Investigation Raises More Questions About Avandia

Sept. 6, 2010— -- On July 15 -- a day after the U.S. Food and Drug Administration completed two days of hearings on the diabetes drug Avandia -- a British advisory commission on drugs concluded that the product should be withdrawn from the market, according to an investigation conducted by BMJ.

The Commission on Human Medicines' opinion was passed on to the U.K.'s regulatory authority, the Medicines and Healthcare Products Regulatory Agency (MHRA), which has now told BMJ that Avandia "no longer has a place on the U.K. market." The evidence for increased risk of heart attacks outweighs any potential benefit, according to an MHRA statement given to BMJ.

Yet six weeks after the commission submitted its recommendations on rosiglitazone, the drug is still on the market in Britain. The MHRA has yet to share its negative assessment of the drug with either physicians or patients.

Read this story on www.medpagetoday.com.

Instead, on July 26 it sent providers a "dear doctor" letter suggesting merely that it would be wise to consider alternatives to Avandia, wrote Deborah Cohen, features editor at BMJ.

The BMJ investigation was detailed in a feature article published online today and also the subject of a BBC news report. The report appears to be the first confirmation that U.K. regulators are ready to withdraw the drug from the market.

The lengthy article reveals no new information about the FDA's handling of Avandia from its approval through two subsequent safety reviews, but it does give insight into the machinations of the approval process in Europe.

For example, the European Medicines Agency initially rejected Avandia, only to come back a year later in 2000 to approve the drug. As a condition of that approval, the EMA ordered a post-marketing study to verify the safety of the drug. That study, called RECORD, was an open-label trial that has been roundly criticized on both sides of the Atlantic for its poor design.

Cohen quoted numerous sources who all pointed to the influence of the drug maker, GlaxoSmithKline (SmithKlineBeecham during the initial approval process), as the reason that the EMA reversed itself on Avandia.

"According to Edwin Gale, a diabetologist and adviser to European regulators, in the years before Avandia's approval diabetologists were also putting pressure on the regulators and clamouring to use this new class of drug. Some of this clamour was fuelled by pharmaceutical analysts touting its blockbuster potential, which at the time they said was crucial to Smithkline Beecham's future growth," Cohen wrote.

Cohen also pointed out that the EMA does not publicly release names of members of advisory panels who review drugs for the EMA. By comparison, she wrote, the FDA process, often the subject of criticism in the United States, is open and transparent.

In a editorial that accompanied Cohen's article, Richard Lehman of the University of Oxford, Dr. John S. Yudkin of University College in London and Dr. Harlan Krumholz of Yale University said there is plenty of blame to pass around in the Avandia saga.

Back in 1999, clinicians were "strongly disposed to welcome a new drug for type 2 diabetes, and it was vigorously promoted to a receptive market," they wrote.

"Our mistake then -- and we have yet to put it right -- was that we did not demand better proof before we embarked on mass medication of a large group of patients who looked to us for advice and treatment."

In a commentary, which was also published with the Cohen article, Nick Freemantle of the University of Birmingham in England, argued that much of the controversy surrounding the thiazolidinediones (the drug class to which Avandia and another diabetes drug, Actos, belong) can be laid at the feet of poor trial design -- so poor that critical questions were not answered.

For example, regulators have been willing to permit high rates of loss to follow-up, especially in trials that rely on surrogate endpoints, a position that he contended "makes no sense."

And "even when trials examine serious morbidity and mortality, loss to follow-up remains a problem. The RECORD trial, conducted to examine the safety of rosiglitazone and sponsored by GlaxoSmithKline in the U.K., failed to follow-up survival in 127 participants (2.9 percent)," he wrote. The loss to follow-up in RECORD meant that one could conclude that rosiglitazone "was associated with either an increase or a decrease in mortality given different assumptions on the fate of those lost to follow-up."