Rush decisions by FDA may subvert drug safety

updated 5:03 p.m. ET March 26, 2008

WASHINGTON - Vioxx, Bextra, Rezulin, Baycol. Looking at drugs yanked off the market, Harvard researchers found a disturbing pattern: Medicines approved right on deadline by the Food and Drug Administration are more likely to cause safety problems later than those cleared with more time to spare.

Congress set strict deadlines for FDA to speed the arrival of new medications, but critics have long complained that the ticking clock spurred a dangerous rush to judgment.

The Harvard analysis of decades of drug approvals, published in Thursday’s New England Journal of Medicine, provides the first scientific evidence supporting some of those complaints.

The FDA challenged the findings with its own statistics. Still, the study sparked calls to re-examine the balance between speed and safety.

“The article is a wake-up call,” said Dr. Steven Nissen, the Cleveland Clinic’s influential cardiology chief who helped sound the alarm on the risks of some of those ultimately doomed drugs.

DEADLINE DRUGS Here are some drugs found to have safety problems after deadline reviews by the FDA: — Avandia, manufactured by GlaxoSmithKline: FDA review in May 2007 showed the diabetes drug increased risk of heart attack and death from heart disease. — Antidepressants in children and young adults: FDA required black box warnings in 2007 and 2005 warning of increased suicidality in children and teens, then in anyone younger than 25, who took selective serotonin-reuptake inhibitors. — Bextra, manufactured by Pfizer: Recalled in April 2005 because of increased risk of cardiovascular problems and dangerous skin reactions. — Vioxx, manufactured by Merck: Recalled in September 2004 after a study found a higher rate of heart attack and strokes than in patients who took placebos. — Baycol, manufactured by Bayer AG: Recalled in August 2001 because of a sometimes fatal severe muscle reaction. — Rezulin, manufactured by Warner-Lambert: Recalled in March 2000 after review showed liver toxicity. — Posicor, manufactured by Roche Laboratories: Manufacturers withdrew the drug in 1998 after finding serious side effects and death, including many caused by heart arrhythmias, following interactions with other drugs. — Seldane, manufactured by Hoechst Marion Roussel: Recalled in 1997 because of problems linked to potential fatal arrhythmias.

“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 reevaluate now whether that’s good public policy.”

Deadlines were first imposed on FDA by a 1992 law that allowed drug makers to pay millions of dollars in fees directly to the cash-strapped agency so it could hire more reviewers and clear a backlog of pending drug applications. In return, FDA had to make a decision — either approve or reject — on 90 percent of all drug candidates within 12 months of their application, or lose money. The deadline was 6 months for drugs so novel or potentially lifesaving to be classified high-priority.

Congress tightened the deadline for most drugs to 10 months in 1997.

Amid concern about risky drugs, Harvard professor Daniel Carpenter took a closer look at the impact. First, he found approval is 3.4 times as likely in the two months leading up to the user-fee deadline as at any other time.

Deadline decisions
Drugs approved in that just-before-deadline period had a four-to five-fold higher rate of later being withdrawn or requiring serious safety warnings, compared with drugs approved faster — presumably slam-dunks — or those that miss the deadline, Carpenter concluded.

The FDA argued the findings weren’t accurate, rushing out its own statistics that showed somewhat more withdrawals among drugs approved just before the deadline but not enough to be statistically significant.

“FDA won’t approve a drug if we are not ready,” said drug chief Dr. Janet Woodcock. “And we have the option of denying approval altogether if there is any question about safety.”

But the Harvard researchers in turn rechecked their statistics, which had passed review by the medical journal, and informed FDA they were standing by the findings.

Among on-the-brink approvals that later caused problems: The painkiller Vioxx, pulled off the market in 2004 for increasing the risk of heart attacks and strokes; its competitor Bextra, gone in 2005; the diabetes drug Rezulin, withdrawn in 2000 for liver problems; and cholesterol-lowering Baycol pulled in 2001 for muscle damage.

More recently, the diabetes blockbuster Avandia was linked to heart risks last year, getting a strict new warning label.

Carpenter acknowledged that everybody works under deadlines.

For FDA, “these deadlines are kind of stand-ins for pressure” to approve, he contended.

Under the gun
“FDA staffers by their own admission feel very much under the gun as these deadlines loom,” added Dr. Jerry Avorn of Brigham and Women’s Hospital in Boston, who co-authored the study. “If they’re forced to make decisions prematurely, they may not make the right decisions. That needs to be debated openly.”

In today’s tight budget climate, industry user fees are unlikely to be replaced with taxpayer dollars. Congress reaffirmed the user-fee provisions last year, and it’s unclear if lawmakers would revisit the deadline issue.

“It clearly is critical that FDA has the time it needs to do a thorough and complete review of new drugs before consumers are exposed to them,” said Rep. Henry Waxman, D-Calif., who chairs the House Government Reform and Oversight Committee. If the user-fee law “is causing undue pressure, we need to fix that.”

MORE FROM HEALTH CARE

Health care Section Front

Senate set for health care debate Records show White House health care talks NYT: Medical debt spurs more bankruptcies NYT: Health bill revives abortion groups Poll: Americans conflicted over health overhaul For Reid, Dodd, clout cuts both ways Senate health bill targets ‘Cadillac’ plans Schumer: Dems can go it alone on health care Senate Democrats at odds over health care bill Consumers’ guide to health reform Health care Section Front   Add Health care headlines to your news reader: