Abstract
Three principal factors affect the stringency of medical researchers’ obligation to provide antiretroviral treatment to participants in non-HIV/AIDS studies that are conducted in developing countries: (1) the centrality of HIV/AIDS to the study design, (2) the extent of the researcher–participant interaction, and (3) the cost relative to the study budget.
I provide a basis for assessing the comparative stringency of the researchers’ obligation to provide this type of ancillary care. Practically, given the range of possible responses to study participants’ needs, calibrating the researcher’s responsibility to provide ancillary care is a useful step in ethical analysis.
Theoretically, a gradation of obligation suggests how research ethics committees or institutional review boards can take multiple, potentially conflicting ethical factors into account without undertaking spurious efforts to quantify their importance.
IT IS NOW WIDELY ACCEPTED that researchers testing new treatments for HIV/AIDS have some moral responsibility to ensure that the treatment remains “reasonably available” to study participants after the study is over.1 Providing preventative and posttrial treatment to participants in HIV-prevention trials has also been discussed.2,3 But what about clinical or epidemiological researchers conducting non-HIV research in developing countries who encounter study participants living with HIV/AIDS?
Although the efforts of such programs as the President’s Emergency Plan for AIDS Relief and The Global Fund to Fight AIDS, Tuberculosis, and Malaria have helped make antiretroviral treatment (ART) more widely available in developing countries, the day when ART is available to anyone who needs it is a long way away.4–6 Where ART is not readily available, what obligations, if any, do researchers who conduct non-HIV trials have to ensure that study participants get ART? If medical researchers and their sponsors have a responsibility to provide ART to trial participants, what does this mean, concretely?
In some contexts, it might mean that they should help to increase the overall availability of ART and skilled personnel in the country or countries hosting the research, if only for the benefit of their trial participants. Providing ART to trial participants can interfere with local priority setting for access to ART or to medical professionals.7 However, because researchers might respond to their ancillary-care obligation to provide ART by working to help enhance a country’s access to ART, this conflict is, in principle, avoidable.
The view defended in this article builds on the partial-entrustment model that Belsky and I have suggested as a general approach to medical researchers’ ancillary-care obligations: their obligation to provide care that research participants need but that is required neither by a study’s design nor by the imperative to avoid harming the participants.8,9 Our position is that just because a study participant’s medical need is ancillary to the research does not mean that the researcher has no obligation to address this need. Here, I argue that researchers who conduct trials that are not HIV/AIDS treatment trials have obligations to provide ancillary care for the HIV/AIDS needs of their participants. The stringency of these obligations in developing country settings depends principally on 3 factors: (1) the extent to which the trial design makes HIV/AIDS relevant to the study, (2) how deeply the researchers interact with the participants, and (3) how large the cost of addressing these needs would be in relation to the study budget. Analyzing researchers’ relevant obligations to provide ancillary care using these factors makes it possible to discern gradations of responsibility in this difficult context.
It makes sense to look for gradations in the stringency of researchers’ obligation to provide HIV/AIDS treatment to participants in non-HIV/AIDS trials, because there are many gradations of possible response to these needs. For persons who suffer with HIV/AIDS in a developing country, researchers might provide any of the following levels of care10: recommend treatment and provide a referral; provide only palliative care for opportunistic infections; provide palliative care and try to arrange funds to pay for ART; provide palliative care and provide or pay for ART; or provide palliative care, ART, and monitoring. For each of these levels, would care be provided just for the duration of the trial? After the trial is over as well? For the participant’s lifetime? The responsibility of researchers to persons who suffer with HIV/AIDS need not be viewed in all-or-nothing terms.
A huge step forward in the ethics of international medical research has been the recognition that participants must be offered an appropriate standard of care for the disease or condition under study. This idea—and the ethical arguments appealing to beneficence, nonmaleficence, justice, and nonexploitation that underlie it—continues to have great power.11–14 Those arguments do not, however, translate easily to the issue of ancillary-care obligations. To be sure, providing ancillary care would be beneficial to study participants, but medical researchers do not have as general an obligation to promote the health of participants as do clinicians. So we need to look at other ways to specify the obligations to provide ancillary care incumbent on researchers. Grounds of distributive justice may charge governments, or the citizens of wealthy countries, with an obligation to help persons who suffer with HIV/AIDS in developing countries, but general appeals to justice are difficult to translate into obligations incumbent on researchers in particular. Nonexploitation may require that some benefits flow to trial participants and to the community from which they are drawn, but it is doubtful that it requires much ancillary care. Accordingly, it is worth looking at obligations to provide ancillary care in their own right—as at least 1 bioethics body has done.15 These obligations will supplement, and not supplant, any obligations incumbent on researchers on the basis of beneficence, nonmaleficence, justice, or nonexploitation.
Although the issue of researchers’ responsibilities to provide ancillary care has begun to come to the attention of persons and institutions responsible for research ethics guidelines, there is no consensus on how to address it. The partial-entrustment model currently appears to be the most fully articulated approach to medical researchers’ obligations to provide ancillary care. Central to the approach is the idea that researchers’ responsibilities to provide ancillary care are limited both in scope and in strength. More-extensive arguments in defense of the partial-entrustment approach to ancillary-care obligations may be found elsewhere.8,9
Although medical researchers are usually physicians, researchers’ obligations to provide ancillary care fall short of the obligations a physician has to his or her personal patient. Research aims to advance general knowledge, not to promote the health of its volunteer participants. Nevertheless, researchers accept special responsibilities when they solicit participants’ permission to conduct studies. By accepting participants’ permissions to handle their bodies, bodily samples, and medical records, researchers come to be entrusted with certain aspects of the participants’ health. Researchers cannot collect such otherwise confidential information about study participants and disclaim all responsibility for expertly responding to that information on the participants’ behalf.
As a result, they come to have some limited responsibility regarding ancillary conditions that may be discovered by carrying out study procedures. For example, malaria researchers who discover schistosomiasis in participants’ urine samples have a responsibility to care for it. Because this rationale for ancillary-care obligations is partial entrustment and not reparation for harm, it does not matter whether or not the schistosomiasis was pre-existing. It is the permission that researchers have to obtain to do a study that determines which aspects of a study participant’s health are within the scope of the obligation to provide ancillary care.
If a disease or condition falls within the scope of the researchers’ ancillary-care responsibility, the question still remains whether they ought to provide care for it. To settle this question, the strength of the participants’ claim to care must be assessed. The general analysis of obligations to provide ancillary care suggests 5 strength factors: (1) participants’ vulnerability (how badly off they would be if they did not receive help), (2) participants’ degree of dependence on the researchers (whether they lack other sources of possible help), (3) participants’ uncompensated risks or burdens, (4) the expected depth (intensity and duration) of the researcher–participant relationship, and (5) the cost to the researchers (in money, personnel, and study power) of providing the relevant care.
To simplify the discussion of gradations in obligations to provide ancillary care for research study participants in developing countries who suffer with HIV/ AIDS, we should focus on those factors that will show the biggest variance from trial to trial. HIV/ AIDS sufferers in developing countries are all terribly vulnerable, and their dependence on researchers for access to HIV/ AIDS care seems likely to vary more from country to country than from trial to trial. What will vary among studies in which HIV/AIDS is likely to arise as an ancillary-care need are the depth of the researcher–participant relationship and the cost of providing a given level of care.
A recent study of the effect of nitazoxanide on Zambian children who have cryptosporidiosis exemplifies how HIV/AIDS care might arise as an obligation to provide ancillary care.16 The trial enrolled 50 HIV-seropositive and 50 seronegative children, all suffering from cryptosporidial diarrhea. The study concluded that although nitazoxanide significantly reduced mortality and morbidity in the children who were not infected with HIV, it was not effective in those who were infected with HIV. In this case, HIV/AIDS care would count as ancillary care; HIV/AIDS care, at any of the levels distinguished above, is required neither by the study’s design nor by trial safety. Nonetheless, HIV/AIDS was central to how the trial was designed and conducted. Although cryptosporidiosis is the disease under study, the researchers were necessarily aware of the HIV/AIDS needs of the 50 children whose seropositivity qualified them for the study.
How clearly a given aspect of the participants’ health lies within the scope of the researchers’ responsibility to provide ancillary care can vary. In the Zambian nitazoxanide trial, participants’ HIV/AIDS status was clearly within the scope of what has been entrusted to them, because the trial design called for stratifying the participants on the basis of their HIV status. Many studies involve more-minimal HIV-related permissions, for example, those that simply request potential participants’ permission to screen for seropositivity, where that is an exclusion criterion. By contrast, some studies that are not HIV/AIDS treatment trials focus on HIV/AIDS even more centrally than do studies that stratify by HIV status. Examples include maternal–fetal transmission studies, HIV vaccine trials, and co-morbidity studies. The widely discussed case of HIV-prevention trials is thus accommodated within this analysis. In a given study, then, HIV/AIDS may be (1) minimally within scope if, for example, HIV/AIDS status is an exclusion criterion, (2) clearly within scope if, for example, HIV/ AIDS status is important to the study design but is not a study endpoint, or (3) centrally within scope if, for example, the study endpoints include aspects of HIV/ AIDS, whether seropositivity, morbidity, or mortality. In all 3 of these variants, HIV/AIDS care is within the scope of what is entrusted to the researchers by the permissions that participants give during the informed-consent process. What the scope gradations reflect are variations in how firmly this fact is embedded in the study’s design.
Variations in the relationship between researcher and participant affect the strength of obligations to provide ancillary care. The longer and more intensely one interacts with someone, the more effort one must make not to treat that person as a mere means. This is as true for researchers and study participants as it is for everyone else. Concern is ever present; however, compare a long-term hospital in-patient who has a life-threatening illness with a healthy person who provides only 1 sputum sample or buccal swab. It takes a lot more effort to avoid treating the inpatient as a mere means.
For research-ethics purposes, it is the expectable depth of the researcher–patient relationship that matters. This should be determined on the basis of the study protocol, rather than on the basis of how things happen to turn out, which will depend on arbitrary variations in individuals’ psychologies. In relation to studies that touch on HIV/AIDS, the following list illustrates how the depth of the researcher–participant relationship can be expected to vary: (1) minimal depth would apply to studies that screen out the persons who are HIV seropositive and studies confined to an analysis of existing medical records; (2) low depth would apply to studies that involve only a few brief interactions with the participants; (3) medium depth would be expected for studies that involve recurrent visits over a few years or intensive interactions over shorter periods; and (4) high depth would be expected for studies that involve frequent follow-up over the long term or involve intensive monitoring of inpatients.
Maternal–fetal transmission studies are typically low-depth, because they ordinarily involve only an enrollment and counseling stage, testing of the mother, some possible monitoring during the pregnancy, and testing of the newborn. The Zambian nitazoxanide trial exemplifies a medium-depth relationship, because it involved ill children (half of whom were also HIV seropositive), who were each hospitalized for the 8-day duration of the study. High-depth studies would include those that involve longer-term hospitalizations, such as studies of HIV-related diarrheal wasting among inpatients,17 and long-term co-morbidity or vaccine studies that involve recurrent interactions with participants over many years.
The social importance of research makes the cost of providing ancillary care a morally relevant concern. A rough way to estimate the degree to which incurring monetary costs will frustrate scientific goals is to assess that cost relative to the relevant research budget. Similarly, the diversion of personnel time should be assessed relative to the availability of research personnel, often a serious constraint in developing countries. Costs that are related to confounding results and dropping participants from a study should be assessed in relation to the degree of difficulty of obtaining significant research results. Here, for simplicity’s sake, I concentrate on the monetary costs of providing ART. I abstract from the difficulties of appropriately monitoring such treatment in places with little medical infrastructure, because although these difficulties may be overwhelming, it is difficult to predict how they will vary from study to study. Ethically, the important question about monetary cost is whether it is low, serious, or heavy in relation to the research budget. It is not the absolute monetary figure that matters. For purposes of comparison, I will focus on the costs of providing ART for a lifetime.
A Phase I HIV-vaccine trial is an example of a study in which the monetary costs of providing lifetime ART to participants who need it is likely to be low in relation to the study budget. Because Phase I trials are relatively short, it is unlikely that many of the participants will become HIV seropositive during the trial, and yet the budgets for such studies are substantial, because close monitoring of participant health is required.
A type of study in which the monetary costs of providing ART to participants who need it is likely to be serious in relation to the study budget is a study of late-stage comorbidities, such as diarrheal wasting. Although all of the study participants may need ART, their life expectancies are so low that the total cost of providing lifetime ART, although appreciable, is unlikely to be very high in relation to the research budget.
Correspondingly, a maternal-to-child transmission study is an example of a study for which the monetary costs of providing ART to participants who need it is likely to be heavy in relation to the study budget. Because the researcher–participant interaction in such studies is relatively low, the research budgets are also likely to be relatively low. Maternal-to-child transmission rates, however, are about 13% when nevirapine is used and almost double that when it is not. Further, the life expectancy of the babies infected with HIV, given that they are provided with ART, will be much longer than that of adults with late-stage comorbidities. The mothers will also need ART. A relatively extreme example within this general category is provided by the observational, community-randomized study of the effects of placental malaria on maternal-to-child transmission that was conducted in the Rakai district of Uganda from 1994 to 1999.18 Because this was an observational study, it was presumably relatively cheap to conduct. However, the maternal-to-child transmission rate was relatively high in this setting (20.4%) because nevirapine was unavailable in rural Uganda during this period.
It would be a mistake to expect a simple ethical calculus to resolve such difficult issues, as it would be to push for a way to quantify the analysis. The relevant factors are mutually incommensurable and resist calibration along a single metric. It is often said that responsible bodies, such as research ethics committees, must “weigh” or “balance” such competing factors, but such talk produces only an illusion of precision.19 At some point, to be sure, principled guidance may run out. In practice, it may be necessary to fall back on one’s intuitive sense of which of 2 factors, in a given set of circumstances, is more important. In this article, however, I illustrate how far one can get, using the factors identified above, without falling back on such intuitive weighing or misleadingly claiming to locate a single, quantitative basis for one’s decisions.
In many cases, it is possible to compare the relative stringency of obligations to provide ART across types of study. Consider the following 4 study types in which HIV/AIDS care would count as ancillary care.
Studies that screen out the HIV-seropositive persons in a setting of high HIV prevalence. In such cases, the obligation to provide ART to screened-out participants will be minimal, because the HIV status of these participants is only minimally within the scope of the ancillary-care obligation, the depth of the relationship is low, and the costs of treatment could well be very high in relation to the study budget. Maternal-to-child transmission studies like the Rakai study. Compare these to the screening out of persons with HIV. Although the depth of relationship remains low and the costs remain high, in the Rakai case, the HIV-seropositive status of the mothers is an inclusion criterion and the HIV status of the infants is an endpoint. Hence, the principal difference between these cases is with regard to scope, which yields a stronger claim on behalf of the Rakai participants. Studies of HIV-related wasting among inpatients. Compare these to the Rakai maternal-to-child transmission study. In both, HIV/AIDS status is central to the scope of the researchers’ responsibility, but the depth of engagement will be higher in the latter and the cost in relation to the study budget will be lower. Hence, the overall case for providing ART to participants who need it is stronger in the HIV-related wasting studies than in maternal-to-child transmission studies. A hypothetical, Phase III HIV-vaccine trial. Compare this to HIV-related wasting studies. Again, the HIV-status is central in each type of study, and the depth of the researcher–participant relationship is high in each (intense in the case of the wasting inpatients, of long duration in the case of the vaccine-trial participants). The predictable difference is in the cost of providing ART in relation to the overall study budget, which will likely be lower in the case of the vaccine trial than in the wasting studies. Accordingly, the obligation to provide ancillary care seems stronger in the vaccine-trial case.1. 2. 3. 4.
Compared with trials that merely screen out HIV-seropositive individuals, the Zambian nitazoxanide trial presents a stronger responsibility: HIV/AIDS care is more clearly within the scope of responsibility to provide ancillary care, the researcher–participant relationship is deeper, and the cost in relation to the study budget will not be greater. By contrast, compared with the HIV-related wasting studies, the Zambian nitazoxanide trial presents a weaker responsibility: HIV/AIDS is not centrally within the scope of ancillary-care responsibility and the researcher–participant relationship is not as deep. However, we do not have a clear basis to rank it in relation to the Rakai maternal-to-child transmission study, because the factor of scope pulls one way and the depth of relationship pulls another.
Figure 1 shows all of these comparative results on a qualitative grid, which displays 4 grades of obligation to provide ancillary care. In these examples, the 2 dimensions of scope and depth of relationship suffice to differentiate the alternatives into 4 grades. The factor of cost does not alter these particular rankings. As one moves farther out on either axis, the case for ancillary-care obligations grows stronger; but because the 2 axes represent mutually incommensurable factors, one can say that the obligations to provide ancillary care pertaining to one context are stronger than those pertaining to another only if the former is farther from the origin on at least 1 of the dimensions and is not closer to the origin on the other. Hence, one cannot compare the strength of the ancillary-care claims of the participants in the Rakai maternal-to-child transmission study with those of the participants in the Zambian nitazoxanide trial. Obviously, in the full range of studies, each of the factors can vary independently, which would make the ranking more complex.
With regard to studies of HIV-related wasting and to HIV-vaccine trials, the ancillary-care argument explored here supplements whatever arguments can be mounted on the basis of justice or a more general beneficence.11,13 The World Health Organization seems to be moving toward accepting such arguments.2 With regard to these cases, the argument offered by the partial-entrustment, ancillary-care model supports the World Health Organization’s conclusions. The argument developed here also generates more specific conclusions, providing a principled basis for recognizing gradations of responsibility for providing ancillary care. Going beyond the range of cases on which the World Health Organization seems to have been focusing, the ancillary-care argument implies that some researchers who are not centrally dealing with HIV/AIDS nonetheless have some obligation to address the HIV/AIDS needs of their participants.
Research ethics committees and other bodies that review clinical and epidemiological research in developing countries need to collaborate with and listen to people in the host countries to develop ethical guidance regarding the obligations of researchers in non-HIV/AIDS studies to address participants’ HIV/AIDS needs. One important reason in favor of accepting that researchers’ ancillary-care obligations regarding HIV/AIDS care are graduated is that the range of possible responses is graduated. The ethical analysis presented in this article cannot begin to indicate which grade of obligation to provide ancillary care corresponds to which grade of response. On the one hand, the difficulties of coordinating and monitoring ART in many settings will make that option unreasonable in many places. On the other hand, creative ways of forming partnerships to help fund ART provision or to lower drug costs may make ART provision more affordable in some contexts.12,13 Further, in all contexts, the social effects of making ART specially available to participants must be considered.7
My analysis is not intended to settle the bottom-line question of what should be done in any given study but rather is intended to provide research sponsors and research ethics committees with well-grounded, gradable, and context-sensitive factors—scope, depth of relationship, and cost in relation to research budget—that they can use to determine in which cases ancillary-care considerations call for non-HIV/AIDS researchers to address the HIV/ AIDS needs of their study participants. As illustrated, the analysis can generate definite, comparative results without attempting to treat the various qualitative factors in a quantitative way. Among the study types discussed here, the case for ART provision appears particularly compelling for later-phase HIV-vaccine trials. The ancillary-care argument for this conclusion converges with the justice-based argument put forward by the HIV Vaccine Trials Network and others.20,21 For other trial types, in which HIV/AIDS is less central to the study design, the question of providing HIV/ AIDS treatment as ancillary care will prove more challenging.
FIGURE 1— Four grades of researchers’ obligation to provide ancillary care in the form of antiretroviral therapy to study participants in different research settings.
The author is grateful for comments received from David Challinor, Ezekiel J. Emanuel, and Christine Grady, as well as from participants in the Advanced Workshop on Research Ethics, Kiwengwa, Tanzania (December 2, 2004), and the Course on the Ethics of Clinical Research, Clinical Center, National Institutes of Health (December 8, 2004). The author thanks Maria Merritt and Christine Grady for helpful comments and for sharing their work in progress on rationing antiretroviral treatment, and Emily Robbins for valuable research assistance.
