Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice

Richard A. Deyo, MD, MPH


J Am Board Fam Med. 2004;17(2) 

In This Article

Pressures for Approval

Perhaps the biggest challenge and source of friction for the FDA is the speed of approvals for drugs and devices. Protecting the public from ineffective or harmful products would dictate a deliberate, cautious, thorough process. On the other hand, getting valuable new technology to the public—to save lives or improve quality of life—would argue for a speedy process. Some consumer protection groups claim the agency is far too hasty and lenient, bending to drug and device company pressure. On the other hand, manufacturers argue that the agency drags its feet and kills people waiting for new cures. Says Kessler: "That's been the biggest fight between the industry, the Congress, and the FDA over the past decade: getting products out fast" (L. Kessler, personal communication).

To speed up the review process, Congress passed a law in 1992 that allowed the FDA to collect "user fees" from drug companies. This was in part a response to AIDS advocates, who demanded quick approval of experimental drugs that might offer even a ray of hope. These fees, over $300,000 for each new drug application, now account for about half the FDA's budget for drug evaluation, and 12% of the agency's overall $1.3 billion budget.[18]

The extra funds have indeed accelerated the approval process. By 1999, average approval time had dropped by about 20 months, to an average of a year. In 1988, only 4% of new drugs introduced worldwide were approved first by the FDA. By 1998, FDA was first in approving two thirds of new drugs introduced worldwide. The percentage of applications ultimately approved had also increased substantially.[18] Nonetheless, industry complained that approval times slipped to about 14 months in 2001.[19] In 2002, device makers announced an agreement with the FDA for similar user fees to expedite approval of new devices, and Congressional approval followed with the Medical Device User Fee and Modernization Act.[20]

Critics, such as 2 former editors of the New England Journal of Medicine, argue that the user fees create an obvious conflict of interest. So much of the FDA budget now comes from the industry it regulates that the agency must be careful not to alienate its corporate "sponsors."[21] FDA officials believe they remain careful but concede that user fees have imposed pressures that make review more difficult, according to The Wall Street Journal.[22]

An internal FDA report in 2002 indicated that a third of FDA employees felt uncomfortable expressing "contrary scientific opinions" to the conclusions reached in drug trials. Another third felt that negative actions against applications were "stigmatized." The report also said some drug reviewers stated "that decisions should be based more on science and less on corporate wishes."[22] The Los Angeles Times reported that agency drug reviewers felt if drugs were not approved, drug companies would complain to Congress, which might retaliate by failing to renew the users' fees[18] (although they were just reapproved in summer, 2002). This in turn would hamstring FDA operations and probably cost jobs.

Another criticism is that the approval process has allowed many dangerous drugs to reach the market. A recent analysis showed that of all new drugs approved from 1975 to 1999, almost 3% were subsequently withdrawn for safety reasons, and 8% acquired "black box warnings" of potentially serious side effects. Projections based on the pace of these events suggested that 1 in 5 approved drugs would eventually receive a black box warning or be withdrawn. The authors of the analysis, from Harvard Medical School and Public Citizen Health Research Group, suggested that the FDA should raise the bar for new drug approval when safe and effective treatments are already available or when the drug is for a non-life-threatening condition.[2]

According to The Los Angeles Times, 7 drugs withdrawn between 1993 and 2000 had been approved while the FDA disregarded "danger signs or blunt warnings from its own specialists. Then, after receiving reports of significant harm to patients, the agency was slow to seek withdrawals." These drugs were suspected in 1002 deaths reported to FDA. None were life-saving drugs. They included, for example, one for heartburn (cisapride), a diet pill (dexfenfluramine), and a painkiller (bromfenac). The Times reported that the 7 drugs had US sales of $5 billion before they were recalled.[18]

After analysis, FDA officials concluded that the accelerated drug approval process is unrelated to the drug withdrawals. They pointed out that the number of drugs on the market has risen dramatically, the number of applications has increased, and the population is using more medications.[3] More withdrawals are not surprising, in their view. Dr. Janet Woodcock, director of the FDA's drug review center and one of the analysts, argued that "All drugs have risks; most of them have serious risks." She believes the withdrawn drugs were valuable and that their removal from the market was a loss, even if the removal was necessary, according to The Los Angeles Times.[18]

Nonetheless, many believe the pressures for approval are so strong that they contribute to employee burn-out at FDA. In August 2002, The Wall Street Journal reported that 15% of the agency's medical officer jobs were unfilled.[22] Their attrition rate is higher than for medical officers at the National Institutes of Health or the Centers for Disease Control and Prevention. The Journal reported that the reasons, among others, included pressure to increase the pace of drug approvals and an atmosphere that discourages negative actions on drug applications. Attrition caused by employee "burn-out" is now judged to threaten the speed of the approval process. In 2000, even Dr. Woodcock acknowledged a "sweatshop environment that's causing high staffing turnover."[18] FDA medical and statistical staff have echoed the need for speed and described insufficient time to master details.[18,19]

An opposing view of FDA function is articulated in an editorial from The Wall Street Journal, by Robert Goldberg of the Manhattan Institute. He wrote that the agency "protects people from the drugs that can save their lives" and needs to shift its role to "speedily put into the market place... new miracle drugs and technologies.... " He argues that increasing approval times for new treatments are a result of "careless scientific reasoning" and "bureaucratic incompetence," and that the FDA should monitor the impact of new treatments after marketing rather than wait for "needless clinical trials" that delay approvals.[23]

Thus, the FDA faces a constant "damned if it does, damned if it doesn't" environment. No one has undertaken a comprehensive study of the speed of drug or device approval to determine the appropriate metrics for this process, much less the optimal speed. It remains unclear how best to balance the benefits of making new products rapidly available with the risks of unanticipated complications and recalls.