TCS Daily

Should the FDA Always 'Err on the Side of Safety'?

By Henry I. Miller - July 20, 2005 12:00 AM

These are turbulent times for the FDA. The almost daily barrage of negative headlines questioning the safety of marketed drugs is likely depleting regulators' individual stocks of aspirin and antacids. But as they try to soothe their own pain, regulators must not forget their mission -- to ease the plight of patients who need new medicines.

Past criticism of FDA mostly concentrated on what arguably remains the agency's most important shortcoming: the delays and escalating expense of getting drugs through the development pipeline and into the marketplace. Lately, however, events have shifted the focus to issues of safety. First there were claims that the labeling of certain antidepressants failed to warn doctors that the drugs caused some adolescents to commit suicide. Then the agency was blind-sided by contamination that made half the nation's flu vaccine supply unavailable. Finally, there were revelations about previously unknown side effects of several widely prescribed anti-inflammatory analgesic drugs.

Regulators' increasing sensitivity to safety concerns may have become contagious: Drug manufacturers, too, seem to have begun to "err on the side of safety" to a degree that causes safe and effective drugs to be taken off the market voluntarily.

Consider Tysabri, only the sixth medication approved -- and the first in several years -- for the treatment of Multiple Sclerosis (MS), a debilitating autoimmune disease that affects the central nervous system. The stunning results of the drug's testing in clinical trials -- the frequency of clinical relapses was cut by more than half -- induced FDA to grant accelerated approval last fall. MS patients eagerly put their names on waiting lists to get the medicine.

But this ray of hope for MS sufferers was short-lived. By the time that several thousand patients were being treated with Tysabri, three confirmed cases of a rare neurological disorder caused by a virus were reported. (Because the drug suppresses certain aspects of the immune response, regulators, clinicians and the drug'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 medicine voluntarily halted production and distribution and withdrew Tysabri from the market. MS victims and many neurologists were bitterly disappointed. Now they can only hope that a comprehensive review that is under way of all the clinical data -- including the results of new diagnostic tests being conducted on Tysabri recipients -- will permit a return of the drug to the market.

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. Regulators' judgments require a global and often difficult calculation of risk and benefit, including consideration of what alternative therapies are available. We would tolerate greater uncertainty and more severe side effects for a potential cure for pancreatic cancer or AIDS, for example, than for treating heartburn. When FDA grants marketing approval, the drug is deemed to be safe and effective for the conditions on the label.

In the current climate of litigiousness and antipathy to big companies, one can understand the haste to withdraw Tysabri voluntarily from the market. What is also understandable (and lamentable) is the chattering classes' hyping of the drug's health concerns and of the stock market impacts of the withdrawal, while ignoring that real people who were able to lead more normal lives with Tysabri are now prevented from obtaining it.

Another casualty of the withdrawal is the ability of patients, after consultation with their health care providers, to make informed decisions about possible treatment options. That fundamental right should not be usurped by risk-averse, publicity-shy bureaucrats, anti-FDA healthcare activists, or members of Congress.

As more breakthrough drugs come before FDA for approval, the agency must curb its paternalistic instincts and find a way to balance more sensibly the assurance of safety with patients' right to assume responsibility for their own medical decisions. This would be a sea change for FDA, which in many areas -- "off-label" prescribing, and dissemination of new information about drug therapy, among others -- has sought repeatedly to limit the discretion of physicians and patients to make treatment decisions.

To this point, FDA has been even-handed in its treatment of Tysabri. The clinical data justified the accelerated approval; the ongoing analysis of safety data is a responsible action; and if the data support it, FDA should work with Tysabri's producers to move rapidly toward reintroduction of the drug. Labeling restrictions, such as a prominent "black box" warning or strict limitations on which patients can receive a drug, are "risk-management" options within FDA's purview. In any case, the agency's actions must be driven by the data.

The notion that FDA should "err on the side of safety" must be qualified for 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 FDA must err, it should be on the side of patients' freedom to choose.

Henry I. Miller, a physician and fellow at the Hoover Institution and Competitive Enterprise Institute, headed the FDA's Office of Biotechnology from 1989-1993. His most recent book," The Frankenfood Myth," was chosen by Barron's as one of the 25 Best Books of 2004.

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