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To those of us who have watched Huntington's Disease for more than a generation, news about actual clinical trials of potential therapies is most welcome. However, such news also carries issues concerning how such therapies can best be evaluated.
Both the just completed CARE-HD trial and the upcoming EPA trial are double-blinded, placebo controlled clinical trials. People have questioned the ethical rationale for this kind of study design. After all, if there is enough reason to expect positive efficacy of a compound or treatment to justify a clinical trial, is it fair to deny the therapy to half of the study participants?
Demonstrating efficacy of a therapy for HD is going to be exceedingly difficult. HD progresses slowly and with a highly variable presentation. The use of placebo controls is intended to provide investigators with the statistical power necessary to detect what may be subtle positive effects of the therapy being tested within a reasonable period of time. It is known from experience that uncontrolled trials do not provide such power.
Those who design clinical trials do not regard people suffering from a life-threatening disease as guinea pigs, and alternatives to placebo controls are employed whenever possible. In trials of new cancer therapies, for example, it is typical to employ the "best available therapy" as the control. Unfortunately, there is no best available therapy for HD at the present time.
Another alternative to using placebo controls is to design a clinical trial so that it is multi-armed, testing multiple potential therapies against each other; this has become the standard for trials of anti-retroviral therapy. While it complicates statistical analysis, the use of multi-armed trials provides all participants with the possibility of receiving effective therapy. It is likely that multi-armed trials will be employed as more potential therapies for HD come on line.
If investigators have enough experience with the natural history of a disease, it is possible to employ historical controls in design of clinical trials, and it has been suggested that data obtained from the control arm of the CARE-HD trial, along with knowledge obtained from the Pharos and Predict-HD studies, could be used in this fashion. However, it must be acknowledged that the use of historical controls will significantly constrain the design of clinical trials. For a clinical trial to be reliable, it is essential that participants enrolled in the treatment and control arms be evaluated using the same criteria, but diagnostic criteria evolve with advances in technology and experience. To use historical controls, disease progress of participants in the treatment arm of a clinical trial would have to be diagnosed using criteria that may not be the most sensitive available at the time that the trial is designed.
It is certainly possible that therapy for HD can be advanced through uncontrolled and historically controlled clinical trials, avoiding the ethical dilemmas inherent in the use of placebo-controlled trials. Whether that can be accomplished with speed and reliability is the challenge that confronts the HD research community and those whom they serve.
Printed: 10 Sep 2010
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Article posted to www.hdac.org on: 06-12-2001