July 14, 2010 -- In the face of mounting evidence that GlaxoSmithKline withheld important safety data on their controversial drug Avandia, some doctors are abandoning use of this diabetes treatment.
Documents released Tuesday morning by the Senate Finance Committee suggested that for more than a decade, the drugmaker deliberately hid study results showing that Avandia could worsen certain risk factors for heart disease and was no better than its market competitor Actos.
The documents include several internal emails that record GlaxoSmithKline officials suggesting that certain unfavorable studies concerning the drug "never see the light of day to anyone outside of GSK."
"It's just not morally or ethically acceptable for companies to withhold data," says Dr. Steve Nissen, chair of Cardiovascular Medicine at the Cleveland Clinic and author of the original RECORD study, which raised public concern over Avandia's safety.
GlaxoSmithKline responded in an official statement that the studies were withheld because they failed to add new scientific information, but the growing evidence against the drug and the possibility of a cover-up is enough to deter some doctors from using the drug.
Release of these documents comes at the start of two days of advisory panel hearings to investigate Avandia's safety. The panel's recommendations could include keeping the drug on the market, calling for further restrictions or pulling the drug from the market altogether.
To Prescribe or Not to Prescribe: The Avandia Question
Avandia's safety was first publically called into question in 2007 when an analysis by Nissen found that those on the drug had a 43 percent higher risk of heart attacks and a 64 percent higher risk of dying from heart disease.
More recently, Food and Drug Administration associate director of drug safety Dr. David Graham called for Avandia to be removed from the market in a February report. He said the drug could be linked to about 500 more heart attacks and 300 more cases of heart failure each month than would occur if its competitor, Actos, were used exclusively.
Though the FDA's verdict is still out on Avandia's safety, the controversy raging over the drug has already had an impact on the doctors and patients who use the drug, physicians say.
"For my patients on Avandia, many of them have already asked to be switched to Actos," said Dr. Andrew Carroll, a family physican based in Chandler, Ariz.
"Based on prior studies I had read, I stopped prescribing Avandia about two years ago, and have been sticking with Actos," he added, saying that until the FDA makes a recommendation or further studies prove the drug is safe, he will be steering clear of Avandia.
Dr. John Sutherland, program director emeritus at Northeast Iowa Medical Education Foundation, said he has been slowly shifting his at-risk patients off Avandia, but said he has a few remaining patients on the drug.
Given the recent evidence that further risks were withheld by GlaxoSmithKline, he said that "we have made a decision to have all of [the few remaining patients on Avandia] switched to another therapy at this time."
Dr. Eric Larson, executive director of Group Health Research Institute, said he does not prescribe Avandia and even cancelled a research study on the drug after earlier reports of the drug's toxicity.
"The Senate documents and FDA hearings only confirm our earlier assessments of the safety of this drug -- it's gratifying to have our decisions confirmed but terribly disappointing that this hasn't been resolved earlier or even by now apparently," he said.
Though the drug has lost more than half of its sales since the 2007 study, it still generated more than $1 billion in revenue and was prescribed to 2.6 million Americans in 2009.
The Hidden Studies
The documents released by the committee highlight a 1999 study, referred to as Study 175, which assessed the effects of Actos on patients. In internal emails included in the document, company officials explain that the point of the study was to determine whether a direct comparison study between Actos and Avandia would cast Avandia in a negative light.
When comparing the Actos results with how Avandia historically performed, GlaxoSmithKline decided not to do such a comparison given that Actos seemed to perform as well as Avandia with fewer cardiovascular side effects.
In a 2001 internal GlaxoSmithKline email sent by executive Dr. Martin Freed to former medical director Dr. Stuart Dollow and other employees, Freed acknowledged that given the positive results of study 175, Avandia would lose in a "head to head" comparison with Actos.
"Per Sr Mgmt request, these data should not see the light of day to anyone outside of GSK," Freed wrote in the email.
Neither this comparison, nor the original study 175 data on Actos were released publically.
The committee also provides email documentation from 2001 in which GlaxoSmithKline executives discuss whether to publish two other studies that found problems with Avandia:
"Not a chance. These put Avnadia [sic] in quite a negative light when folks look at the response of the [Avandia] arm. It is a dificult [sic] story to tell and we would hope that these do not see the light of day."
GlaxoSmithKline denied covering up safety concerns of Avandia saying that the Senate Finance Committee "cherry-picked" only 158 pages of 14 million pages the company turned over to the committee, according to GlaxoSmithKline's official response by director of U.S. media relations, Mary Ann Rhyne.
Even after concerns over Avandia's cardiovascular safety were made public, the company fought against placing a black box warning on the drug.
In fact, according to a deposition by Dr. Rosemary Johann-Liang, a former supervisor in the drug safety office at the FDA, the FDA's Division of Drug Risk Evaluation knew about the increased risk of congestive heart failure by early 2006 but failed to issue a black box warning at the time.
Johann-Liang said she recommended a black box warning in February 2006 to Dr. Mark Avigan, director of the Division of Drug Risk Evaluation, but was scolded for making a recommendation on heart risk when she was only asked to look into the possible risk of fluid buildup in the eye, also known as macular edema.
"Based upon all of the information that was currently available, I thought, actually, the black box warning for in 2006 for congestive heart failure was late," she said.
According to Johann-Liang, before 2006, "there were many reports, some very telling reports of patients who have been hurt, patients who have died on the drug."
The FDA advisory panel is set to announce whether it recommends pulling Avandia from the market Wednesday evening.