Safeguarding Healthy Research Subjects: Protecting Volunteers from Harm
INTRODUCTION
The following guidelines were developed to enhance protection of individuals who participate in biomedical research in New York State, with particular focus on normal healthy subjects. The purpose of the guidelines is to
- enhance the capability of institutional review boards (IRBs) to ensure the protection of human research subjects;
- educate researchers about key principles for maximizing the protection of research subjects;
- encourage institutions to provide adequate fiscal and resource support to IRBs and training for researchers in principles of human subject protection.
These are guidelines, not regulations. They are intended as a framework to provide IRBs, researchers, and institutions with a broad range of considerations for designing, reviewing, and implementing protocols involving normal healthy subjects. IRBs and researchers are encouraged to adapt these guidelines to the specific circumstances of individual studies. The guidelines are fully consistent with existing federal and state regulations.1
Research with normal healthy subjects who will derive no direct benefit from participation is fundamentally different from research with patient-subjects who may derive personal benefit from the study. Nonetheless, while the focus of these guidelines is the normal healthy research subject, many of the principles are applicable to human research subjects in general.2
The initial impetus for the guidelines was a Department of Health investigation into the circumstances surrounding the death of a healthy college student who participated in a research study in New York State.3 To enhance protection of human subjects statewide, the Department established a workgroup to develop guidelines for research institutions.
The workgroup was composed of a distinguished group of bioethicists, researchers, and consumer advocates. The chairperson of the workgroup was Nancy Neveloff Dubler, L. L. B.
The scope of the guidelines and the major concepts that underlie them are described below:
What is meant by the term “normal healthy subject”?
The term applies to research subjects who are free from diseases or medical conditions that might be affected by or have an impact on the research.4 The term is used generally to distinguish such subjects from those who are participating in research specifically because they have a condition or disease that the research is intended to ameliorate directly or indirectly. It also is used to distinguish such subjects from ones who are excluded from a study because they have a condition or disease that might be affected negatively by participation in the study. For example, in a sleep study in which subjects are awakened every hour to see the effects on their sleep activity and awake functioning, individuals with acne or a dental bridge would probably be considered normal healthy subjects. However, if the study involved having an orotracheal tube in place while falling asleep, the individual with a dental bridge might not be considered a normal healthy subject. Thus, the term normal healthy subject is relative, defined according to the inclusionary and exclusionary criteria of a specific protocol.
How does research with normal healthy subjects differ from research with patient-subjects?
Most biomedical research involving human subjects is clinical research conducted with patients who have specific conditions, diseases, or symptoms, generally for the purpose of finding a more effective therapy or cure. Patients often have a personal interest in the outcome of research in which they are participating. For these subjects, the risks of the proposed intervention may be balanced to some degree by the possibility of direct benefit.
In contrast to therapeutic research with patients, research with normal healthy subjects generally offers no anticipated direct benefits to the well-being of the subjects (except in limited contexts, such as immunization studies (see page 4). Because of this critical distinction, the IRB must judge whether the benefit of new knowledge anticipated by the study justifies inviting a healthy person to undertake the risks. Justifications for engaging normal healthy subjects in research include (1) the importance of acquiring significant information related to normal physiology; (2) the likelihood that a healthy subject will tolerate interventions or drugs better than someone who is sick; and (3) the possibility that researchers can exercise more control over confounding variables in subjects unencumbered by illness.
Normal healthy subjects have a special vulnerability that is based on their apparent invulnerability. Researchers, for the most part, recognize the need to maximize protection of patient-subjects who are participating in research. Patients are already weakened or in some way debilitated by their condition. As a result, researchers exercise special cautions not to aggravate the patientsubject’s health status.
On the other hand, with normal healthy subjects there may be an underlying expectation that nothing can go wrong and that routine protections are sufficient for all participants. There may be less attention paid to possible idiosyncratic responses or different levels of tolerance. There may be less focus, in general, on the issues of discomfort and harm.
In a relationship between a physician or other health care provider and a patient, there is an inherent belief shared by both that the health care provider’s primary mission is the patient’s well-being.5 The investigator-subject relationship is more complex because, while the investigator has an obligation to protect the welfare of the subject, the investigator’s charge is the successful conduct of the research.6 This may be especially true with research involving normal healthy subjects, where the research has no possibility of a direct therapeutic impact.
However, subjects coming to a medical facility to participate in research in an office staffed by nurses, physicians, and other care-providers may not be able to relinquish the expectation of direct benefit even when they are not patients and the researcher is not their personal health care provider. As a result, they may experience a “therapeutic illusion.”7
Therein lies the crux of the challenge for IRBs, researchers, and research institutions — how to ensure that a normal healthy research subject is cognizant of the risks of participating in the research and of the fact that promoting the subject’s well-being is not the researcher’s basic objective.
What issues are outside the scope of these guidelines?
These guidelines focus on the issues facing IRBs, researchers, and institutions with respect to research involving normal healthy subjects that affords no direct benefit to the participants. There are, however, studies involving normal healthy subjects that may yield a direct benefit the subjects, generally in the form of disease prevention or enhanced well-being. Examples include immunization studies or studies of the long-term benefits of wine in preventing cardiovascular disease. Such studies present a different risk-benefit calculus and are not the focus of these guidelines.
Another body of studies beyond the scope of these guidelines are studies involving patients that offer no direct benefit to the participants. An example would be a study of blood and spinal fluid levels of serotonin in patients with schizophrenia. These studies present special considerations that are different from those involving normal healthy subjects and are therefore beyond the scope of these guidelines.
These guidelines are limited in applicability to research involving normal healthy subjects who are legally capable of providing informed consent. The guidelines do not apply to those who lack decision-making capacity because of mental illness or other factors. They also do not apply to children, who generally cannot consent to participating in research without parental or legal guardian authorization.8 In addition, the guidelines do not address the special issues of research with adolescents, who under some conditions can legally consent to research on their own without parental consent.9
While many of the principles in these guidelines may have relevance to the above populations, the special considerations that apply to each of these groups are beyond the scope of the guidelines.
Two key principles underlie these guidelines:
- IRBs, researchers, and institutions must recognize the special vulnerability of normal healthy subjects enrolled in studies in which there is no direct personal benefit to offset risk and must provide protections appropriate to the unique qualities of each individual subject and the risks of the protocol.
- While IRBs and their sponsoring institutions are responsible for establishing and promoting “cultures of compliance” with regulations and policies to safeguard human research subjects, researchers have the primary responsibility to protect the safety and welfare of individual subjects. Researchers have an obligation to monitor the risk experiences of individual subjects and to modify or terminate an intervention when a subject’s experiences differ substantially from what was described in the protocol or informed consent.
The guidelines identify mutual obligations of IRBs, researchers, and institutions:
- IRBs — The IRB is responsible for the review and approval of studies involving human subjects, including an assessment of each study’s risks and benefits and the content and process of informed consent.10 One of the essential roles of the IRB is the periodic monitoring of research studies.11 Each IRB must develop intervals and procedures for periodic review and reassessment of risks and benefits. This ongoing review takes on special significance in the case of research involving normal healthy subjects for whom there are no direct benefits.
- Researchers — Researchers have an independent obligation to protect human subjects in ways that transcend the IRB’s general informed consent and protocol review process. They must assess the appropriateness and specific experience of each subject involved in the protocol and provide safeguards to minimize individual risk.
- Institutions — Institutions that promote and conduct research are required to convene an IRB. Institutional responsibilities for meaningful protection of research subjects extend further: Institutions must demonstrate a commitment to the protection of human research subjects through the training and recognition of IRB members, the provision of adequate fiscal and resource support to IRBs, and education of researchers in the principles and practices of human subject protection.
1 45 C. F. R. § 46 (1998); 21 C. F. R. §§ 50, 56 (1998); N. Y. Pub. Health L. §§ 2440-2446 (McKinney 1998).
2 Contemporary ethical principles guiding human subject research were initially set forth in the Nuremberg Code, restated and expanded in the Declaration of Helsinki, and refined in the Belmont Report. For a general discussion of the development of these documents, see Final Report of the President’s Advisory Committee on Human Radiation Experiments (New York: Oxford University Press, 1996), 74-104. None of the documents specifically addresses protections for normal healthy research subjects.
3 Nicole Wan, a nineteen-year-old college student, died of heart failure after participating in a medical research project at the University of Rochester Medical Center. For details of the case, see E. Rosenthal, “N. Y. Seeks to Toughen Rules on Medical Research,” The New York Times, September 27, 1996, B4. New York State Health Commissioner Barbara A. DeBuono called the case “a wake-up call to the medical community that research on human subjects needs to be taken very seriously.” Ibid.
4 A report by the British Royal College of Physicians defines a healthy volunteer as “an individual who is not known to suffer any significant illness relevant to the proposed study, who should be within the ordinary range of body measurements such as weight, and whose mental state is such that he is able to understand and give valid consent to the study.” Royal College of Physicians, “Research on Healthy Volunteers: A Report of the Royal College of Physicians,” Journal of the Royal College of Physicians 20 (1986): 245.
5 N. E. Kass et al., “Trust: The Fragile Foundations of Contemporary Biomedical Research,” Hastings Center Report 26, no. 5 (1996): 25; R. J. Levine, “The Physician-Researcher: Role Conflicts in the Physician-Researcher,” in Alzheimer’s Dementia: Dilemmas in Clinical Research ed. V. Melnick and N. Dubler (Clifton, NJ: Humana, 1985), 41-42.
6 For a discussion of the investigator-subject relationship, see H. K. Beecher, “Experimentation in Man,” Journal of the American Medical Association 169 (1966): 461, 467; R. J. Levine, Ethics and Regulation of Clinical Research, 2d ed. (New Haven: Yale University Press, 1988), 98; L. De Castro, “Exploitation in the Use of Human Subjects for Medical Experimentation,” Bioethics 9 (1995): 25.
7 Human Radiation Experiments, 79-82. A discussion of the “therapeutic illusion” appears in a report on a conference on the “Concept of Consent in Clinical Research” convened by the Law Medicine Research Institute of Boston University in 1961. The conference reviewed research in which there was intentional nondisclosure of experimental procedures to subjects. However, a “therapeutic illusion” can be maintained despite full disclosure.
8 In New York State, any person who is eighteen years of age or older or is the parent of a child or has married may give effective consent for medical treatment. N. Y. Pub. Health L. § 2504( 1) (McKinney 1998).
9 J. S. Santelli et al., “Guidelines for Adolescent Health Research: A Position Paper of the Society for Adolescent Medicine,” Journal of Adolescent Medicine 17 (1995): 270; A. S. Rogers et al., “Guidelines for Adolescent Participation in Research: Current Realities and Possible Resolutions,” IRB 16 (July-August 1994): 1.
10 10 C. F. R. § 46.108-46.109 (1998); 21 C. F. R. § 56.101 (1998); N. Y. Pub. Health L. § 2444 (McKinney 1998). For an overview of the role and responsibilities of the IRB, see H. Edgar and D. Rothman, “The Institutional Review Board and Beyond: Future Challenges to the Ethics of Human Experimentation,” Milbank Quarterly 73 (1995): 489, 490-493; C. McCarthy, “Challenges to IRBs in the Coming Decades,” in The Ethics of Research Involving Human Subjects Facing the 21st Century, ed. H. Y. Vanderpool (Frederick, MD: University Publishing Group, 1996), 127.
11 45 C. F. R. § 46.109( e) (1998); J. A. Robertson, “Taking Consent Seriously: IRB Intervention in the Consent Process,” IRB 4 (May 1982): 1; N. A. Christakis, “Should IRBs Monitor Research More Strictly?” IRB 8 (March-April 1988): 8; E. J. Heath, “The IRB’s Monitoring Function: Four Concepts of Monitoring,” IRB 1 (August-September 1979): 1.
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