Wide variation in response to FDA rosiglitazone warning

November 25, 2010

Rochester, MN - Doctors do not respond adequately to FDA boxed warnings on drug labels, resulting in significant exposure of patients to potentially unsafe medications, according to researchers, who use the rosiglitazone saga as an example[1].

Writing in a perspective article in the November 25, 2010, issue of the New England Journal of Medicine, a team led by Dr Nilay Shah (Mayo Clinic, Rochester, MN), describe large variations in response to the FDA's boxed warning about an increased risk of MI with rosiglitazone, issued in 2007[2].

Shah commented to heartwire : "Although prescriptions for rosiglitazone fell dramatically after the FDA boxed warning, use in certain parts of the country were still high. You would think that with the large number of other of options available and the concerns that had been voiced about rosiglitazone, use would be a lot lower."

Shah et al conducted a retrospective analysis using two databases from IMS Health, which computed the number of rosiglitazone prescriptions per month for each US state. This shows that the combination of the Nissen meta-analysis[3], the FDA warning, and the associated media coverage in May 2007 caused a 70% reduction in the use of rosiglitazone, with the absolute number of filled prescriptions for rosiglitazone decreasing from 1.3 million monthly in January 2007 to slightly more than 317 000 in June 2009.

You would think that with the large number of other of options available and the concerns that had been voiced about rosiglitazone, use would be a lot lower.

But they note that significant residual use of the drug occurred—at a rate of 3.8 million prescriptions per year—despite the lack of any specific benefits of rosiglitazone in patients with type 2 diabetes and the existence of several different treatment options.

While rosiglitazone prescriptions decreased substantially in all states between 2005 and 2009, there was a large variation among states in use of the drug, both before and after the 2007 FDA warning. This variation actually increased from a factor of two before the warning was issued to a factor of three by 2009.

In 2005, rosiglitazone use was highest in Wyoming (16.5% of all prescriptions for diabetes medications) and lowest in North Dakota (7.8%). By 2009, the highest use was in Oklahoma (5.6%) and the lowest in North Dakota (1.9%). The researchers note that this suggests patients received different care depending on where they sought it.

Impact of FDA warning: Rosiglitazone prescriptions as % of all diabetes scrips over time

Quartile March 2007 August 2007 June 2009
1 13.8 7.6 3.9
2 12.0 6.5 3.1
3 11.1 6.2 2.9
4 9.7 5.3 2.5

Shah commented to heartwire : "All we can do is hypothesize as to why these variations occur. They could have been due to more coverage of rosiglitazone in certain health plans, more local champions of the drug in certain places, differences in availability of specialist endocrinologists, and differences in pharmaceutical marketing in that it can be harder to gain access to physicians' offices in some areas."

He also pointed out that in contrast to the FDA boxed warning in 2007, the American Diabetes Association (ADA) warning in January 2009, advising against the use of the drug, had "practically no effect." "Rosiglitazone accounted for 7% of diabetes prescriptions before the ADA warning and still accounted for 6% in June 2009. Perhaps this was because the ADA warning was geared mostly toward diabetologists and endocrinologists and not primary-care doctors," he said.

Decision-making tools available

Shah et al suggest that to help doctors make better decisions regarding prescribing drugs that have been issued with warnings, the FDA may need to provide decision-making tools into which patient information can be incorporated, in order to enable the best translation of the additional warnings into practice.

They write: "Until the FDA hearings in July 2010, most physicians' organizations and the FDA had recommended that patients taking rosiglitazone discuss with their clinician whether to continue or discontinue its use. The extent to which these conversations yielded decisions that reflected both the available evidence and patients' values and preferences is uncertain, and the process was probably haphazard. Tools, such as decision aids that may facilitate unbiased knowledge transfer, patient engagement, and shared decision-making, were not provided by any organization after the FDA warning was issued. Had such tools been in common use, the resulting variations in practice might have been justified."

Shah added that even the latest severe restriction in the form of a risk evaluation and mitigation strategy (REMS) still requires clinicians to discuss the risks and benefits of rosiglitazone with patients. "The new REMS strategy will significantly limit use, but there still need to be discussions between physician and patient; it doesn't offer any standardized format of how those discussions should go." Shah pointed out that the Mayo Clinic has developed a tool that helps that process, frankly titled, "A little help for docs and patients still thinking about rosiglitazone."


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