed, or knowledge generated, will be made reasonably available for the benefit of that population or community.
There are two important rationales supporting this guideline, including concerns about exploitation and promotion of justice, namely the idea that research should leave low resource communities better off, or at least no worse off.
Alex emphasized that there is an important division of labor between research and health systems, and that research is not the avenue by which health care ought to be provided. Thus, the extent of post-trial responsibilities should cover the interstitial space between the end of a trial and transitioning to the health care system more generally. However, post-trial responsibilities are not exclusive to new interventions, but may also apply to sharing information, knowledge, and services; research-related capacity building; and concern for research-related injury.
Alex emphasized that under the CIOMS guidelines the recipients of post-trial responsibilities include host countries and communities, as well as study participants. No one agent bears all responsibilities, but instead, study sponsors and researchers are directed to work with stakeholder representatives, national governments, local health authorities, communities, and others to develop appropriate plans. Ultimately, investigators and sponsors are shepherds of the planning process.
Finally, Seema Shah (NIH) discussed pots-trial obligations and policy approaches around the globe. Seema identified several categories of regulatory approaches to post-trial access, ranging from silence on the topic (in the US) to requiring description of access plans, referral to care, ensuring access, and most stringent, actually providing access. Even those regulatory bodies on the more stringent end of the spectrum generally include important caveats in the responsibilities imposed however, for example limiting requirements only to later phases of research and treatments deemed beneficial and safe.
In addition to regulatory bodies, research funders may also have policies regarding post-trial responsibilities in research they fund. Often, these policies show an important tension: refusing to provide funds for post-trial access, but demanding that plans be made. Such policies could have the important unintended consequences of diverting research away from places where post-trial access would be very difficult to implement.
Comparing the existing regulations to available ethical guidance, Seema noted some important similarities: there is no clear consensus in either as to the proper scope and intricacies of post-trial responsibilities; there is an emphasis on advanced planning; and responsibilities are limited to interventions identified as beneficial. There are also some important contrasts. For example, regulations seem to be less stringent, with more caveats and nuance, than ethical guidelines. Regulations are also generally directed to a single stakeholder, where ethical guidelines call for groups of stakeholders to work together and share the burden on post-trial responsibilities. In practice, Seema noted that the emphasis is usually on short term access to care, and transitioning patients to longer-term plans.
Next up: Session II on Important Perspectives, including commentary from FDA, PhRMA, investigators, and communities.