GSK's Avandia should be pulled from the market in light of recent studies, a number of physicians and industry experts have argued. However, others believe that there is not yet sufficient data to warrant such a conclusion.
Avandia increased the risk of heart attacks by 42% and doubled the risk for heart failure, according to a recent edition of Journal of the American Medical Association. The Journal also found that Takeda's Actos – which is in the same drug class as Avandia – had a protective benefit, and lowered the risk of heart attacks, stroke and death by 18%. Still, the drug reported a slight risk of increased heart failure.
Dr Steven Nissen, chief of cardiovascular medicine at the Cleveland Clinic and co-author of one study, said the fact that another drug in the same class has a protective benefit will put a lot of pressure on the FDA.
"The FDA is currently working on a statement and I think they are looking at the issue of removing Avandia," said Robert Spanheimer, Senior Director of the US Diabetes Division at Takeda Pharmaceuticals.
The two studies involving Avandia add to two existing ones which show an increased risk of heart attack. Nissen pointed out that the study is the first meta-analysis that shows that Actos has a protective benefit.
"There are cheaper, safer alternatives," said Dr Sonal Singh, lead author on the Avandia analysis. Metformin is a safer drug, and maybe physicians should use insulin earlier, he noted.
The availability of newer drugs on the market, such as Merck's Januvia or Amylin's Byetta, will not be relevant in the FDA's decision, as physicians need drugs in different classes for use in combination treatment, explained Nissen.
Singh said there is accumulating evidence that both Actos and Avandia can double the risk of bone fractures in diabetic women. "These drugs are both linked to blindness due to fluid accumulation," he added.
Avandia shows four hard outcomes, including increased risk for blindness, fractures, heart attacks and heart failure, said Singh.
However, others take a more nuanced view.
"Avandia wasn't designed to stop cardiovascular disease, it was just designed to treat diabetes," said Dr Nir Barzilai, a director at the Institute for Aging Research at the Albert Einstein College of Medicine in New York. Barzilai says that Avandia could be pulled from the market, and placed back with restricted labeling.
"I'm not a huge supporter of Avandia, but I'm not a supporter of reacting to data that is not conclusive," he added.
Meanwhile, Dr Narinder Duggal, pharmacy specialist and medical director at Liberty Bay Internal Medicine in Washington state, pointed out that Actos has a more favorable lipid profile as it does not increase the triglycerides and HDL and so has a more favorable effect.
But Avandia's critics remain adamant.
Singh said that for every 220 diabetic patients in one year, one will have an additional heart attack due to Avandia. "For heart failure, it's one in 30 patients," Singh added.
Dr Peter Lurie, deputy director of the Health Research Group at Washington-based safety group Public Citizen, is continually tracking patients who report congestive heart failure through the Adverse Events Reporting System (AERS). The FDA relies on this system to flag potential safety issues and identify drugs for further study, which may lead to drug labeling changes, letters to health care professionals, or market withdrawals.
Avandia stands for a very clear case of division between the safety branch and the approval branch of the FDA, said Lurie. The controversy surrounding Merck's Vioxx drug should have underlined to the FDA that those two branches need to be more independent of each other, he said.
In 2004, Vioxx was one of the most widely used drugs ever to be withdrawn from the market due to increased cardiovascular risk. It was alleged that the number of deaths reported in the study that preceded Vioxx's introduction was reduced.
In the case of Vioxx, the FDA allowed Merck to drag the entire negotiation procedure out, said Lurie. Vioxx had sales of USD 2.5bn before the company announced a voluntary recall.
The most important thing for drug safety is the removal of the drug safety division from being underneath the Center for Drug Evaluation and Research (CEDR). "That is not likely to be part of the conference negotiations since it was not proposed at the House. It also failed narrowly in the Senate," said Lurie.
"There is a conflict of interest where the agency is addicted to industry funding," he said. Dr Narinder Duggal views the testing methodology as being key.
"The problem is a relative risk of increase, and unless it is greater than three, it is probably meaningless," said Duggal. The larger the relative risk, the stronger the evidence for causality.
However, it has been well documented that a meta-analysis, which is a combination of results from previous studies, is usually hypothesis generating and does not imply causation.
Duggal said a clearer picture can only be established by a randomized double-blind pseudo-control trial, which is currently on-going in Avandia.
The FDA has historically been cautious in the use of meta-analyses in support of regulatory decisions, said FDA Commissioner, Andrew C. Von Eschenbach in a previous statement made before the FDA Committee.
Still, Dr Joel Zonszein, director of the clinical diabetes center at Montefiore Medical Center in New York said he did not think Avandia should be compared to Vioxx. Two-thirds of the physician community currently believe there is not enough evidence to pull Avandia from the market, said Zonszein.
At the current time, the relative risk does not appear to be significant based on the total breadth and depth compiled to date. That is why the FDA is having a problem, as there is not enough evidence or support, said Duggal.
Takeda's Actos is the current market leader in the non-insulin therapy market for type II diabetes, with 40% market share. Avandia reported USD 3.3bn in sales last year, but has seen a steep drop in sales in light of recent controversy.
"There is no question that most doctors right now who have litigation aversion will stop Avandia," said Duggal. Lawsuits against GSK have already been filed.