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FDA doesn't usually write a black box warning "without some pretty good data," said Robert Temple of FDA's Office of Medical Policy. Overuse of the black box can both dilute its impact and limit access to needed treatment.
The campaign against unsafe drugs is escalating on all sides. FDA is requesting postmarketing studies for just about every innovative new medicine—not just those receiving accelerated approval. FDA advisory committees are urging black box warnings at the least hint of adverse events. Legislation has been proposed to overhaul FDA oversight of drug safety and to require pharma companies to complete promised Phase IV studies. Meanwhile, members of Congress have been calling for more public disclosure of emerging safety issues.
Unfortunately, critics seem to be paying little attention to the possibility that "transparency" may confuse prescribers and patients, and curb access to effective treatments. An overly risk-averse FDA may be slow to bring new therapies to market. And more extensive preapproval studies will likely raise the already astronomical cost of drug development, without producing much useful information.
FDA is caught in the middle. If agency officials question the need for more safety warnings, they'll look like they're in the pharmaceutical industry's pocket. But if they demand heightened warnings on more and more drugs, they run the risk of teaching doctors and patients to ignore them. Getting the risk-benefit equation right is never easy, and it's getting harder.
Case in point: At its February meeting, FDA's Drug Safety and Risk Management Advisory Committee unexpectedly recommended black box warnings for medicines that treat attention deficit/hyperactivity disorder. Advocates of the move pointed out that patients taking similar drugs ran an increased risk for myocardial infarction and stroke—and that some one million adults (as well as four million children) now take these medicines. Although the vote was close (eight to seven) on the black box proposal, the panel was unanimous in recommending that MedGuides be distributed with these drugs.
For their part, FDA officials questioned whether the new warnings were justified by the evidence. At a post-meeting briefing, Robert Temple, director of the Office of Medical Policy, acknowledged that there are concerns about people with heart problems using these drugs. But FDA doesn't usually write a black box warning "without some pretty decent data," he said. Robert Laughren, director of the Division of Psychiatry Products, pointed out that overuse of the black box warning could both dilute its impact and limit access to needed treatment—as has occurred since black box warnings were added to antidepressants.
More severe warnings will go on ADHD drugs, however, if Senator Charles Grassley (R-IA) has anything to say about it. Grassley, who chairs the Senate Finance Committee, has added FDA oversight to his committee's agenda. (Now that Medicare is paying for prescription drugs, Grassley says the panel is responsible for ensuring that taxpayers pay only for safe and effective medicines.) The committee has been probing FDA activities and drug safety, and Grassley backs legislation to strengthen FDA enforcement authority and to establish a new office to oversee drug safety, separate from the drug approval process.
A current Grassley target is supposedly lax FDA oversight of medical device safety. The committee recently issued a lengthy report criticizing the director of FDA's Center for Devices and Radiological Health (CDRH) for approving expanded use of Cyberonics' nerve-stimulation implant to treat persistent depression in addition to epileptic seizures, despite CDRH staff concerns about safety problems and weak efficacy data. Whether or not FDA made the right call, such public scrutiny will make agency officials even more reluctant to approve controversial applications in the future.
Politically inspired attacks on FDA regulatory decisions are not limited to over-prescribing of medications with hidden cardio risks. They also open the door for politicians to challenge the safety and effectiveness of birth control and other controversial therapies. Conservative Republicans have been calling for increased scrutiny of the abortifacient Mifeprex (mifepristone or RU-486), following reports of several deaths among women using the drug. Danco Laboratories has marketed the treatment since 2000 with black box warnings that highlight the need for careful administration and follow-up.
Now emerging safety problems are encouraging its critics to try to kill RU-486 altogether. Scientists and regulators hope to address the medical issues involving this drug at a private meeting sponsored by the Centers for Disease Control and Prevention (CDC). The question is whether the deliberations can be kept focused on the medical issues.
Supposed safety concerns might also provide an excuse to keep the over-the-counter version of the emergency contraceptive Plan B off the market—perhaps the most heated issue on the science-versus-politics debate list. At the recent House committee hearing on FDA's budget for 2007, members of Congress took acting commissioner Andrew von Eschenbach to task, demanding to know what he was doing to end the delay. FDA's leader pointed out that the agency had 10,000 comments on the issue to analyze, and avoided making predictions on the prospects of a final decision.
Meanwhile, a number of states have approved OTC versions of the drug, a situation that undermines FDA efforts to persuade state regulators to defer to labeling decisions made by the federal agency. FDA and industry don't want 50 different policies governing medical-product marketing, but FDA has only it own inaction on Plan B to blame for compromising its preemption claims.
To deal with mounting safety controversies, FDA has adopted a more open approach to disclosure. When data appeared in February indicating that the Ortho Evra birth control patch might increase the risk of blood clots, agency officials held a press conference to explain why they await further analysis, rather than immediately pull the product off the market.
Johnson & Johnson's Ortho-McNeil unit has obtained conflicting preliminary safety results from two epidemiologic studies. One study indicated no increased risk of heart attack and stroke compared with pills, but the other showed a two-fold higher risk of blood clots. Because the patch is beneficial to women who have trouble taking a pill every day, FDA wants to wait and see before curbing access to the product. In fact, FDA has just announced that it will launch a broader study of patch safety.
At the same time, the need to prevent pregnancy among women taking Roche's acne medication Accutane and generic isotretinoin prompted FDA to go ahead with an aggressive risk management program for the drug. The iPledge program requires physicians, distributors, pharmacists, and patients to register; women who take the drug have to use two forms of birth control and submit monthly pregnancy test results.
Dermatologists pressured FDA to postpone implementing this complex program until sponsors fix glitches in the registration and verification process, but FDA officials emphasized the importance of taking steps to prevent pregnancy among Accutane patients. Past risk management initiatives have not worked, and the agency said it's time for doctors and pharmacists to get with the program, despite its Big Brother characteristics.
No Oversight? FDA's Drug Safety and Risk Management Advisory Committee didn't limit itself to criticizing drugs at its February meeting. It also had a few words for the agency's Drug Safety Oversight Board (DSOB). Formed about a year ago as a forum for internal FDA discussion of drug safety, the board has been criticized for operating behind closed doors and limiting membership to FDA and other government personnel. FDA explains that DSOB is not a public body, but the confusion persists-partly because of the board’s name, which implies broad oversight functions.
One anticipated task for DSOB is to decide which emerging drug safety issues should be posted on a planned FDA Drug Watch Web site. The idea was to reveal emerging safety signals gleaned from databases and adverse event reports before waiting for a full analysis to confirm a real problem. But pharma companies have objected loudly that such disclosure could raise needless fears among patients, along with serious liability threats. FDA says it's re-examining the Drug Watch plan, but is under pressure to publicly disclose safety concerns whenever they appear.
Jill Wechsler is Pharm Exec's Washington correspondent. She can be reached at firstname.lastname@example.org