BMJ papers increase pressure on Avandia

A trio of papers in BMJ are turning up the heat on rosiglitazone (Avandia), prompting the editor-in-chief of the journal, Fiona Godlee, to say that she believes rosiglitazone “should not have been licensed and should now be withdrawn.”

The detailed investigative report by BMJ features editor Deborah Cohen reviews the long and troubled history of rosiglitazone, with a focus on the deficiencies of the European and British regulatory process. Cohen writes that “we still have no clear picture of why, after initial rejection in October 1999, the EMA gave market authorization to rosiglitazone in July 2000 in the absence of new evidence.” She also reports for the first time that in July of this year the UK’s Commission on Human Medicines unanimously recommended that the Medicines and Healthcare products Regulatory Agency (MHRA) withdraw rosiglitazone from the market but “a ‘dear doctor’ letter sent to UK doctors in July advised doctors to ‘consider alternative treatments where appropriate’.”

In an accompanying editorial, Richard Lehman, John Yudkin, and Harlan Krumholz  shift some of the blame for the Avandia crisis to clinicians, noting that “we had lost sight of the main reason for treating this complex and progressive disease, which is not to reduce glycemia but to prevent complications.”  The important lesson to be learned before allowing new drugs to enter the market is that “surrogate end points are not enough, robust evidence of benefits and harms is needed.”

In an accompanying commentary, Nick Freemantle points out that to avoid problems like rosiglitazone in the future it will be essential for regulatory agencies to require companies to provide much better data from clinical trials.

In a related development, GSK has posted the audio recording of a May 10, 2007 meeting between Steven Nissen and GSK officials. The existence of the tape, which was recorded surreptitiously by Nissen, was disclosed in February by theNew York Times.

This post is republished with permission from CardioExchange, a new website for cardiovascular healthcare professionals from the New England Journal of Medicine.CardioBrief readers who are healthcare professionals are invited to join the site.

Here is the BMJ press release:

BMJ report into top-selling diabetes drug raises concerns about the drug regulatory system

Feature: Rosiglitazone: what went wrong
Editorial: Licensing drugs for diabetes
Commentary: What can we learn from the continuing regulatory focus on the thiazolidinediones?

A BMJ investigation into the top-selling diabetes drug rosiglitazone (Avandia) raises concerns about its safety and the whole system by which drugs are evaluated, regulated, and promoted around the world.

BMJ Editor in Chief, Dr Fiona Godlee, believes that the drug should not have been licensed and should now be withdrawn. She also calls for more robust regulatory processes and better access to the raw data used to license drugs to allow scrutiny by the scientific community.

The investigation reveals that in July the Commission on Human Medicines advised the MHRA to withdraw the drug as the “risks of rosiglitazone outweigh its benefits and that it no longer has a place on the UK market”.

In light of these concerns, doctors are also advising that no new patients should be started on rosiglitazone, and patients already taking it should be reviewed and alternative treatments considered. Those at higher risk of heart disease should be advised to stop taking the drug.

Rosiglitazone, manufactured by Glaxo SmithKline (GSK) was approved by the US Food and Drug Administration (FDA) in 1999 and by the European Medicines Agency (EMA) in 2000 to help lower blood sugar levels in patients with type 2 diabetes.

Since its approval, several studies have suggested that rosiglitazone may lead to a small overall increase in the risk of heart attacks, but in July an FDA scientific advisory panel recommended that it was safe enough to stay on the market.

In her report, Dr Deborah Cohen investigations editor of the BMJ, obtained documents under the Freedom of Information Act that note a paucity of evidence during the European approval process and outline concerns from some panel members about the long term risks and benefits of rosiglitazone. Other experts have since remarked on the poor evidence base and lack of long term data on cardiovascular safety.

The report also raises concerns about the quality of the data used by GSK to show that rosiglitazone did not lead to increased heart problems compared to other diabetes drugs, the lack of publicly available trial results for independent scientific scrutiny, a lack of transparency in the European system, and the ability of the European regulator to assess individual patient data.

Pressures on regulatory agencies by diabetologists to approve rosiglitazone, and failures by the agencies to act swiftly on emerging safety information are also highlighted in the report.

Two experts comment on today’s report.

Professor Nick Freemantle at the University of Birmingham, calls for an overhaul in the standards of regulatory trials to minimise the risk of a similar situation occurring in other clinical areas in the future. “In order to learn from our mistakes, we must improve the quality of safety data from clinical trials on all new health care interventions, not just antidiabetic drugs,” he says.

Professor John S.Yudkin of University College London believes doctors must focus on what matters to patients. “Ten years after the release of rosiglitazone, we still cannot accurately quantify the harm to which we were exposing our patients,” he says. He admits that some of the blame lies with clinicians for not insisting on better proof of long-term benefit, and adds: “We need to be absolutely certain that our long term treatments for type 2 diabetes are not causing the very harm they are meant to prevent. And if the regulatory bodies do not insist on clear evidence of greater benefit than harm, they are failing in their basic purpose.”

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