Avandia is back in the headlines as a pair of US senators have questioned the safety of GlaxoSmithKline’s diabetes drug and criticised the Food and Drug Administration for allowing an “unethical” trial comparing the treatment with Takeda’s Actos to proceed.

Max Baucus and Chuck Grassley have released the details of a Senate Finance committee report based on a two-year inquiry of Avandia (rosiglitazone). Investigators reviewed more than 250,000 pages of documents provided by GlaxoSmithKline, the FDA “and several research institutes” after the New England Journal of Medicine published a study in May 2007 warning of the possible cardiovascular risk of the drug.

In a letter to FDA Commissioner Margaret Hamburg, the senators claim that “the totality of evidence suggests that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public”. They add that based on this knowledge, “GSK had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner” but instead, company executives “intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that the rival drug Actos (pioglitazone) might reduce cardiovascular risk”.

The report also cites an analysis conducted by two FDA safety officials, David Graham and Kate Gelperin, conducted in October 2008 that “raises some alarms”. For instance, they wrote that there is “no evidence that rosiglitazone confers any unique health benefits over pioglitazone while there is strong evidence that rosiglitazone confers an increased risk of [heart attacks] and heart failure compared to pioglitazone”.

“Even more alarming”, claim the senators, the FDA officials concluded that “any proposed head-to-head trial of rosiglitazone versus pioglitazone would be unethical and exploitative.” However that trial, called TIDE, is currently recruiting patients and the senator have asked the Food and Drug Administration to describe what steps it has taken to protect patients in the study and why it is allowed to continue, “given that the FDA itself estimated that the drug caused approximately 83,000 excess heart attacks between 1999 and 2007”.

Sen Grassley said “there’s a real problem when FDA’s office that reviews drugs that are on the market is an unequal player in drug safety efforts”. He added that “it doesn’t make any sense to have these experts…under the thumb of the officials who approved the drug in the first place and have a natural interest in defending that decision”.

Sen Grassley concluded that the Avandia case “may be the most alarming example of the problem”, saying that the FDA and Congress “need to take every step possible to establish independence for post-market surveillance…it’s a matter of sound science and public safety. Americans have a right to know there are serious health risks associated with Avandia and GSK had a responsibility to tell them”.

GSK has come out fighting saying the Senate report “are based on analyses that are not consistent with the rigorous scientific evidence supporting the safety of the drug”. The company adds that the report “cherry-picks information from documents, “which mischaracterises GSK’s comprehensive efforts to research Avandia and communicate those findings to regulators, physicians and patients”.

GSK goes on to say that “contrary to the assertions in the report, and consistent with the FDA-approved labelling, the scientific evidence simply does not establish that Avandia increases cardiovascular ischemic risk or causes myocardial ischemic events”. It adds that in the years since the FDA addressed these questions about the cardiovascular safety of rosiglitazone, “seven large, prospective, randomised, clinical trials have reported results” and none of these studies, “which remain the gold standard for evaluating scientific and medical questions”, show a statistically significant association between the drug and heart attacks or other ischemic cardiovascular events.

As for TIDE, the protocol has also been approved” by an independent review board and appropriate safety boards”, GSK said, concluding that “it does not condone any effort to silence scientific debate”. However, when it believes that “statements made by others don’t accurately present information on its products or its actions, GSK corrects inaccuracies and misstatements”.

As for Commissoner Hamburg, she said she is waiting for the recommendations of an advisory committee looking at Avandia and meanwhile, “I am reviewing the inquiry made by Sens Baucus and Grassley and I am reaching out to ensure that I have a complete understanding and awareness of all of the data and issues involved.”