Novel Potential Perils of Volunteering for Clinical Trials Stephen B Hanauer

EDITORIAL

www.nature.com/clinicalpractice/gasthep Novel potential perils of volunteering for clinical trials Stephen B Hanauer

On June 11 2005, a news article in The Lancet …the patients who volunteered for these clinical trials: reported on the court case of two patients unexpected discontinuation of a helpful therapy and exclusion with Parkinson’s disease who had been from trying other potential new therapies. enrolled in a phase II trial of glial-cell-line- pitfalls brought Another example of potential ‘harm’ from derived neurotrophic factor (GDNF) and were to light by enrolling in a clinical trial pertains to patients suing Amgen, the drug manufacturer. Amgen these events who volunteered for early trials of infliximab had discontinued the trial because of safety have exposed (Remicade®, Centocor Inc., PA/Schering- concerns identified in monkeys that had potential Plough Corp., NJ) for Crohn’s disease. received infusions of GDNF and later developed Volunteers entering the Phase I and II trials who cerebellar lesions. The patients claimed conflicts received only a single infusion or an induction that they had reductions in tremors and no regarding series of three infusions were not eligible for safety issues, and asked the court to prevent benefits subsequent, open-label dosing. When these Amgen from withholding treatment. The report and risks in individuals were re-exposed to infliximab after highlighted the “…lack of a suitable mechanism 6–24 months, it became apparent that the through which evidence from individuals can be presenting initial dosing regimens were actually priming taken into account in decision-making about informed the patients for the development of immuno- experimental treatments…” and that patient consent… genicity (antibodies to infliximab), with the choice is virtually eliminated within the realm potential for delayed hypersensitivity reactions, of clinical research. acute infusion reactions, and/or eventual loss Of late, gastroenterologists and their patients of response to the otherwise highly efficacious have entered into similar clinical research monoclonal antibody. controversies. Clinical trial reports on the The GDNF and natalizumab examples benefits of natalizumab (Tysabri®, Elan Corp., emphasize the importance of patient choice— Ireland/Biogen Idec Inc., MA) for Crohn’s related both to consent for enrolment in a trial, disease have been published in the New as well as to the need to develop mechanisms England Journal of Medicine, along with reports for involving patient volunteers in the decision- of progressive multifocal leukoencephalopathy making process when the full spectrum of risks occurring after treatment with natalizumab. This and benefits have not been fully elucidated. led the manufacturers to remove the drug from The natalizumab and infliximab examples the US market shortly after its approval for use have also taught us that enrolling in a trial in multiple sclerosis. Supplies of natalizumab might have unexpected negative outcomes, for patients receiving open-label therapy for including exclusion from subsequent trials, Crohn’s disease, even after its apparent success or subsequent benefit once the therapy is in clinical trials, were also withdrawn. For those approved by regulatory authorities. The inflixi- multiple sclerosis and Crohn’s disease patients mab example also reveals a potential issue who were benefiting from natalizumab, most of SB Hanauer is Editor- regarding informed consent—enrolment in whom had failed to respond to other agents, the in-Chief of Nature a clinical trial might preclude the volunteer option of continuing on therapy was removed. Clinical Practice from obtaining optimal benefits from the Gastroenterology & What is even worse, is that because of Hepatology. experimental agent, if and when it becomes their exposure to natalizumab and its poten- commercially available. tial long-latency effect on the development of Competing interests I am a supporter of clinical trials but the progressive multifocal leukoencephalopathy, The author declared unexpected pitfalls brought to light by these competing interests; go to these patients are now also excluded from the article online for details. events have exposed potential conflicts participating in most subsequent clinical trials. regarding benefits and risks in presenting www.nature.com/clinicalpractice This equates to a double whammy for the doi:10.1038/ncpgasthep0239 informed consent to potential volunteers.

AUGUST 2005 VOL 2 NO 8 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 337