"I wanted our actions to put a roadblock in a rapid approval that I thought would present a danger to patients. I'm trying to avoid another Vioxx," said study author Dr. Steven Nissen, medical director of the Cleveland Clinic Cardiovascular Coordinating Center. "In the manuscript, I have clearly requested that a large outcomes trial be done before approval, and I believe that the FDA will see that that's a wise thing to do."
Ironically, Nissen and study co-author Dr. Eric Topol were the ones who first raised safety issues about Vioxx back in 2001. "Nobody listened then because it was already on the market being advertised," Nissen said. "I saw this as a potential to stop a potentially risky drug before it got out of the gate."
His study and an accompanying editorial were released Thursday by the Journal of the American Medical Association because of the public health implications.
The medication, muraglitazar, is one of a class of drugs called dual peroxisome proliferator-activated receptors (PPARs), which affect both cholesterol levels and blood sugar levels in diabetic patients. Many people with diabetes suffer from both problems, and this drug was earlier hailed as a way to kill two big birds with one stone or one pill, as it were.
Two other drugs in the class, pioglitazone and rosiglitazone, are already on the market. A third, troglitazone, was withdrawn due to liver toxicity problems.
Muraglitazar was developed by Bristol-Meyers Squibb, which has signed a marketing agreement with Merck.
Briefing documents on muraglitazar were made available to the public on Sept. 8, and were reviewed by an FDA advisory committee a day later. The committee voted 8-to-1 in favor of approving the drug to control blood sugar in patients with type 2 diabetes.
On Oct. 18, the FDA issued an "approvable letter" for the drug, meaning that muraglitazar could be approved once the agency received and reviewed additional information.
Nissen said he accessed the briefing documents as soon as they became available on Sept. 8, and saw "what appeared to be a very strong signal for excess cardiovascular events." He immediately set about doing an analysis, writing a manuscript and submitting it for publication. A process that usually takes months or even years was completed in only slightly more than a month.
"I treated this as a public health emergency," Nissen said. "A drug that had an 8-to-1 vote in favor of approval and that could any day be approved by the FDA to be used by any of 18 million Americans with type 2 diabetes was, by my analysis, doubling of risk of serious irrevocable cardiovascular events like death, heart attacks and stroke. I dropped everything."
Nissen, Topol and biostatistician Kathy Wolski, all of the Cleveland Clinic, analyzed the information that had been made available by the FDA. In all, it included data from five clinical trials that involved 3,725 people randomized to receive either muraglitazar, pioglitazone or a placebo, either alone or in combination with other diabetes drugs. Participants took the drugs from 24 to 104 weeks, considered to be a relatively short period of time.
In the muraglitazar group, 1.47 percent of participants experienced death, heart attack or stroke, compared with 0.67 percent of those in the two other groups, meaning that those taking muraglitazar had a 2.23 times higher risk of one of these outcomes.
When congestive heart failure and mini-strokes were added to the analysis, the combined incidence of these events was 2.62 times higher in the muraglitazar group.
Because people with type 2 diabetes already have a high incidence of cardiovascular disease (it represents the cause of death in about 80 percent of these patients), drugs need to be carefully screened in terms of heart attack and stroke risk, the researchers noted.
The accompanying editorial also pointed out numerous methodological issues in the original studies that may have skewed the results. For one thing, those researchers included doses of 2.5 milligrams or less, doses that were significantly lower than the 5-milligram dose for which FDA approval is being sought. Overall, this made the drug look safer. The populations studied also appeared to be healthier than the general diabetic population. In addition, an increased incidence of cancer was seen and needs to be studied further. Last but not least, the editorial stated, the researchers limited peer-review publication of the results before going for FDA approval "so as to minimize scrutiny and debate."
Nissen acknowledged the studies yielded a relatively small number of actual adverse events, which does introduce "some uncertainty" into the equation.
When any drug is developed and brought to market, benefits need to be weighed carefully against risks. In this case, the researchers stated, the efficacy is not so dramatic that it overrules safety concerns.
"The drug's benefits are simply to lower blood sugar, something that is not a morbidity and mortality advantage, so my view is that safety has to be very clear before you're going to approve it, and we have 15 other drugs to lower blood sugar," Nissen said. "In my view, it didn't make any sense to approve the drug."
In response to the journal article, Merck & Co. issued a formal statement Thursday that said, "Following the receipt of an approvable letter for Pargluva (muraglitazar) earlier this week, Bristol-Myers Squibb and Merck said that we are eager to begin discussions with the FDA to address more fully the cardiovascular safety profile of the compound and to determine what additional information may be necessary. Pargluva was extensively studied and all available data were reported to the FDA."
The new findings points up now familiar problems with the U.S. drug approval and regulatory process.
"I felt that that committee that voted 8-to-1 was simply missing the boat," said Nissen, who has served on FDA advisory committees. "I didn't think they connected the dots."
Problems on the committee reflect problems at the FDA, Nissen added.
"There are some big problems," he acknowledged. "The FDA is under-funded. Given all the things that seem to get money in the United States, the FDA is not pork. It is protecting the public health, and it is under-funded and under-supported, and getting good advisory panels is hard."
The question now, the editorial points out, "is which safety message will the FDA buy?"
"We are fully aware of the results of the Pargluva clinical trials, both with regard to safety and efficacy, and likewise appreciate the need for careful assessment of risk vs. benefit for all drugs, particularly those indicated for long-term, preventive therapy," said FDA spokeswoman Crystal Rice. "The application is still pending before the agency and, as such, we can't comment further at this point."
"While we cannot specifically discuss this particular drug further, the FDA has made significant investments of resources and expertise in developing fundamentally better methods for identifying and monitoring cardiovascular safety issues with all drugs," she added.
More information
To learn more about type 2 diabetes, visit the American Diabetes Association.
