Reciprocity and post-trial access for participants in antiretroviral therapy trials

Introduction

Rationing antiretroviral therapy (ART) when need exceeds available supply raises many important and challenging questions ^[1–8]. Here, we focus on a particular ethical question that faces research sponsors, investigators, and policy-makers in various settings. Should research participants in ART trials have preference for further treatment over compatriots who have not participated, but who have a similar need and clinical eligibility for ART?

A growing consensus holds that researchers and their sponsors have some responsibility to help assure post-trial access to beneficial treatments ^[9–11]. One possible means of discharging this responsibility, as suggested by recent guidance from the US National Institutes of Health, is to coordinate plans with host-country stakeholders in order to include ART trial participants, post-trial, in local treatment programs supported by the Global Fund to fight AIDS, Tuberculosis, and Malaria, the President's Emergency Plan for AIDS Relief (PEPFAR), and others ^[12].

For individuals benefiting from ART in a trial, the prospect of no longer receiving it simply because the trial ends seems unfair and inexcusable ^[11]. Yet, in a country where only a fraction of HIV-infected people who need ART are able to get it, and rationing is inescapable, why should the fact that someone participated in ART research confer priority for continued ART through international assistance programs, while equally needy compatriots go without? An influential view invokes ‘justice as reciprocity’, which involves ‘what people deserve as a function of what they have contributed to an enterprise or to society’ ^[13] and calls for ‘providing something in return for contributions that people have made’ ^[8]. In return for participants' contributions to the social good that ART trials produce, it seems fitting for their country to offer them priority for post-trial access to ART ^[8].

Here, we question the reciprocity-based justification for offering priority access to ART trial participants when ART must be rationed. Whether reciprocity justifies such a policy depends on several variables, including the quantity of ART available, the number of people in the country who need ART, and whether the country's concurrent allocation policy selects specific subpopulations (such as HIV-infected mothers of young children) for priority. We conclude that only under some circumstances, at best, does reciprocity justify giving ART trial participants priority over equally needy HIV-infected compatriots. (When reciprocity falls short, it might still be legitimately decided to give priority to ART trial participants for ART post-trial, but such a decision would be based on other or further considerations, such as to prevent the emergence of drug-resistant HIV strains.)

Reciprocity

Any reason why ART trial participants might be fairly entitled to priority access to internationally funded ART in their community must be relevant to the relationship between them and their community, including their compatriots who also need ART. Here the idea of reciprocity – returning good for good – seems to make sense. Generally, in a reasonably well-functioning society, each member assumes some of the burdens necessary to create the benefits of social cooperation, and depends upon others to do likewise. The underlying fact of social interdependence may generate reciprocal obligations between members of society to benefit each other ^[14]. Especially when contributions to shared social goods are readily traceable to the activities of identifiable persons, others may incur reciprocal obligations to return benefits to those persons.

ART trial participants accept risks in the service of general knowledge about treating HIV/AIDS, helping to create at least potential or prospective benefits, and perhaps actual benefits, for current and future compatriots who live with HIV/AIDS.

Do such benefits justify asking those compatriots who urgently need ART to accept the postponement of their own access to ART in deference to trial participants? Even if there are obligations of reciprocity, are they fairly discharged by asking needy non-participants, who for various reasons may not have had the opportunity to participate in research, to let research participants get treatment first?

Two considerations undercut the presumption that reciprocity justifies asking needy non-participants to accept such arrangements. First, reciprocity does not obligate the recipient of a benefit to make a contribution or sacrifice disproportionately greater than the one to which it is a response. Yet the postponement of non-participants' access to urgently needed life-saving treatment may be a loss vastly disproportionate to the temporary research-related risks and burdens that ART trial participants typically assume. Second, non-participants would be asked to give up in the name of reciprocity the very benefit they are supposed to have received through participants' activities. The primary social benefit of ART research is knowledge about treating HIV/AIDS in order to reduce morbidity and mortality. However, if non-participants are made to reciprocate by accepting postponement of their own access to ART, in deference to participants, they postpone their own opportunity for reduced morbidity and mortality.

How variables matter

The impact of these two considerations depends on facts that may vary from case to case, such as the quantity of ART available and the number of people who need ART. Consider a hypothetical example. Suppose a developing country's Ministry of Health (MOH) estimates that as an interim goal, with the help of international assistance programs, it can scale up to offering ART to at most 10 000 people, even though 100 000 need it so urgently they will likely die if they do not receive it. If ART distribution is by random lottery, each person in urgent need has 10% odds of receiving it. Now suppose that the MOH plans to host a foreign-sponsored ART trial, expecting the results to be of value for local HIV/AIDS treatment programs.

During the trial, ART for participants is funded and supplied by research sponsors, thus not drawing down the supply of ART generally available through the Global Fund, PEPFAR, and the like. In fact, for the length of the trial, total ART will temporarily increase in step with trial size. Accordingly, participants' access to researcher-funded ART not only benefits participants themselves but also improves (albeit only slightly and temporarily) each non-participant's odds of receiving ART through international assistance programs. It is only when participants exit the trial that the challenge of providing post-trial ART arises. If participants then have priority for internationally funded ART, non-participants' odds will worsen. For example, if 3000 participants exit the trial in our hypothetical scenario, non-participants' odds worsen from about 1 in 10 (10%) to about 1 in 14 (7%).

How bad is it to go from 1 in 10 to 1 in 14 odds? Can we specify a range of worsened odds for needy non-participants that (a) is roughly proportionate to the range of risks and burdens normally assumed by ART trial participants, and (b) preserves to a meaningful extent non-participants' preexisting odds of receiving ART? Only when these two threshold conditions are met would justice as reciprocity apply to the relationship between ART trial participants and their compatriots who also need ART.

What if a different group already has priority?

Even if we can develop a principled account of how to determine when a particular case meets the threshold conditions – a conceptual problem not yet solved – there may still be cases that do not meet them, so that justice as reciprocity fails to apply. Furthermore, even in the cases that do meet threshold conditions, so that justice as reciprocity does apply, it may not alone provide a decisive reason why trial participants ought to have priority in rationing. We now illustrate each type of case.

Countries might decide to select specific population groups for priority access to ART: for example HIV/AIDS activists, mothers of young children, or healthcare workers ^[6]. The World Health Organization's ethical guidance for rationing ART acknowledges a need for possibly prioritizing specific population groups and rests the ultimate weight of justification for such decisions on fair process. A fair process includes all stakeholders, is publicly transparent, enforceable, and revisable, and it bases decisions on relevant evidence, reasons, and principles ^[3,7,8].

Suppose that the MOH in our example has already decided, through a fair process, to offer priority access for ART to a specific subpopulation in urgent need, for example mothers of young children, in order to avert the social breakdown of orphaning too many children. If the MOH now considers hosting an ART trial, the question arises whether to assure participants of post-trial access to internationally funded ART. This scenario plays out differently depending on the number of mothers in need relative to the quantity of ART available through international assistance programs.

On one hand, available ART could exceed the number of mothers in need. Then all mothers are assured of ART even if, in addition, trial participants are guaranteed post-trial access. But needy patients who are neither mothers nor trial participants will suffer significantly worsened odds when participants exit the trial. For example, if there are 7000 mothers in need and 3000 participants exiting the trial, the odds of ART for non-participants who are not mothers will fall from approximately 1 in 31 (3.2%) to zero. Since this worsening of odds is a total loss, it clearly does not meet the threshold conditions. Justice as reciprocity fails to apply. On the other hand, the number of mothers in need could exceed available ART. (In this case, those who are neither mothers nor trial participants are left with odds of zero in any event.) Then the only way to assure trial participants of priority for post-trial access through internationally funded aid programs would be to reduce the quantity allocated to mothers as a group. This would distort the country's existing priorities.

Might the country then deliberately revise its existing priorities to accommodate trial participants? Under the terms of fair process, revising priorities in favor of ART trial participants at the expense of another group is at most an ethically permissible option, not an ethical requirement. Even if the worsening of odds for members of the other group (like mothers, in our hypothetical example) is moderate enough to meet threshold conditions (so that justice as reciprocity does apply to the relationship between them and trial participants), it is only one principle comparable to other competing principles that support prioritizing different groups (such as giving priority to mothers to avoid social breakdown). In general, depending on what else is at stake, whatever principles support existing priorities might still override the principle of justice as reciprocity toward ART trial participants, in which case no revision would be called for.

So, reciprocity notwithstanding, the MOH could legitimately stick to existing priorities, hosting the trial but not assuring participants of priority for post-trial access to ART. Responsibility for post-trial ART would instead fall to other interested parties, which could include, but is not necessarily limited to, researchers and sponsors. Other funding arrangements may be available, perhaps through recruiting private donors and non-governmental organizations to dedicate funds specifically to post-trial ART. Examples of groups that have developed alternative funding structures include the HIV Vaccine Trials Network (HVTN) and the HIV Netherlands, Australia, Thailand (HIV-NAT) Research Collaboration Program ^[15,16].

The extent and sustainability of funders' responsibility for post-trial treatment over time (2 years, 20 years, for life?) is an issue with practical and ethical complexities that go beyond the scope of this article ^[10]. Even if trial participants received priority for access to ART through programs like the Global Fund, however, that would not solve the problem of responsibility over time.

Possible effects on research participation

It is possible that if access to post-trial ART is an incentive for research participation, then not granting priority for post-trial access to ART through programs like the Global Fund could deter participation. It is also possible that research participants are sufficiently motivated by the benefits of participation itself, including receiving ART for a defined period of time. In either case, the worry has to do with whether post-trial access should be offered. Here we have focused on how post-trial access might be assured, by addressing and arguing against reciprocity as always justifying priority post-trial access in local programs funded by international aid programs. Even when reciprocity does not justify priority for post-trial access for research participants, however, other considerations may sometimes justify a similar policy (e.g. to prevent the emergence of drug-resistant viral strains); alternatively, post-trial ART could be made available through other funding structures via research sponsors or targeted by donors to specific research sites.

Conclusion

While the principle of justice as reciprocity has intuitive appeal, its use requires care. Those who make a social contribution through accepting burdens of research risk should receive benefits in return, but not by disproportionately increasing burdens on others. Several variables affect this balance. When priority access for trial participants would drive non-participants' odds of receiving ART to zero or close to zero, justice as reciprocity fails to apply and provides no reason to select trial participants. Even when justice as reciprocity provides some reason, it has no special force to override existing (fairly decided) priorities in favor of different groups. At most, it might prompt an optional revision of existing priorities. Local facts about these matters should inform judgements about whether and why it is appropriate, in particular cases, to use host-country Global Fund or PEPFAR programs as a means of ensuring that ART trial participants will have access to ART post-trial.

Acknowledgements

For their contributions to our initial work on this article, we thank Ezekiel Emanuel, Reidar Lie, Gordon DuVal, and the audience at a panel presentation for the National Institutes of Health (NIH) Department of Clinical Bioethics 2005 Reunion Retreat, financially supported by NIH. For helpful discussion and comments on drafts, we thank Ezekiel Emanuel, Reidar Lie, Arthur Applbaum, Stuart Chaitkin, Norman Daniels, Samia Hurst, Debra Mathews, Henry S. Richardson, Walter Sinnott-Armstrong, Gopal Sreenivasan, Dennis F. Thompson, the 2005–6 Faculty Fellows' seminar at the Edmond J. Safra Foundation Center for Ethics (Harvard University), and the audience at a talk that Maria Merritt gave on this topic at the Phoebe R. Berman Bioethics Institute, John Hopkins Bloomberg School of Public Health (October 2005).

Sponsorship: This study was funded by the National Institutes of Health Department of Clinical Bioethics 2005 Reunion Retreat. Maria Merritt gratefully acknowledges financial support from the Edmond J. Safra Foundation Center for Ethics in the form of a Faculty Fellowship, and from the College of William and Mary in the form of a research leave. Funding sources had no role in the writing of this paper or the decision to submit it for publication.