When New Drugs Go Wrong: Role of the FDA Debated
Federal officials responsible for ensuring that medications are safe face a major limitation of drug research: Although a new drug is often tested on a few thousand patients, a serious side-effect may not be fully recognized until its users number in the hundreds of thousands.
“To a real degree, the people who get the drug in the first few years after its approval are being experimented on,” said Dr. Brian L. Strom, a professor of biostatistics and epidemiology at the University of Pennsylvania.
Now, pushed by an acknowledged safety disaster with one drug and heightened suspicions about several others, Congress is considering steps to limit the risks of what Strom and others see as the “experiment” of newly marketed drugs.
But opinions are diverging widely on what changes should be made, if any, at the nation’s drug watchdog, the Food and Drug Administration.
The FDA says that it can fix problems on its own. Its critics are calling for lawmakers to impose changes on the agency and possibly on the drug industry -- with some even calling for a ban on advertising new drugs until their safety is more established.
The debate has gained new force after an unusual hearing before the Senate Finance Committee on Nov. 18, in which government and expert witnesses said that federal regulators and drug maker Merck & Co. had seen early indications of safety problems with Vioxx, Merck’s blockbuster painkiller.
Merck took Vioxx off the market Sept. 30, after about 20 million Americans had taken the drug, when tests showed that Vioxx nearly doubled the risks of heart attack and stroke among those who took it for at least 18 months.
At the same hearing, a veteran FDA drug reviewer, Dr. David J. Graham, said that five other widely used medications deserved reappraisal for possible safety problems. And in a sharp criticism of the current drug-monitoring system, the editors of the Journal of the American Medical Assn. this week called for considering a new board, independent of the FDA, that would track the safety of drugs and medical devices after they were on the market and in wide use.
The system of FDA oversight “requires a long-overdue major restructuring,” the journal said in an editorial. Until then, it said, “the United States will still be far short of having an effective, vigilant and trustworthy system ... to protect the public.”
Some lawmakers are focusing on whether the FDA is structured properly so that it can both approve drugs and then look for problems in those drugs, a situation some critics have said presents a conflict for the agency. Some people outside the agency want new measures to guarantee the independence of the safety office that tracks already approved drugs.
In addition, some experts say Congress needs to grant the FDA authority to mandate safety studies of approved drugs, and that lawmakers should revisit the issue of allowing new drugs to be advertised directly to consumers, who are generally unaware of the nuances that can come into play in balancing medical risks and benefits.
And then there is the question of whether user fees paid by the drug companies for FDA review of new drug applications have created a conflict of interest. The fees were part of an earlier measure enacted by Congress to streamline the approval of drugs needed to combat AIDS and other diseases.
Legislative prospects for FDA reform are uncertain but should become clearer by early next year. Two powerful committees are clearly interested in the drug safety issue. In addition to the Senate Finance Committee, which held the Nov. 18 hearing on Vioxx, the House Energy and Commerce Committee has begun an investigation.
The FDA, which is saying it can handle any problems itself, has asked the prestigious Institute of Medicine, which is part of the National Academies, to undertake a study of the drug safety system. That could take months, even longer than a year. Congress may wait for the institute’s findings before making any final legislative changes.
A spokesman for the pharmaceutical industry trade group said drug makers recognized there were valid concerns, but that they had confidence in the FDA’s ability to set it right.
“We believe that the FDA is the gold standard,” said Jeff Trewhitt, spokesman for the Pharmaceutical Research and Manufacturers of America. “We are encouraged that the FDA has commissioned a study because concerns have been raised. The FDA has taken a responsive and constructive course.”
“There will be a lot of hearings,” said William B. Schultz, who served as an FDA deputy commissioner for policy from 1994 to 1999. “Whether there will be legislation, I don’t know. The drug industry is very powerful.”
A quick fix may make matters worse, by overlooking some issues that need to be addressed. “People are going to try to put a patch on a system that needs broad thought,” said Dr. Raymond L. Woosley, vice president of the University of Arizona Health Sciences Center. “Some of those potential patches could make the system worse.”
The FDA also has pledged to develop a better process to handle professional disagreements among its drug reviewers so that top officials get to hear the minority view. And it plans to issue new guidelines to drug makers for monitoring adverse reactions.
“We understand that there are concerns by members of Congress and the public about our system,” said Dr. Sandra Kweder, deputy director of the agency’s Office of New Drugs. “We will ... change, if that is what is needed.”
Yet the agency’s reform plan is silent on fundamental changes that some medical experts say are needed to protect consumers. Currently, the FDA is largely dependent on drug makers and doctors to voluntarily report problems with new drugs. It lacks the authority to routinely order the kind of painstaking investigative studies needed to identify problems.
“The FDA’s resources and authority over drugs after they are on the market is very limited,” said Schultz, the former FDA deputy commissioner. “If there is legislation, it should look at those two areas. The agency needs authority to order post-market studies. It needs the resources to carry out those studies.”
Some doctors believe that new drugs should be regarded as “experimental” until they have proven themselves on the marketplace. Strom, of the University of Pennsylvania, advocates a three-year “conditional approval” during which doctors would be allowed to prescribe a new drug but manufacturers would not be able to advertise it directly to patients.
“Let the first people exposed to the drug be the people who really need it,” Strom said.
Arizona’s Woosley sees little benefit in allowing direct advertising of powerful medicines. “In our current model, that is very dangerous,” he said. “You take a new drug, and you rapidly expose millions of people to that drug before you have gained experience with it.” The government lifted restrictions on broadcast ads in the late 1990s.
The relationship between FDA scientists who review and approve new drugs and those who are responsible for monitoring their safety after they are on the market is certain to be at the heart of any legislation, if Congress decides to move ahead.
Graham told the Senate that his safety office was subordinate to the part of the agency that approved new drugs. Some critics say the FDA has developed an institutional bias toward approving drugs before all their risks are fully understood.
Although there is agreement that the oversight of new drugs needs to be strengthened, there are wide differences over the degree of independence that the safety office should have.
Some believe it should be an independent agency, modeled on the National Transportation Safety Board, which investigates air crashes and hazards in all forms of transportation. Others believe it should remain under the FDA, but as a truly independent office.
For now, the critics seem to have momentum.
“The FDA’s [internal] reform is largely a farce,” said Dr. Sidney Wolfe of the consumer advocacy group Public Citizen. “It’s not terribly different from what has not been working in the past.”
