Science and Engineering Ethics (2005) 11, 53-59
Making Human Research Safe: Why We Cannot Afford to Fail Marjorie A. Speers Association for the Accreditation of Human Research Protection Programs, Washington, DC
Keywords: human subjects’ protection, accreditation
ABSTRACT: This paper was given as a keynote address at the international conference on Ethics of Intellectual Property Rights and Patents held in Warsaw, Poland on April 23-24, 2004. The address was the introductory presentation to the important topic of protecting individuals who participate in research as research subjects.
The human research enterprise is an essential and integral part of society, for such research holds the promise of new treatments, new cures, and improvements in quality of life. The benefits of research are recognized by all – government, investigators, and the public- and reflected in the partnership that exists between government and the research community, a partnership that lies at the heart of the scientific enterprise. The research community has enjoyed many benefits from the partnership, including the selection of research projects based on merit and federal investment of research studies and education for the next generation of investigators. In return, the research community has given its assurance that research is conducted with integrity and ethically. In the United States, the partnership between the research community and government as reflected in our medical schools and teaching hospitals demonstrates the value and necessity of government involvement: in the last 30 years, the number of basic science faculty has increased 2-1/2 times, the number of clinical faculty has increased 5 times, there is 50% more space for faculty to conduct research, and the number of research grants to faculty from the National Institutes of Health has increased 4-1/2 times.1 In part due to improved government regulation for commercialization of drugs and devices, industry’s investment in clinical trials and Address for correspondence: Marjorie Speers, Ph.D., Executive Director, Association for the Accreditation of Human Research Protection Programs (AAHRPP), 915 15th Street NW, Suite 400, Washington, DC 20005, USA; email:
[email protected]. 1353-3452 © 2005 Opragen Publications, POB 54, Guildford GU1 2YF, UK. http://www.opragen.co.uk
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other forms of research has tripled in the past decade.2 Such an investment in research could not occur without the public’s tacit endorsement and explicit trust that research is conducted ethically. Yet, our history of protecting human research subjects suggests that we have not always lived up to our obligation to be accountable thereby compromising the public’s trust and support of research. Prior to 1949, the United States had not considered the ethics of conducting research involving humans. It was only when the American prosecutors of the Nazi physicians at Nuremburg asked the American Medical Association for its code of ethics did we begin to consider what constituted the ethical conduct of such research. The American Medical Association developed a set of ethical principles for research, which became the Nuremburg Code.3 However, the Code was not embraced in the United States, mainly because we did not see its relevance. That is, it was those Nazi doctors that committed abuses; this behavior was not present in the American research. As shown in Table 1, in 1964, abuses and violations of research subjects by American scientists became known with the publication of the Brooklyn Jewish Chronic Disease Hospital experiments.4 Elderly patients were injected with cancer cells without their knowledge or permission. Henry Beecher’s article in the New England Journal of Medicine5 followed two years later. Beecher reported that infringements on the rights and welfare of research subjects occurred in many research studies and were committed by well-respected scientists affiliated with prestigious institutions of higher learning. Several years later the public became aware of the Willowbrook School for the Mentally Retarded experiments in which families were forced to enroll their children in research studies in order for their children to be admitted to the school. Then, in 1974, the press reported on the Tuskegee Syphilis Study, a study that took place over 40 years involving the deliberate deception of black men who had syphilis.6 These men were denied treatment even after penicillin became widely available, causing not only great harm to them but also to their family members who became infected. The Tuskegee Syphilis Study was halted by the federal government. The U.S. Congress established the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research to, among other things, develop ethical principles that would govern the conduct of human research. In 1979 the final report of the National Commission – The Belmont Report – was released.7 This report described three ethical principles: respect for persons, beneficence, and justice. Today these three principles are still followed. Table 1 Precipitating Events to Promulgation of Federal Actions 1964 1966 1971 1974 1979 54
Discovery of abuses in Brooklyn Jewish Chronic Disease Hospital experiments Henry Beecher’s article in the New England Journal of Medicine Discovery of abuses in Willowbrook School for the Mentally Retarded experiments Discovery of Tuskegee Syphilis Study abuses Release of the Belmont Report Science and Engineering Ethics, Volume 11, Issue 1, 2005
Making Human Research Safe: Why We Cannot Afford to Fail
The United States is one of the few countries that governs human research through law and regulations; most govern through guidelines or codes. One can correlate the history of precipitating abuses with regulations4 (see Table 2). For example, in 1966, the Public Health Service, a division within the then Department of Health, Education and Welfare, released a policy requiring independent review of all extramural research funded by the National Institutes Health (NIH). For over a decade the NIH required independent review by an institutional review board (U.S. term for ethics committee) of its intramural research, only for studies involving health volunteers, not patients. In response to Beecher’s article, the requirement for independent review was expanded to research funded at the universities. In 1971 and 1974, respectively, the Department of Health, Education, and Welfare issued the “Yellow Book” setting forth more requirements for independent review and later codified the requirements in regulations, which carry the force of law. In 1981, the Department of Health and Human Services, along with the Food and Drug Administration, issued regulations based on the Belmont Report. Ten years later, 16 other federal agencies agreed to adopt or follow similar regulations. The aggregate of all the regulations is called the Common Rule. Table 2 History of Regulations to Protect Research Subjects in the United States 1966 1971 1974 1981 1991
Public Health Service policy requiring independent review of extramural research Department of Health, Education and Welfare issues “Yellow Book” guidance on independent review boards Department of Health, Education and Welfare issues regulations based on the “Yellow Book” Department of Health and Human Services and Food and Drug Administration issue similar regulations for human subjects protection Sixteen other federal agencies adopt regulations collectively called the “Common Rule” The Department of Health, Education and Welfare changed its name to Department of Health and Human Services.
While there were regulations, they were loosely enforced and adhered to. Evidence that the protections for research subjects were not adequate began to surface in 1994 when the Advisory Committee on Human Radiation Experiments released its report indicating that the Committee had grave concerns with the informed consent process in many studies.8 Basically, subjects did not understand the purpose of the research studies in which they participated, the risks and potential benefits associated with the research studies, and just generally what the studies entailed. In the years following, there were numerous government reports describing institutional review boards as overworked, under-prepared to review the vast array of studies, and lacking resources.9
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The oversight system, primarily defined in terms of institutional review boards was in grave danger of failing. The reality of this warning was witnessed when seven institutions had their research programs suspended by the federal government as shown in Table 3. These shutdowns were indicative of a sea change: the federal government was enforcing the regulations for protecting human research subjects much more aggressively than it had in the past. In each of the closures, the regulating agency found systemic problems with the institutional review board or the organization’s ability to protect human subjects. The triggering event for the investigation, such as the death of a healthy volunteer, provoked the investigation but not the outcome. The suspensions were highly publicized media events. Major newspapers, magazines, television and radio stations, and trade publications covered the suspensions, each questioning the safety of research studies. The famous Time Magazine cover in April 2002 where a woman was held in a cage said it all: American scientists were treating humans like guinea pigs. Lawsuits followed and to this day some are still in litigation. Table 3 Suspension of U.S. Federal Support Research Programs 1998 1999 1999 1999 2000 2001 2001
Rush Presbyterian St. Luke’s Medical Center Greater Los Angeles Health Care System, West Los Angeles VAMC Duke University Medical Center University of Illinois, Chicago Virginia Commonwealth University University of Oklahoma Health Sciences Center Johns Hopkins Medical Institutions
The government reports, suspensions of research programs at prestigious academic medical centers, media attention, and legal actions created a new environment of concern. Everyone was questioning protections of research subjects. The more the federal government scrutinized and found problems, the more pressure there was for it to respond. The federal government, under its limited authority, could do only three things: 1.) issue more regulations, 2.) interpret existing regulations more stringently, or 3.) enforce through existing mechanisms the existing regulations. None of these powers was likely to evoke the desired response of better protections and greater safety in research. Equally of concern was the possibility of the public’s diminished trust in research, a trust that is essential to a healthy, thriving partnership between government and the research community. The research community relies upon the public’s trust in research for federal support of research and for enrollment of patients and healthy volunteers in clinical research, especially clinical trials. Perhaps better described as a “social contract”, the research community must live up to its obligation to conduct research with integrity and to demonstrate its commitment to ethically sound research to ensure public support of research.
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Therefore, a strong response from the private sector is not only warranted, but also justified, as the federal government, alone, cannot provide protections for research participants. Meaningful protections occur through the investigator, institutional review board, and the organization. In other words, protections occur at the local level. Government and the research community should work in concert: government sets the expectations and the research community follows them. Thus, it is critical for the research community to embrace sound ethical research and strong protections for research participants as priorities. A strong response from the private sector – research community – is likely to lead to deeper penetration and consistency in regulatory compliance. More importantly, a strong private response should reflect a change in culture from one of mere compliance to one of concern by shifting the focus to “doing the right thing.” Not being bogged down by rigid bureaucratic processes, a private sector response is faster, more flexible, and more meaningful. With the support of the leading research institutions, change to a system of better protections could occur within a matter of a couple of years, which is not long compared to an average of three years to change federal regulations, ten years to create the Common Rule, and no change to the federal regulations to protect human research subjects since 1991 even though there have been efforts and recognized need for change.4 Over the past few years we have witnessed a number of efforts by the research community to improve research protections. These include stronger institutional commitment at the highest levels and increased resources, educational programs offered by professional organizations and within research institutions, e.g. annual education conferences, monitoring of investigators and institutional review boards by organizations and sponsors, involvement from professional organizations in creating policy statements10 and accreditation.11 This noticeable private sector response should help to build or restore public trust in research and instill confidence in government sponsors and regulators of research. It is the last of these private sector activities that I would like to address because it is the newest and perhaps the most promising. Accreditation is a time-tested process used to help a profession or industry to self-regulate.12 It has been used for more than 100 years to raise standards in higher education and professional training, such as medical education;13 more than 50 years in health care delivery;14 and animal use and care. Accreditation in the field of human research protection was created in an environment of concern. Discussions about whether accreditation would be a viable mechanism for raising the standard of protection for research subjects began in the late 1990s partially in response to government reports describing deficiencies with institutional review boards: they were overworked and overwhelmed, and unprepared to review the full research portfolio under their purview.9 When the suspensions of research programs in large, respected academic medical centers occurred, the research community responded swiftly with the founding of the Association for the Accreditation of Human Research Protection Programs (better known as AAHRPP), a non-profit organization offering accreditation to organizations that conduct or review Science and Engineering Ethics, Volume 11, Issue 1, 2005
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research involving humans worldwide.11 Accreditation was founded on the premises that well-founded research ethics are an integral component of a sound and qualitydriven research policy and that the focus of responsibility for protection of human subjects must be expanded to include investigators and organizations.15 The focus cannot be solely on the institutional review board. For this reason, the locus of accreditation is the “human research protection program”; such a program encompasses all the policies, procedures, and activities that comprise a comprehensive program of protection. Accreditation recognizes the roles and responsibilities of institutional review boards that have the primary responsibility to ensure that research studies are ethically justifiable and that protections are in place to make the research study as safe as it can be given the inherent risks associated with any clinical study. Accreditation also recognizes the roles and responsibilities of investigators and research staff who conduct research studies. These individuals often design the research study, administer the consent process, obtain consent, carry out the procedures and interventions, analyze the data, report findings to subjects when appropriate and do all the other things that researchers do. Their obligation to protect research subjects is just as strong as that of the institutional review board. Finally, institutional review boards and investigators cannot perform their duties without the support of their organizations. Thus, the focus of accreditation on a program of human research protection brings together all these roles and responsibilities and acknowledges that protection is a shared responsibility in which the system is as good as the weakest link. AAHRPP’s accreditation model has three distinct characteristics that should lead to the desired outcome of improved protections for research subjects. Accreditation is a voluntary and non-governmental process. The research community drives selfregulation through accreditation. Organizations seek accreditation because they place a high priority on protection and wish to demonstrate their commitment to a high quality protection program by having it recognized by an external body. By being nongovernmental, standards are set higher than the floor set by the federal government and are able to address known weaknesses in the federal regulations. AAHRPP’s accreditation program is peer-driven. Standards and procedures were agreed upon by those who would be affected: ethicists, institutional review board professionals, researchers, and research subjects. During the accreditation process, peers speak with peers within the organization that is applying for accreditation. Other areas of accreditation have shown that when site visitors are respected colleagues, organizations listen.12 Finally, the accreditation program is based on the premise that education will help to drive continuous improvement. Many of the lapses in research protection can be traced to a lack of knowledge or awareness. For years widespread educational programs did not exist. In fact, it is only recently that graduate and professional schools have begun to include research ethics training into the curriculum. Certification of institutional review board professionals began only in 2000.4 As accreditation strives to the move the research community to a higher level of protection, it aims to bring about change through education rather than coercion. 58
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Like other private sector responses, the goals of accreditation are to improve protections for research subjects, improve research quality, and build public trust. In the next three to five years, it is expected that accreditation will become the standard of practice for organizations engaged in human research. As more organizations become accredited the value of accreditation and pressure to achieve it will become apparent. Moreover, sponsors, governmental and industrial, will become more comfortable in working with accredited organizations and placing research at accredited organizations. Accreditation will take hold because the costs to the research community of not self-regulating are much higher. Not only in the United States, but worldwide, research organizations must live up to their obligation to make research as safe as it possibly can be. To not try to meet the highest ethical principles and standards is to ignore the social contract with the public. We cannot afford to fail.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12. 13. 14. 15.
Cohen, J. (2003) AAMC President’s Address 2003: Our Quest for Meaning. AAMC’s 114th Annual Meeting, Washington DC. Pharmaceutical Manufacturers of America (PhRMA) (2004) Pharmaceutical Industry Profile 2004. PhRMA, Washington, DC. Annas, G.J. and Grodin, M.A. The Nazi Doctors and the Nuremberg Code. Oxford University Press, New York. National Bioethics Advisory Commission (2001) Ethical and Policy Issues in Research Involving Human Participants. US Governmental Printing Office, Washington DC. Beecher, H.K. (1966) Ethics and clinical research. New England Journal of Medicine 274(24): 1354-1360. Jones, J.H. (1981) Bad Blood: The Tuskegee Syphilis Experiment. The Free Press, New York. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979) Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Department of Health, Education and Welfare, Washington, DC. Advisory Committee on Human Radiation Experiments (1994) Final Report. US Government Printing Office, Washington DC. Office of Inspector General, Department of Health and Human Services (1998) Institutional Review Boards: A Time for Reform. OEI-01-97-00193 Department of Health and Human Services, Washington, DC. Task Force on Financial Conflicts of Interest in Clinical Research (2001) Protecting Subjects, Preserving Trust, Promoting Progress – Policies and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research. Association of American Medical Colleges, Washington, DC. AAHRPP (May 23, 2001) New National Accrediting Entity Launched. (Press release) Accessed at www.aahrpp.org on July 18, 2004. Hamm, M.S. (1997) The Fundamentals of Accreditation. American Society of Association Executives, Washington, DC. Kasselbaum, D.G., Eaglen, R. H., and Cutler, E. R. (1997) The meaning and application of medical accreditation standards. Academic Medicine 72(9): 808-818. Joint Commission on Accreditation of Healthcare Organizations. (2001) 50 years of progress in health care quality and safety. Perspectives 21(11): 1-5. Institute of Medicine. (2001) Preserving Public Trust: Accreditation and Human Research Participant Protection Programs. National Academies Press, Washington, DC
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