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VIEWS & REVIEWS: Ying Kuen Cheung, Paul H. Gordon, and Bruce Levin Selecting promising ALS therapies in clinical trials Neurology 2006; 67: 1748-1751 [Abstract] [Full text] [PDF]

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Selecting promising ALS therapies in clinical trials

Jonathan D. Glass, Michael Benatar, Meraida Polak   (14 January 2007)

Reply from the Authors

Ying Kuen Cheung, Paul H Gordon and Bruce Levin   (14 January 2007)

Selecting promising ALS therapies in clinical trials 14 January 2007
Jonathan D. Glass, Emory University ALS Center 615 Michael Street, Atlanta, GA 30322, Michael Benatar, Meraida Polak Send Correspondence to journal: Re: Selecting promising ALS therapies in clinical trials jglas03{at}emory.edu Jonathan D. Glass, et al.	The article by Cheung et al [1] leaves out a very important aspect of "selection of promising ALS therapies for clinical trials." They discuss methodology but do not address how we choose drugs for trial or what types of pre-clinical data should be required before testing a new treatment in humans. Their hypothesis is that past trials may have been negative because the trials did not include multiple drugs that might affect multiple mechanisms of disease. It is possible. However, another possibility is that the choice of drug (or drugs) for these trials was based on prior therapeutic success in an animal model of ALS (the SOD1-ALS mouse). The translation of a drug treatment in mice into an effective therapy for humans requires a number of assumptions. The first is that the SOD1 mouse, which really represents a model of SOD1-related familial ALS, adequately models sporadic ALS. The second is that success in the mouse based on presymptomatic initiation of therapy is relevant to the human scenario in which therapy is instituted after the onset of disease. A third assumption is that we understand the complexities of pharmacokinetics in both mouse and man and know how to select the appropriate dose and route of administration for human studies based on experience in the mouse. Even though trial design is important, we believe it is equally important to reassess how we choose drugs for trial and how we select the patient populations in which to try them. Reference 1.Cheung YK, Gordon PH, Levin B. Selecting promising ALS therapies in clinical trials Neurology 2006; 67: 1748-1751. Disclosure: The authors report no conflicts of interest.
Reply from the Authors 14 January 2007
Ying Kuen Cheung, Columbia University 722 West 168th Street, Room 641, New York, NY 10032, Paul H Gordon and Bruce Levin Send Correspondence to journal: Re: Reply from the Authors yc632{at}columbia.edu Ying Kuen Cheung, et al.	We thank Dr. Glass and his colleagues for their comments and agree that choosing the right drugs for clinical trials is an important aspect for the eventual success of phase III clinical trials. On this topic, readers may find a recent assessment of neuroprotective agents for clinical trials in ALS interesting. [2] Given the space limitations, our article focused on selecting the right drugs in clinical trials, and our objective was to review trial designs that would allow efficient drug selection for phase III trials in the presence of a large number of possible candidates. Regarding choice of appropriate dose for human studies, for example, the continual reassessment method reviewed in our article is a very efficient dose-finding design that can zero in on the right dose quickly in phase I human trials, even if the correspondence between pharmacokinetics in mice and that in humans is not perfectly understood. Reference 2. Traynor BJ, Bruijn, L, Conwit R, et al. Neuroprotective agents for clinical trials in ALS: A systematic assessment. Neurology 2006;67:20-27. Disclosure: The authors report no conflicts of interest.