Rosiglitazone: what went wrong?


530 BMJ | 11 SEPTEMBER 2010 | VOLUME 341 I t was, as one Food and Drug Administration (FDA) adviser put it, a “perfect regulatory storm”—a combination of problematic data, uncertain clinical need, politics, and poor drug company behaviour. Now, 10 years after its approval by regulators in the United States and Europe, the widely prescribed blockbuster diabetes drug rosiglitazone may be about to fold. Two months ago, in July 2010, the FDA convened a 33 member expert advisory panel to decide whether it should be withdrawn from the market in the light of evidence that it may increase the risk of myocardial infarction. Earlier this year a US Senate finance committee report had detailed concerns about the paucity of evidence to support the use of rosiglitazone and about the way in which the drug was evaluated and licensed.1 At the advisory meeting, members of the public heard a damning analysis of the RECORD trial, commissioned by the European Medicines Agency (EMA) when it approved the drug in 2000 in order to determine its safety. Millions of prescriptions later and with the drug still on the market around the world, this trial and other post-marketing surveillance have failed to resolve the concerns. To date, the FDA and the EMA have decided that the drug is safe enough to stay on the market. But the story reflects badly on almost everyone involved: the regulators, the manufacturer, GlaxoSmithKline, and the clinical community. It has also raised a host of questions. Why did the regulators accept such poor evidence on benefit and safety for rosiglitazone? Did GlaxoSmithKline mislead the regulators? Should the drug have been licensed in the first place and should it now be withdrawn? Why haven’t patients in the UK and Europe been made aware of the concerns about rosiglitazone’s effects? And is the current drug regulatory system up to the job? The FDA meeting was held in the open, in front of a packed audience including the world’s media. Ahead of the meeting, the FDA published the 765 page report circulated to panel members. This is far removed from the secrecy shrouding proceedings at Europe’s regulator, the EMA. The BMJ has talked to a range of experts close to the European regulatory process and submitted a series of Freedom of Information requests to the EMA, but we still have no clear picture of why, after initial rejection in October 1999, the EMA gave market authorisation to rosiglitazone in July 2000 in the absence of new evidence. Neither have doctors and patients been told that in July the UK’s Commission on Human Medicines— in an unanimous vote— advised the Medicines and Healthcare products Regulatory Agency (MHRA) to withdraw the drug. In a statement, the MHRA has confirmed that the evidence now suggests that the risks associated with rosiglitazone outweigh the benefits and “that it no longer has a place on the UK market.” But a “dear doctor” letter sent to UK doctors in July advised doctors to “consider alternative treatments where appropriate.”2 The MHRA said that it used the information provided by the Commission on Human Medicines to push for a UK withdrawal as part of the Europe-wide review by the European Medicines Agency. Rosiglitazone is one of two available glitazones known to reduce blood sugar and was heralded as a much needed new approach to improving outcomes and long term complications, including cardiovascular disease, for people with type 2 diabetes. Of the other glitazones, troglitazone was withdrawn in 1997 in the UK and in 2000 in the USA because of hepatotoxicity; pioglitazone remains on the market as a competitor to rosiglitazone.3 A paucity of evidence Concerns were expressed early on about the paucity of evidence to support rosiglitazone’s use. According to documents obtained under the Freedom of Information Act, advisers to the EMA noted the lack of good evidence during its approval process. In comments sent to the EMA approval meeting in 1999, one expert adviser noted that without a long term study with hard primary endpoints it was not clear whether rosiglitazone would have any beneficial impact on cardiovascular disease. This adviser also questioned whether you could put a drug on the market without these long term data and was unconvinced that rosiglitazone in combination therapy offered any advantages over what was already available—metformin and sulphonylurea combined, or insulin. Another adviser pointed out that safety problems were evident in the data presented by GlaxoSmithKline (then SmithKline Beecham) and asked the panel whether they should postpone approval until better data were available. Silvio Garattini, a member of the EMA panel in 2000 that approved the drug and director of the Mario Negri Institute for Pharmacological Research, told the BMJ that the documentation presented for approval was initially poor and that the studies were of a relatively short duration. The initial decision to reject the drug was overturned despite there being no new evidence, he says. When rosiglitazone was approved, even clinicians who were nominally supportive of the drug remarked about the poor evidence base and lack of long term clinical trials.4 After approval, three EMA panel members— whose names were redacted from the minutes ROSIGLITAZONE WHAT WENT WRONG

DOI: 10.1136/bmj.c4848
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@article{Cohen2010RosiglitazoneWW, title={Rosiglitazone: what went wrong?}, author={Deborah J. Cohen}, journal={BMJ}, year={2010}, volume={341}, pages={c4848} }