New Diabetes Drug Increases Mortality / Morbidity – FDA "approvable" letter Challenged

New Diabetes Drug Increases Mortality / Morbidity – FDA “approvable” letter Challenged

Fri, 21 Oct 2005

Today’s newspaper reports about a lethal new diabetes drug that the FDA was poised to approve makes abundantly clear that The New York Times got it wrong when it gave the FDA high marks on safety. [1] Rather than demonstrating increased attention to drug safety concerns during the pre-approval evaluation process, FDA officials have NOT modified the way the agency evaluates the safety of new drugs. Lethal drugs are still deemed “approvable” by the FDA and its rubber stamping advisory panels.

A major data analysis by leading cardiology specialists in the Journal of the American Medical Association (JAMA) found that patients who were prescribed a new diabetes drug in clinical trials–a drug that the FDA deemed “approvable” last week–were at substantial increased risk of death, myocardial infarction (MI), stroke, congestive heart failure (CHF), and transient ischemic attack (TIA) in diabetic patients treated with muraglitazar (Pargluva) compared with controls.

JAMA rushed the analysis to the public online prior to its publication date “to head off a Vioxx-like fiasco.”

The distinguished analysts (from the Cleveland Clinic), Steven E. Nissen, MD; Kathy Wolski, MPH; Eric J. Topol, MD, found that even though patients with current or previous cardiovascular problems were excluded from the trial, deaths, heart attacks or strokes occurred in 35 of the 2,374 patients on muraglitazar (Pargluva) compared to nine such events among 1,351 patients in a combined group either on another drug or on placebo.

The authors note that “the real world exposure would likely substantially amplify the risk. Taken as a whole, these data demonstrate that it is likely that muraglitazar, if approved by the FDA, would constitute an unacceptable patient hazardŠ.constituting a public health catastrophe”

The Washington Post notes that the JAMA analysis “raises new questions about how the agency handles drug safety concerns.” Indeed, an analysis by an F.D.A. safety officer also noted the doubling of cardiovascular risks associated with the drug, but concluded that there was no clear pattern.

The JAMA authors noted a distinct pattern: “Muraglitazar appears to increase the risk for morbidity and mortality in diabetic patients during relatively short-term treatment. The estimated magnitude of this risk is substantial with [relative risks] RRs indicating a doubling for irrevocable, major end points and composite outcomes. The consistency of these RRs suggests that this result is not due to chance. Accordingly, muraglitazar should not be used or approved to treat patients with diabetes until an appropriate dedicated trial to assess cardiovascular outcomes is performedŠ.This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial.”

See: http://jama.ama-assn.org/cgi/content/full/294.20.joc50147v1

The Associated Press reports: “Critics including Nissen have accused the FDA of lax drug surveillance because of Vioxx and other recent safety issues, such as evidence linking some antidepressants with a greater risk of suicidal thoughts in youngsters.

The FDA appeared to be heading down the same road with Pargluva despite that criticism, said Dr. Catherine DeAngelis, JAMA’s editor in chief.

“It is beyond me why individuals who are supposed to be overseeing the safety of the public would take a chance when it’s not necessary,” DeAngelis said.

A JAMA editorial by Dr. James Brophy of McGill University, notes that the new analysis contrasts sharply with data company sponsors presented to the FDA showing no significant excess risk of death or cardiovascular problems.” “Company-provided data might have fostered an “illusion of safety.”

This case confirms, once again, that pharmaceutical companies cannot be trusted to provide the FDA with unbiased data analysis of their clinical trial data. When the financial stakes are billions of dollars, FDA’s reliance on drug manufacturers’ manipulated analyses of the evidence, as proof of safety and efficacy, is just plain preposterous.

See: THE NEW YORK TIMES : F.D.A. Responds to Criticism With New Caution By GARDINER HARRIS    August 6, 2005 http://www.ahrp.org/infomail/05/09/30.php

Contact: Vera Hassner Sharav
212-595-8974
veracare at ahrp org

Study: New Diabetes Pill Deemed Dangerous
By LINDSEY TANNER
The Associated Press
Thursday, October 20, 2005; 11:02 PM

CHICAGO — A new diabetes pill that was headed for government approval has been linked to deaths, heart attacks and strokes, a medical journal reported Thursday in an analysis it said was rushed online to head off a Vioxx-like fiasco.

The study by leading heart researchers found twice as many deaths and cardiovascular problems in diabetic adults taking the drug Pargluva as those on dummy pills or a competing drug.

Developed by Bristol-Myers Squibb and Merck & Co., the drug, known generically as muraglitazar, was endorsed by a Food and Drug Administration panel last month. It is a treatment for Type 2 diabetes, the most common form of the condition and one that occurs most often in people who are overweight.

The Journal of the American Medical Association said it posted the analysis on its Web site Thursday ahead of next month’s publication date because of public safety concerns. The study was by Cleveland Clinic doctors who reviewed data the FDA made public before the panel vote.

If the analysis is correct, the drug could have meant a “public health catastrophe” given that 18 million Americans have diabetes, said Dr. Steven Nissen, who worked on the analysis with Dr. Eric Topol and a clinic statistician.

“This is the Vioxx that isn’t going to happen,” Nissen said, referring to the popular painkiller Merck removed from the market last year after it was linked with serious heart problems. Nissen has done consulting work for several drug companies, including Merck and makers of other diabetes treatments, but said he does not accept fees for that work.

Critics including Nissen have accused the FDA of lax drug surveillance because of Vioxx and other recent safety issues, such as evidence linking some antidepressants with a greater risk of suicidal thoughts in youngsters.

The FDA appeared to be heading down the same road with Pargluva despite that criticism, said Dr. Catherine DeAngelis, JAMA’s editor in chief.

“It is beyond me why individuals who are supposed to be overseeing the safety of the public would take a chance when it’s not necessary,” DeAngelis said.

In a statement, the FDA said it appreciates “the need for careful assessment of risk versus benefit for all drugs, particularly those indicated for long-term, preventive therapy.”

“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.”

Bristol-Myers Squibb and Merck issued a written statement Thursday that said Pargluva “was extensively studied and all available data were reported to the FDA.”

Pargluva would be the first diabetes drug on the market designed to lower blood sugar, reduce fatty triglycerides and increase levels of “good” cholesterol, Nissen said. Other drugs achieve those results individually, said Dr. Peter Lurie, deputy director of the Public Citizen Health Research Group, a consumer advocacy group.

The analyzed data involved 3,725 patients who took Pargluva or a drug called pioglitazone or dummy pills in different studies lasting from 24 weeks to 104 weeks. Deaths, heart attacks or strokes occurred in 35 of the 2,374 Pargluva patients versus nine of 1,351 patients in a combined group on the other drug or on dummy pills. Increased risks for mini-strokes and heart failure also were found among Pargluva patients.

A JAMA editorial notes that the new analysis contrasts sharply with data company sponsors presented to the FDA showing no significant excess risk of death or cardiovascular problems.

Company-provided data might have fostered an “illusion of safety” because of numerous omissions, such as excluding patients most likely to face cardiovascular risks, including elderly diabetics, said editorial author Dr. James Brophy of McGill University.

The drug had been projected to bring the companies $1 billion yearly, and DeAngelis contended that money appeared to trump safety.

Pargluva’s makers said earlier this week they had received a letter from the FDA that indicated the drug was “approvable” but which also asked for more safety data on the drug’s cardiovascular effects.

Nissen said final FDA action had been expected next week. The agency often follows recommendations from its advisory panels.

It’s uncertain how quickly the companies can produce the data FDA wants, but the new analysis now puts approval in doubt, said Lurie, the official with Public Citizen, which had presented similar safety concerns to the FDA panel.

“An article by two such prominent cardiologists could be the nail in the coffin for this drug,” he said. “It’s going to make it much more difficult for (the FDA) to look at whatever data the companies submit and conclude that the drug should be approved.”

Even without the JAMA article, the drug likely would not have hit the market for at least several months, Lurie said.

In their written statement Thursday, Bristol-Myers Squibb and Merck said that after receiving the FDA’s letter requesting more data, they were “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.”

© 2005 The Associated Press

 

washingtonpost.com
New Diabetes Drug Poses Major Risks, Panel Says
Review Finds FDA Overlooked Data on Life-Threatening Cardiovascular Effects of Pargluva
By Rob Stein and Marc Kaufman
Washington Post Staff Writers
Friday, October 21, 2005; A02

A diabetes medicine poised to win Food and Drug Administration approval sharply increases the risk of heart problems, strokes and death, researchers reported yesterday in an analysis that raises new questions about how the agency handles drug safety concerns.

The drug, Pargluva, the first in what had been considered a promising new class of drugs for millions of diabetics, more than doubles the risk of life-threatening cardiovascular complications, the researchers concluded after analyzing the same studies the drug’s maker presented to the FDA. They said the agency should not approve the drug until additional research is conducted.

“I do not think it’s wise to approve the drug or see the drug marketed until there’s a dedicated cardiovascular safety trial,” said Steven E. Nissen of the Cleveland Clinic Foundation, who led the analysis. “We have to put safety first.”

The FDA notified Bristol-Myers Squibb on Tuesday that the drug was “approvable” pending additional information about the safety issue, but it did not specifically request a new study to examine the risk of cardiovascular problems.

The critique comes as the FDA is struggling to restore its credibility after a series of embarrassing revelations and controversies, including the withdrawal of the blockbuster painkiller Vioxx last year because of serious side effects, a protracted battle over the Plan B morning-after contraceptive, and the abrupt resignation of Commissioner Lester M. Crawford, which remains shrouded in mystery.

The latest controversy underscores the heightened concern over drug safety, with the scrutiny this time on an earlier stage in the FDA approval process. But to some, it also reflects a continuing FDA reluctance to fully embrace drug safety as a paramount concern.

“I think this shows again a system failure at the FDA, that the agency still doesn’t give safety the full attention it needs,” said Curt Furberg, a drug safety specialist from Wake Forest University and until recently a member of the FDA advisory panel on drug safety. The reviewers and experts on the advisory panels “don’t necessarily have a good understanding of safety,” he said.

In a statement yesterday, the FDA said it was taking steps to better identify cardiac problems that might be caused by drugs. “While we cannot specifically discuss this particular drug, 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,” the statement said.

Pargluva, also known as muraglitazar, is the first of a new class of drugs known as dual-action PPARs. Several similar drugs are already on the market for the nation’s 16 million people with Type 2 diabetes, the most common form. The drugs lower levels of blood fats known as triglycerides, raise levels of “good cholesterol” and increase the effectiveness of insulin. Pargluva was designed to combine those effects in a single pill.

As part of its standard drug-review process, the FDA convened a panel of experts on Sept. 9 to examine Pargluva. The committee voted 8 to 1 to recommend approval.

Nissen and two colleagues, alarmed that the only heart specialist on the FDA panel had recused himself because of a conflict of interest, independently reviewed the data from five studies involving 2,374 patients that Bristol-Myers Squibb had submitted. The analysis found those taking the drug had more than twice the risk of death, heart attacks and strokes, and nearly triple the risk when all types of heart problems were included.

The Journal of the American Medical Association released the study yesterday, five weeks ahead of its Nov. 23 publication, because of its public health implications. While the number of patients in the analysis was relatively small, the trends were so consistent that it would be surprising if the higher risk was because of chance, Nissen said, especially as patients in the studies tended to be healthier than the typical diabetic.

Catherine DeAngelis, the journal’s editor, agreed with Nissen’s call for more research on the drug’s safety. “I’m somewhat perplexed that individuals who are supposed to be looking after the safety of the public would not have asked for the definitive tests before they approve this drug,” DeAngelis said.

In a statement, Bristol-Myers Squibb said it is “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.” The firm will provide additional safety data to the FDA from ongoing studies and confer with the agency about whether additional studies are needed, a spokesman said.

Nissen, who until recently was chairman of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, criticized the FDA advisory panel that reviewed Pargluva for failing to scrutinize the drug more carefully.

“I think this particular FDA advisory panel completely missed the point and did not probe deeply enough,” he said. “The company, as expected, presented the data in a way that was favorable to the drug. The FDA did identify these adverse trends but left it to the committee to decide their importance. The panel members did not probe to get beneath the surface. They did not connect the dots.”

At the Sept. 9 hearing, David Orloff, the director of the FDA’s Division of Metabolic and Endocrine Drugs, set the tone by saying the evidence that the drug may pose a risk was “based on very small numbers of events in individual studies and on small numbers overall.”

Bristol-Myers Squibb’s Rene Belder told the panel the company had collected safety data equal to 500 patient-years, and that “the results show that the incidence in cardiovascular events, when corrected for duration of exposure, is similar for [Pargluva] and placebo.”

But Peter Lurie of Public Citizen’s Health Research Group, a consumer group, advised against approval, citing safety concerns. Referring to the FDA’s experience with Rezulin, a similar drug that was withdrawn in 2000 because it caused liver problems, Lurie said the “wisest course is to pay attention to the clinical data.”

In the end, only Dean Follmann, head of biostatistics at the National Institute of Allergy and Infectious Diseases, voted against recommending approval, saying that because Pargluva is in a new class of drugs, it needed further study before being marketed to millions of people.

The single-action PPAR drugs on the market, Avandia and Actos, have been sold long enough to alleviate concerns they may pose similar risks, Nissen said.

© 2005 The Washington Post Company

THE NEW YORK TIMES
Questions Raised About Proposed Diabetes Drug
October 20, 2005
By STEPHANIE SAUL

New safety questions about the proposed diabetes treatment Pargluva were raised today in an article in the influential Journal of the American Medical Association, which urged the Food and Drug Administration to require a long-term study of the drug’s cardiovascular risks before deciding whether to approve it.

The article, posted this morning on JAMA’s Web page (http://jama.ama-assn.org/), concludes that clinical studies submitted so far to the F.D.A. revealed twice the number of heart attacks, strokes and other cardiovascular problems among those taking the drug compared with a control group. The consistency of the findings indicated that the doubling of risks were not due to chance, the article said.

An F.D.A advisory panel last month recommended that the Pargluva treatment be approved. And earlier this week the F.D.A. notified its maker that the drug, known generically as Muraglitazar, was approvable, but said it needed more safety data.

According to a press release issued by the drug’s sponsors, Bristol-Myers Squibb and Merck, the data requested by the F.D.A. involved studies that were already completed. But a cardiovascular safety study of the type proposed by the JAMA article would delay approval of the drug for at least two years, probably longer. Neither company issued an immediate response to the JAMA article and editorial.

The article was written by two well-known cardiologists and a statistician, all of whom are affiliated with the Cleveland Clinic. An accompanying editorial, written by Dr. James M. Brophy of McGill University, , also suggests that a prudent course would involve a long-term pre-marketing study of the cardiovascular safety of the drug, which is made by Bristol-Myers Squibb and would be co-marketed by Merck.

Dr. Brophy’s editorial also said that the F.D.A. submission by Bristol-Myers and Merck contained “perhaps unintended but nevertheless disingenuous” methodology that may have contributed to an overstatement of the drug’s safety profile.

The article also appeared to call into question parts of the F.D.A. review process. In an interview, one of its co-authors, Dr. Steven Nissen, criticized the F.D.A. advisory panel that reviewed the drug last month and voted to recommend its approval by 8-1. Even though the agency’s primary questions about the drug involved its cardiovascular safety, there were no cardiologists serving on the panel that recommended approval.

An analysis by an F.D.A. safety officer, submitted before the panel’s vote, also noted the doubling of cardiovascular risks associated with the drug, but concluded that there was no clear pattern.

Dr. Nissen said in the interview that “The advisory panel did not do a good job of evaluating cardiovascular safety.” He added: “The advisory committee had the information that they needed to recognize that there was a strong signal for cardiovascular harm. But they didn’t act on that signal.” Xxxxxx cut xxxxx

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