By Barbara Tone, RN
November 15, 1999
Photo: Comstock

Seems the Food and Drug Administration can't win these days. Long criticized for slow approval times, the FDA is now under scrutiny for a record number of drug withdrawals in recent years, with some experts suggesting that the solution to the first problem may have caused the second.

Five drugs were taken off the market between September 1997 and September 1998-an unprecedented number. Before that, the most recent withdrawal was in 1992, and withdrawals were rare overall. "Many years, there were no withdrawals at all," said Thomas Moore, a health policy analyst at George Washington University, "and in a big year, maybe one."

Many question whether the drug approval process in the United States is working as well as it should. "The FDA is under increasingly sophisticated pressure from [Congress and the pharmaceutical] industry to approve more rapidly and to accept higher levels of risk," Moore said.

Others echo concerns about political pressure. "There are a lot of very dedicated people within the FDA whose first concern is for the public, but sometimes they are not making the final decisions," said Larry Sasich, PharmD, MPH, research analyst for Public Citizen's Health Research Group.

A question of speed

The debate has its roots in a law passed in 1992. That's when Congress, under pressure from both the pharmaceutical industry and AIDS activists, passed the Prescription Drug User Fee Act, which allowed the FDA to charge drug manufacturers a fee for the FDA approval process. The influx of money, reportedly $325 million over a five-year period, enabled the FDA to hire 600 additional reviewers and dropped approval times from an average of three years to an average of 12 months.

The FDA maintains that the change in approval times did not represent a lowering of standards. The FDA reviewed the five drugs withdrawn in '97-'98, looking for any correlation between the withdrawals and the decreased approval time. The findings, published in the May issue of the Journal of the American Medical Association, noted that the overall rate of drug withdrawals has remained relatively unchanged over several decades, and that two of the five drugs were approved before the 1992 changes. The authors of the study concluded that "there is no obvious thread linking these five drug withdrawals to any fundamental problem with the FDA review process itself, including increased review speeds."

The consumer group Public Citizen, however, questions the FDA assertion. In 1998, it mailed a questionnaire to 172 FDA medical officers responsible for reviewing new drug applications. Nineteen of the 53 who responded identified a total of 27 new drugs approved over a three-year period that they thought should not have been approved. Seventeen medical officers categorized the current standards as "lower" or "much lower" than three years earlier, and 12 named 25 new drugs in the preceding three years that they thought had been approved too quickly.

The FDA said this kind of disagreement comes with the territory. "My comment is that dissent is part of the robust scientific process," said Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research. "If we didn't have dissent, we would be in trouble."

Representatives of the pharmaceutical industry also believe there is no cause for alarm. "Of the 500 new medicines approved in the past 15 years, there have been about 15 products withdrawn," said Jeff Trewhitt, spokesperson for Pharmaceutical Research and Manufacturers of America (PhRMA). "The rest remain on the market, doing what they are supposed to do. The safety record is still pretty strong."

But other experts and some legislators are worried. "It can be easy to second-guess the FDA with 20/20 hindsight," said Rep. Henry Waxman, D-Calif., in a statement. "But the large number of recent drug recalls is why I and some of my colleagues have asked the General Accounting Office to investigate post-market drug safety."

Some consumer groups would like to see Congress investigate the issue. "It's been since 1992 that any congressional oversight hearings of the FDA were held," said Public Citizen's Sasich. "We can speculate all we want, but until Congress discharges its public responsibility, we won't know what changes need to be made."

Looking at benefit

But what if time is not the problem at all? "I personally think the review time issue is a red herring," said the FDA's Woodcock. "The real issue is 'what should the standards be?' If everyone is concentrating on the time issue, we aren't having substantive discussions about issues like safety databases and comparative effectiveness."

Right now, FDA effectiveness standards only require that a drug submitted for approval be more effective than a placebo. The agency doesn't try to decide whether there's a need for a second or a 50th pain medication or anti-inflammatory drug. If it is shown to be effective and safe, the FDA is obligated to approve it.

It might be time to change that, Sasich said. "We're probably at a point in the evolution of drug regulation where the bar has to be raised for the approval of drugs. We are now using laws written in 1962, when I don't think anybody anticipated there would be 20 NSAIDs and mass merchandising of these drugs," he said. "Instead of a standard that says a new drug has to be more effective than a placebo, it may be time to change the standard so that a drug has to have greater benefit than existing therapy."

Watching for problems

Methods for monitoring drugs once they're on the market are also a major concern. One problem: Funding for post-marketing surveillance has not kept pace with funding for the approval process.

Fees collected under the Prescription Drug User Fee Act help fund the approval process, but none of that money goes to monitoring the drugs after approval. With new drugs hitting the market with unprecedented speed, follow-up is a serious issue. "It is clear that more resources are needed for post-marketing surveillance," Woodcock said. The FDA has requested money in the congressional budget and is awaiting the outcome of the budget process.

Some, however, think that the funds for monitoring should come from the pharmaceutical industry. "They got an unusually good deal," said George Washington's Moore. "Why should they be allowed to contribute only to regulations that contribute to their bottom line? The nuclear and airline industries pay for the safety aspects of their industry."

Woodcock said pharmaceutical companies have balked at the idea. They see the monitoring of drugs that are already on the market as part of the FDA's enforcement responsibilities, she said. PhRMA hasn't take on a position on the issue, according to Trewhitt.

Taking it seriously

In any case, the issue of adverse drug reactions needs to be looked at in a serious and comprehensive way, according to Woodcock. "There are an estimated 100,000 deaths each year from adverse drug reactions," she said, "and it's the system as a whole that we have to work on. This problem can't be solved by saying, 'The FDA should do this.' It's really a systems problem. We have to stop looking for someone to blame and, instead, get together and talk about the problem."

An FDA task force report on risk management recently recommended a new approach to the issue. The report calls for the FDA, healthcare practitioners, the pharmaceutical industry, and consumers to work in an integrated way to deal with the growing issues involving the actions and interactions of drugs used by the American public.

"People ought to know that the FDA is working on the issue of making drugs safer," Woodcock said, "but drugs are never going to be 100 percent risk free. All any of us can do is try to minimize those risks."

In the meantime, consumer advocates advise health professionals to exercise caution when prescribing new drugs. Sasich thinks health professionals "should do a little more research than the shiny brochure given to them with a new drug."