Medications Approved by FDA Under Deadlines Set by Congress More Likely To Have Safety Problems Later, NEJM Study Finds

Prescription drugs that receive FDA approval shortly before the deadline for deciding on new drug applications are more likely to have safety issues than those that are given additional time and scrutiny, according to a study published Thursday in the New England Journal of Medicine, the Wall Street Journal reports.

Currently, FDA promises to reach a decision on 90% of new drugs within 10 months after an application is submitted, and within six months for so-called priority drugs. According to the Journal, the approval schedule has "substantially cut" FDA review times from an average of 33 months in 1991 to 19 months in 2001. While no law requires FDA to meet the deadline, Congress has linked periodic reauthorization of the agency's authority to collect user fees from drug makers to its performance in meeting the deadlines. User fees account for about half of the $680 million FDA will spend on new drug reviews this year.

According to the study -- led by Daniel Carpenter, a professor of government at Harvard University -- of the 313 drugs FDA approved between 1993 and 2004, 97 were approved within two months of the deadline. Those 97 drugs had a 14% rate of severe safety problems, compared with 3% of the other 216 drugs. In addition, drugs approved near the deadline were more than four times as likely to be withdrawn from the market because of safety issues or to require a "black box" warning on the label years after approval, the study found. Of the 21 drugs that were withdrawn or received black box warnings since 1993, 14 were approved within two months of the deadline.

Reaction
Carpenter said that it is impossible to determine whether FDA rushed to make a decision on any of the drugs or whether the deadlines led to later safety problems. He said, "You can't point to any single case and say, 'Well, an extra two months would have made the difference.'" However, he questioned whether tying the deadlines to user fees was the best way to speed drug approvals, adding, "Congress would be much better off relying less upon these deadlines and relying more on a big increase in full-time employees" (Winstein, Wall Street Journal, 3/27).

Steven Nissen of the Cleveland Clinic called the analysis a "wake-up call," saying, "It puts the FDA in a very difficult situation when they're trying to make complex decisions under these very, very tight deadlines." He added, "We've got to re-evaluate now whether that's good public policy" (Neergaard, AP/Philadelphia Inquirer, 3/27).

FDA said its own database of drug approval times differed from Carpenter's. The agency said it is sending a detailed letter to NEJM to dispute the results of the analysis. In a statement, Janet Woodcock, the agency's drug evaluation director, dismissed the suggestion that the deadlines affect drug safety. Woodcock said, "FDA won't approve a drug if we're not ready," adding that deadlines are "guidelines." FDA spokesperson Christopher DiFrancesco said that John Jenkins, an agency official who directs new drug reviews, earlier this year "authorized our managers to miss" a deadline "if that needs to happen" (Wall Street Journal, 3/27).

An abstract of the study is available online.

American Public Media's "Marketplace" on Wednesday reported on the study. The segment includes comments from co-author Jerry Avorn of Harvard Medical School, Clark Nardinelli of FDA and Les Funtleyder of Miller Tabak (Babin, "Marketplace," American Public Media, 3/26). Audio and a transcript of the segment are available online.

FDA Overhaul
In related news, FDA Commissioner Andrew von Eschenbach on Wednesday at a Food and Drug Law Institute conference said that the agency is facing difficulties and a shortage of resources as it works to implement changes approved by Congress last year, CongressDaily reports. He said that a provision of the law that requires FDA to make quicker decisions on applications for generic drugs will cause problems, adding, "In order to meet that deadline, this will require effort, or additional effort, but the legislation did not come with additional resources for that additional effort, so as a result, FDA has to reprioritize within existing resources and risk not meeting existing current responsibilities."

The provision applies to petitions brand-name drug companies file when a generic drug maker seeks approval of a lower-cost version of a drug. Lawmakers were concerned that many petitions were filed as a way to delay generic drug approval. Under the new law, FDA must provide a response to the petitions within 180 days, which von Eschenbach called "a substantial decrease" from the agency's average response time. Von Eschenbach would not elaborate on how the agency plans to reprioritize existing resources.

According to CongressDaily, the agency "is moving steadily on other provisions in the bill," including measures intended to better balance the focus on drug approval with consumer experience after a drug reaches the market. FDA also released a list of 16 approved drugs that already take special precautions and must submit risk mitigation proposals to comply with the new law by Sept. 21 (Edney, CongressDaily, 3/26).

Opinion Piece
Mismanagement and adherence to "flawed policies and programs are some of the FDA's most severe problems, and merely throwing more resources at the agency is likely only to give us more of the same," Henry Miller, an FDA official from 1979 to 1994 and a current physician and fellow at Stanford University's Hoover Institution, writes in a Washington Times opinion piece. Miller, citing a recent interview in the Journal with von Eschenbach, writes, "If Dr. von Eschenbach were willing to trim, revise or eliminate programs that are ill-conceived and counterproductive, he would both free resources for essential functions and improve the efficiency and effectiveness of FDA regulation."

Miller offers several suggestions for reducing spending at FDA. He concludes, "The FDA may lack needed resources for inspections and safety monitoring of approved drugs, but there is also poverty of sound management and insight," adding, "Dr. von Eschenbach, who is a surgeon, should take out his scalpel and start cutting" (Miller, Washington Times, 3/27).