Monitoring Human Subjects and Clinical Trials

Institutional review boards (IRBs)--whether independent or located at hospitals, academic health centers, or universities--have an imposing charge: They must sift through and analyze a profusion of clinical research trials to ensure that participating human subjects will be treated ethically and without undue risk. But for a variety of reasons, many IRBs aren't getting the job done--this according to an April report from the Office of Inspector General (OIG) in the U.S. Department of Health and Human Services (HHS). 1 The report, which was the focus of a May 3 congressional hearing, was intended to be an update on the reaction of the National Institutes of Health and the Food and Drug Administration (FDA) to a 1998 OIG report. Based on investigations of more than 75 IRBs, discussions with IRB members and institution leadership, and a review of relevant documents, the report harshly criticized the IRB process. Two additional follow-up reports on aspects of the IRB process are due out in late May; one examines recruitment of human subjects, the other looks at oversight provided by the FDA after trial completion but before drug approval. According to the April report, titled "Protecting Human Research Subjects," the NIH's Office for Protection from Research Risks (OPRR) and the FDA have cracked down on some institutions as a result of the 1998 report. The OPRR and FDA found performance problems at many of the institutions investigated; the OPRR required seven institutions, including high-profile universities such as Duke University and the University of California, Los Angeles, to actually suspend their research. To improve the system and elevate OPRR's stature, HHS has decided to relocate OPRR from NIH to the Office of the Secretary of HHS and to establish an advisory committee for scientific and ethical oversight. Paul Root Wolpe A joint FDA/NIH statement responding to the April report suggested that there has been a "dramatic rise in the enforcement of federal requirements" and that educational efforts to promote a "greater understanding of patient protection efforts" will continue. "OPRR has put the fear of God into a lot of medical centers," says Paul Root Wolpe, a medical sociologist at the Center for Bioethics at the University of Pennsylvania. In a 1998 article in JAMA:The Journal of the American Medical Association, 2 Wolpe and his colleagues criticized the IRB systems for many of the same reasons included in the 1998 HHS report. "[The 1998 report] served as a wake-up call not only for IRBs, but also for institutions and the federal government," comments Ernie Prentice, associate dean for research at the University of Nebraska Medical Center and cochair of its IRB. Prentice would like to see a more proactive OPRR with better resources. Also in response to the 1998 report, some institutions have changed procedures--for example, more frequently using "data and safety monitoring boards" to keep abreast of ongoing trials. But IRBs have very limited and weak ongoing oversight, according to Wolpe, despite investigators' usual requirement to report yearly to the IRB. It's one of several problems that continue to plague the system. The April report calls for better, more comprehensive education of investigators, quicker response from IRBs, more IRB members, better resources, and less burdensome workloads. "Fundamentally, we're not there yet," comments George Grob, HHS deputy inspector general for evaluation and inspections and primary author of the 1998 report. "While there have been some beginnings, they are at best beginnings in terms of structural reforms." "While there have been some beginnings, they are at best beginnings in terms of structural reforms." --George Grob Although enforcement of existing regulations has brought improvements (properly filling out and filing informed consent forms, for example), wholesale reforms aiming to "raise the bar" rather than meet existing standards haven't materialized. IRB members, many of whom volunteer or are asked to take part, usually have little training in research ethics. Also, most institutions offer already busy investigators little reward or incentive, monetary or otherwise, for doing a thorough job; often participation is considered service to one's institution. Grob cites one potential solution for enabling researchers themselves to get up to snuff on ethical practices without taking part in time-consuming ethics education sessions: a mandatory self-test on current regulations, recently put in place for the first time by the University of Rochester Medical Center. To ensure that IRB members consistently meet a high standard of education, many advocate widespread IRB accreditation. It is, for example, one of the primary initiatives of an organization called Public Responsibility in Medicine and Research (PRIM&R), a body founded in 1974 by a group of research scientists from eastern Massachusetts who feared that waning public confidence and a complex regulatory climate threatened the credibility of clinical investigations and investigators. Wolpe, who calls the April OIG report on the mild side despite its criticisms, claims that the system's fundamental flaw is investigators' willingness to alter their informed consent forms instead of altering increasingly risky protocols. According to Wolpe, researchers often amend informed consent forms to adjust for risk under the philosophy that as long as you tell the subject about protocol changes, anything you do is OK. "The charge of IRBs originally was to look at research, weigh its risks and benefits, and disallow research where the risks were great," he remarks. "IRBs have virtually completely abandoned that function .... It's a fundamental distortion of what the function of the IRB was supposed to be." George Grob As industry-based funding sources become more common, IRBs face a more complex problem. Drug companies often write up protocols for multisite drug studies, then look for an IRB at a university. An IRB member who thinks that something is awry is forced to request that the protocol be changed at all participating sites. If a drug company consistently runs into roadblocks with one IRB, it might pull out and take its business to some other university. As a result, IRB members shoulder potentially enormous pressure. Independently operated IRBs, a relatively recent phenomenon, may be part of the solution. According to Mark R. Yessian, primary author of the April report, contributor to the 1998 report, and regional deputy inspector at the Office of Evaluation and Inspections in Boston, use of independent IRBs is increasing as more research takes place outside the medical center. Often faster and afforded larger staffs, independent IRBs, such as the well-established Western IRB in Olympia, Wash., may offer industry and academia more objectivity. Wolpe, though, worries that independent IRBs aren't immune from the pressures of profit. As with university IRBs, if clients disapprove of the cost of a review, independent IRBs aren't likely to get a lot of repeat business. "It's going to take a while for them to establish themselves in the standing that professional auditors have," says Wolpe. The National Bioethics Advisory Commission (NBAC) continues to study ethical issues in the treatment of human subjects as it works toward a comprehensive report, and the OIG will continue to study aspects of the process based on its initial report. Grob and Yessian, though, emphasize that administrative machinery can only do so much. The burden inevitably falls on the researcher, whom the subject is most likely to approach if he doesn't understand the informed consent form or is concerned about his involvement in the study. Unlike subjects 20 or 30 years ago, human subjects today, according to Yessian, aren't likely to participate in studies for the "benefit of mankind." They're looking for real improvements in their condition, and Yessian worries that studies often advertise potential benefits without paying sufficient attention to the risks. In the most recent high-profile example of protocol problems, the FDA reprimanded a gene therapy researcher for improperly conducting a peripheral artery disease clinical trial--misconduct that might have contributed to the death of at least one patient. According to a warning letter from the FDA sent April 28, 3 the study leader, Tufts University scientist Jeffrey Isner, committed several gross violations including enrolling a subject who had lung cancer. In fact, in trying to promote blood vessel growth to treat cardiac disease using vascular endothelial growth factor (VEGF), the experimental treatment may have, according the FDA's letter, effectively fed the patient's tumor, exacerbated his condition, and contributed to his death. The letter also scolded Isner for informed consent violations and failure to notify his IRB of all study complications, including the death of this patient. Said the letter: "Deviations in these studies appear to be the result of a serious lack of knowledge of your responsibilities as principal investigator ...." Isner now faces possible disqualification as a clinical investigator. "Consent forms, data boards, IRB review--there is this machinery that can be improved and upgraded," says Grob. "But none of that can quite reach down to the confidence that the researcher and the research subject have in one another .... If the process of protecting human subjects isn't working right there, the researcher could wish it away on the IRB, they could wish it away on the global economic forces that are at work, ... they could wish it away on the research institutions and the sponsors. But, in fact, they can't run away from it. It is their responsibility to make sure the person's protected." S Eugene Russo can be contacted at erusso@the-scientist.com. References 1. www.dhhs.gov/progorg/oei/whatsnew.html 2. J. Moreno et al., "Updating protections for human subjects involved in research," JAMA:The Journal of the American Medical Association, 280:1951-8, 1998. 3. www.fda.gov/foi/warning_letters/m3661n.pdf

Monitoring Human Subjects and Clinical Trials

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Eugene Russo

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May 2000

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