The Rule rather than the Exception

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  • 03/02/2006

CMPI advisory board member Henry Miller on the troubles with Tysabri …

March 2, 2006

Paternalism Costs Lives

Decisions about drug safety and efficacy are far from easy. Tysabri, a multiple sclerosis (MS) drug that was voluntarily withdrawn from the market last year after the appearance of a previously unknown side effect, illustrates some of the conundrums.

In advance of the publication of three critical new studies on Tysabri in this week’s issue of the New England Journal of Medicine, a major news organization recently asked me, as a physician and former FDA official, whether I knew of examples of prescription drugs that have “efficacy but [also] serious safety issues.” That is, I responded, the rule rather than the exception.

Obvious examples include the antimetabolites used for traditional chemotherapy. Because these drugs are no more than poisons administered in a way intended to be more toxic to cancer cells than normal ones, it is not surprising that their side effects are often serious and even life-threatening. When I was a medical resident three decades ago, hospital gallows humor included referring to BCNU, an experimental cancer drug, as “Be seein’ you.” Approved in 1977, it is still widely used.

A more recent example is aldesleukin, a drug that has offered new hope to victims of kidney cancer and malignant melanoma. It is highly effective in a small proportion of patients but exhibits significant toxicity. The patient information booklet warns that those taking the drug “frequently experience serious, life-threatening or fatal adverse events,” including dangerously low blood pressure and reduced organ perfusion, impaired function of infection-fighting white blood cells, disseminated infection and autoimmune disease.

Antibiotics are another class of wonder drugs that sometimes manifest significant toxicity. Chloramphenicol, a drug that is effective against a wide spectrum of bacterial infections, causes rare cases of fatal aplastic anemia, so it is used only sparingly. The potent antibiotic gentamicin is often lifesaving but can cause damage to the kidneys, nerves and ears. And significant numbers of patients are allergic to other important antibiotics, including the penicillins and cephalosporins.

But let us return to Tysabri, only the sixth medication approved — and the first in several years — for the treatment of MS, a common and debilitating autoimmune disease that affects the central nervous system. The impressive results of the drug’s testing in clinical trials — the frequency of clinical relapses reduced by more than half — induced the FDA to grant accelerated approval in 2004. By the time that several thousand patients were being treated with Tysabri, however, three had contracted progressive multifocal leukoencephalopathy (PML), a rare neurological disorder caused by a virus. (Because the drug suppresses certain components of the immune response, regulators, clinicians and the product’s developers had from the beginning been sensitive to the possibility of infections as a side effect.) Immediately — some would say prematurely — the manufacturers of the drug voluntarily halted production and distribution and withdrew Tysabri from the market. MS patients and many neurologists were bitterly disappointed.

The three clinical studies reported this week in the New England Journal of Medicine bolster our confidence about the safety and efficacy of Tysabri. In a study of almost a thousand patients that compared Tysabri to placebo, the drug cut the rate of clinical relapses by 68% (to 0.24 from 0.75), reduced by 83% the number of new or expanding brain lesions found on MRI, and slowed the clinical progression of disease. (The other currently used drugs for MS lower the occurrence of acute relapses by roughly one-third.) Similar results were obtained in a second trial which compared two-drug therapy with Tysabri plus interferon beta-1a to the interferon alone.

Finally, a third study found no additional cases of PML in more than 3,000 patients (exposed to an average of 17.9 monthly doses) who had participated in clinical trials of Tysabri. The investigators concluded that the incidence of this serious side effect is approximately one in a thousand patients treated with the drug. However, it should be noted that all three of the original cases of PML occurred in patients treated with interferon beta or other immunosuppressive agents in addition to Tysabri, so the risk might be significantly lower in patients treated with Tysabri alone.

The “safety” of a drug is a relative thing. Safety and efficacy, the two criteria required for marketing approval of a drug, are inextricably linked. The judgments of regulators (and practicing physicians) require a global and often difficult calculation of risk and benefit, including consideration of what alternative therapies are available. For a given drug, we are willing to tolerate greater uncertainty and more severe side effects for a potential cure for pancreatic cancer or AIDS, for example, than for a new drug that treats heartburn. When FDA grants marketing approval, the drug is deemed to be sufficiently safe and effective to be used for the conditions on the label.

In light of the just-published data — to which the FDA should have had access months ago — it is clear that this drug belongs back on the market, probably with new warnings about PML in the labeling.

The notion that the FDA should “err on the side of safety” sounds like a tautology but is an affront to patients with incurable or poorly treatable diseases: For them, there is no safety in the status quo, and we only damage them further with paternalistic public policy that prevents individuals from exercising their own judgment about risks and benefits. If the FDA must err, it should be on the side of patients’ freedom to choose.

Mr. Miller, a physician and fellow at the Hoover Institution, headed the FDA’s Office of Biotechnology from 1989 to 1993.


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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