UK Experts Advised Rosiglitazone Withdrawal in July

September 08, 2010

September 8, 2010 (London, United Kingdom) — The diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) is once again in the media spotlight, this time in the UK, where it has emerged that experts from the UK Commission on Human Medicines (CHM) decided unanimously at the end of July that the drug should be withdrawn.

This recommendation was not made public, however, in line with protocol. It was communicated to the British drug-licensing agency, the Medicines and Healthcare Products Regulatory Agency (MHRA), which instead sent out "Dear doctor" letters reiterating safety information with regard to rosiglitazone from 2007, including a suggestion to consider alternative treatments where appropriate [1].

After the news emerged earlier this week, many press reports have criticized what they say was a decision to keep patients and doctors in the dark on the subject[2]. But Jennifer Kyne, a press officer for the MHRA, told heartwire : "It is not common practice for the MHRA to provide information publicly about the CHM advice during ongoing regulatory discussions." Once it became clear, however, that the CHM’s advice had become public, Kyne said she was able to confirm that the withdrawal of rosiglitazone was unanimously recommended by the CHM in July.

However, she stressed that the UK MHRA itself cannot act alone on this advice, because rosiglitazone was approved centrally, by the European Medicines Agency, for the whole of the European Union. "Only EMA can revoke the license," she noted.

Only EMA can revoke the license [for rosiglitazone].

In fact, the EMA met today to discuss rosiglitazone, but no final decision was made about the drug. In a statement to the press, the agency said that it "identified a number of further questions that it is putting to the marketing authorization holder, GlaxoSmithKline. The responses to these questions will help the committee to reach its opinion on whether the marketing authorizations for rosiglitazone-containing medicines should be maintained, changed, suspended, or revoked." A final decision on the product should be made at a plenary meeting on September 20-23.

In July, a US FDA advisory panel sent a mixed message regarding what should be done about this drug--while a majority of panelists favored a tightening of restrictions on rosiglitazone use, a substantial minority called for the drug's withdrawal. The US agency has yet to make a final decision regarding what action it will take on rosiglitazone, however.

Rosiglitazone "No Longer Has a Place on the UK Market"

In a statement emailed to heartwire , the MHRA says: "To inform its input into the European debate on rosiglitazone, the MHRA has conducted its own assessment of the safety of rosiglitazone and sought the advice of the UK's CHM . . . [which] advised in July 2010 that the risks of rosiglitazone outweigh its benefits and that it no longer has a place on the UK market."

The MHRA has used the CHM advice to "robustly put forward the UK’s position. The MHRA continues to play an important role in Europe, pushing hard for these issues to be considered and for a swift European consensus," the statement adds.

The secrecy surrounding proceedings at the EMA and the MHRA has been highlighted--and contrasted with the transparency evident at the recent US FDA advisory committee meeting on rosiglitazone--in a feature article in BMJ published online September 6, 2010 [3] and also in a 30-minute BBC documentary [4], Panorama, aired the same day called "A risk worth taking?"

The documentary sketches the history of rosiglitazone, as chronicled by heartwire , up to and including the US FDA advisory committee meeting this summer. It points out that over a million prescriptions for rosiglitazone were written in the UK last year and features interviews with two patients who believe they may have suffered cardiac side effects from the drug. It also, however, interviews one woman who says that her diabetes is well-controlled on the drug and that she is happy with her treatment and plans to continue with it as long as the drug remains available.

But ultimately the program ponders "whether we can trust that the regulators put patient interests before industry." It claims that the UK MHRA could have temporarily suspend the license for rosiglitazone in July, if it wanted to, without waiting for the EMA to make a decision, and questions whether the EMA can be trusted, given that it "takes most of its funding from the drug industry."

In response to the program, GlaxoSmithKline put out a statement [5]: "We strongly refute any allegation that our actions have put patients at risk. We continue to believe that Avandia is safe and effective when it is prescribed appropriately."

Patient organizations in the UK have advised people taking rosiglitazone not to discontinue treatment as a result of viewing the documentary without first seeking medical advice, a point that was also stressed by the program makers [6].

GlaxoSmithKline Releases Secret Nissen Tape

As a result of the BBC documentary, GlaxoSmithKline has also posted on its website an audio recording [7] of a meeting with Dr Steve Nissen (Cleveland Clinic, OH) that took place in 2007.

It states: "On 10 May 2007, four GlaxoSmithKline medical and clinical experts met with Dr Nissen to discuss the scientific data on Avandia. An audio recording of this meeting was made covertly by Dr Nissen. At no stage before or during the meeting was GlaxoSmithKline informed that the meeting was being recorded. Selected extracts from this audio recording have already been provided by Dr Nissen to the New York Times newspaper."

Last Friday, September 3, GlaxoSmithKline obtained a copy of the audio recording following the issuing of a subpoena to Nissen, because it had been informed that the Panorama program would feature the recording. "The decision to post the full audio recording was taken so that all interested parties can hear all the comments made at this meeting in their full context," the company says.

It adds in its statement with respect to the BBC documentary: "We regret that comments made by GlaxoSmithKline during a meeting with Dr Nissen might be misinterpreted as seeking to stifle an independent view of the science around Avandia." 

Nothing New: Doctors in UK Will Wait for EMA Decision

Asked by heartwire to comment on these latest developments, Dr Colin J Kenny (editor, Diabetes and Primary Care, London, UK), who is also a GP specializing in the treatment of diabetes, said that nothing really new has happened in the UK this week.

Pressed as to whether he thought the EMA would recommend withdrawal of rosiglitazone, he said, "It wouldn't be a surprise," but added, "This is a very complex decision. After all, it split the FDA [advisory committee] effectively in two. The EMA kicked it into the long grass for a while. . . . It will be interesting to see what decision they make toward the end of this month."

Regarding the Panorama program, Kenny said he has had patients calling concerned about the issues. The documentary "was very black and white, but the evidence is not as black and white as they portrayed it. There has been no excess mortality from rosiglitazone--although there has been excess heart failure and myocardial infarction in the retrospective analyses, and that's worrying--but I think that's why the FDA advisory committee didn't vote to withdraw the drug."

Kenny said that it has been apparent from prescribing evidence from the UK that "very few people" are starting patients on rosiglitazone now, something that has been occurring since advice to avoid its use in those with heart failure or ischemic heart disease was issued in 2007.

But the problem, he says, is "that a lot of GPs have patients, with no ischemic heart disease or HF, who have been very well controlled for long periods of time on the drug." Also, many patients are taking a combination agent, rosiglitazone and metformin. However, he said there is now a comparable product with the other glitazone, pioglitazone (Actos, Takeda Pharmaceuticals), combined with metformin, so in theory it should be relatively easy to switch patients if rosiglitazone is subsequently withdrawn.

Nevertheless, this would be a headache, he said. "There would be a considerable workload, because most doctors wouldn't do this over the telephone or by letter, they would take the opportunity to review the patients' overall care and find an appropriate replacement."

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