NEWS - FDA committees say it's time to raise the bar on NSAID trials

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FDA committees say it's time to raise the bar on NSAID trials

Rheumawire

Mar 9, 2005

Gandey

Gaithersburg, MD - US Food and Drug Administration committees reviewing the

benefit-to-risk considerations of COX-2 inhibitors and nonsteroidal

anti-inflammatory drugs (NSAIDs) complain that trials of these drugs have

been grossly inadequate. " In arthritis, you can't conduct placebo-controlled

trials, " said committee member Dr Nissen (Cleveland Clinic

Cardiovascular Coordinating Center, OH). " We therefore need more clarity and

consistency in comparators. " The committees opted for naproxen as the new

comparator of choice and urged the FDA to raise the bar on future NSAID

studies.

The decision to make NSAID drug approvals tougher does not bode well for

etoricoxib (Arcoxia, Merck & Co) and lumiracoxib (Prexige, Novartis), which

have yet to be approved for use in the US. But panelists were concerned

about a lack of data of older agents as well as newer COX-2-specific drugs.

Their concerns spanned a wide range of products, including ibuprofen,

meloxicam (Mobic, Boehringer Ingelheim), and the coxibs.

In a presentation reviewing epidemiologic studies on cardiovascular risk

with NSAIDs, Dr Graham from the FDA's Center for Drug Evaluation and

Research agreed that data have been sparse. " I submit to you that you know

very little about the population benefit of these drugs, " Graham told

panelists. " You don't have the data you need from an epidemiological

standpoint. "

Graham's talk had been the topic of much controversy leading up to the

meeting. Questions about what he would or would not be allowed to say had

been the subject of many news articles. Meeting chair Dr Alastair Wood

(Vanderbilt University Medical Center, Nashville, TN) was quick to point out

that Graham was free to speak openly and was encouraged to do so. But

despite assurances, Graham frequently responded to questions specifying that

he was speaking for himself and not the agency.

Graham pointed out that many trials that should be conducted never are

because of expense. " Companies don't want to do them and there is no

incentivewe are not requiring them to do so, " he said. Graham also argued

that too much emphasis has been placed on efficacy and not enough on safety.

Graham showed panelists an overview of recent studies evaluating the risk of

acute MI with naproxen. Among the many studies, he highlighted 4 positive

naproxen studies: one by Rahme and colleagues that showed a benefit of

naproxen over other NSAIDs, another by Kimmel and his team that showed a

reduced cardiovascular risk with naproxen, as well as studies by and

colleagues and and his group. " None provide critical evidence of a

protective effect of naproxen, " Graham said.

Nissen suggested that one immediate way to create incentive for companies

would be to offer industry the opportunity to drop the cardiovascular

warning on products in exchange for adequate trials demonstrating safety.

" We've learned this the hard waythe very difficult waylast fall, but we've

learned it and now we have to set the bar accordingly, " he said.

Dr Temple from the FDA's Center for Drug Evaluation and Research

agreed. " When you have priors, you have to make changes. We know something

here. "

Nissen noted that he'd like to see a trial of naproxen 500 mg twice daily

and celecoxib 200 mg. " Do that trial and add a third arma nonnaproxen NSAID

such as diclofenac, which appears to be in a class similar to celecoxib, " he

said. Nissen added that in absence of a placebo, naproxen should be the new

comparator against which all new drugs are assessed.

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org