FDA Moves to Improve System

In September, startling announcements were made about several blockbuster drugs. The Food & Drug Administration revealed that some popular antidepressants may double the risk of suicidal behavior in children and adolescents. Then Merck said that its widely used drug Vioxx elevates the risk of heart attack and stroke in patients who take it for arthritis and severe pain. On Sept. 28, the company told FDA that it planned to withdraw Vioxx from the market.

In the wake of these revelations, FDA is under pressure from the public and Congress to make fundamental changes in the way it approves and tracks the safety of drugs on the market.

In response, FDA has already made a few moves to review and upgrade its system for evaluating the safety of drugs, particularly those already on the market.

Most important, it has set up a new process for dealing with disagreements among FDA scientists. Under the new system, when there is a failure to reach consensus, an ad hoc panel will be convened. The panel members will be scientists who were not involved in the original decision-making process, including some from outside the agency. The panel will have 30 days to make a recommendation to the director of FDA's Center for Drug Evaluation & Research (CDER).

The agency has commissioned the Institute of Medicine (IOM) to do a comprehensive review of the effectiveness of the agency's safety monitoring procedures. FDA will also hold a series of public meetings on safety topics, focusing on emerging issues related to products that are going through the approval process or are already marketed. In addition, the agency will finalize guidelines that drugmakers will use to detect risks as drugs are going through development and after they are marketed. And FDA is beginning a nationwide search for a director of its Office of Drug Safety, a position that has been vacant for more than a year.

"Medicines that receive FDA approval are among the safest in the world," says Acting FDA Commissioner Lester M. Crawford. "The measures we are taking are designed to strengthen this quality as well as our consumers' confidence that FDA's processes ensure the highest protection of the public health."

"I would argue that the FDA as currently configured is incapable of protecting America against another Vioxx."

HOWEVER, critics such as Senate Finance Committee Chair Charles E. Grassley (R-Iowa) and other observers of the agency, are asking for much more profound changes. On Nov. 18, Grassley held a hearing to discuss what steps are needed to prevent another Vioxx debacle. At the close of the hearing, he said he would be pushing for an autonomous board at FDA to track the safety of drugs after they are marketed. The board would have the power to make label changes and to withdraw drugs from the market.

The steps FDA announced were developed to address long-standing problems. For example, some agency scientists have complained over the years that their views about potential dangers are often ignored in order to keep profitable drugs on the market. In September, it was revealed that Andrew D. Mosholder, an epidemiologist in FDA's Office of Drug Safety, had tried earlier this year to convince his superiors that antidepressants as a class nearly double the risk of suicidal behavior in pediatric patients, but his supervisors did not allow him to present his views at an FDA advisory committee meeting held in February. Afterward he reanalyzed his data, reaching almost exactly the same conclusions, and presented his reanalysis at an advisory committee meeting in September. Shortly after, FDA issued strong warnings about the pediatric use of antidepressants.

David J. Graham, associate director for science and medicine in FDA's Office of Drug Safety, claimed at the Senate hearing that his superiors tried to get him to change his conclusions after he, with other researchers, conducted a large study that found Vioxx increased the risk of heart attack and sudden death 3.7-fold at high doses and 1.5-fold at low doses, compared with the similar-acting drug Celebrex. Graham reported the results of this study to FDA in August. He estimated that Vioxx may have caused nearly 28,000 excess cases of heart attack or sudden cardiac death. "Today, in 2004, we are faced with what may be the single greatest drug safety catastrophe in the history of this country," Graham told the Senate panel. "I would argue that the FDA as currently configured is incapable of protecting America against another Vioxx."

Steven Galson, acting director of FDA's CDER, disagrees. The new system for adjudicating disputes among FDA reviewers will ensure that all of their opinions will be incorporated into the decision-making process, he tells C&EN. In most cases, open discussion of differences in scientific opinion leads to agreement about a course of action, he says. "But sometimes, consensus is difficult to reach, and an employee may feel that his or her opinion has not been considered enough. There is no need for an overwhelming cultural change."

Some FDA critics, however, say the changes in the drug review process do not go nearly far enough. The proposal for an IOM study focuses mainly on postmarket safety surveillance of drugs, says Larry D. Sasich, a pharmacist with Public Citizen's Health Research Group. "We think they are missing the mark there. Some attention is long overdue for the drug approval process," he says. In other words, he explains, FDA's entire system for reviewing drugs, including postmarket surveillance, should be reevaluated.

ANOTHER REFORM that Sasich advocates is a complete separation between FDA's Office of Drug Safety, which does postmarket surveillance, and its Office of New Drugs, which reviews new drugs and currently has much more power than the Office of Drug Safety. The two offices are both part of CDER, but the Office of Drug Safety has no independent power to make labeling changes or drug withdrawals. The Office of Drug Safety "should not have to play the poor handmaiden to the Office of New Drugs," Sasich says. "If an FDA official has gone to a great deal of trouble to review and approve a drug, and then has to consider withdrawing it, this creates a potential conflict of interest."

Daniel P. Carpenter, a professor of government at Harvard University, agrees that the Office of Drug Safety should be more autonomous. "Once FDA approves a drug, it may not have enough incentive to dig up negative information about it," he says. "Basically, what we need is more good information, and nothing in the pharmaceutical marketplace provides strong incentives to generate that information," he says. Industry does postmarket trials of its drugs mainly to find new indications or to satisfy FDA requirements, he says.

The idea of having an independent board to track the safety of drugs after they are marketed has come up periodically over the years, Galson says. "But once you separate these two functions [review of new drugs and review of marketed drugs] completely, it is very challenging for a decisionmaker to consider all the important things--the benefits and the risks--that difficult public health decisions entail," he adds. Another issue, he says, is that "we are in a very resource-constrained environment. If we had extra hundreds of millions of dollars sitting around, we might consider this more readily," he says. "If you were to create a new independent board, you'd have to re-create a lot of the expertise that we already have [in the Office of New Drugs]. It doesn't seem to make a lot of sense."

At Grassley's hearing, Gurkirpal Singh, adjunct clinical professor of medicine at Stanford University School of Medicine, testified that almost two years elapsed between a clinical trial published in 2000 that showed a 500% increased risk of heart attack and a 50% reduction in stomach bleeding with high doses of Vioxx and FDA's request to Merck that it revise the product label to reflect its risks. Even then, the information was not prominently displayed as a warning. It was simply added to the "Precautions" section under "Cardiovascular Effects."

"As the delay in [changing] the Vioxx label shows," Singh said, "the current process of labeling is one of negotiations. If the 'sponsor' does not agree with what the FDA wants, it can continue to stall or worse," he said. "It took two years for the label change of Vioxx to take effect, and even then, the change supported mostly Merck's position, not the one advanced by FDA's own reviewers in public hearings," he explained. "This process needs to be fixed."

Graham stressed over and over in his testimony that the situation at FDA often leads to needless deaths. The figure of 28,000 excess heart attacks and strokes because FDA and Merck ignored the warning signs on Vioxx is conservative, he said. For example, Eric J. Topol of the Cleveland Clinic recently estimated in an article published in the New England Journal of Medicine [351, 1707 (2004)] that Vioxx caused up to 160,000 such cases.

In August, after Graham had completed a large study on Vioxx, concluding that high doses of the drug should not be prescribed, he was pressured by his superiors at FDA to moderate his conclusions and recommendations, he said. "My experience with Vioxx is typical of how CDER responds to serious drug safety issues in general," he said. "When a serious safety issue arises postmarketing, CDER's reaction is one of denial, rejection, and heat," he explained.

Over his long career at FDA, Graham said, most of the drugs he has recommended be withdrawn have eventually been pulled from the market, but often after long delays. There are five widely used drugs currently on the market that he believes should be withdrawn or much more sharply restricted: the cholesterol-lowering drug Crestor, the weight-loss drug Meridia, the painkiller Bextra, the acne medication Accutane, and the asthma medication Serevent. The companies that make these drugs say they are safe if used as directed.

Sandra Kweder, deputy director of FDA's Office of New Drugs, said at the hearing that Graham's view of FDA "is not the FDA I know." She said the agency is dedicated to protecting consumers and that drug safety is central to its activities.

Kweder denied that FDA intimidates scientists whose opinions differ with superiors'. She claimed that the original database for Vioxx at the time of approval included about 5,000 patients and "did not show an increased risk of heart attack or stroke." After Vioxx's approval, she said, FDA continued to monitor the scientific literature reviewing several retrospective epidemiologic studies. "Some suggested an increased cardiovascular risk, while others did not," she explained. It was only after Merck presented the results of its latest study that the company and FDA both realized the drug should be withdrawn from the market, she said. Under intense questioning, however, she admitted that the idea of having an independent division for reviewing approved drugs "is worth looking into."

As C&EN goes to press, Grassley remains committed to trying to make major changes at FDA. Given the public outrage over Vioxx and the shortage of flu vaccine, he is likely to succeed.