Advisory panel approves Vioxx and other -2 drugs

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Dear Group,

This was the front page lead article of today's Los Angeles Times:

FDA ADVISORS OK DISPUTED PAIN RELIEVERS

Medical experts acknowledge that the drugs, including Vioxx and Celebrex,

pose dangers. They call for stronger warnings.

By Alonso-Zaldivar and Gellene, Times Staff Writers

WASHINGTON -- A Food and Drug Administration advisory panel voted Friday to

let doctors prescribe -2 painkillers, including Celebrex and Vioxx, but

recommended stronger warnings about the risk of heart attacks and strokes.

Doctors, scientists and other experts on the 32-member panel overwhelmingly

agreed that -2 inhibitors -- hailed as a breakthrough in treating severe

arthritis pain when they first won FDA approval -- all significantly

increased the risk of cardiovascular problems in patients.

The panel proposed that Celebrex, Vioxx and Bextra, the third -2 drug

cleared by the FDA, carry " black box " warnings -- the strongest

admonishment the FDA can give to doctors. Such warnings are likely to

discourage use of the drugs.

The panel's decisions, made during three days of hearings and

deliberations, sought to balance the health risks against the benefits the

drugs provide to tens of millions who take them. In what amounted to a

series of split verdicts, panel members divided over the risks posed by

individual drugs in the -2 inhibitor group.

In the case of Vioxx -- which was taken off the market voluntarily last

fall by its maker, Merck, after a company-sponsored study confirmed the

dangers -- panel members voted to approve its use by a margin of two votes.

The FDA, which has pledged prompt regulatory action on the panel

recommendations, likely will have to tailor different responses to each of

the three drugs. The agency typically follows its panels' recommendations.

Beyond the effect of its decisions on patients and on billions of dollars

in revenues for drug makers, the blue-ribbon panel was widely seen as a

test of the FDA's readiness to deal with problems that had embroiled the

agency in controversy for more than a year.

Comprised of two FDA advisory committees, the panel was convened in

response to evidence of weaknesses in the FDA's system for monitoring the

safety of drugs after it had approved them for market.

In particular, critics had charged, the FDA was too slow and too dependent

on self-reporting by manufacturers when it came to problems that emerged

once huge numbers of people began using the drugs.

A leading FDA congressional critic, Sen. E. Grassley (R-Iowa) said

Friday: " The joint advisory committee meetings this week were valuable for

their transparency and respect for the scientific process. "

But " I remain troubled by the FDA's reluctance to be fully transparent and

prioritize issues of drug safety, " Grassley said. He has complained that

the agency does not give sufficient resources to monitoring the safety of

drugs already on the market, and he has charged that it has tried to muffle

internal critics.

The -2 inhibitors which have been taken by about 50 million people

worldwide presented the FDA with a particularly difficult dilemma. On the

one hand, the drugs offered benefits that many doctors and patients

considered vital; there also were indications that the painkillers might

have value in treating other diseases, including colon cancer. On the other

hand, there was strong evidence of cardiovascular risks.

The panel's effort to balance risks and benefits was evident in members'

comments: " Clearly someone who is leading a poor quality of life [due to

pain] and understands the risks is a good candidate [for Celebrex], " said

Dr. Domanski of the National Institutes of Health. " I don't think

we should take this pill out of the hands of doctors. "

Said Dr. Shafer of Stanford University: " I voted last night when my

father, an 89-year-old man with no cardiac risk factors, asked me if he

should continue his Celebrex. " I said yes. "

For Vioxx, the committee's vote could mean a new lease on life. Merck said

in a statement that the company looked forward to discussions with the FDA.

Celebrex and Bextra, which have remained on the market during the safety

controversy, are produced by Pfizer. ph Feczko, Pfizer's president of

worldwide development, told Bloomberg news service Friday that the

decisions gave the company " some more clarity about how the experts thought

of these drugs and steps to go forward. "

Committee members were nearly unanimous in recommending that Celebrex

remain available. The votes on Vioxx and Bextra were much closer. On Vioxx,

17 members voted to keep the drug, 15 to ban it. On Bextra, 17 voted to

keep it, 13 to ban it, and two abstained.

As for traditional painkillers known as nonsteroidal anti-inflammatory

drugs, or NSAIDs, the committee recommended that labels be changed to

caution that the long-term heart risks were not known. However, the

committee largely absolved naproxen the active ingredient in Aleve, a drug

whose safety has been questioned.

Many panel members said the FDA should narrow the pool of patients who can

receive Celebrex, and also limit the doses that can be prescribed.

Following the panel's decisions, Pfizer shares rose $1.74 to $26.80, and

Merck's shares gained $3.76 to $32.61 -- both on the New York Stock

Exchange. Merck faces more than 500 lawsuits from patients claiming they

were harmed by the pain medication. Ramon Rossi , a Newport Beach

lawyer involved in Vioxx-related litigation, said he was surprised by the

vote, but didn't consider the result a setback for his case. " I don't think

it is good news for a drug when 15 of 32 scientists say it is not safe

enough to keep on the market, " he said. " A drug is either safe or it's not. "

Napodano, a pharmaceutical industry analyst with Zacks Independent

Research in Chicago, said Vioxx would not return to the market anytime

soon. " They are going to have to meet with the FDA and decide exactly what

the label will say, and that will take time, " he said. In addition to the

lawsuits, Napodano said, one of the biggest problems facing Vioxx might be

insurance reimbursement. Even before Merck withdrew the drug, managed-care

plans had removed it from their formularies because some studies had shown

signs of cardiac risk. " It is going to be difficult for Merck if patients

have to pay for this out of pocket, " he said.

Napodano said it was not clear how the black-box warning would affect sales

of Celebrex. " In a sense, it might be good for Pfizer to get this

uncertainty cleared up, " he said. " A black-box label is never good for a

drug, but knowing how to take it and avoid the risks is better than not

quite knowing. " He said the panel vote could help slow the slide in

Celebrex prescriptions, which are off 50% from a year ago.

-2 inhibitors were developed as a stomach-friendly branch of the family

of NSAIDs. -2 is a form of the cyclooxygenase enzyme, which is thought

to be responsible for inflammation and pain in the digestive system. By

suppressing the -2 enzyme, the inventors of the drugs sought to prevent

ulcers and bleeding in patients regularly taking doses of painkillers for

arthritis.

But it turns out that the enzyme plays an important role in another of the

body's systems: It helps prevent blood platelets from clumping together.

Suppressing -2 helped prevent ulcers, but it also increased patients'

risk of heart attack and stroke by increasing the likelihood of blood

clots. Several committee members noted that the risk for the heart was the

mirror image of the -2 drugs' benefit for the digestive system.

There is also another way in which -2 drugs can damage the heart: Like

other NSAIDs, long-term use can raise blood pressure.

Concern over the -2 drugs erupted last fall after the Merck-sponsored

study confirmed early signs that taking Vioxx could lead to heart attacks.

Weeks later, a National Cancer Institute study also indicated a risk for

patients taking high doses of Celebrex. Both drugs had been market

blockbusters.

The ensuing controversy spotlighted the weaknesses in how the FDA kept tabs

on drugs after approval.

The agency's panel of doctors and scientists heard details of studies that

indicated several of the drugs could increase risks of heart attacks and

strokes, although the evidence for Celebrex was weaker, particularly at the

lower doses taken by most patients.

By some estimates, tens of thousands of Vioxx patients have suffered heart

attacks. Based on risk levels suggested by Merck's studies and clinical

trials, Dr. J. Graham, a whistle-blower in the FDA's drug safety

office whose initial warnings went unheeded, estimated that as many as

139,000 Americans who took Vioxx may have suffered serious side effects.

" Of these, 30% to 40% probably died, " Graham told a Senate panel. " For the

survivors, their lives were changed forever. " Graham's estimates, disputed

by his FDA superior at the hearing, suggested that 26,000 to 55,600

patients might have died as a result of taking Vioxx.

Merck's study showed that the drug nearly doubled the risk of heart attacks

and strokes among people taking it for at least 18 months. About 20 million

Americans have taken the drug.

DRUGS AT A GLANCE

How the FDA advisory board voted on whether to allow Bextra, Celebrex and

Vioxx, and suggested changes for the painkillers.

* Celebrex, 31 for, 1 against

* Bextra, 17 for, 13 against (2 abstained)

* Vioxx, 17 for, 15 against

Suggested restrictions:

* Placing strong " black box " warnings on the drug boxes.

* Including more patient information.

* Restricting which patients could get the drugs.

* Possibly banning direct-to-consumer advertising.

Sources: Food and Drug Administration, IMS Health, Chicago Tribune

Alonso-Zaldivar reported from Washington and Gellene from Los Angeles.