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Mar 22, 2010
 |  BioCentury  |  Regulation

Last chance on LABAs

FDA ordered safety studies for asthma drugs could be hugely expensive

Although it's not yet possible to determine the final cost of potentially huge post-marketing studies to evaluate the safety of LABAs to treat asthma, it's clear they will not be cheap and will take resources away from other drug development programs.

Even so, the regulatory and political dynamics suggest that the three pharma companies with LABAs on the market will move forward with the studies - the first such trials FDA is requiring under new authorities granted by the FDA Amendments act of 2009 (FDAAA).

FDA has already concluded that monotherapy with long-acting adrenergic receptor beta 2 (ADRB2) agonists (LABAs) increases the risk of asthma-related exacerbations, including hospitalizations and death. The question now is whether the risk is mitigated when an inhaled corticosteroid (ICS) is added to the therapy.

There are strong opinions about the answer to that question, as was evident at a joint meeting of FDA's Pulmonary-Allergy Drugs and Drug Safety and Risk Management advisory committees on March 10-11.

At one end of the spectrum, Andrew Mosholder of FDA's Division of Epidemiology presented a case that LABAs should be removed from the market entirely and that any further study would be unethical. Mosholder made clear that the views he presented were his and those of David Graham of the FDA Office of Surveillance and Epidemiology, and not those of the agency or OSE.

On the other end were Thomas Alexander Platts-Mills and Jerry Krishnan, two pulmonologists who repeatedly questioned the need for any safety trials given the documented benefit of LABAs in asthma patients and what they deemed to be a lack of any evidence of a safety crisis.

Platts-Mills is director of the asthma and allergy disease center at the University of Virginia Medical Center, and Krishnan is associate professor of medicine and health studies at the University of Chicago. Both are voting members of the Pulmonary-Allergy committee.

The rest of the panelists fell between those two extremes. John Jenkins, director of the Office of New Drugs in FDA's Center for Drug Evaluation and Research (CDER), noted that this broad range of opinions was based on the same data, which is what prompted the agency to require the new trials.

"We knew that this was going to be a very controversial topic," Jenkins told the panel. "This is probably our last, best chance to get an answer to these questions."

He added: "It would be nice to avoid the inevitable second-guessing down the road: 'Well, if you'd asked for this or if you'd asked for that, you would have gotten a better answer.' We're asking you prospectively to help us design the best studies we can to get the best answer we can."

Companies that are being required to do the trials are GlaxoSmithKline plc, which markets Advair salmeterol/fluticasone and Serevent salmeterol; AstraZeneca plc, which markets Symbicort formoterol/budesonide; and Novartis AG, which markets Foradil formoterol. Salmeterol and formoterol are LABAs; fluticasone and budesonide are corticosteroids.

It is unclear whether similar trials will be required for future approval of LABAs that are in development.

The evidence

Short-acting adrenergic receptor beta 2 (ADRB2) agonists (SABAs) were first marketed to treat asthma in the 1930s. Over the ensuing decades, some inhaled SABAs were associated with marked increases in asthma-related deaths, for example isoproteronol forte in the U.K. in the 1960s and fenoterol in New Zealand in the mid-1970s. As a result, current treatment guidelines for asthma do not recommend daily long-term use of any SABAs.

Serevent was the first LABA to reach the market: in 1990 in the U.K. and 1994 in the U.S. Concern arose in 1993, when the Serevent Nationwide Surveillance (SNS) study of about 25,000 asthma patients showed chronic use was associated with a small and statistically non-significant increase in asthma-related deaths compared with chronic use of the SABA albuterol (0.07% vs. 0.02%).

To further study this signal, GlaxoSmithKline began the Salmeterol Multicenter Asthma Research Trial (SMART) in 1996. The double-blind trial compared Serevent vs. placebo when added to standard therapy, such as ICS, methylxanthines, leukotriene modifiers and other ADRB2 agonists.

The company stopped the trial in 2003 when a planned interim analysis suggested salmeterol might be associated with an increased risk of severe asthma exacerbations, including deaths. Specifically, there were 13 deaths out of 13,176 patients treated with Serevent for 28 weeks, compared with 3 out...

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