FDA Standards – Good Enough for Government Work?

FDA Standards – Good Enough for Government Work?

Fri, 23 Sep 2005

An essay in The New England Journal of Medicine, by Jerry Avorn, M.D., professor of medicine at Harvard Medical School and chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital, chalolenges FDA’s “minimalist” drug approval process. Dr. Avorn argues that unlike in any other area of biomedicine, “the government allows – even defends – a minimal standard that would be unacceptable anywhere else in research.”

He challenges the FDA’s extraordinarily low standard of evidentiary requirements for the approval of new drugs, likening the agency’s “single-minded” preoccupation with “the meticulous performance of a series of relatively simple acts” to a patient with obsessive-compulsive disorder. The agency “is single-mindedly preoccupied with demanding – proving that a new medication is superior to a usually irrelevant comparison treatment (such as placebo) in achieving a potentially irrelevant outcome (such as a surrogate measure)”–instead of looking at clinically important criteria for evaluating a drug’s safety and benefit.

Dr. Avorn cites the approval criteria for several of the most lucrative drugs that were tested in a small number of people with “a real clinical problem” but aggressive promotion resulted in such drugs being taken by millions of people for extended periods who do not have a clinical problem, but rather use such drugs for mere cosmetic, or “life-style” enhancemnt. Some of these drugs turned out to be lethal.

For example, diet-pills such as dexfenfluramine (fen-phen) was approved on the basis of a trial in which patients were randomly assigned to placebo–those on the drug lost 6 lbs more than those on placebo. However, the drug “was known to cause pulmonary hypertension that could be fatal, and its d-isomer was expected to do so as well.” Despite this risk, the drug was approved on the basis of placebo contolled trials in which patients randomly assigned to receive dexfenfluramine lost an average of about six pounds more than those assigned to placebo. However, “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."

Similarly, sleeping pills that are widely used by millions of people who are not sick, have been approved on the basis of brief sleep laboratory studies using one or two night assessments. But, as Dr. Avorn points out, these drugs pose serious risks: “they can cause next-day drowsiness, cognitive impairment, and an increased risk of falling, especially among older patients who are their most frequent users. How does one weigh these very real risks against benefits defined in the sleep laboratory, especially in the case of long-term use? How much better will the new agents be than their predecessors in terms of these clinically relevant matters? The FDA’s usual trial standards ignore these questions, and comparative studies of different agents are not part of the evaluation process.”

To determine whether a drug is safe enough for clinical use, requires “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.”

Dr. Avorn correctly points out, “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.”

Achieving acceptable drug safety evaluation standards is perfectly feasible, it’s a matter of political will to put the public health first, commercial considerations second.

The article, FDA Standards – Good Enough for Government Work?– appears in the September 8 isue of the NEJM,

Contact: Vera Hassner Sharav
212-595-8974