GAITHERSBURG, Md. -- The two major FDA critics of rosiglitazone (Avandia) again denounced the diabetes drug during the first day of an advisory committee meeting that will end with a vote on whether the agency should pull it from the market.
FDA staff reviewers David Graham, MD, and Kate Gelperin, MD, first called for rosiglitazone to be taken off the market in February, in a report published by the Senate Finance Committee, which has been investigating the diabetes drug for several years.
Graham and Gelperin, who both work in the FDA's Center for Drug Evaluation and Research (CDER) reiterated their position -- that rosiglitazone, manufactured by GlaxoSmithKline, doesn't work any better than competitor pioglitazone (Actos) but that it presents an unacceptable cardiac risk -- in briefing documents published last Friday in advance of this week's hearing.
And they again shared their views on the first day of a two-day meeting of a joint panel of the Endocrinologic and Metabolic Drugs and the Drug Safety and Risk Management Advisory Committees.
First Gelperin took the podium to discuss the FDA staff's review of seven published epidemiologic studies that looked at the cardiovascular risk of rosiglitazone versus pioglitazone. Two of the studies came out in favor of rosiglitazone while five favored pioglitazone.
"My view is that it's highly likely that rosiglitazone therapy is associated with increased risk of cardiovascular outcomes," Gelperin said.
Next up was Graham, who warned the packed hearing room that what he was about to say might offend some people.
He proceeded to criticize GlaxoSmithKline's trial design, and said that higher-ups within the FDA continually ignored staff guidance on the design issue.
However, not everyone agrees with Gelperin and Graham.
FDA Staffers Fall into Three Camps
An FDA reviewer who blasted the company's RECORD trial -- the same trial that the company says is proof that their drug is safe and effective -- explained the "three factions" within the agency.
The first faction, according to Thomas Marciniak, MD, was involved with early approval of the drug and in the 2007 decision that the benefits of rosiglitazone outweigh the risks discovered since approval of the drug.
"It's not surprising that they don't want to reverse" their decision, said Marciniak, who works in the Department of Cardiovascular and Renal Products at CDER.
The next faction at the FDA is comprised of researchers who have maintained since 2007 that there is indeed a strong safety signal in rosiglitazone that needs to be taken seriously.
Marciniak called himself a tie-breaker because he hasn't been involved in the agency's work on rosiglitazone for long. However, he admitted that it's always easier at the FDA to favor a drug.
"If I approve a drug, my bosses say 'good job,' and my work is done," he said. "If I don't approve a drug, it's endless meetings."
Primary Focus on the RECORD Trial
Although it might be easier to support a drug, Marciniak did nothing of the sort in his review of the RECORD trial, which he scathingly criticized for poor design, conduct, and results.
"Our review of RECORD leads us to conclude that its design and execution were biased in a manner that consistently favored not finding a cardiovascular effect if it was present," Marciniak wrote in documents released in advance of this week's meeting. "In our view, it provides no credible evidence of rosiglitazone's cardiovascular safety."
In fact, the RECORD trial took a lot of heat Tuesday. Not surprisingly, some of that criticism came from Steve Nissen, MD, of the Cleveland Clinic.
Nissen -- whose meta-analysis sparked the firestorm that has culminated in the current meeting -- told the panel they shouldn't use the flawed trial to influence a decision that "affects the lives of so many hundreds of thousands of people."
He said that the GlaxoSmithKline researchers overstepped boundaries for unblinding in the trial. From the start of the open-label trial researchers knew which patients were getting rosiglitazone and which were receiving pioglitazone and could connect adverse events to specific patients, Nissen said.
"From the very beginning this study was unacceptable," Nissen said. "In approving rosiglitazone, the mistake got made, the genie got out of the bottle, and we've been trying to put the genie back into the bottle every since."
Not everyone agreed.
Ellis Unger, MD, deputy director of CDER's Office of Drug Evaluation, disagreed with Marciniak's assessment of the RECORD trial.
While he called Marciniak "one tenacious reviewer," he said he didn't agree with the way Marciniak analyzed the RECORD data. He said Marciniak's review of the data can't be examined as "anything other than exploratory."
"I find the result pretty reassuring," he said.
TIDE Comes in for Criticism, Too
As expected, Graham also slammed the company's TIDE trial, an ongoing head-to-head postmarketing outcomes trial comparing rosiglitazone with pioglitazone.
Graham explained that TIDE -- ordered by the FDA -- was always meant to explore whether rosiglitazone was more harmful than pioglitazone and that enrolling patients in a trial designed to detect harm is unethical.
"When you go into a trial, you expect to get something good out of it," Graham said. "[In the case of TIDE] the best they can hope for is to not get a drug that causes a problem."
The company requires consent forms for TIDE participants, but Graham said the form is misleading. After explaining that the trial will compare adding a thiazolidinedione (either rosiglitazone to pioglitazone) to placebo, the consent form mentions that vitamin D's effect on fighting cancer would also be examined. The consent form goes on to mention vitamin D 18 times, which Graham said was meant to mislead patients.
"It was probably intended to mask the bad deal nature of the study," Graham said.
Finally, Graham criticized the FDA for requiring evidence of "definitive proof of harm" for drugs it has already approved.
Graham said because rosiglitazone offers no obvious benefit over pioglitazone, "you'd think it would be an easy decision. But the way FDA works is you have establish definitive proof."
GlaxoSmithKline officials and experts, speaking on the company's behalf, defended its drug during an early morning presentation.
"There is no suggestion that anything increases on rosiglitazone with the exception of heart failure" and distal fracture rate, said Philip Home, MA, professor of diabetes medicine at Newcastle University in England, who was the chairman of the RECORD steering committee.
"Statistically ... there is no evidence that rosiglitazone is inferior to pioglitazone," he said.
Meeting Draws the Top Brass
The meeting was kicked off by FDA commissioner Margaret Hamburg, MD.
"It's not typical for an FDA commissioner to speak, although I have done it before," she said, referring to her presence at the FDA's inaugural meeting of its new tobacco committee.
"With the amount of media that this issue and this meeting has been receiving, I thought it appropriate to speak with you before this session begins," she said. "Your job is to try and cut through all of that and to focus on the evidence. Review the facts, give your best advice on them. That is all we ask you to do today."
Rosiglitazone was approved by the FDA in 1999 to treat type 2 diabetes. Controversy over the drug began three years ago when a 2007 meta-analysis of data from 42 clinical trials found a 43% increase in relative risk of myocardial infarction among patients treated with rosiglitazone.
Last week, FDA reviewers issued harsh reviews of several of GlaxoSmithKline's rosiglitazone trials.
As Tuesday's advisory committee was gearing up, news broke that the Senate Finance Committee released documents that seemed to show GlaxoSmithKline failed to release early trial data that indicated rosiglitazone was less safe than pioglitazone.
The company said the data in question was for a pioglitazone-only study that didn't find anything new.
The advisory committees will continue deliberations through Wednesday. At the end of the day, the panel will take a number of votes meant to guide the FDA in a decision on whether to pull rosiglitazone from the market.
The FDA does not have to follow the advice of its advisory committees, but it usually does.