Ethical issues in research with healthy volunteers: risk-benefit assessment

Abstract

Most ethical commentary on clinical research concerns studies involving patient-subjects. Several reasons may account for the relative neglect of ethical appraisal of research with healthy volunteers. Clinical research is often understood ethically within the context of, or in contrast to, the physician-patient relationship characteristic of medical care. In addition, research involving healthy volunteers is less likely to evoke ethical concern. Because these research subjects are not ill and, more specifically, do not have a condition with the potential to compromise decision-making capacity, there is no reason to question their ability to give informed consent. Similarly, they are free from the “therapeutic misconception” that causes some, perhaps most, patients to be confused about the differences between research participation and medical care. Not being dependent on the advice of physicians, they are less likely than patients to feel pressure to participate in research. However, ethical concern has been focused on “coercion” or “undue inducement” associated with payment as an incentive for healthy volunteers to participate in research. Moreover, the death in 2001 of a healthy research subject in a study aimed at understanding the pathophysiologic characteristics of asthma brought attention to the risks of research with healthy volunteers and to the imperative to ensure adequate subject protection. The correspondence in this issue of the Journal regarding severe neutropenia among healthy clinical trial participants exposed to standard doses of rifabutin underscores the importance of scrupulous design and conduct of clinical investigation to protect research subjects. Research with healthy volunteers has particular ethical interest because it places in bold relief the moral context of all clinical research: Some individuals are exposed to risks of harm for the potential benefit of future patients and society. From a medical perspective, healthy volunteers have no chance to benefit from research participation. The risks to which they are exposed can be justified only by the value of the knowledge to be gained from their research participation. A variety of clinical studies with healthy volunteers pose more than minimal risks of harm or discomfort. These include phase 1 trials of investigational drugs, psychiatric symptom-provoking studies, infection challenge experiments, and toxicology research involving monitored drug overdoses. In this commentary I will focus on the pre-eminent ethical requirement of all clinical research, involving healthy or patient volunteers, that the research must pass the test of having a favorable risk-benefit ratio. Although informed consent is often considered to be the cornerstone of research ethics, informed consent does not come into play as an ethical requirement unless research is judged to have adequate potential value to justify any risks to which participants are exposed. It is important to recognize that risk-benefit assessment of research is primarily prospective. As Henry Beecher noted in 1966, “An experiment is ethical or not at its inception. It does not become ethical post hoc.” Obviously, the fact that valuable scientific knowledge may have resulted from abusive studies that exploited research subjects does not justify such research. The converse of Beecher’s observation about prospective assessment is also relevant: Research does not become unethical post hoc. If a healthy volunteer dies as a result of research participation, this does not imply that the research was unethical. The most careful attention to study design and safety monitoring cannot eliminate remote chances of exposing healthy subjects to serious, irreversible harm. Because research involves experimentation under conditions of uncertainty, it cannot be From the Department of Clinical Bioethics, National Institutes of Health. The opinions expressed are those of the author and do not represent the position or policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. Received for publication May 19, 2003; accepted Aug 20, 2003. Reprint requests: Franklin G. Miller, PhD, Department of Clinical Bioethics, Clinical Center, National Institutes of Health, Bldg 10, Room 1C118, Bethesda, MD 20892-1156. E-mail: fmiller@nih.gov Clin Pharmacol Ther 2003;74:513-5. Copyright © 2003 by the American Society for Clinical Pharmacology & Therapeutics. 0009-9236/2003/$30.00 0 doi:10.1016/j.clpt.2003.08.006