FDA Whistleblower Warns of Cox-2 Risks

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FDA Whistleblower Warns of Cox-2 Risks JoAnn Guest Aug 18, 2005 17:15 PDT

 

 

 

Health: Arthritis News

 

February 17, 2005 08:41:28 PM PST

By Amanda Gardner

HealthDay Reporter

 

 

THURSDAY, Feb. 17 (HealthDay News) -- FDA whistleblower Dr. David Graham

delivered damning testimony on Vioxx and other cox-2 inhibitors Thursday

at government hearings on the drugs.

 

" There's a one-in-50 chance that a male aged 65 to 74 will have a heart

attack this year. Increase that fivefold with high doses [of Vioxx], "

Graham testified before a standing-room-only crowd as the second of

three days of Food and Drug Administration hearings commenced in

Washington, D.C.

 

" That's what happened with VIGOR [a 2000 manufacturer's trial comparing

gastrointestinal effects of Vioxx and another painkiller, naproxen]. If

you have millions of people taking high doses, you're going to get

numbers that balloon out. Because of the high background rate of the

underlying event, there are many more cases. "

 

The fact that randomized controlled trials such as VIGOR tend to include

healthy people may have skewed the perception of risk, the FDA scientist

added during two hours of testimony.

 

" People are harmed by rofecoxib [Vioxx], " Graham bluntly told the panel

of FDA advisers who are reviewing the safety issues of all the cox-2

inhibitors, the class of painkillers originally designed to reduce the

risk of gastrointestinal danger.

 

Vioxx was pulled off pharmacy shelves by its manufacturer Merck & Co.

last fall after trials showed an increased risk of heart and stroke

damage. The two other cox-2s still on the market, Celebrex and Bextra,

have also shown increased cardiovascular risks in more recent studies.

 

The committee of 30 scientists and doctors -- who make up two FDA

advisory groups on drug safety and arthritis -- will weigh all the

testimony from manufacturers, scientists and the public before making

their recommendations, which could come as soon as Friday and could

range from banishing all cox-2s to providing sterner labeling for any or

all of them.

 

Meanwhile, the European Medicines Agency, Europe's most powerful drug

regulators, on Thursday trumped the FDA and mandated stronger warnings

about cardiovascular risks for all cox-2 painkillers. It stopped short,

however, of calling for the drugs to be taken off the market, the

Associated Press reported.

 

The U.S. meeting is one that Graham is partially responsible for

bringing about. The medical officer for the FDA's Center for Drug

Evaluation and Research is a longstanding critic of Vioxx who said he

was censured for trying to reveal information about the drug. At

Thursday's hearing, he thanked acting FDA Commissioner Dr. Lester

Crawford who " exercised great leadership " in allowing him to present the

information he wanted to present.

 

In their testimony, both Graham and Dr. Richard Platt, of Harvard

Medical School, tried to demystify the different types of studies

available on nonsteroidal anti-inflammatory drugs (NSAIDs), the group of

medications that includes cox-2s.

 

While Platt was matter-of-fact in his descriptions of how different

studies are designed and how that might affect outcomes, Graham was more

forthcoming on which specific studies he deemed good or bad.

 

Graham said he believed the negative cardiovascular effects of Vioxx

were dose-dependent, meaning higher doses had a bigger effect, and that

the risk kicked in immediately, within the first 30 days. Both issues

have been subjects of debate.

 

Celebrex had no effect on the heart at doses of 200 milligrams or less,

Graham added, but did have an increased risk at higher doses. Naproxen,

which is a traditional NSAID, has no protective effect, he contended.

 

" Unless you're willing to believe that naproxen confers lifelong

immunity from heart attacks, none of the positive studies provide

credible evidence of a protective effect, " he said.

 

The little information that exists on Bextra indicates no risk at small

doses, he added.

 

Graham seemed to contradict himself when asked whether the committee

should issue warnings for specific drugs or should consider a warning

for the entire class of cox-2 drugs.

 

" There doesn't appear to be a need for cox-2 selective NSAIDs, " Graham

first said.

 

But later, he added, " We need to weed the garden of bad actors, try to

identify drugs that, based on the evidence we have, appear to be less

risky. I'd be trying to identify right off the bat the bad actors and

let's get rid of them. And things that actually look safe, don't appear

to have cardiovascular risk, let's identify them and shift the market

towards that end. "

 

" We maybe need to look at it drug by drug, " Graham acknowledged.

 

" We need to look for consistency across studies, " he added. " Some light

in the storm is better than no light in the storm. "

 

On Wednesday, the panel heard testimony from the drug manufacturers and

the FDA officials who reviewed the drug data before giving their

approval.

 

=====================================================================

 

Heart Failure Drug Stirs Controversy

 

 

 

 

July 14, 2005 08:40:52 PM PST

By Amanda Gardner

HealthDay Reporter

 

 

WEDNESDAY, July 13 (HealthDay News) -- A hard-hitting article in one of

the nation's most prestigious medical journals claims the maker of the

widely used heart failure drug Natrecor is circumventing concerns over

patient safety while watching revenues soar.

 

One of the country's top cardiologists asserts that Scios Inc., a

subsidiary of Johnson & Johnson, continues to aggressively market

Natrecor even as the drug comes under increased scrutiny for links to

kidney failure and death.

 

" It's a pattern. We saw it with Vioxx and some of the cox-2 inhibitor

drugs, and we're seeing it now with Natrecor, " said Dr. Eric Topol,

author of the article, which appears in the July 14 issue of the New

England Journal of Medicine. " The twist here is that the aggressive

marketing is through the medical community. With other drugs, it's

direct-to-consumer advertising. "

 

" Other than that, we have the themes of manuscripts published in

prestigious journals with key omissions of data, the FDA approving drugs

without mandating key trials, and companies aggressively pursuing sales

and marketing of their drugs, " continued Topol, who is chairman of the

department of cardiovascular medicine and chief academic officer at the

Cleveland Clinic in Ohio.

 

Natrecor (nesiritide) was approved by the FDA in 2001 for the treatment

of acute, decompensated congestive heart failure, a stage of heart

failure characterized by increased severity and long hospital stays.

According to the company, it is the first member of a new drug class,

human B-type natriuretic, and is manufactured from E. coli bacterium

using recombinant DNA technology.

 

Today, tens of thousands of patients in the United States are receiving

" tune-ups " with the drug on an outpatient basis, an indication for which

the drug is not approved, Topol said. In fact, the drug, which costs

about $500 per dose, is now being used 10 times more often in outpatient

clinics than in acute hospital settings.

 

Sales for Natrecor are projected to be $700 million for 2005, Topol

wrote, nearly double what they were last year.

 

According to Topol, studies have shown that Natrecor contributes to

kidney dysfunction, and may even cause death. One trial found kidney

problems were occurring at a rate three times that found in patients

taking a placebo. Another trial found a 50 percent increase in the risk

of death at 30 days. And when data from three trials was pooled,

researchers led by Dr. Jonathan Sackner-Bernstein, a New York

cardiologist, found an 81 percent increase in the death rate vs. a

placebo.

 

" It hardly does any better than placebo, " said Sackner-Bernstein,

associate chief of cardiology and the director of the Heart Failure

Program at St. Lukes-Roosevelt Hospital Center, in New York City.

 

He added that he had great difficulty getting his data published in any

medical journals, although two Natrecor studies conducted by his team

did eventually appear in Circulation and the Journal of the American

Medical Association earlier this year. He also took his data to the

company.

 

Particularly troubling to Topol and others has been the aggressive

marketing undertaken by the company even after safety issues had been

raised.

 

According to the article, Scios is encouraging physicians to start their

own " infusion centers, " which would be billed to Medicare; it has also

set up a toll-free telephone hotline for " Natrecor Reimbursement

Support " and published a 46-page reimbursement and billing guide that

provides doctors with specific Medicare billing codes.

 

" If a drug is off-label, the FDA basically takes a blind-eye approach, "

Topol said. " There's a very fuzzy line about promotion. The company

would say we're not promoting the outpatient tune-up. Well, how come

they have a hot line, and any doctor can call and set something up? Is

that not promoting it? Come on, help me. Where do you draw the line? "

 

A spokeswoman for the FDA said, " The safety problems that were

identified [with Natrecor] were fully considered by FDA and the advisory

committee, the appropriate information was put into the labeling and FDA

was also advised that labeling has been updated with information for all

the trials on the mortality issue. "

 

In June, an expert panel convened at Scios' request recommended

additional trials to assess the safety and efficacy of Natrecor. The

panel also stated that use of the drug should be restricted to patients

coming to the hospital with acutely decompensated congestive heart

failure (ADHF).

 

" Scios shares Dr. Topol's commitment to the appropriate use of medicine

for acute decompensated heart failure, " Scios spokesman Mark Wolfe said

late Wednesday. " Scios does not recommend, nor do we promote, Natrecor

for scheduled intermittent use in patients with ADHF. " Wolfe noted that

95 percent of Natrecor sales since the drug's launch has been to

hospitals.

 

" Dr. Topol's piece doesn't offer new data regarding Natrecor, and it

also contains some inaccurate statements, " Wolfe added.

 

An example of an inaccurate statement, Wolfe said, was regarding higher

death rates. The label has also been updated, he said. And the

reimbursement guide was developed to clear up confusion.

 

" The reimbursement guide was developed to provide hospitals and other

medical staff with comprehensive information, not selective information,

to accurately code a patient's condition under Medicare requirements.

There was significant confusion in terms of how physicians should bill, "

Wolfe said. " These kinds of guides are not uncommon. They don't

encourage inappropriate use of medicines. "

 

Scios has also been working with the FDA to implement a physician

education program to comply with the expert panel's recommendations, and

Wolfe said that a letter they're in the process of disseminating has

been posted on the Web site in the past day or two.

 

Last but not least, he said, " Scios will be conducting a large outcomes

trial as part of a recommendation from the panel. We're in the process

of designing and getting approval from the FDA. That doesn't happen

overnight. "

 

If Scios was committed to doing more research, Sackner-Bernstein said,

" I would have expected to hear more from them by now... I would think

Johnson & Johnson would like to prove to the world that they do care

about patients, that they do have ethics, and it's pretty clear to me

that it's not their motivation. "

 

The ideal situation, as Sackner-Bernstein sees it, would have been for

him and others to go to the company (which they did), and for the

company and FDA to have worked things out.

 

" The fact that the FDA doesn't have much enforcement capability is a

problem, " Sackner-Bernstein said. " Then again, where are the ethics? The

people involved at Scios and others who knew about this data should be

hanging their heads. There's no other way to look at it. What is wrong

with everybody that you've got a drug that increases renal dysfunction

and death, and costs 50 times as much as a regular treatment, and yet

it's given to hundreds of thousands of people? "

_________________

JoAnn Guest

mrsjo-

www.geocities.com/mrsjoguest

 

 

 

 

AIM Barleygreen

" Wisdom of the Past, Food of the Future "

 

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