Protecting human research subjects is hot stuff right now--one only needs to look as far as the cover story of the 22 April 2002 issue of Time magazine entitled "At Your Own Risk." Indeed, I would argue that the United States is experiencing a national crisis of public trust in academic research involving human subjects. This crisis has been ignited by the deaths of research subjects at two prestigious academic medical centers and by federal sanctions levied against a host of excellent academic institutions.
The future of human subjects research is a central question for social and behavioral scientists, clinical investigators, graduate students, undergraduates, professors, deans, university presidents, political leaders, and the lay public. Given current circumstances, it would be easy to be alarmist. A more accurate perspective is gained by taking history into account, and by considering how the ethics of research with human subjects have evolved over the last 60 years.
A pattern of "crisis and response" has prompted an evolution of research ethics to the current system of human subjects protections in the United States. The process looks something like this:
Crisis: Whistleblowing and/or coverage in the popular press raises public and professional alarm over particularly egregious ethics violations. Beginning with the Nazi Doctors' Trial at the 1946 Nuremberg Trial (1), coverage includes publication of Henry Beecher's "Ethics and Clinical Research" (2), The New York Times exposure of the public health service syphilis study in Macon County, Alabama (the infamous "Tuskeegee case") (3), the University of Pennsylvania/Gelsinger gene transfer case, and The Washington Post series on international clinical drug testing abuses (4).
The government responds with hearings, expert panels, and appointed commissions. Guidance, laws, and procedural safeguards emerge, such as the Belmont Report (5)--the "Common Rule"--the code of federal regulations governing all federally funded research with humans, the establishment of the Office for Human Research Protections (OHRP), and national advisory committees such as the National Human Research Protections Advisory Committee (NHRPAC).
Thus, as with any field of ethics, the process of research ethics is one of evolution--of reaction and adaptation. Or, as bioethicist Carol Levine wryly observes, "the basic approach to the ethical conduct of research and approval of investigational drugs was born in scandal and reared in protectionism" (6).
And adapt the system must, for the research enterprise is changing dramatically. Between 1986 and 1995, federal funding for biomedical research almost doubled, with half of those dollars allocated to academic research, and much of that portion allotted to medical schools. During the same period, expenditures in the private sector tripled, and among pharmaceutical companies expenditures rose by a factor of 14. Private-public research partnerships have emerged as a result of constraints imposed by managed care and loss of clinical revenues. In addition, there are growing expectations that the research arm of academic medicine must, like the clinical arm, be a revenue source--thus the new alliances with industry, especially in the area of technology transfer.
Industry is reaching far beyond the academic medical center, its traditional partner, to private contract research organizations and private physician networks to help operate clinical trials. The percentage of industry-sponsored clinical trials in academic medical centers fell from 80% in 1991 to only 49% in 1998. Large, multicenter trials are now the norm for clinical trials.
The face of research has changed, and the question begged by recent unfortunate events such as the deaths of research participants Jessie Gelsinger and Ellen Roche is whether our system of human subjects protections has kept apace. This is the exact question posed by former Secretary of Health and Human Services Donna Shalala in a Sounding Board article published in The New England Journal of Medicine after Gelsinger's death. In what was really a lament, former Secretary Shalala observed that: "Unfortunately, the public's confidence in our work, our competence, and our ethics has been seriously shaken." Moreover, this young man's death led to the discovery by the NIH of many hundreds of unreported adverse events among volunteers enrolled in gene-transfer experiments (7).
Shalala's concerns are not new. Indeed, they were clearly articulated in a 1997 report by the National Bioethics Advisory Commission to then President Bill Clinton that identified key areas of concern (see box).
1. Federal protections for persons serving as subjects of research do not yet extend to all Americans.
2. Despite widespread implementation of federal regulations by those departments and agencies sponsoring substantial amounts of biomedical research, a number of departments and agencies who sponsor primarily nonbiomedical research or little research overall have failed to implement fully these federal protections.
3. Federal protections do not always include specific provisions for especially vulnerable populations of research subjects.
4. Many federal agencies find the interpretation and implementation of the Common Rule confusing or unnecessarily burdensome.
5. Federal protections are difficult to enforce and improve effectively throughout the federal government, in part because no single authority or office oversees research protections across all government agencies and departments.
6. New techniques are needed to ensure implementation at the local level.
Many of these concerns have or are being addressed at both the federal and local levels. The former Office for Protection from Research Risks--now known as the OHRP--has been moved from NIH to the Office of the Secretary at the Department of Health and Human Services (DHHS). Also, NHRPAC was formed to advise the government and research community about human research protections. The Institute of Medicine, at the behest of DHHS, has convened a committee on "Assessing the System for Protecting Human Research Subjects." The committee's first report, Preserving Public Trust: Accreditation and Human Research Participant Protection Programs, was issued in 2001. Its second report, a comprehensive review of the nation's public and private human research enterprise, with recommendations for systemic reform, is due in September 2002.
Emerging themes in the evolving ethical conduct of research with humans include a major increase in the participation of research subjects, and the lay public, in the research and oversight worlds. Research participants should have meaningful involvement in helping universities set their research agendas, in the protocol review process, and in educating investigators and others involved in research.
Informed consent to research, which, along with institutional review board (IRB) review, constitutes one of the twin pillars of human subjects protections in the United States, should undergo a sea change in its implementation. Rather than a static event involving investigator disclosure of a litany of potential risks and benefits culminating in the subjects' signature on paper, informed consent should be conceived of as an ongoing decision-making process, a conversation between investigator and subject that occurs at each study encounter or intervention.
Another theme involves broadening the locus of institutional accountability for protecting research subjects. As Greg Koski, director of OHRP, says, "We need to take the 'I' out of IRB." This means that the institution, whether a public university or a private sponsor, must establish a human research participant protection program (HRPPP) with multiple levels of responsibility and accountability, from the IRB (which, by federal law, prospectively reviews all federally funded human subjects research protocols) to the chief administrator (Chancellor or CEO) to the investigator, staff, and students, to the research participants. And the HRPPP must have a local, iterative process for quality improvement, the success of which will most likely be measured by voluntary, private accreditation at the national level. Finally, the costs of protecting research subjects should be shared at multiple levels of the research enterprise.
These are but a few responses to the current "crisis." They are timely, paradigm altering, and expensive. They should, however, make a significant difference in the outcome of research. And the benefits, my colleagues, will accrue not just to research participants, investigators, and sponsors, but to YOU!
1. U.S. v Karl Brandt et al., ("The Medical Case") Trials of War Criminals Before the Nuremberg Military Tribunals Under Control Council Law 10. Nuremberg, October 1946 to April 1949. 2 vols. (Washington, D.C.: U.S. Government Printing Office). See also The Nazi Doctors and the Nuremberg Code: Human Rights as Human Experimentation by George Annas and Michael Grodin (New York: Oxford University Press, 1992).
2. Henry Beecher, "Ethics and Clinical Research," NEJM 274(24), 13154 (1966).
3. J. Heller, "Syphilis Victims in U.S. Study Went Untreated for 40 Years," The New York Times, 26 July 1972: A1.
4. The Washington Post series ran from Sunday, 17 December 2000, through Friday, 22 December 2000. Headlines included: "Exporting Human Experiments," "Overwhelming the Watchdogs," "Failure of Consent," "Harvesting China's Blood," "The Global Drug Lab," and "Perils of Placebos."
5. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (Washington, D.C.: U.S. Government Printing Office, 1979).
6. Carol Levine, "Has AIDS Changed the Ethics of Human Subjects Research?" Journal of Law, Medicine, and Ethics, 16: 3-4 (Winter 1988).
7. Donna Shalala, "Protecting Research Subjects--What Must Be Done," NEJM 343(11), 808 (2000).