New Diabetes Drug Increases Mortality / Morbidity_FDA approvable letter Challe

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[sSRI-Research] New Diabetes Drug Increases Mortality /

Morbidity_FDA " approvable " letter Challenged

 

 

 

 

New Diabetes Drug Increases Mortality / Morbidity_FDA " approvable "

letter Challenged

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

FYI

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 hazard..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 performed..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

 

 

 

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

 

 

http://www.washingtonpost.com/wp-dyn/content/article/2005/10/20/AR2005102001145_\

pf.html

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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