Future Challenges to Human Subject Protection

Illustration: A. Canamucio The death of a young man, Jesse Gelsinger, in a 1999 gene therapy experiment has focused attention on the challenges of research with human subjects. This issue had been simmering just below the surface for the past eight years. The media reports on human subject abuses in a wide variety of research settings could sufficiently arouse public distrust of human research and endanger the recruitment of patients in future clinical trials. The explosive growth in res

Adil Shamoo
Jun 25, 2000

Illustration: A. Canamucio
The death of a young man, Jesse Gelsinger, in a 1999 gene therapy experiment has focused attention on the challenges of research with human subjects. This issue had been simmering just below the surface for the past eight years. The media reports on human subject abuses in a wide variety of research settings could sufficiently arouse public distrust of human research and endanger the recruitment of patients in future clinical trials.

The explosive growth in research with human subjects is attributable to an aging population, increased attention to health care issues, and an unprecedented increase in federal funding. Existing regulatory infrastructures at the federal and local levels, however, have not kept pace with this growth. As a consequence, protection of human subjects is lagging far behind the research needs.

There is no question that there is a great need for research using human subjects. Society demands improvements in health care and will demand newer and better medications and treatments. Desperate patients may even seek unproven remedies if research results are not forthcoming.

Two documents have formed the cornerstone for the protection of human subjects in research. The first, created by the tribunal judges in one of the trials of Nazi doctors in Nuremberg in 1946, became known as the Nuremberg Code. The second is the Helsinki Declaration issued by the World Medical Association in Helsinki, Finland, in 1964. The two documents, though differing in some aspects, premiered safety and the voluntary consent of patients over the need for scientific progress. The Helsinki Declaration in the most recent revised text in 1991 unequivocally affirmed, "The interest of science and society must never take precedence over consideration related to the well-being of the subject." This month, the Association of American Medical Colleges, in a proclamation, reaffirmed that the potential benefits to the individual and society exceed any known risks before the start of the research protocol.

In the United States, we have had several disconcerting events. The Tuskegee syphilis study of 400 African Americans, begun in 1932, left patients untreated until 1973 despite the fact that penicillin became available in the early 1940s. In 1997, President Clinton offered a public apology to the victims. In the '60s, retarded children at Willowbrook New York State School were injected with hepatitis virus. Henry Beecher, a Harvard doctor, chronicled 22 cases of patients who had undergone risky experiments without their knowledge. Another major case besides Tuskegee was the radiation experiments reexamined recently.1 President Clinton issued an apology to the unwitting subjects, and some were compensated financially.

The past eight years have brought increasing criticism of psychiatric research practices involving sudden withdrawal of drug treatment and administration of chemicals that provoke psychotic episodes. Allegations of abuse of psychiatric patients with questionable decisional capacity include exposure to needless risks and in some cases attempted and successful suicides. These allegations have come from patients, patients' advocates, family members, researchers surveying the published literature, conferences, media, hearings of the National Bioethics Advisory Commission (NBAC),2 and congressional hearings. In 1999 Steven Hyman, director of the National Institute of Mental Health (NIMH), acting on the advice of a review panel he appointed, suspended 29 intramural clinical trials while reviewing an additional 50 out of 108. Hyman initiated a process to screen all clinical trials for "high risk" to avoid harm to patients. The recent suspension of the Veterans Administration hospital in Los Angeles by the federal Office of Protection from Research Risks (OPRR)3 was in large part due to concerns regarding abuse of psychiatric patients. As a recent issue of Science stated: "Patient activists and ethicists have been calling for a revolution in the way clinical studies in psychiatry are monitored."4 NBAC has weighed in: "A cogent case can be made for requiring additional special protections in research involving as subjects persons with impaired decision- making capacity."5

Conflict of interest charges have also surfaced regarding researchers being paid large sums of money per subject recruited for clinical trials. Frequently, those researchers own an equity interest in the company conducting the research. Two cover stories illustrate the media attention on these issues. U.S. News and World Report (Oct. 11, 1999) headlined the story "Dying for a Cure" with a large picture of skull and bones. More recently, the Atlantic Monthly (March 2000), in a cover story titled "The Kept University," had a picture of a corporate executive hugging a university administration building. These events culminated in OPRR's temporary suspension of part or all research with human subjects at major research institutions such as Duke University, Virginia Commonwealth University, and the University of Pennsylvania.

  Gaps in Regulations

The U.S. federal regulations were enacted in the early 1970s and were accepted by 16 federal agencies as the "Common Rule" in 1991, ensuring voluntary consent and safety of patients. The OPRR was established in 1972 with a skeleton staff. At present, OPRR has insufficient staff members to supervise 4,000 federally funded research institutions. OPRR has jurisdiction over all Department of Health and Human Services (HHS) funded projects. Other federal agencies have similar mandates. The Food and Drug Administration (FDA) is mandated by law to regulate drugs, biological products, medical devices for human use, and food and color additives. The FDA reviews all applications for drugs and products for safety and efficacy. Therefore, the FDA eventually will pass judgment on the use of human subjects in clinical trials if the research results are "FDA bound."

Recently, OPRR was renamed as the Office of Human Research Protections (OHRP) and elevated to HHS department level. Between the OHRP and the FDA, all federally sponsored research with human subjects and all FDA-bound research with human subjects is covered. Privately sponsored research that does not result in an FDA application is not regulated by any federal agency. Unregulated research could amount to half of all research with human subjects, but no one knows the actual figure.

This contrasts with the use of animals. The Animal Welfare Act has regulated animal use in research, regardless of the source of funding, since 1966. There is no comparable act for humans. In a May 4, 1999 letter to the president, the NBAC reported: "NBAC finds that the absence of Federal jurisdiction over much privately funded research means that the U.S. government cannot know how many Americans currently are subjects in experiments, cannot influence how they have been recruited, cannot ensure that research subjects know and understand the risks they are undertaking, and cannot ascertain whether they have been harmed."

The linchpins for protection of subjects in research are the institutional review boards (IRBs), loosely linked to OHRP and FDA. The IRB system is highly decentralized, with nearly 5,000 or more (no one keeps tabs on numbers) across the country. IRBs are the local gatekeepers for judging the adequacy of the research protocol and ensuring compliance with federal regulations. It is at this local level that informed consent is enforced. The director of then-OPRR acknowledged (personal communication, 2000) that informed consent violations have occurred in most of the cases investigated by his agency. The HHS inspector general in 1998 and the U.S. General Accounting Office in 1996 both expressed great concerns at the failure of the IRB system to protect human subjects.

The IRBs are structurally flawed. IRB members are employees of the research institutions, with a built-in conflict of interest. Federal regulations require that the research institution appoint only one member from the community. One member out of 10-20 members is no guarantee of unbiased deliberations and decisions.

  Positive Steps

The following steps can be taken to advance human subject research and to restore public trust.

1. Enact a National Human Subjects Protection Act to cover all human subjects regardless of the source of funding. Legislation sponsored by Rep. Diana DeGette (D-Colo.), Rep. John Mica (R-Fla.), Rep. Dennis Kucinich (D-Ohio), and Rep. Henry A. Waxman (D-Calif.) was introduced this month.

2. Require that 51 percent of IRB members be scientists and community representatives not affiliated with the institution. All members should receive training and education in medical ethics and issues related to human subject protections. HHS secretary Donna Shalala announced this month that all clinical investigators must attest at the time of application for research grants that they have had training in research ethics.

3. Establish an independent federal review board to guide and oversee research involving vulnerable human subjects. NBAC has recommended a similar board to the president in its 1998 report.

4. Establish a national databank for human subject research to facilitate information sharing, avoid duplications, and quickly report adverse events.

5. To allay public distrust immediately, industry and academia have to take a strong leadership role in addressing public concerns and move forward to protect the vast enterprise of human subjects in research. The above suggestions should help in achieving that goal. S

 

Adil E. Shamoo, Ph.D. (ashamoo@umaryland.edu), is a professor in the department of biochemistry and molecular biology, and a member of the graduate faculty in applied and professional ethics, at the University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201. He also is editor in chief of the journal Accountability in Research and a cofounder of Citizens for Responsible Care and Research.

 

References

1. Advisory Committee on Human Radiation Experiments (ACHRE), Final Report, Washington, D.C., U.S. Government Printing Office, October 1995.

2. A.E. Shamoo, ed., Accountability in Research, 7:[2-4]:101-309, 1999.

3. Office of Protection from Research Risks, "Letter of March 22, 1999, from OPRR to VA Greater Los Angeles Healthcare System."

4. E. Marshal, "NIMH to screen studies for science and human risks", Science, 283:464-5, 1999.

5. National Bioethics Advisory Commission, "Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity," 1:1-88, December 1998.