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 today’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

“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.”

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.

Drugs approved in that just-before-deadline period had a four- to five-fold higher rate of later being withdrawn or requiring serious safety warnings, compared with drugs approved more quickly – presumably slam-dunks – or those that miss the deadline, Carpenter concluded.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 drug Avandia was linked to heart risks last year, getting a strict new warning label.