How far will the FDA go with Avandia, will Actos get a pass

How far will the FDA go with Avandia, will Actos get a pass

Based on the draft questions for the committee a clearer picture is emerging of how Monday’s meeting might go and what the agency hopes to accomplish. As expected, part of the day will be spent debating the strengths and weaknesses of Dr. Nissen’s meta-analysis which prompted the FDA to hold this meeting. The committee will also take a look completed and ongoing clinical studies for Avandia. (It should be noted that at the panel discussion on Avandia on the last day of the ADA conference, several physicians were already discounting the RECORD study basically saying this yet to be completed study will yield little, if any, useful information.) Finally the committee will be asked to vote on two questions:

Do the available data support a conclusion that Avandia increases cardiac ischemic risk in the type 2 diabetes mellitus?

If yes, is there evidence that the risk is greater than other available therapies for the treatment of type 2 diabetes mellitus?

Does the overall risk-benefit profile of Avandia support its continued marketing in the US?

If yes, please comment on what FDA should do to maximize the risk-benefit considerations (e.g., limit to certain patients, incorporate a boxed warning….)

Diabetic Investor has also examined the supporting documentation from the FDA and GlaxoSmithKline (NYSE:GSK). Looking over GSK’s documentation it appears the company plans to stand behind Avandia and claim the drug has a comparable risk profile to other diabetes drugs. According to their document:

“Across these multiple sources of data, there is no consistent or systematic evidence that rosiglitazone increases the risk of myocardial infarction or cardiovascular death in comparison to other anti-diabetic agents.”

Diabetic Investor sees this as a rather risky strategy for GSK based on all available evidence. Furthermore, such a strategy could have greater implications beyond Avandia. Basically what the company appears to be saying is all anti-diabetic agents carry this risk not just Avandia. Should physicians buy this argument it would create havoc when prescribing medications for their type 2 patient population.

At first glance it appears the FDA isn’t planning on taking any action with regards to Actos, another TZD. However the FDA’s documentation states;

“Following a high level discussion of the issue of the cardiac safety of the PPAR agents (rosiglitazone and pioglitazone) at a Center-wide briefing in April 2007, the following was decided:

1. Because of persistent reports in the spontaneous adverse events reporting system of the PPAR agents being utilized in a manner inconsistent with labeling and what

is known about risk of heart failure, the prominent warnings with regard to the risk for heart failure and edema with these agents would be appropriate for a

boxed warning for both rosiglitazone and pioglitazone. (This action is ongoing and is not the subject of this Advisory Committee meeting ).

2. With regard to the signal of CV ischemic events with rosiglitazone, FDA was to call in the sponsor (GSK) for a meeting in the near future to discuss their thinking

on this risk and to see if they could provide other data or information that would better clarify or quantify the signal of risk. (That meeting took place on May 16th,

2007). In the meantime, FDA was to work on a communication strategy for alerting the public to our ongoing concerns and plans, above and beyond the data

already in the rosiglitazone labeling on CV ischemic events.

3. FDA planned to take both the issue of heart failure for both drugs and the CV ischemic signal to an Advisory Committee meeting in the late summer or early


This statement leads Diabetic Investor to believe that Actos, while not the main topic on Monday, could well receive a Black Box warning as well.

One unfortunate consequence of all this discussion is the impact it has on patients and physicians. It is a well known fact that patient non-compliance with their current therapy regimen is high and one reason 75% of patients fail to achieve adequate control. With the attention the Avandia controversy has received it gives patients one more reason not to take their medications. This would be truly sad and carry devastating long term consequences.

Taken as a whole Diabetic Investor continues to believe that there is little hope GSK can salvage Avandia and the possibility of pulling the drug off the market is increasing. While we see little chance of Actos coming off the market, it’s difficult to see how the drug can escape the guilt by association effect.

David Kliff
Diabetic Investor
847-634-4646 fax
224-715-3761 mobile