A consumer watchdog group has accused the makers of a popular asthma drug of manipulating safety data submitted to the FDA two years ago to create the impression the drug Serevent is safer than it is.
GlaxoSmithKline officials vehemently denied the charge, made by Public Citizen's Health Research Group in a letter in this week's issue of the British medical journal The Lancet.
"Throughout this process, GlaxoSmithKline communicated ... with a sense of urgency, to ensure that healthcare professionals and patients had access to the results of the study as they became available," a GlaxoSmithKline statement said.
Serevent or salmeterol, known as Advair when combined with the steroid fluticasone, carries a black box label warning of a small but significant increase in asthma-related deaths among patients who use it. But officials with the Health Research Group, which has Serevent on its list of "Do Not Use" drugs, say the warning labels don't go far enough.
The controversy surrounds a large 28-week trial involving tens of thousands of patients, called the Salmeterol Multicenter Asthma Research Trial, or SMART. The trial was initiated in 1996 because of concerns about possible health risks associated with Serevent, a long-acting beta agonist used to help open airways by relaxing muscles during an asthma attack.
The trial was designed as a 28-week randomized controlled trial, but Health Research Group officials charged that when GlaxoSmithKline submitted its final study results to the FDA on April 29, 2003, the company mixed in data about patient deaths that occurred six months after the trial ended.
"They were just adding noise," said Dr. Peter Lurie of the Health Research Group, co-author of the letter in Lancet. "And in each case, the addition of the post-study data noise reduced the apparent risk of the drug."
During the 28-week trial, for example, patients taking Serevent suffered 13 asthma-related deaths, more than four times as many as the subjects taking the placebo, who had three asthma-related deaths.
But six months after the trial ended, patients in the Serevent group had suffered 15 deaths, 2.5 times as many as the placebo group, which by then had six asthma-related deaths.
Kathy A. Rickard, a GlaxoSmithKline vice-president who responded to the letter in Lancet, wrote, "The only dataset analyzed for the interim analysis included events from the 28 week plus 6 month period. ... Subsequently, the FDA requested that GSK further refine the analysis to included data from the 28-week treatment period." That data was submitted to the FDA in May 2004, Rickard wrote.
But the company had no intention of misleading the FDA, spokeswoman Patty Johnson said yesterday. "That's how it was submitted. It wasn't hidden in any way."
FDA officials did not respond to telephone calls requesting comment yesterday. However, FDA documents available on the government Web site reflect the drug reviewers' concerns about the data that was initially submitted. "The [FDA] Division disagrees with the inclusion of the post-study adverse event data in the analysis," a review summary states.
The controversy came to light when documents about the drug were made public prior to an FDA Pulmonary-Allergy Drugs Advisory Committee meeting July 13. Results of the SMART study have not been published in a journal.
"Our position is that this is not a drug patients should be using," said Lurie of the Health Research Group. "There are short-acting beta agonists that are effective that have not been associated with increased mortality. ... This is consistent with previous findings about other long-acting beta agonists."
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