Leading Doctor Cites Obesity Drugs in Attack on FDA Approval Process
A leading physician, writing in one of the world's most influential medical journals, cited the 1990s diet drug fenfluramine and the new anti-obesity drug rimonabant in an article charging that the U.S. Food and Drug Administraton approves drugs based on "a minimal standard that would be unacceptable anywhere else in research."
Dr. Jerry Avorn, of Harvard Medical School and Brigham and Women's Hospital in Boston, wrote in the Sept. 8 issue of the New England Journal of Medicine that the FDA is single-mindedly preoccupied with "proving that a new medication is superior to a usually irrelevant comparison treatment (such as placebo) in achieving a potentially irrelevant outcome."
Avorn expressed particular concern over the approval process for "the most lucrative kind of medications: those taken for extended periods by huge numbers of basically healthy people. Such 'lifestyle' drugs may initially be evaluated for the treatment of a real clinical problem, such as severe obesity, but there may be no clear consensus defining the 'mild' end of the disease–nondisease continuum."
"As a result, the market can be cranked up by aggressive promotion to both patients and prescribers," Avorn wrote.
He argued that in the case of these drugs, "the comparison of a drug's benefits and risks is vitally important, but the government generally does not require such assessment.
"The most notorious example of an appetite-control drug that the FDA deemed good enough for approval was dexfenfluramine (Redux), the d-isomer of the decades-old, minimally effective fenfluramine that became part of the fen–phen diet-pill craze of the late 1990s," Avorn wrote. "Fenfluramine was known to cause pulmonary hypertension that could be fatal, and its d-isomer was expected to do so as well.
"But despite this risk, the drug was approved in light of the supposedly more worrisome epidemic of obesity that it might help to thwart. What were the medication's credentials? In its pivotal preapproval trials, patients randomly assigned to receive dexfenfluramine lost an average of about six pounds more than those assigned to placebo. No meaningful improvement was demonstrated in blood pressure, lipid levels, or glycemic control. But the costly product worked better than nothing at the P<0.05 level, and it was therefore approved.
"Practitioners and "pill mills" throughout the country then used it to treat millions of women who wanted to shed a few pounds for cosmetic reasons. The expected pulmonary hypertension complications occurred, as did an unanticipated side effect, cardiac valvulopathy. The blockbuster was withdrawn from the market in its first year of use.
"We now await the FDA's review of rimonabant (Acomplia), the first endocannabinoid-receptor inhibitor to be brought before it. The drug is said to reduce appetite, lipid levels, and the desire to smoke.
"If its manufacturer seeks an antiobesity indication, the agency may well use its favored criterion: modestly greater weight loss than that achieved with placebo, even if it is only temporary.
"Patients who took the drug in controlled trials had higher rates of withdrawal because of neuropsychiatric and gastrointestinal disorders than did control subjects.1 But if the FDA applies its usual standards, the drug could be on the market despite these problems," Avorn concluded.
Avorn recommended that "the approvability of a drug should take into account whether its risks are acceptable in light of its real-world effectiveness.
"This would require evaluating clinical benefit by means of a more relevant measure than short trials with surrogate outcomes. It would also require consideration of a drug's efficacy and safety as compared with alternative therapies. If such studies are not required as part of the approval process, it seems that we don't have any way to ensure that they are ever conducted; as a result, they usually are not," Avorn added.
The FDA declined to comment on the article, according to agency spokeswoman Christine S. Parker.