FDA review slams Avandia study that omitted heart failures

WASHINGTON — A federal drug official Friday dealt a severe blow to the popular diabetes drug Avandia, issuing a scathing review of a major clinical trial its maker has been using to argue the drug is safe.

The reviewer, Dr. Thomas Marciniak of the Food and Drug Administration (FDA), found a dozen instances in which patients taking Avandia appeared to suffer serious heart problems that weren't counted in the study's tally of adverse events.

Such mistakes "should not be found even as single occurrences" and "suggest serious flaws with trial conduct," Marciniak wrote.

The detailed report could prove crucial next week, when a panel of experts will meet to consider whether to recommend to the FDA that the manufacturer, London-based GlaxoSmithKline, withdraw Avandia from the market or restrict its sale.

The panel's decision will have broad consequences for Glaxo, the FDA and perhaps the drug-approval process. The agency rarely does clinical trials on its own, depending on drug companies to conduct them appropriately.

Avandia, which helps patients with Type 2 diabetes get better control of blood-sugar levels, has come under intense criticism. It has been shown to increase the risks of bone fractures and to cause swelling that can lead to heart failure and eye problems.

A number of studies, including some by GlaxoSmithKline, suggest it also could increase the risks of heart attacks, strokes and death. But the company has relied heavily on the major clinical trial, nicknamed Record, to show those risks are exaggerated.

Marciniak's review of the Record study calls that assertion into question. He found one case in which a seizure patient was hospitalized for bleeding in the brain, but all mention of the episode was deleted. Another patient was hospitalized for 67 days after a severe stroke, but the study record showed no sign of a cardiovascular problem.

Another patient died after being hospitalized for a serious heart problem, but the death was listed as arising from an unknown cause and not heart-related. Correctly interpreted, Marciniak concluded, the study supports critics' contentions Avandia may cause heart attacks and strokes.

"One does not have to be a mathematician or to perform calculations," he wrote, to come to the conclusion that a combined look at all the trials of Avandia would demonstrate it causes heart attacks.

Mary Anne Rhyne, a spokeswoman for GlaxoSmithKline, said the study showed Avandia is safe, and she added, "The Record study was conducted according to good clinical practices, and the data are reliable."

The European Medicines Agency, which evaluates medicines used in Europe, said Friday it also will review the safety of Avandia in light of new developments.

Marciniak's review is part of a reassessment of Avandia's safety by FDA medical officers to educate the panel, which will meet Tuesday and Wednesday in Gaithersburg, Md. The panel will advise the FDA whether Avandia should be withdrawn, after millions of prescriptions, billions of dollars in sales and 11 years of widespread use.

FDA Commissioner Margaret Hamburg will make the decision on Avandia after getting the panel's recommendation. The FDA is not obligated to follow the recommendations of its advisory committees, but it usually does.

The agency's initial review of the Record trial, in 2007, found no problems. But independent researchers who have examined the health records of thousands of patients taking Avandia have found hints the drug is more dangerous than GlaxoSmithKline has claimed. So Marciniak took an unusually close look at the Record study, demanding to see records the agency rarely examines. Only then did he turn up the study's many problems. If given more time, he wrote, he would probably have found more.

It was the FDA's delay in issuing stronger warnings about Avandia that led Congress in 2007 to give the agency greater powers over drugmakers.

Within the FDA, some officials insist the evidence is mixed and others say it is strong enough to merit the drug's withdrawal. An advisory meeting in 2007 concluded Avandia increased heart-attack risks but should stay on the market.

In response, Avandia's sales fell sharply, to $1.2 billion last year from a peak of $3.2 billion in 2006. But while endocrinologists have advised against its use, Avandia remains popular, with nearly 2 million prescriptions last year. If the drug is withdrawn, GlaxoSmithKline — facing lawsuits claiming Avandia caused injuries — would see its liability soar.

Conducted at 338 sites in 23 countries, the Record study involved 4,447 patients with Type 2 diabetes who were recruited between April 2001 and April 2003 and followed for nearly six years. Half of the patients received two older diabetes medicines while the other half were given Avandia in combination with an older diabetes medicine.

The study was paid for by GlaxoSmithKline and conducted in part by Quintiles, a clinical-trials company. A spokesman for Quintiles declined to comment.

Avandia's critics have long asserted the Record study was weakly designed and too short to prove anything. An inquiry by the Senate Finance Committee found GlaxoSmithKline may have improperly influenced the independent experts in charge of the study.

An editorial in The New England Journal of Medicine on Friday accused GlaxoSmithKline of interfering with the trial and said the system for hiring trial-safety experts should change.

One reason Marciniak's critical review of the Record trial is so important is that he works at the FDA's office of new drugs, which has long defended Avandia's safety against criticism from a separate safety office.

Analyses of Avandia's safety from other reviewers in the office of new drugs that were posted on the agency's website Friday were not as critical as Marciniak's, but his defection suggests Avandia's support within this crucial office has weakened.

Material from The Associated Press is included in this report.