The Avandia Votes   (July 18, 2010)

As I mentioned these past two weeks, there was an FDA Advisory Committee (AdComm) meeting on July 13 and 14 [2010] that reviewed the safety of the diabetes drug Avandia (rosiglitazone). Transcripts of the sessions will someday be posted at the FDA website, at 2010 Meeting Materials, Endocrinologic and Metabolic Drugs Advisory Committee but until then, I've found an excellent resource that reviews the proceedings, session-by-session, at Forbes.com.

The FDA proposed a list of questions that the Advisory Committee was asked to vote upon; they are posted at the FDA website (the outcome of the votes are mentioned in the Forbes.com blogs). To me, the key question was the following: "Based on the available data, which of the following regulatory actions do you recommend FDA pursue regarding rosiglitazone?" The options the 33 Advisory Committee members were given were:

"A. Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding an increased risk of ischemic CV events, or
B. Allow continued marketing and make no changes to the current label, or
C. Allow continued marketing and revise the current label to add additional warnings (e.g., contraindications for certain patient populations, recommendation for second-line use in patients intolerant of or uncontrolled on other anti-diabetic agents); or
D. Allow continued marketing, revise the current label to add additional warnings, and add additional restrictions on use (such as restricting prescribing to certain physicians or requiring special physician and patient education)
E. Withdrawal from the U.S. market."

The results of the voting for this question are fascinating:

* No one voted for option A, to remove the restrictions that already exist in the Avandia label. No surprise here, as the panel clearly thought, based on earlier votes, that Avandia has a cardiovascular risk.

* Three members of the AdComm voted for option B, to continue the present wording of the label without any changes.

* Seven voted for option C, to revise the wording of the label to make it scarier.

* Ten voted for option D, to revise the wording of the label to make it scarier, and also to restrict the use of Avandia in other ways.

* Twelve voted for option E, to withdraw Avandia from the U.S. market.

* And one AdComm panelist chose not to vote.

Some writers have spun the story that the majority (21 out of 33) are willing to allow continued marketing of Avandia. Others have pointed out that 22 out of 33 want the use of Avandia curtailed either mostly or completely. But the big issue is how the FDA will interpret the Advisory Committee's votes. Remember that the FDA is not obliged to automatically follow the recommendations of their Advisory Committees, even if the vote was overwhelmingly one way or the other. In this case, the split decision by the panelist leaves the FDA with a very unclear message on exactly which path to take: to strengthen warnings and restrictions on its sale or have the drug removed from the market.

I think that it's likely that the FDA will soon ask the manufacturer to withdraw Avandia. It made a similar request about another glitazone, Rezulin (troglitazone), a drug which was found to have liver toxicity. In that case, the FDA pointed out that there were other glitazones available (Avandia and Actos) that did not share the liver problem, and that Rezulin had no niche where it was more efficacious than the other glitazones. It would be easy for the FDA to claim that Avandia is another "outmoded drug," as it decided Rezulin was back in 2000. After all, there is another glitazone available (Actos) that does not share the cardiovascular problem, and Avandia has no niche where it is more efficacious than the other glitazone. And there are new classes of drugs for type 2 diabetes that didn't exist when the glitazones were approved, so patients could be transferred to Actos or other classes of diabetes drugs.

For those of you taking Avandia, a reminder of what I've previously said: If you have no history of heart disease or stroke, and have no risk factors such as hypertension or smoking, and if it is clear that Avandia is helping to control your glucose levels, there's no rush to change from Avandia to any other diabetes medication. Your doctor and you can decide whether to switch to the other drug in the same class as Avandia (Actos, AKA pioglitazone) or perhaps try treating your diabetes without glitazones.

If you are on Avandia, have no history of heart disease, and it is not helping to control your glucose levels, you probably should be switching to another diabetes medication, or adding insulin therapy. There are numerous other oral diabetes drugs that could be tried, and insulin always works (maybe it's time for you to start insulin therapy!) - you should discuss all the options with your diabetes team.

If you are on Avandia, and have a history of heart disease or stroke, you should already have advised to switch from Avandia to another diabetes treatment. Hints about Avandia's increased risk has been out there for over two years, and there are now several studies that imply that staying on this drug is increasing your risk of more heart problems. You should talk to your physician about switching as soon as convenient - and I wouldn't wait for your next appointment if it's many months away.

Finally, if you are on Avandia, do not stop taking it just because of the adverse publicity. Talk things over with your diabetes team about what options you have.

[Editor's Note: For the FDA's decision, see the FDA Press Release of September 23, 2010, FDA significantly restricts access to the diabetes drug Avandia]