Stanford Report, March 15, 2006

Letters

To the Editor:

Readers of the March 8 article "Could deaths in clinical trials have been avoided?" may be left with a serious misunderstanding of the issues. The article concerns a sometimes-fatal viral brain infection, PML, which developed in three of about 3000 patients taking a new medication for multiple sclerosis. The medication (Tysabri, or natalizumab) was voluntarily withdrawn by the manufacturer, but an FDA advisory panel has recently recommended that it be marketed again, with precautions.

The article quotes my colleagues, Lawrence Steinman, MD, and Annette Langer-Gould, MD, who "warn of the pitfalls of testing a drug with unknown side effects in patients who would do fine without it." Two issues deserve clarification. By the time a medication has passed Phase 1-3 testing and is marketed, its side effects are not unknown, but they are often incompletely known. In part, this is because the safety testing has not involved sufficient numbers of patients to detect all potentially serious but infrequent complications. It is the FDA-mandated post-marketing surveillance system that is intended to identify such rare complications. The way to strengthen this process is to demand larger numbers in the safety trials and to make post-marketing surveillance more rigorous.

The second issue is that the course of MS is notoriously difficult to predict. It is well established that the disease may re-activate after long periods of quiescence and may be subclinically active even when the patient is asymptomatic. Hence, no patient can be assured that they will "do fine." Moreover, no treatment is able to reverse the long-term neurologic disability that often develops. Like many sufferers from chronic illness, MS patients are usually well-informed about their condition and understand the importance of long-term prophylactic suppressive treatment to keep the disease in check. For some—probably a small proportion—this might even involve a 1:1000 risk of a fatal complication. It is our role to help educate our patients so that they understand the risk: benefit ratio in any proposed treatment, and, together with the patient, to consider and decide on the best course for that particular individual.

Les Dorfman, MD

Professor of neurology and neurological sciences

Director, Stanford Multiple Sclerosis Clinic