On June 11 2005, a news article in _The Lancet_ reported on the court case of two patients with Parkinson's disease who had been enrolled in a phase II trial of glial-cell-line-derived

neurotrophic factor (GDNF) and were suing Amgen, the drug manufacturer. Amgen had discontinued the trial because of safety concerns identified in monkeys that had received infusions of GDNF

and later developed cerebellar lesions. The patients claimed that they had reductions in tremors and no safety issues, and asked the court to prevent Amgen from withholding treatment. The

report highlighted the “...lack of a suitable mechanism through which evidence from individuals can be taken into account in decision-making about experimental treatments...” and that

Medicine_, along with reports of progressive multifocal leukoencephalopathy occurring after treatment with natalizumab. This led the manufacturers to remove the drug from the US market

shortly after its approval for use in multiple sclerosis. Supplies of natalizumab for patients receiving open-label therapy for Crohn's disease, even after its apparent success in

clinical trials, were also withdrawn. For those multiple sclerosis and Crohn's disease patients who were benefiting from natalizumab, most of whom had failed to respond to other agents,

the option of continuing on therapy was removed. > ...the unexpected pitfalls brought to light by these events have > exposed potential conflicts regarding benefits and risks in > 

presenting informed consent... What is even worse, is that because of their exposure to natalizumab and its potential long-latency effect on the development of progressive multifocal

leukoencephalopathy, these patients are now also excluded from participating in most subsequent clinical trials. This equates to a double whammy for the patients who volunteered for these

clinical trials: discontinuation of a helpful therapy and exclusion from trying other potential new therapies. Another example of potential 'harm' from enrolling in a clinical

trial pertains to patients who volunteered for early trials of infliximab (Remicade®, Centocor Inc., PA/Schering-Plough Corp., NJ) for Crohn's disease. Volunteers entering the Phase I

and II trials who received only a single infusion or an induction series of three infusions were not eligible for subsequent, open-label dosing. When these individuals were re-exposed to

infliximab after 6–24 months, it became apparent that the initial dosing regimens were actually priming the patients for the development of immunogenicity (antibodies to infliximab), with

the potential for delayed hypersensitivity reactions, acute infusion reactions, and/or eventual loss of response to the otherwise highly efficacious monoclonal antibody. The GDNF and

natalizumab examples emphasize the importance of patient choice—related both to consent for enrolment in a trial, as well as to the need to develop mechanisms for involving patient

volunteers in the decision-making process when the full spectrum of risks and benefits have not been fully elucidated. The natalizumab and infliximab examples have also taught us that

enrolling in a trial might have unexpected negative outcomes, including exclusion from subsequent trials, or subsequent benefit once the therapy is approved by regulatory authorities. The

infliximab example also reveals a potential issue regarding informed consent—enrolment in a clinical trial might preclude the volunteer from obtaining optimal benefits from the experimental

agent, if and when it becomes commercially available. I am a supporter of clinical trials but the unexpected pitfalls brought to light by these events have exposed potential conflicts

regarding benefits and risks in presenting informed consent to potential volunteers. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Editor-in-Chief of Nature Clinical Practice

Gastroenterology & Hepatology, Stephen B Hanauer Authors * Stephen B Hanauer View author publications You can also search for this author inPubMed Google Scholar ETHICS DECLARATIONS

COMPETING INTERESTS The author declares that he has received clinical research support from Abbott Labs, Ashahi, Celltech, Centocor, Elan, Genentech, Otsuka, Procter & Gamble, Protein

Design Labs and Prometheus Laboratories. He has acted as a consultant for Abbott Labs, Ashahi, Celltech, Centocor, Elan, Ferring, Genentech, Otsuka, Procter & Gamble, Protein Design Labs

and Shire. He is a speaker for Centocor and Procter & Gamble. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hanauer, S. Novel potential perils of

volunteering for clinical trials. _Nat Rev Gastroenterol Hepatol_ 2, 337 (2005). https://doi.org/10.1038/ncpgasthep0239 Download citation * Issue Date: 01 August 2005 * DOI:

https://doi.org/10.1038/ncpgasthep0239 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative