Drug Nearing OK Comes Under Fire
A diabetes drug on track to win approval from the Food and Drug Administration doubled the risk of death, heart attack and stroke, researchers reported Thursday in a study that renewed concerns about the government’s safety screening for new medications.
Researchers at the Cleveland Clinic analyzed data provided to the FDA by the drug’s developers and found that the medicine, Pargluva, also more than doubled the risk of congestive heart failure and transient ischemic attacks, also known as mini strokes.
The study was published online Thursday by the Journal of the American Medical Assn. just days after the FDA issued a letter notifying Bristol-Myers Squibb Co. and Merck & Co. that their drug was “approvable” once some follow-up safety information was provided. An FDA advisory committee, in an 8-1 vote, recommended approving Pargluva to treat Type 2 diabetes last month.
The medical journal said it published the study early on its website because of its “timeliness and potential importance for public health.”
Dr. Steven Nissen, lead author of the study, said the failure of the FDA panel to recognize the drug’s health risks showed a continuing weakness in the government’s drug-approval process.
“I think the FDA advisory committee was asleep at the switch,” Nissen said. “The question is, did they not get it, or did they get it and were not willing to stand their ground?”
In an editorial accompanying the study, Dr. James M. Brophy of McGill University said that the drug makers skewed the data to downplay Pargluva’s safety risks.
He said they excluded many patients with existing heart troubles and included patients who took dosages well below the levels they planned to market to make Pargluva seem safer.
David Rosen, a spokesman for Bristol-Myers Squibb, said experts at the company were examining the new journal reports and weren’t ready to comment on their specific conclusions.
But he said the safety and efficacy studies of Pargluva were conducted by “outside experts and thought leaders in diabetes treatment.”
“These trials that were conducted on Pargluva were designed like other clinical trials for a diabetes drug,” Rosen said.
Merck issued a statement saying that “Pargluva was extensively studied and all available data were reported to the FDA.”
The FDA said it could not comment on Pargluva because its application was pending. But the agency said it had recently launched a number of initiatives to better monitor cardiovascular safety for all medications.
Pargluva is considered a promising drug for Bristol-Myers and Merck, and is expected to generate sales of $300 million to $900 million in its peak year, Wall Street analysts said.
The drug, generically known as muraglitazar, is the first of a new class designed to combat Type 2 diabetes, which affects more than 16 million Americans, said the Centers for Disease Control and Prevention.
Type 2 diabetes is closely associated with obesity and occurs when the pancreas reduces its output of insulin or when cells elsewhere in the body become resistant to the effects of insulin.
There are several drugs already on the market to increase a patient’s sensitivity to insulin or to combat the high-cholesterol problems that often accompany diabetes.
Pargluva is the first combination drug to tackle both problems at once.
Dr. Michael Bryer-Ash, director of the Gonda Diabetes Center at UCLA’s David Geffen School of Medicine, said the new reports made a strong case that the FDA should conduct larger studies focused on cardiovascular safety before giving Pargluva final approval.
“It’s nice to have a combination drug, but since we have a number of available drugs that will do the job, we shouldn’t leap to embrace a drug too quickly just because it’s a combination,” he said.
Nissen said he was prompted to study Pargluva after hearing concerns from colleagues.
When the FDA posted data from the drug’s ongoing trials in advance of the advisory committee hearing, he conducted a cursory analysis and discovered a high number of deaths, heart attacks, heart failure and mini strokes, he said.
“I assumed the drug would be rejected unanimously,” he said. When it was approved, “I was just stunned. I said, ‘We’ve really got to do something.’ I felt it was a potential public health catastrophe.”
The Cleveland Clinic researchers examined data from five clinical trials and excluded patients who received the highest doses of the drug because the companies decided not to market those dosages, Nissen said.
Of the 2,374 people who took Pargluva, 35 patients, or 1.5%, experienced heart attacks, strokes or death, they reported. That rate was 2.2 times greater than for patients who took an existing diabetes drug called pioglitazone or a placebo.
Nissen said if Pargluva was approved it probably would be used by diabetics in worse shape than those in the clinical trials.
“I was concerned that high-risk cardiovascular patients would get it and that would further amplify the risks we’re seeing” he said.
The criticism of the FDA over Pargluva echoed some of the complaints made last year when Merck took the popular painkiller Vioxx off the market after studies confirmed it increased the risk of heart attacks and strokes.
FDA medical reviewers were aware of at least a theoretical possibility that Vioxx could raise blood pressure, according to testimony before a Senate panel that held hearings on the issue. However, the agency did not seek follow-up heart safety studies from Merck.
The Vioxx debacle called into question the FDA’s system for overseeing drug safety, particularly because one of the epidemiological studies the agency ignored was produced by one of its own scientists.
The release of the studies Thursday had little effect on the stock price of Bristol-Myers, which dropped 38 cents to $21.67, or Merck, whose shares were unchanged at $26.92.
Analysts noted that the drug was not expected to reach the market until 2007.
Times staff writers Ricardo Alonso-Zaldivar in Washington and Thomas H. Maugh II and Denise Gellene in Los Angeles contributed to this report.
