FDA review finds flaws in clinical trial for diabetes drug Avandia

By Christopher Rowland, Globe Staff

WASHINGTON – A key clinical trial that drug maker GlaxoSmithKline has relied upon to defend the risk profile of Avandia, a drug to treat type-2 diabetes, was thrown into doubt today by a new FDA analysis.

The finding gave GlaxoSmithKline more bad news in advance of a Food and Drug Administration advisory panel meeting next week on Avandia, which has been beset by safety questions since 2007.

The advisory panel has been asked to advise the FDA whether the drug should be removed from the market because of warnings that it increases the risk of heart attacks and other serious cardiovascular events.

Surveys of clinical trials and Medicare patient outcomes data have shown elevated risks of Avandia, compared to a competitor drug, Actos, manufactuered by Takeda Pharmaceutical Co.; one FDA researcher has estimated that 100,000 additional adverse events may have resulted from Avandia’s use since its approval in 1999.

In defense of its drug, GlaxoSmithKline has cited some clinical trials, particularly one called RECORD, that it said showed Avandia was safe.

"Large, long-term study shows Avandia has no increased overall cardiovascular risk compared to other commonly used diabetes medicines,’’ the company said in a press release about the RECORD results a year ago.

But an FDA reviewer, in a June 14 analysis that the agency released today in advance of next week’s meeting, said the RECORD trial contained flaws and could not reliably support that assertion.

"Our summary is that RECORD was inadequately designed and conducted to provide any reassurance about the (cardiovascular) safety’’ of Avandia, wrote the reviewer, Thomas A. Marciniak, medical team leader in the division of cardiovascular and renal products.
"The results do confirm and extend the recognized concerns regarding increased heart failure (HF) and HF deaths,’’ he wrote.

Extending a pattern of disagreement and debate within the agency, another FDA official took issue with some of Marciniak's findings: "With respect to cardiovascular safety, the strength of reassurance provided by RECORD can (and will) be debated, but, aside from the known risk of heart failure, the study does not appear to demonstrate harm,'' that dissenting analysis said.

In response today, GlaxoSmithKline pointed out that in another document, FDA notes that three of its inspections of clinical sites where the RECORD trial was conducted did not reveal anything that would undermine reliability of the data.

"The RECORD study was conducted according to good clinical practices and the data are reliable,’’ the company said. "This was the largest and longest prospective clinical trial examining Avandia's cardiovascular safety; RECORD demonstrated that Avandia was not associated with an overall increase in cardiovascular hospitalization or cardiovascular death.’’