The Food and Drug Administration's withdrawal from the market of two widely used diet drugs has spurred calls to give the agency broader regulatory powers. The discovery of dozens of cases of unusual abnormalities in heart valves of patients taking a combination of weight-loss drugs known as "fen-phen" (fenfluramine and phentermine) is worrisome, to be sure. But there are both alternative explanations for the heart problems and alternative actions the FDA could have taken, short of asking for the recall of fenfluramine and its close analogue, dexfenfluramine. (Phentermine remains on the market.)
For example, because most of the reported cardiac problems involve the fen-phen combination, it is possible that fenfluramine by itself is safe. And, as all of the affected patients are obese, it is possible that some of the abnormalities are due not to the drugs, but to obesity itself. We will have some answers within the next few weeks. American Home Products, the manufacturer of the withdrawn drugs, quickly organized a national study to examine the heart valves in 1,200 patients--400 who have taken dexfenfluramine, 400 who have taken the fen-phen combination and a 400-patient control group, matched by age, weight and other demographic characteristics to the patients in the other groups.
In the meantime, the FDA's concern is warranted. More than nine million prescriptions were written for fenfluramine and dexfenfluramine in 1996 alone. But what action is appropriate?
In July, immediately after the first reports of cardiac-valve disease, the FDA sent out a Public Health Advisory that described the findings and reminded physicians that the drugs "were approved more than 20 years ago as individual agents for short-term use." This should have dramatically reduced the use of the fen-phen combination. In the absence of extenuating circumstances, any physician who thereafter prescribed the combination and caused damage to a patient would arguably be guilty of malpractice.
Newly discovered side effects in drugs on the market are common, and the FDA has an array of options for addressing them. In the fen-phen case, the agency could have changed the drugs' labeling both to prohibit their use in combination and to limit their use to cases of "morbid obesity," in which the patient is more than double his ideal weight and subject to life-threatening complications. The FDA could also have required a prominent warning about possible side effects to all patients receiving either drug.
A recall may seem the most prudent course, but similar drastic actions in the past have proved profoundly damaging. A prominent example was the FDA's premature action on silicone breast implants. Studies subsequently failed to show a strong association between the implants and connective tissue diseases, and actually presented evidence of some protection from breast cancer. But the agency's headline-making decision to remove the implants from the market terrified thousands of women, fostered spurious litigation, drove Dow Corning into bankruptcy and interrupted the availability of silicone for other essential medical applications.
A lesser-known case, in 1993, is potentially even more calamitous. It arose from the discovery that fialuridine, a drug for hepatitis, actually made the disease worse (this had been difficult to ascertain because the side effects resembled the usual progression of the illness). The FDA hastily drafted a new regulation to require that clinical researchers report side effects more quickly and that they presume that a new drug is to blame anytime a patient gets sick or sicker during a study. Yet careful analyses by the National Institutes of Health and the National Academy of Sciences found that the existing system of clinical safeguards had worked effectively to identify and call proper attention to fialuridine side effects.
The FDA's new regulation reconfigured the burden of proof so that all new drugs are now considered harmful until conclusively proven safe. The agency created an arbitrary and significantly lower regulatory threshold for stopping a clinical trial, making the entire drug-development process unnecessarily risk-averse, slower and more expensive.
The responses from academia and industry illustrate the negative effects of this regulation. The DuPont-Merck Pharmaceutical Co. estimated that its reporting burden doubled for each prospective drug in development. Amgen Inc. described the substantial practical difficulties of estimating the expected incidence of death and serious adverse events that arise not from the drug, but from underlying disease or concomitant medications. Medical researchers at the Johns Hopkins University's Center for Clinical Trials meticulously compared two clinical trials, one performed according to the old regulations and one under the new, and found that the new requirements cost $24 million more--with no commensurate advantage to patients. (Already the FDA had pushed the average cost of developing a drug from $359 million to more than $500 million between 1990 and 1993.)
Regulators' decisions are difficult. They affect human lives, the viability of companies and the vulnerability of physicians to illegitimate malpractice claims. They sometimes must be made on the basis of incomplete data, under time pressure and in the glare of media attention. The challenge is to ensure public safety with minimum interference in personal choices and the marketplace. In many cases, the FDA has failed to rise to that challenge, and the costs have been high.
Dr. Miller is a senior research fellow at the Hoover Institution and author of "Policy Controversy in Biotechnology: An Insider's View" (Academic Press, 1997). He was an FDA official from 1979 to 1994.
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