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8.1 Research Involving Vulnerable Populations

Cheryl Mack, MD, MA, FRCPC

Learning Objectives

  1. To be able to define and identify vulnerable populations as they pertain to medical research
  2. To understand why populations within developing countries should be considered vulnerable as test populations
  3. To highlight the ethical concerns that arise specifically when engaging in medical research in developing countries
  4. To understand the safeguards that are typically implemented to decrease the incidence of exploitation
  5. To be made aware of the ongoing debate that arises when we discuss ethical universalism, ethical imperialism and ethical relativism

Case

ABC Pharmaceuticals has discovered what it hopes to be the next generation of antiretroviral drugs. Animal studies have been promising and demonstrate an ability to prevent the transfer of HIV through vertical transmission. Phase II human clinical trials have been completed, and researchers are hoping to test this drug in a high-risk population in an economically depressed region of Africa that has been suffering through both drought and political unrest. It is hoped that this drug will be shown to be at least as effective as present therapies but with less toxicity and simpler dosing. You represent the research ethics board that, along with the local African review board, is assessing the adherence to ethical guidelines prior to giving approval. The population the researchers are seeking to study has a high prevalence of HIV infection, and the predominant strain of HIV seems to be unique to that area of Africa. Vertical transmission has been identified as a grave concern in the area, with numerous infants testing positive. Presently, the proposed test population does not have a reliable source from which to obtain antiretroviral medications. As a member of the research ethics board, you have concerns regarding the test population.

Questions

  1. What is the definition of a vulnerable population, and does the test population in question qualify as one?
  2. When engaging in multinational research, what can emerge as a source of conflict when assessing protocols for their adherence to ethical standards of care?
  3. Given that research ethics committees reviewing multinational research protocols are often confronted by variable ethical standards that can conflict with international standards emphasizing Western-based ethical viewpoints, the universality of these viewpoints is often questioned when dealing with other cultures. How should these differences be resolved?
  4. Why is the relevancy of research to the population involved in the study such a concern, and does the study design in the illustrated case satisfy the ethical guideline of relevancy in the test population?
  5. Does the study design address the long-term interests of both the test population and the wider community? Name a primary component of post-study design.
  6. Should the study design be allowed to include a placebo control group?

Discussion

Q1. What is the definition of a vulnerable population, and does the test population in question qualify as one?

A vulnerable population in terms of research populations could be defined as any group that is unable to protect its members' self-interests in the course of being test subjects. Although not exhaustive, this definition could include those population characteristics that can limit the ability to obtain proper informed consent; these include language or cultural barriers and the lack of the necessary exposure to or understanding of the scientific method to comprehend risk or trial design. Other groups that can be viewed as vulnerable are those subject to guardian or proxy consent secondary to minor age or lack of capacity and populations that are so economically and socially disadvantaged that participation in medical research is viewed as the only option to access otherwise unavailable medical treatment.

The subjects in this case fulfil the criteria for being identified as vulnerable. The community is from an economically disadvantaged area that has minimal access to adequate health care. There is reason to be concerned regarding their ability to give informed consent, particularly in light of language and cultural barriers. Additionally, their comprehension of the scientific method is potentially limited, placing them at risk for therapeutic misconception (whereby the goals of research are mistakenly presumed to emphasize the therapeutic interests of the individual test subject).

Q2. When engaging in multinational research, what can emerge as a source of conflict when assessing protocols for their adherence to ethical standards of care?

Ethical standards such as informed consent and the right of refusal of treatment, as they exist in Western medicine and law, are an expression of individual autonomy that has evolved from our liberal social and political past. This embedded notion of our inalienable right to self-determination is not shared by all cultures. There exists an ongoing debate revolving around any absolute requirements to adhere to Western-based ethical principles. Many cultures rely on a more communitarian approach that places emphasis upon what is best for the community. What defines "the community" is variable; it can, for example, refer to the immediate or extended family, an ethnic or religious group, or a social or geopolitical assembly of persons.1 No matter how it is defined, some communities exist that emphasize group interests over those of the individual. Ethical differences can become more than a source of debate: they can threaten the viability of ongoing foreign-sponsored research in many developing nations.

Q3. Given that research ethics committees reviewing multinational research protocols are often confronted by variable ethical standards that can conflict with international standards emphasizing Western-based ethical viewpoints, the universality of these viewpoints is often questioned when dealing with other cultures. How should these differences be resolved?

Central to this debate is whether it is appropriate to insist upon adherence to our more Western-based ethical standards. Does this correspond to a form of ethical imperialism, where we force cultures who are dependent on our support for essential medical research to relinquish their own moral beliefs? Alternatively, does adjusting our standards to fit with those of the test population represent a descent into moral relativism? The answer is not completely clear. Certainly, our ethical standards have grown out of our past experiences where harm and exploitation have occurred as the result of medical research. Our ethical goals then are to prevent absolutely any reoccurrences of such outcomes. How this is achieved can perhaps be modified to allow for local standards to be incorporated into the study design. The goal of the ethics review is to facilitate the ongoing need for valuable research to proceed in the developing world, but the research undertaken must not be associated with unacceptable risk to the individuals or the communities involved.

Benatar discusses the implementation of a reasoned contextual universalism as an approach toward finding a solution to this debate.2 He first draws important distinctions between various positions on global ethics. First, he defines moral absolutism as a belief in the immutable nature of ethical principles. He then contrasts absolutism with moral relativism, which sees ethical principles as historically and socially contingent. Between these two extremes, Benatar posits two more moderate positions. The position of reasoned global universalism understands ethics to be more of a process, whereby progress is achieved through moral reasoning using abstract principles. When our moral reasoning also takes into account relevant local factors, we are using what Benatar terms reasoned contextual universalism. The use of relevant contextual factors aids in the application of abstract moral principles to real-life issues.2 This balance of context and universalism is not easy because it requires our ability to practically weigh which factors should be considered within the reasoning process and which ones are inappropriately at odds with our moral principles.

This position of reasoned contextual universalism must of course be consistent with our absolute goals of minimizing harm. If we cannot ensure fully informed consent, confidentiality or the ability to opt out of a study, we must ensure that risk is minimized. This may mean altering protocols, ruling out some placebo control trials and limiting study designs to less risky phase III clinical trials. The goal is to enable relevant research to proceed with the least risk of harm and exploitation.

Q4. Why is the relevancy of research to the population involved in the study such a concern, and does the study design in the illustrated case satisfy the ethical guideline of relevancy in the test population?

Research should be relevant to the population involved in the study in order to avoid exploitation. Developing countries are limited in their ability to address public health care crises because of dire political, economic, environmental and social conditions. They are disproportionately afflicted with a large percentage of the world's disease. They do not have the ability to adequately address these diseases independently, either with supportive care, standard treatments or research into innovative therapies.3 The result of this imbalance in access to adequate standards of living is unacceptably high rates of morbidity and mortality. The actual patterns of disease within these countries also vary due to poor sanitation, limited access to clean water and inadequate access to primary health care. Of the 18 million people who die yearly from infectious and parasitic diseases, 16 million are from the developing world. In 1998, the World Health Organization estimated that 11 million deaths from infectious diseases could have been prevented at a cost of only $20 per life saved.3 Despite these statistics, the developed world allocates 90 per cent of its health research budgets toward diseases that cause only 10 per cent of the disease burden on a global scale.4 This disparity represents a global injustice that must be addressed.

The realities of today's market-driven drug research means that the emphasis is on drug therapies that will not only recoup research and development costs but also establish a profit. The incentive to develop drugs that target resource-poor communities, who will be unable to afford the drugs after the research stage, is limited. Additionally, research funding for academic medical research is also increasingly reliant upon industry, so that research from these institutions is also tied to market forces. The result has been more effort being applied toward the development of drugs targeting the lifestyle and disease profile of developed countries. This situation combined with an increasing reliance on large multicentre trials has drug companies looking to enrol large numbers of subjects in order to fast-track drugs to market.5 This reality necessitates that the drugs being tested in developing countries be relevant to the needs of the population. When these populations are treated merely as a pool of test subjects to facilitate drug development for the developed world, with little regard for their immediate needs, exploitation results.

Relevancy also includes addressing the conditions that increase people's susceptibility to parasitic and infectious diseases. Drug development must be conducted in parallel with efforts to aid the host countries in alleviating poor sanitation and the lack of access to clean water and reliable food sources. This requires a combined effort that not only involves the communities in the research itself but also empowers them to work in concert with the international community to find long-term solutions to these public health emergencies.6

In the case population described, with high HIV prevalence and evidence of significant vertical transmission, a study that addresses this problem is relevant. If the drug were proven to be at least as effective as standard therapy with less toxicity and simpler dosing, it would also be desirable for the increased compliance and the decreased need for toxicity monitoring, both of which can be difficult to ensure in a disadvantaged area. This study design should also address the need to decrease the incidence of HIV transmission through an educational component that teaches safe sexual practices and provides access to condoms.

Q5. Does the study design address the long-term interests of both the test population and the wider community? Name a primary component of post-study design.

The "Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects" states (in paragraph 30): "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."7 This statement strongly protects the interests of the actual test subjects, but it falls short in addressing the relevancy and interests of the host community and surrounding regions.

In a less strongly worded paragraph (19), the Declaration states: "Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research."7 The wording of this paragraph exemplifies the difficulty in ensuring widespread benefit to developing countries while not discouraging important research from being undertaken in communities that may not otherwise have access to such care under normal circumstances. The ethical dilemma arises because there is a dire need for medically relevant research to be carried out in these communities, but if the bar is set too high it may be prohibitive to further research being carried out. How do we define that population which would stand to benefit? Ideally, we would hope that the best-proven methods would be made readily available to all, but realistically and logistically that may not be possible due to a myriad of obstacles beyond the scope of this paper.

Therefore, as discussed, all the test subjects must have access to the best-proven therapy at the conclusion of the study. The more contentious area will be the implementation of the therapy in the wider community. What defines the wider community? Does it encompass the local community, the region, the country or all persons at risk (as it should ideally)? Who covers the cost of the drug, ensures its distribution and provides necessary follow-up care? What time frame is acceptable for the successful implementation to occur? These are all issues that need to be discussed prior to initiation of the study. Relevancy for the host population must include implementation.6

Q6. Should the study design be allowed to include a placebo control group?

The Declaration of Helsinki highlights the issue of clinical trials and control groups in paragraph 29, as follows:7

The benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

So, while the guidelines make room for the use of placebo control groups, this particular study would ethically be best designed as an equivalency trial comparing the new drug with the established antiretroviral regime used to prevent vertical transmission. The lack of access to antiretrovirals in the pretest period does not lessen the obligation to provide the control arm with the best-known prophylactic therapy. Even if the new drug were unique in having been tested in earlier phases of development against the distinctive strain in the region, the existence of other strains and the lack of evidence for the standard therapy having no efficacy against this novel strain would still be reason enough for an equivalency trial.

References

  1. Weijer C. Protecting communities in research: philosophical and pragmatic challenges. Cambridge Quarterly of Healthcare Ethics 1999; 8: 501–13.
  2. Benatar S. Towards progress in resolving dilemmas in international research ethics. Journal of Law, Medicine & Ethics Winter 2004; 32(4): 574–82.
  3. Benatar S. Reflections and recommendations on research ethics in developing countries. Social Science and Medicine 2002; 54: 1131–41.
  4. Dickens BM, Cook RJ. Ethical and legal issues in reproductive health: challenges of ethical research in resource-poor settings. International Journal of Gynecology and Obstetrics 2003; 80: 79–86.
  5. Benatar S. Avoiding exploitation in clinical research. Cambridge Quarterly of Healthcare Ethics 2000; 9: 562–5.
  6. Dowdy DW. Partnership as an ethical model for medical research in developing countries: the example of the "implementation trial." Journal of Medical Ethics 2006; 32: 357–60.
  7. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. World Medical Association [adopted 1964; last updated 2004]. Available from: http://www.wma.net/e/policy/b3.htm

Resources

  • Angell M. Ethical imperialism? Ethics in international collaborative clinical research. New England Journal of Medicine 1988; 319: 1081–3.
  • Angell M. The ethics of clinical research in the Third World. New England Journal of Medicine 1997; 337: 847–9.
  • Benatar SR. Commentary: justice and medical research: a global perspective. Bioethics 2001; 15: 333–40.
  • Lurie P, Wolfe S. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. New England Journal of Medicine 1997; 337: 853–5.
  • Macklin R. Against relativism: cultural diversity and the search for ethical universals in medicine. Oxford: Oxford University Press; 1999