Doctors were able to retrieve formerly private GlaxoSmithKline studies for the 2007 NEJM article because the pharmaceuticals giant was required to post its clinical studies on its website as part of a lawsuit settlement involving another one of its drugs, Paxil. Paxil had been linked to increased rates of suicide among teenagers.
Last week, the British Medical Journal published a comprehensive examination of the GlaxoSmithKline/Avandia hide and seek drama. The resulting narrative reads similar to The Insider, the 1999 movie starring Russell Crowe. The Insider details a giant tobacco manufacturer's attempts to cover up the poisonous products used to increase the addictive qualities of nicotine.
The BMJ article, "Riglitazone: What went wrong" probes why the drug was ever allowed on the market and why the drug was tolerated well after it was known the drug increased risk of heart failure.
The final answer is broad: drug maker GlaxoSmithKline, regulators, clinicians, and journals are all accountable in the Avandia case.
The most convincing evidence of why the drug was allowed for so long is Avandia’s appeal to a market that no longer wanted to combat diabetes with needles and injections. During approval discussions in both Britain and the USA, the long-term evidence did not exist and consequently, the drug was approved before a link to myocardial infarction could be definitively made.
“The drug was conceptually very interesting because it allowed the liver and the muscles to regain their sensitivity to the action of insulin and rid of their fat,” said Professor Andre Grimaldi a diabetes expert in Paris.
Another member of the 2000 EMA (European Medicines Advisory) that approved the drug for use in Britain told the British Medical Journal that the “documentation for approval was initially poor and the studies were of a relatively short duration. The initial decision to reject the drug was overturned despite there being no new evidence.”
So when the drug was approved, “even clinicians who were nominally supportive of the drug remarked about the poor evidence base and lack of long term clinical trials,” the British Medical Journal article says.
At the time, 3 EMA panel members were still worried that the “long term risk/benefit” of the drug was unknown and the drug still prompted “safety concerns.”
Those safety concerns included weight gain, with possible serious cardiovascular effects, the induction of anaemia, and that rosiglitazone raises blood lipids.
Avandia as a new diabetes treatment drug had a great appeal.
Nevertheless, Avandia’s appeal as a new drug that “affected the body and its energy metabolism in whole new ways” was fascinating and interesting. Furthermore, it was strongly felt that the Avandia drug could be used as a primary, rather than secondary antidiabetic medicine.
Safety concerns “swamped” the FDA, WHO, and EMA from 2004 – 2007, but still the drug continued to sell. In 2004, WHO was notified of “adverse events” of increasing numbers of people related to rosiglitazone. WHO sent an alert to GlaxoSmithKline about cardiac disease.
In 2006, GlaxoSmithKline conducted tests and confirmed an increase in the cardiac events to the FDA and EMA. But, according to the BMJ, the public was not notified. Thus the FDA “has been accused of sitting on the reports and not sufficiently alerting the public.”
A professor of medicine at Harvard said the data was withheld because of the “acceptance of the proprietary nature of companies’ trial results.” In Europe, however, Avandia was marketed with an updated status that cautioned users about cardiovascular risks.
Still, this didn’t stop GlaxoSmithKline from winning approval for a combined product of rosiglitazone and glimepiride in US and Europe. In 2007, Avandia sales were up and Avandia was the company’s biggest drug, raking in $3 billion per year.
But in 2007, the hidden GlaxoSmithKline report was disclosed in the New England Journal of Medicine. The story said rosiglitazone was associated with a “significant increase in the risk of myocardial infarction” compared with placebo or other antidiabetic regimens. After that report, sales dropped by half.
In February of 2010, a Senate committee finance report accused the drugmaker’s executives of “focusing on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk.” In May, GlaxoSmithKline settled approximately 700 lawsuits for $60 million. A paltry amount considering the billions the drug raked in per year during its heyday.
Alternatives to Avandia are being studied and dismissed for similar reasons as Avandia. The rosiglitazone alternative, pioglitazone, has also been associated with an increased risk of oedema, heart failure, and bone fracture. At this point, no one is willing to “assume” that pioglitazone is safe.
Other antidiabetic drugs are in development and the history of Avandia and other glitazone drugs “have not deterred manufacturers.” Companies are still working on other glitazone drugs and discussing the possibilities of placing the drugs in European and American markets.
But it is highly unlikely that the newer glitazone drugs will get a free pass like Avandia did from regulators, clinicians, or the pharmeuceutical industry.