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In July 2011, FDA approved indacaterol, Novartis's new once-daily long-acting beta agonist, for the treatment of chronic obstructive pulmonary disease. In contrast to its European counterpart (EMA), which approved indacaterol there at doses up to 300 mcg, FDA only approved indacaterol in the 75 mcg daily dose. The FDA's Badrul Chowdhury explains why in the December 2011 New England Journal:
- The initial criteria FDA gave Novartis stipulated that the approved dose of indacaterol would have to beat both tiotropium and formoterol on the measures of 24-hour trough FEV1, and FEV1 area-under-the-curve from 1 to 4 hours after a dose. In response, Novartis rationally pushed for higher doses of the drug (150 and 300 mcg) to be tested, so as to maximize the likelihood of meeting the efficacy criteria, Chowdhury believes.
- However, FDA's interpretation of the dose response curves was that the 75, 150, and 300 mcg doses were all on a plateau -- there was no added benefit of bronchodilation with doses higher than 75 mcg.
- The FDA was worried about adverse events in people with asthma getting this new LABA off-label or as treatment for misdiagnosed COPD. There was a small numerical increase in adverse respiratory events and death among people with asthma who took indacaterol at 300 or 600 mcg doses in the preapproval trials.
- The 75 and 150 mcg doses were never compared head-to-head, but in the separately conducted trials, FDA did not see a clinically meaningful benefit of the higher 150 mcg dose.
There have been 23 trials on indacaterol in over 11,700 subjects. FDA's analysis concluded there was no signal there of a serious risk from either the 75 or 150 mcg dose.
There is a business backstory here, too, one not mentioned in the genteel NEJM. According to a 2011 Reuters story, Novartis had a strong financial interest in the approval of the 150 mcg dose, because they would have been able to more quickly roll out QVA149, a once-daily combination inhaler containing indacaterol and a long-acting antimuscarinic. Novartis is rushing to beat GlaxoSmithKline to be first to market with such a product. Having to reformulate the QVA149 combination product for the 75 mcg indacaterol dose may push Novartis back a year, reducing QVA149's market share.
Clinical Takeaway: In the end, it sounds like FDA was not really concerned about the safety of 150 mcg of indacaterol, but they didn't see any clinical benefit either, and made the most conservative decision. That's understandable, given their ongoing postmarketing experience with LABAs for asthma (the most recent major development there: FDA's commissioning of Big Pharma to conduct 5 huge trials to assess LABAs' safety in people with asthma; results are expected in 2017).
Chowdhury BA et al. The Risks and Benefits of Indacaterol — The FDA's Review. N Engl J Med 2011;365:2247-2249. FREE FULL TEXT
Other articles we've reviewed on indacaterol: