Healthy Skepticism Library item: 13393

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Publication type: news

Winstein KJ.
Late Drug Approval Linked To Safety Issues
The Wall Street Journal 2008 Mar 27D1
http://online.wsj.com/article/SB120656190873766273.html

Full text:

Study Says Medicines FDA Clears Under Deadline Rush Are More Prone to Problems

Although every unsafe drug is different, most of them have something in common: last-minute approvals by the Food and Drug Administration, according to a new study.

Liver problems led Pfizer Inc. to withdraw its diabetes drug Rezulin from the U.S. market in 2000. Bayer AG pulled cholesterol-lowering Baycol in 2001 because it caused muscle damage in some patients. Vioxx, Merck & Co.‘s controversial painkiller, was withdrawn in 2004 because it sometimes caused heart attacks and strokes.

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DOWN TO THE WIRE

Researchers at Harvard University found that:
• Of the 313 drugs approved from 1993 to 2004, 97 were approved within two months of deadline.
• Out of 21 withdrawals and black-box warnings for drugs approved since 1993, 14 were related to drugs approved within two months before the deadline.These and other unsafe drugs all received approval shortly before the FDA deadline for deciding on new-drug applications.
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Since 1993, the 97 drugs approved near the FDA’s deadline had a 14% rate of severe safety problems down the road, compared with 3% for 216 other drugs. That’s according to an analysis in Thursday’s issue of the New England Journal of Medicine by Daniel Carpenter, a professor of government at Harvard University. The FDA says some of Dr. Carpenter’s data are inaccurate, and disputed his conclusions.

The study is the latest to take aim at the controversial decision deadlines the FDA has set as goals since 1992. In exchange for agreeing to quick approval of drug applications, the FDA gained the legal authority to collect substantial fees from companies with business before the agency. Industry fees now account for about half of the $680 million the FDA will spend on reviewing new drugs this year.

Currently, the agency promises to reach a decision on 90% of new drug applications within 10 months after a company submits an application. For so-called priority drugs, the deadline is six months. The schedules have substantially cut the time it takes the FDA to review a new drug — from 33 months on average in 1991 to 19 months in 2001. Several analyses have found that, overall, approving drugs more quickly likely saves lives.

But tighter schedules also led to what the FDA’s drug-evaluation director, Janet Woodcock, has called “a sweatshop environment that’s causing high staffing turnover” among employees who review the voluminous data each company submits on new drugs. Dr. Woodcock’s comment appeared in an FDA newsletter posted on its Web site in 2000.

An FDA spokesman said Dr. Woodcock no longer agreed with that sentiment. “The reason she said that publicly … is because in 2000 we were lobbying for additional resources,” said Christopher DiFrancesco, the spokesman. “She wouldn’t say that about the environment today.”

Of the 313 drugs the FDA approved between 1993 and 2004, 97 drugs were “just-before-deadline” approvals — meaning they were approved within two months of the deadline, according to Dr. Carpenter’s study. But those drugs were more than four times as likely to be withdrawn for safety reasons or require a severe “black box” warning on the medicine’s label years later, the study found.

Out of 21 withdrawals and black-box warnings for drugs approved since 1993, 14 were for drugs approved within two months of the deadline. This includes Baycol, Vioxx and Rezulin, all of which were approved in the last three days before the deadline and later withdrawn for safety reasons.

In an interview, Dr. Carpenter said it was impossible to say whether the agency was rushed to make a decision in any particular case and made a sloppy decision as a result. “You can’t point to any single case and say, well, an extra two months would have made the difference,” he said. But he questioned whether setting deadlines tied to industry funding was the best way to speed up drug approvals. “Congress would be much better off relying less upon these deadlines and relying more on a big increase in full-time employees,” he said.

The FDA said its own database of drug-approval times didn’t match Dr. Carpenter’s data and said it suspected his database contained errors. “We just are unable to replicate the numbers,” said Clark Nardinelli, an FDA economist. The agency said it is sending a detailed letter disputing the results to the New England Journal of Medicine.

No law requires the FDA to meet the deadlines, but Congress has linked its periodic reauthorization of the agency’s authority to collect fees to its performance at meeting the deadlines. The FDA disputes the notion that its judgment is impaired by looming deadlines. “FDA won’t approve a drug if we are not ready,” Dr. Woodcock said in a statement, adding that the deadlines are “guidelines” that the agency has the freedom to miss if necessary.

And the agency may be moving toward more flexibility. Earlier this year, John Jenkins, an FDA official who directs new-drug reviews, “authorized our managers to miss” a deadline “if that needs to happen,” said the FDA’s Mr. DiFrancesco.

Sometimes, last-minute approvals seem to tell a story. When Pfizer applied for permission to sell Rezulin in 1996, the drug was the first in a new class of diabetes drugs called thiazolidinediones, or TZDs. So the FDA gave Pfizer’s application priority status — meaning the agency had a six-month deadline to reach a decision. It met the deadline, with two days to spare, in January 1997.

But evidence emerged that Rezulin was toxic to the liver. So when GlaxoSmithKline applied in 1999 to sell its own TZD called Avandia, the FDA again awarded it priority status — and met the deadline on the very last day, in May 1999. The next year, with GlaxoSmithKline’s seemingly safer drug now available to patients, the FDA asked Pfizer to stop selling Rezulin.

But in rushing approval of Avandia because of Rezulin’s liver problems, the FDA didn’t recognize Avandia’s own increased risk of cardiovascular problems, said Steven Nissen, a cardiologist at the Cleveland Clinic who has been critical of GlaxoSmithKline and the FDA. Last year, after a critical review by Dr. Nissen, the FDA asked GlaxoSmithKline to add a severe warning to Avandia’s label.

A GlaxoSmithKline spokeswoman declined to discuss Avandia, but said, “in our experience the FDA will approve a drug when they feel they have sufficient data to do so.” She said that was “usually” at the deadline.

“It’s a tough balancing act,” Dr. Nissen acknowledged. “If you have a drug for cancer that can extend survival in a very tough group of patients, by all means, give it priority review,” he said. But for other drugs, “I don’t know that we need to be in quite such a hurry,” he said.