Avandia Again?   (June 10, 2013)

I’ve written about the diabetes drug Avandia a dozen times already, but once again, this zombie drug has arisen from the near-dead to haunt the world of diabetes. This time it’s the FDA who breathed life into the drug, convening another Advisory Committee (AdCom) meeting earlier this month to review the manufacturer’s latest attempt to revive their profits at the expense of people with diabetes who might have naïve (or downright ignorant) physicians prescribing for their diabetes.

Avandia (rosiglitazone) was first approved by the FDA for treatment of type 2 diabetes a dozen years ago, at which time it was one of three “glitazones” (troglitazone, pioglitazone, and rosiglitazone) who were the new kids on the block. The glitazones (also known as thiazolidinediones or TZDs) promised a new and better way to treat diabetes besides the old standbys of insulin and sulfonylureas and metformin: they reduced insulin resistance, which allowed an astonishing degree of improvement in diabetes control. Even better, any of these three new drugs could be given in combination with any of the older diabetes drugs to gain even better glucose control than could be obtained with use of one drug at a time.

But it soon became apparent that the glitazones had nasty unsuspected side effects. Troglitazone (brand name Rezulin) was the first of the three to be approved by the FDA, and the first to be removed from the market, because of cases of liver failure with risk of liver transplant or death. Rosi and pio seemed much less likely to cause liver disasters, but issues with the heart (primarily with Avandia/rosi) and bladder cancer (with Actos/pioglitazone) surfaced.

Three times, in July 2007, in July 2010, and again this month, the FDA has hosted joint meetings of the Endocrinologic and Metabolic Drugs Advisory Committee with the Drug Safety and Risk Management Advisory Committee to discuss the cardiovascular safety data on rosiglitazone. The first two meetings resulted in FDA actions to warn physicians and patients about the risks of rosi. Indeed, as a result of the 2010 review, the FDA essentially disallowed new starts, restricting new use of rosi to "patients not already taking rosiglitazone who are unable to achieve glycemic control on other medications and, in consultation with their health care professional, decide not to take pioglitazone for medical reasons." Whether a new patient or a patient already on Avandia, the physicians were asked to document in the medical record that the patient has been informed of "complete risk information." Canada and Australia have also restricted its sale. Think that’s strict? Well, many countries took even more aggressive action, and suspended sales of Avandia completely. It’s no longer available in Europe, New Zealand, and South Africa.

But some companies never learn. Rather than quietly withdraw Avandia from the US market, the manufacturer has spent more money to try to resuscitate its zombie drug by hiring an “independent” organization (the Duke Clinical Research Institute) to reassess a huge rosiglitazone trial about cardiovascular outcomes, which had been named RECORD (“Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes”). In case you haven’t guessed, the RECORD trial was also sponsored by the manufacturer. The RECORD study has had considerable criticism, as it was open-label and unblinded. And the criticism of the company hiring someone to take a second look at the data has been scathing; as one major critic of Avandia is quoted as saying "You have a company that still faces billions in lawsuits providing files to Duke for adjudication. What do you think the outcome is going to be?"

This year, after reviewing the Duke reassessment of RECORD, however, the FDA’s advisory committees seem to be backtracking on the cardiac risks of Avandia. Twenty of the 26 members of the AdComs voted to remove or modify rosiglitazone's highly restrictive label and distribution system. Only five panelists voted to keep the restrictions as at present, and one lonely brave soul voted to remove the drug from the market.

Is Avandia actually safer than previously thought? Were the data presented by the manufacturer this year skewed by the faulty design of the study? Or perhaps the AdCom members were awed by the Duke presentation? It’s hard to say, but none-the-less, Avandia seems likely to remain on the US market.

The FDA doesn’t have to follow the advice of its AdComs, and there apparently is no deadline for the FDA to decide whether to modify its restrictions on the sale of Avandia. I’d suspect the FDA will dawdle on its decision-making, and let the Avandia zombie continue to haunt diabetes doctors for years to come.

And what should the manufacturer do? I've said it several times before, and I'll say it yet again:

“Avandia (rosiglitazone) should be voluntarily taken off the market. Avandia has had cardiac safety problems resulting in label changes and it is becoming less-and-less profitable for the manufacturer. In an unexpected fit of ethics, the manufacturer would make it clear that they consider ethics more important than satisfying their shareholders. FDA officials, newspaper editors, and financial analysts worldwide will be utterly amazed.”