August 19, 2010
Dr. David Graham, of the Food and Drug Administration, called Glaxo's summary “biased, misleading and not truthful.”
Federal drug regulators ordered GlaxoSmithKline to send a letter to crucial doctors describing a hearing in July where an expert advisory panel discussed the risks of Avandia, the company’s controversial diabetes medicine.
But a federal official and some members of the panel now say the company’s letter is misleading and could endanger patients. The dispute is occurring just weeks before the Food and Drug Administration is expected to announce whether Avandia’s label must include new warnings, whether sales of the drug will be restricted or whether Avandia must be withdrawn from the market.
Doctors who received the letter, dated July 28, are investigators in a study called the Tide trial, which was intended to compare the heart risks of Avandia with those of Actos, a similar drug made by Takeda Pharmaceuticals.
Results of the trial, which was requested by the F.D.A., are not expected for years. The ethics of the Tide trial were a point of contention at the advisory committee hearing, and the F.D.A. ordered GlaxoSmithKline to stop recruiting new patients into the trial, although current patients could continue.
Dr. David Graham, an F.D.A. medical officer, made an impassioned presentation at the advisory hearing arguing that the study should be stopped because thousands of patients in the trial were being exploited. None of these arguments were mentioned in GlaxoSmithKline’s letter.
“This summary is biased, misleading and not truthful,” Dr. Graham said in an interview. “The whole purpose of this letter is so that they can reassess whether this is an ethical trial going forward, but the step-by-step ethical flaws and problems with the Tide trial are not even referenced.”
Several members of the advisory committee complained that the company’s letter was biased.
“This letter is really deceptive,” said Dr. Clifford J. Rosen, a panel member. He added that the letter also did not refer to a presentation at the hearing by members of an Institute of Medicine study panel that said observational studies could be useful.
Dr. Curt D. Furberg, also a panel member, described the letter as a “very Avandia friendly” document that ignored much of the discussion criticizing the validity of GlaxoSmithKline’s studies. Other panel members expressed similar reservations.
But another panel member, Dr. Sanjay Kaul, disagreed, saying the letter “faithfully reflects the deliberations of the Avandia advisory meeting.”
Erica Jefferson, an F.D.A. spokeswoman, said that after ordering GlaxoSmithKline to send a summary of the hearing to the Tide trial investigators, the agency had relied on the company to provide a balanced account. “F.D.A. did not preclear or approve the content,” she said.
Mary Anne Rhyne, a GlaxoSmithKline spokeswoman, said the company had only one week to write the 10-page summary, which was necessarily brief. But the company and the leader of the Tide trial agreed that the letter “reflected the science and data discussed at the advisory committee meeting,” Ms. Rhyne said.
Dr. Steven Nissen, a Cleveland Clinic cardiologist who made a presentation before the committee arguing for Avandia’s withdrawal, said that GlaxoSmithKline’s letter did not mention that the committee had concluded that Avandia carried a higher risk of heart attack than Actos.
“Since the Tide trial compares these two alternative therapies, this omission does not meet any reasonable ethical standards,” Dr. Nissen said.
The dispute is part of a continuing battle over what the 33-member committee actually decided in July. The committee’s most important vote was on whether Avandia should remain on the market and, if so, how.
Five options were offered. No panel members voted for continuing the marketing of the drug and removing from the label the boxed warning and other warnings involving increased risk of stroke or heart attack.
Three panel members voted for no change; seven voted to add more warnings to the drug’s label; 10 voted to severely restrict the drug’s marketing; and 12 voted that the drug should be withdrawn. One abstained.
Some commentators emphasized that a majority of the panel had voted to keep the drug on the market. Others said that a majority had voted to withdraw or severely restrict the drug’s sales. The former group interpreted the meeting as largely positive for GlaxoSmithKline; the latter said it had been a blow to the company, which is based in Brentford, England.
If the drug is withdrawn, this latest dispute will disappear because the Tide trial itself will most likely end.
The F.D.A. usually follows the advice of its advisory committees, but not always.
* After Avandia: Does The FDA Have A Drug Problem?
Massimo Calabresi with Alice Park, TIME Magazine