Regulating Clinical Research: Informed Consent, Privacy, and Irbs
| Author | Sharona Hoffman |
| Pages | 71-91 |
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During the past two decades, the United States has experienced dramatic developments in the area of biomedical research.1 Expanding budgets,2 augmented computer capabilities, and the Human Genome Project3 have all significantly enhanced research capabilities.4Consequently, the number of research projects conducted in this country is ever growing,5 and the enrollment of an adequate number of human subjects is becoming an increasingly challenging task.6 In the words of one commentator, "never have so many human clinical trials been underway and offered so much promise for improving human health . . . [and] never have the economic and regulatory challenges been as great.7"
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Clinical research involving human participants is governed by federal regulations that have been promulgated by the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA).8In light of the proliferation of medical research, however, an increasing number of critics are voicing serious concerns about inadequate enforcement of the regulations and unacceptable research risks.9 In recent years, several subjects have died as a result of treatment received in clinical trials and several well-publicized lawsuits have been filed against researchers, research institutions, and institutional review boards (IRBs).10The most prominent case is that of Jesse Gelsinger, an eighteen-year old man with a rare metabolic disease, who died while undergoing experimental genetic therapy administered in a clinical study at the University of Pennsylvania.11 In addition, a healthy research volunteer died as a result of an experiment relating to asthma that was conducted at Johns Hopkins School of Medicine.12 Two recent lawsuits involve individuals who received an experimental melanoma vaccine in a clinical trial conducted at the University of Oklahoma Health Science Center in Tulsa13 and patients who participated in blood cancer trials at the FredPage 73 Hutchinson Cancer Research Center in Seattle.14 Intensifying concerns about both human subject welfare and potential liability are stimulating urgent calls for regulatory reforms.
Part I of this Article provides a brief historical overview of Twentieth Century research abuses and the development of regulatory oversight in the United States. Part II discusses informed consent, IRBs, and the regulations that govern them. Part III analyzes contemporary deficiencies in the regulatory system. Finally, Part IV offers recommendations for reform.
During World War II, the Nazis conducted large-scale, experiments on concentration camp prisoners that were designed not only to gather medical data, but also to torture and kill the subjects. In some camps, German doctors infected numerous healthy inmates with yellow fever, smallpox, typhus, cholera, and diphtheria germs that caused hundreds of them to die.15 In other camps Nazi physicians conducted experiments relating to high altitude, malaria, freezing, mustard gas, bone transplantation, sea water, sterilization, and incendiary bombs.16 The full scope and ghastliness of the Nazi medical experimentation was revealed and documented during the Nuremberg Trials after World War II.17
In the United States, medical research was conducted for many decades without any regulatory oversight.18 Perhaps not surprisingly, in an environment devoid of regulation and monitoring, an alarming number ofPage 74 research abuses occurred in this country as well.19 In the early 1950s, nearly one hundred percent of participants in Phase I clinical trials, the first and riskiest phase of human research studies,20 were prisoners.21 In Ohio, for example, live cancer cells were introduced into both forearms of many prisoners.22 Two weeks after the injection, the affected area of one arm would be surgically removed for study, while the malignant cells were left in the other forearm for further observation.23 At the Ionia State Hospital in Michigan, at least 142 inmates were recruited for secret CIA psychological experiments.24 As late as 1969, eighty-five percent of new medications were still tested on prisoners.25
Research abuses in the decades following WWII were not limited to the prison environment but also involved other vulnerable populations.26For example, patients at the Jewish Chronic Disease Hospital in Brooklyn had live cancer cells injected under their skin, and retarded children in the Willowbrook State School on Staten Island were infected with a mild strain of hepatitis.27 The experiments were done without the subjects' knowledge or consent.28
In 1972, news of the notorious Tuskegee syphilis study highlighted the problem of mistreatment of medical research subjects in the United States.29 The Tuskegee study, whose participants were all African-American men, was conducted from 1932 until the beginning of the 1970s and sought to analyze the natural progression of untreated syphilis.30 The researchers, therefore, did not provide patients with penicillin, an antibiotic that is a fully effective cure for syphilis and was widely available as earlyPage 75 as 1953.31 The subjects, who believed they were receiving adequate care, continued to suffer unnecessarily from the debilitating effects of the disease.32
The federal government finally responded to publicity concerning research abuses by promulgating oversight regulations. The FDA and the National Institutes of Health (NIH) developed internal policy guidelines in 1966 and 1971, respectively, and these became federal regulations in 1974.33 The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research was established through the National Research Act of 197434 and operated for four years, until 1978.35 Pursuant to the Commission's recommendations, the federal regulations underwent revision in 1981, and they have remained in effect since then.36
Research studies, generally termed "clinical trials," for the development of new drugs and devices are regulated by the FDA.37Medications that are the focus of study in clinical trials are called investigational new drugs (INDs).38 Clinical trials that involve treatmentsPage 76 other than drugs and devices, such as surgery or bone marrow transplants, are not regulated by the FDA and are subject to DHHS regulation only if they are "conducted, supported or otherwise subject to regulation by any federal department or agency...."39
Research that is conducted, supported, or regulated by DHHS, the FDA, or another federal agency must be reviewed by an IRB.40 An IRB is a committee designated by an institution to provide initial approval and periodic monitoring for biomedical research studies.41 The IRB's primary purpose is to protect the rights and welfare of human subjects.42 The IRB reviews a document known as the "protocol" for each proposed clinical trial, which describes the objectives of the research, its procedures, eligibility requirements for participants, the number of subjects to be tested, and other details.43 The material submitted to the IRB also includes a document known as the "informed consent" form, which is given to all potential enrollees in order to provide them with a detailed explanation of the clinical trial and an opportunity to agree to participation in the study.44
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After the IRB approves the informed consent form, all those who wish to become human subjects must sign a copy of the document, affirming the voluntariness of their choice.45
The structure and duties of IRBs are governed by the DHHS and FDA regulations.46 Each IRB must be composed of at least five members with diverse cultural and ethnic backgrounds, and both men and women should be included.47 At least one member of the IRB should be a person whose principal concerns are in the scientific realm, and one individual's expertise should be nonscientific (e.g. a lawyer or minister).48Furthermore, to enhance its objectivity, each IRB must include at least one member who is not otherwise affiliated with the research facility and who has no immediate family members affiliated with the entity.49 According to DHHS's Office for Protection from Research Risks (OPRR), now renamed the Office for Human Research Protection (OHRP), eighty-six percent of IRB members in 1995 were affiliated with academic research institutions as full-time faculty (56%), clinical and research staff (18%), and administrators (6%).50 Academic institutions do not compensate IRB members for their work, and thus these individuals must volunteer their time without receiving payment or relief from other job duties.51
Unless an expedited review is conducted, research protocols must be reviewed at IRB meetings at which a majority of members are present, including a member whose expertise is nonscientific.52 Decisions concerning approval of each study are made by majority vote.53
The IRB may approve, disapprove, or require modifications to the proposed research activities.54 Investigators must be given written notification of the IRB's decisions, and IRBs are required to monitor the clinical trials they approve at...
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