Have I Been Misreading the FDA?

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  • 07/26/2007
Gardiner Harris has GSK all but sued...no big surprise there since the trial attorneys have been putting together their game plan for months. But Avandia off the market?

Maybe I and others are fighting an uphill battle and Avandia will get creamed. Certainly the number crunchers take a "take no chances" approach to the TZDs which would mean depriving people of use of these drugs based on a fear of uncertainty which is in turn based on a lack of data. I think in this environment that might be enough to crush the TZD's into a purgatory. What is disgusting is the double standard -- accusing the FDA of not acting fast enough when it is apparent that the process of constructing long term trial and evaluating it takes a long time and raising second guessers and sloppy studies from Nissen and Graham to heroic standards.

For what it's worth here are comments from other reviewers that sparked hope that the FDA might, just might, show some cojones....

"Finally, the observation that longer term studies in the meta-analysis had similar risks between rosiglitazone and comparators highlights the importance of looking to these long-term controlled studies to confirm this finding..."

and in a nod that some folks in the FDA know the value of a real world studies compared to churning claims data (that's you, long suffering Dr. Graham)....

"The interim results (mean followup of 3.75 years) from RECORD show that 6% of
patients in the rosiglitazone group and 11% of patients in the metformin +
sulfonylurea group have been switched to insulin.
The protocol does not specify the rationale for discontinuing rosiglitazone upon
initiation of insulin, but the most likely explanation is that combination
rosiglitazone and insulin therapy is contraindicated in the European Union.
Exposures to rosiglitazone may be longer than exposures to the comparator
drugs (metformin and sulfonylurea), because rosiglitazone-treated patients can
be treated with three oral anti-diabetic agents before switching to insulin whereas
the non-rosiglitazone treated patients initiate insulin upon failing dual
combination therapy.

This amendment was added because some patients
strongly expressed reluctance to initiate insulin therapy. The protocol does not discuss how study personnel should manage other CV risk factors during the course of the study (e.g., blood pressure, lipids, and the use of aspirin). Because this is an open-label trial, differential management of these CV risk factors in the rosiglitazone and non-rosiglitazone treated patients could bias results."

In other words, insulin and Avandia combos were being avoided in the real world to begin with. As for the other risks, it would appear they are manageable by physicians but they may never get the chance and neither may GSK.

The killer is not the drug, its the politics of uncertainy. It's the risk of lawsuits and the limited tolerance of risk which I predict will drive up overall death due to diabetes if the SSRI policy by fear model applies here.

I am adding a PS to my post. Vioxx was yanked by Merck because a pain killer was shown in a RCT to have a relative risk of MI events of 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. All the problems cropped up after. And still both the FDA and Canadian Health advisory panels recommended returning Vioxx to the market for many patients under some conditions. In each case panelists believed that uncontrolled pain was a greater risk than the absolute risk of a heart attack from long term use associated with any NSAID.

In Avandia's case, we have no clear cut evidence of MI in any long term data except in the insulin population that doctors tend not to give Avandia to in the first place. So for the FDA to say Monday's meeting is not about Nissen is misleading. It is all about Nissen. It would not be meeting July 30 if not for his end run with his "study." More to the point, the FDA the failed to ask if uncontrolled glucose levels was a greater risk than the absolute risk of a heart attack from long term use associated with any oral diabetes drug.

That's the Nissen effect.

Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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