GlaxoSmithKline Plc's diabetes pill Avandia came under intense scrutiny on both sides of the Atlantic on Friday, leaving the drug's future uncertain as its maker battles a growing tide of lawsuits.
In London, the European Medicines Agency (EMA) launched a new review into the risks and benefits of the medicine, adding to pressure on a product that already faces a grilling from U.S. experts next week over its cardiovascular safety.
More than 700 pages of documents, released to the public on Friday ahead of the July 13-14 advisory meeting, showed scientists at the U.S. Food and Drug Administration deeply divided over Avandia's heart risks.
Both the FDA and EMA will consider a range of options for Avandia, including whether the medicine should be pulled from the market. Some FDA staff and outspoken critics have called for a ban on future sales.
Avandia was once Glaxo's second-biggest drug but its sales have plunged since safety fears erupted three years ago. Revenues totaled 771 million pounds ($1.17 billion) in 2009, equivalent to 2.7 percent of Glaxo's group sales.
The big worry for investors, though, is litigation.
Concerns about the medicine's adverse impact on the heart have triggered a slew of lawsuits in the United States and fresh criticism of the drug from regulators is likely to make matters worse by playing into the hands of plaintiff lawyers.
Glaxo has vigorously defended the medicine, based in part of study called Record that the British drugmaker said found no higher rates of heart-related hospitalizations or deaths.
An FDA cardiology expert sharply criticized the study in a memo prepared for the advisory panel.
The trial was inadequately designed and conducted to provide any reassurance about the cardiovascular risks of Avandia, wrote Dr. Thomas Marciniak, a medical team leader in the FDA division that reviews heart drugs.
But Dr. Ellis Unger, a deputy director in FDA's drugs center, said aside from the known risk of heart failure, the study does not appear to demonstrate harm from Avandia. The drug's warning label already warns about heart failure risk.
Morgan Stanley analyst Andrew Baum said the FDA documents were in-line with expectations and shed little new light on the direction the agency is leaning.
Glaxo's European medical director, Tony Hoos, said Avandia was an important treatment option for appropriate Type 2 diabetes patients.
The FDA usually follows recommendations from advisory panels but is not required to.
Glaxo shares were down 0.6 percent in New York Stock Exchange afternoon trading after closing unchanged in London, where they recovered from being down as much as 2.6 percent.
Persuading doctors and patients of the benefits of a drug is becoming an uphill battle, with two recent anti-Avandia studies.
In one study, Dr. Steven Nissen, a cardiologist at Ohio's Cleveland Clinic and an outspoken Avandia critic, offered even more ammunition to his 2007 analysis that first suggested Avandia raises heart risks.
In the second, FDA reviewer David Graham found Avandia was more dangerous to the heart than Actos.
Both Graham and Nissen believe the drug is too risky to stay on the market and will speak to the panel.
An FDA analysis released in Friday's documents compared the risks of Avandia and a competitor, Takeda Pharmaceutical Co's Actos.
A review of several clinical trials found heart attacks, strokes or related deaths were lower for Actos compared with other diabetes drugs or a placebo. FDA reviewers added, however, that differences in study design limited the ability to directly compare Avandia and Actos.
There is not complete unanimity within the FDA about the interpretation of these data, Dr. Janet Woodcock, head of the FDA's drugs center, told reporters.
A current trial called Tide was designed to directly compare Avandia and Actos. Some critics who see Actos as safer have called the study unethical. The FDA will ask the advisory panel if the study should continue.
TEST OF FDA
Ambrian Partners analyst Mike Ward said the ultimate downside would be a panel recommendation for Avandia's withdrawal, which FDA would not have to act upon but probably would, given the politics of the situation.
More likely, is yet further tightening of Avandia's label or maybe a restriction on its use to patients failing on Actos therapy, Ward said.
The Avandia controversy is seen as a test for the FDA under Democratic President Barack Obama and his chosen leader, Commissioner Margaret Hamburg. Doctors, drugmakers, investors and patient advocates are closely watching the decision as a sign of how the agency will handle future medicines.
Concerns have dogged Avandia since 2007 when Cleveland Clinic researchers linked the pill to a higher heart-attack risk. An advisory panel that year agreed the data suggested Avandia may increase the chances of a heart attack for some patients but said the medicine should remain an option.
European regulators have also concluded in a number of previous reviews -- the last of which was early this year -- that the overall risk-to-benefit balance was favorable.
But that verdict may not last and the EMA said it would decide once relevant data was analyzed if Avandia's marketing authorization should be revoked, suspended or changed.
Experts from the agency's Committee for Medicinal Products for Human Use will discuss the issue at their next plenary meeting in London on July 19-22.
(Additional reporting by Susan Heavey; Editing by David Cowell and Tim Dobbyn)