Faculty View: Reducing the Perils of Participating in Research on Human Subjects

by Jesse A. Goldner
John D. Valentine Professor of Law

Nicole Wan was a 19-year-old freshman at the University of Rochester in 1996. Ellen Roche was a 24-year-old laboratory technician at Johns Hopkins University’s Asthma and Allergy Center in 2001. Jesse Gelsinger was an 18-year-old who lived in Arizona in 1999. What the three had in common was that each participated in a clinical research study. Each died as a result. 

Wan and Roche were “healthy volunteers.” Gelsinger suffered from Ornithine Transcarbamylase Deficiency, a genetic disorder that causes excessive amounts of ammonia to appear in the blood. While without treatment the disorder can lead to behavioral disorders, mental retardation, coma or even death, Gelsinger had been doing well on his then current medication regime. The study was a “leading edge” gene transfer investigation, conducted at the University of Pennsylvania, that the researchers thought might ameliorate the condition. Though some federal regulations mandate review of many proposed studies such as these, little monitoring occurs regarding how those reviews are conducted. Investigations after the deaths in each situation concluded that appropriate guidelines for the conduct of the research had not been followed at the institutions.

In 1965 leading veterinarians and researchers organized what is now known as the American Association for Accreditation of Laboratory Animal Care International, as a private, nonprofit organization. Over the last 41 years it has accredited more than 670 operations worldwide (including organizations such as Saint Louis University, Stanford University, the National Institutes of Health and GlaxoSmithKline pharmaceuticals), elevating the standard for research laboratory animal care to new levels. Rather strangely (and cynically, some might observe), it was only a mere five years ago that a similar organization, the Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP) was created to offer a comparable program to institutions that conduct or review biomedical, social and behavioral science research in which human beings serve as research subjects.

AAHRPP was established by seven founding organizations, including groups such as the Association of American Medical Colleges, the American Association of Universities and the National Association of State Universities and Land Grant Colleges. A national organization based in Washington, D.C., it developed in the wake of a series of disciplinary measures against research institutions taken by various federal agencies, such as the Food and Drug Administration and the U.S. Department of Health and Human Services, which are responsible for overseeing the manner in which such research occurs. Those actions involved stopping or severely limiting the conduct of research at some of the country’s leading medical centers including, among others, Duke, Johns Hopkins and the University of Pennsylvania after the deaths of Wan, Roche and Gelsinger. As one small example of the effects of the federal agencies’ actions, the annual budget for human subject participant protection programs at Duke increased from approximately $100,000 to over $1 million in the course of a few months as it attempted to meet requisite federal standards.

In response to the resulting public concern for protecting research participants, AAHRPP was established “not only to ensure compliance with federal regulations, but to raise the bar in human research protection by helping institutions reach performance standards that surpass the threshold of state and federal requirements.” The organization also aims to “promote scientifically meritorious and ethically sound research by fostering and advancing the ethical and professional conduct of persons and organizations that engage in research with human participants.” AAHRPP achieves its mission by using an accreditation process based on self-assessment, peer review and education.

In 2002 I was invited to join AAHRPP’s initial Council on Accreditation, which determines the status of applicant organizations. In 2005 I served as the Council’s first chairperson and continue to participate by serving as a member of the group and by conducting site evaluation visits on its behalf. The invitation to join the Council came about for three reasons, each related to my work at SLU: (1) For some eighteen years I had been a member of (and, from 1998 through 2003, had chaired) SLU’s Institutional Review Board (IRB). This is an interdisciplinary group, including both scientists and non-scientists, primarily comprised of faculty from throughout the University, but also including non-University-affiliated individuals. The IRB, through a peer review process, evaluates individual proposals to conduct research involving human subjects by faculty, staff and graduate students at the University. The purpose is to ensure that ethical principles are followed, primarily by seeing to it that investigators are minimizing risks to research participants and obtaining appropriate informed consent from these subjects. (2) Much of my academic writing in the last decade has focused on the regulation of research. Most recently, I co-authored a law school casebook on the subject. (3) Since 1988 I had regularly conducted site evaluations of other American law schools for purposes of their accreditation on behalf of the Accreditation Committee of the American Bar Association’s Section on Legal Education and Admissions to the Bar. This familiarized me with the accreditation process, albeit of a very different type.

How does AAHRPP work? AAHRPP is not affiliated with the government. It is institutions, including universities, hospitals and free-standing research facilities, that voluntarily apply to AAHRPP for accreditation. Applicants must complete a wide-ranging questionnaire and submit extensive supporting materials, including their policies and procedures, all relating to how their institution goes about protecting the rights of those who serve as research participants. This is in an effort to evaluate that they meet some twenty different standards that include seventy-five separate elements. Among the issues explored are the involvement of organizational leaders and the adequacy of resources they provide to the process. In reviewing the competency and sophistication of the institution’s research review units (typically the IRBs), we examine their abilities to (a) assess risks and benefits; (b) oversee the appropriate recruitment and selection of subjects; (c) protect participants’ privacy and the confidentiality of the data obtained; and (d) monitor the process of obtaining informed consent from participants and the content of the information provided to them.   

Another focus is that of the investigators themselves: their familiarity with research ethics, their abilities to follow applicable laws and regulations and their understanding that the protections of the rights and welfare of research participants is their primary concern. Attention also is paid to the nature of the contractual relationship between the organization itself and outside agencies such as pharmaceutical and medical device companies that sponsor research. This involves ensuring that there is appropriate communication of information that might affect the ongoing oversight of research protocols by IRBs as well as maximizing the likelihood that the benefits of the knowledge obtained through research are realized and the interests of current and future participants are protected. Finally, the standards address how the organization responds to concerns of research participants and engages in outreach efforts by offering educational opportunities to participants to enable them to better understand research.

After the submitted materials are reviewed, AAHRPP appoints a site evaluation team, typically comprised of two to five members who have training and experience in conducting evaluations and who have no affiliations with the applicant institution. They will spend between two and five days at the institution, depending on its size and number of research projects at the institution. They then draft a lengthy and highly detailed report describing what they encountered at the institution, including an examination of protocols and other records and interviews with investigators, staff and members of the IRB.  Ultimately, these reports are reviewed by the Council on Accreditation which determines if the standards have been met so as to merit accreditation. Not infrequently, institutions are placed in an “accreditation pending” category when the Council determines that additional efforts need to be made by the institution. At the present time some thirty-nine institutions have met accreditation standards, though nearly four hundred are “in the pipeline” and will be site visited within the next year or two.

The process, both for institutions and for those who conduct site evaluations and participate in Council reviews, is an arduous one. As critical as the development of ongoing scholarship in this area may be, it is equally important that those of us who spend much of our time in the proverbial ivory tower, recognize the need to “descend” and expend some of our efforts in the hands-on work that may more directly affect the ability of researchers and their institutions to protect research participants like Nicole Wan, Ellen Roche and Jesse Gelsinger. As AAHRPP accreditation becomes more prevalent, it is quite likely that the safety of research subjects will increase and the lives and health of countless others will benefit as well.