UPDATE 1-U.S. FDA panel hears risks with asthma drug

Wed Dec 10, 2008 7:30pm EST

(New throughout with disagreement at FDA, company comments)

By Lisa Richwine

ROCKVILLE, Md. Dec 10 (Reuters) - U.S. drug reviewers publicly clashed on Wednesday over how to handle a higher risk of death and serious complications seen with a class of asthma medicines now used by millions of patients including children.

The inhaled drugs include one of the world's top-sellers, GlaxoSmithKline PLC's (GSK.L) Advair, as well as AstraZeneca PLC's (AZN.L) Symbicort.

Food and Drug Administration staff who monitor drugs after approval told an advisory panel they felt none of the medicines known as long-acting beta-agonists (LABAs) should be given to children with asthma. They also urged revoking approval of two lesser-used medicines, Glaxo's Serevent and Novartis AG's(NOVN.VX) Foradil, for asthma patients of any age.

"We now know with high certainty that LABAs increase asthma mortality. Do the health benefits justify that?" asked FDA drug safety reviewer David Graham, who has been outspoken on medication risks and criticized the FDA's ability to manage them.

Graham said the answer clearly was no, as he saw little improvement among asthma patients treated with LABAs, particularly children. He estimated that as many as 14,000 deaths could be attributed to LABAs since 1994.

By contrast, the FDA division that reviews asthma drugs concluded products containing LABAs offered important benefits with serious risks for a "small" number of patients and should remain available for asthma treatment with appropriate warnings, division head Badrul Chowdhury said.

If the FDA decided otherwise, patients might take other short-acting beta agonists at high doses on a chronic basis, Chowdhury said.

"This will shift back asthma treatment and asthma care to where it was about 20 years ago. This shift will not reduce mortality but may increase it," Chowdhury told the panel.

Chowdhury also said drug-safety reviewers had relied on data with several limitations.

The FDA will ask the advisory panel to weigh in Thursday.

Glaxo strongly disagreed with Graham's analysis and defended LABAs as safe and providing benefits of better lung function, symptom relief and fewer asthma attacks. AstraZeneca and Novartis said the benefits of their drugs outweighed the risks when used as directed.

"There is absolutely no clinical scientific evidence that Advair caused any excess deaths. The public health risk is from uncontrolled asthma" if proper therapy is not used, Glaxo Chief Medical Officer Ellen Strahlman said in an interview.

Asthma is a chronic disease marked by restricted breathing and wheezing and is often made worse by exercise, cigarette smoke and other factors. About 20 million people in the United States have asthma, according to the National Institutes of Health. Uncontrolled asthma can lead to potentially fatal attacks.

LABAs help relax airways to prevent spasms but come with strong warnings about a higher risk of asthma-related deaths in light of findings from a Glaxo study halted in 2003.

Advair and Symbicort combine a LABA with an inhaled steroid. Serevent and Foradil, which Schering-Plough Corp SGP.N markets in the United States, contain LABAs alone.

Advair is Glaxo's best-selling drug with $5.6 billion in worldwide sales through the first nine months of the year. Symbicort's sales for the same period were $1.5 billion.

The FDA combed data from 110 clinical trials of about 61,000 people. Reviewers found 2.8 more serious asthma-related complications, including deaths and hospitalizations, for every 1,000 patients treated with a LABA.

Glaxo argued that adding a steroid to an LABA, as with Advair, protected against serious risks. Data that raised concerns came from early studies when it was less common to pair Serevent with a steroid, the company said.

"Denying access to these life-changing medicines would be extremely detrimental to patient care," Elaine Jones, a Glaxo vice president, told the panel.

AstraZeneca and Novartis also said their drugs offered meaningful benefits and should remain available for asthma treatment.

The advisory panel is set to vote on Thursday on whether the benefits of each drug outweigh the risks for asthma patients.

Approval of the LABAs for asthma could be revoked, but sales of Advair, Serevent and Foradil could continue for treating chronic obstructive pulmonary disease (COPD). AstraZeneca has applied to have Symbicort FDA-approved for COPD.

The FDA usually follows panel recommendations. (Reporting by Lisa Richwine; Editing by Richard Chang; editing by Carol Bishopric)

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