Avandia - the aftermath

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When the May 21st issue of The New England Journal of Medicine hit the shelves last year, GlaxoSmithKline switched into crisis mode. From soothing full-page adverts in the US press, to publishing interim findings from its "Record" trial, the world's second largest drug company pulled out all the stops to turn the tide of public opinion.

The cause of the turmoil was a meta-analysis, authored by Dr Steven Nissan and hotly disputed by GSK, which concluded that the firm's blockbuster diabetes pill Avandia (rosiglitazone) increased the risk of ischemic cardiovascular events by 43%. Within a week of its publication, jittery physicians had voted with their scripts. Data released by the monitoring group IMS Health showed a 16% tumble in Avandia prescriptions in the US; a dramatic slump for a drug that previously notched up US$4.5 million a month in sales.

The accompanying media coverage - branded an "overreaction" by GSK chief executive, Jean-Pierre Garnier - also had an immediate effect on rosiglitazone's estimated seven million patients worldwide. Physicians reported a stream of requests from patients anxious to change their medication, a scene reflected in practices across the Middle East. "Many returned to the clinic expressing concern...that ‘it causes heart attacks'," explains Dr Essop Solomon, consultant internist at Saad Specialist Hospital, Saudi Arabia. "They wanted our opinion.

In September, an additional meta-analysis, published in the Journal of the American Medical Association, found rosiglitazone increased the risk of myocardial infarction by 42% while pioglitazone reduced it. Then followed the inevitable spiral of claims, counter-claims and media mudslinging. In an attempt to cool the furore, GSK broke with scientific practice and rushed out interim data from the Record trial. The findings, it claimed, could reassure physicians on the question of Avandia's safety. The trial will not be completed until 2009 but has been summarily dismissed by Nissan, who says tightly; "If you ask a drug company about their drug, you're going to get an answer.

Decision time

The data behind the initial meta-analysis is far from definitive. It is, Nissen admits, a complicated picture. As part of the team that revealed the risks of taking Vioxx, long before a patient trial came to the same conclusion, Nissen is fast being seen as a de facto drug regulator. In the case of rosiglitazone, however, critics have questioned his decision to open Pandora's box without conclusive evidence, accusing him of unncessary fireworks. But the man himself is unrepentant. "I considered the alternative absolutely ethically and morally impossible," he says flatly. "I would rather your phone is ringing off the hook, that patients have a dialogue about the risks and benefits of the drugs that they take, than be left in the dark.

Without clearcut evidence, however, physicians were unsure how to respond, debating whether to watch and wait or take action. GCC physicians have been divided in their responses. For Solomon, the solution was simple. "I've stopped prescribing rosiglitazone and changed existing patients to alternative agents," he says matter-of-factly. "I believe in the principle of ‘cause no harmsto patients'."

The decision has been less clear-cut for Dr Bassam Zouhir Al Masri, consultant in internal medicine at the International Modern Hospital, Dubai. Rosiglitazone has become a mainstay of diabetes treatment, he says, because of its effectiveness in lowering glycated haemoglobin (A1C), so physicians are reluctant to discard it altogether. Local health ministries have offered muted direction, if any, leaving doctors floundering. "We base our opinions on the data - the drug is still on the market, the data is inconclusive," Al Masri notes, "but patients still have a right to know. It is my responsibility to give them that choice, but we absolutely need more guidance [from the Ministry of Health].

Full disclosure

Regardless of the fate of Avandia, the episode has highlighted the need for fuller disclosure of, and access to, study data. The findings Nissan analysed in his paper were taken from 42 trials - 35 of which had never been published. He was only able to access the data because of a clause in a lawsuit involving GSK three years ago. The legal spat, concerning the antidepressant medication Paxil, required GSK to publicly disclose the results of its clinical trials. The first posting on the website set up to honour the settlement included more than 60 studies on Avandia.

"If this had been any other company, those unpublished 35 trials, I would not have had access to them," Nissan muses. "There is some considerable irony in that.

For Al-Masri, there is considerable concern that physicians were not confronted with the information sooner. "Absolutely, GlaxoSmithKline had an obligation to tell physicians and patients."

On a local scale, he notes, regional drug representatives are typically badly informed. There are marked time lags between drug updates published in international journals, and the information filtering into the local market. "If I raise an issue with the pharmaceutical company here, they'll say ‘I am not aware of this'," he explains. "The market here is often uninformed. This is a question we need to direct to the companies.

But Professor Massimo Massi-Benedetti, director for research and education at the Dasman Center for Diabetes, Kuwait, argues that local physicians can't pass the buck to the pharmaceutical companies. The widespread response to the Avandia coverage, he believes, is symptomatic of a problem in itself; namely the inappropriate and overzealous use of a single drug. "The issue here is prescribing," he says frankly, "not the product.

A heavily-funded promotional campaign, he argues, coupled with the legitimate benefits of rosaglitazone won GCC physicians over, leading to poor prescribing judgment. "This mass use of the drug is related to a massive promotional campaign, but prescribing should be an activity," he stresses. "There is no need for a blind, blanket prescription for all diabetics - the burden is on doctors to be knowledgeable and not follow the crowd.

Most worrying, he continues, is that it takes a controversy on this scale to alert doctors to the risks of failing to prescribe to the region's burgeoning diabetic community on a case-by-case basis. "It takes scandals that raise the threshold of concern for the population," he argues. "Where is the truth on Avandia? It is difficult to say. But a cautious decision is a safe decision."

Clinical collateral

Neither the anti-Avandia or pro-Avandia camps have yet been proved comprehensively right. The FDA - which did previously have access to the data used in Nissan's paper - has responded by adding a black-box label to the drug, warning of the risk of chest pain or myocardial infarctions. The European Association for the Study of Diabetes and the American Diabetes Association have also updated their consensus statement recommending "greater caution in using thiazolidediones".

What no one disputes is that, in the debate over rosiglitazone's safety profile, the largest casualty to date has been its manufacturer. Following the flurry of negative publicity, GlaxoSmithKline listed third quarter sales of just $225m last year, in comparison to $368m in the corresponding period of 2006. In October, the company also announced it would embark on a $1.5 cost-cutting exercise to levy its losses. As rival pioglitazone (Actos) mops up the fallout, industry analysts doubt whether even positive study results would see rosiglitazone re-take its position as the drug of choice for diabetics.

More questions than answers remain on the risks of rosiglitazone, Nissen notes, and only time and further research will decide. "But we need to make decisions today for our patients," he says, "and I want prescribing physicians to have all the information possible.

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