β-2 agonists, both short and long-acting (SABAs and LABAs) have been a mainstay of therapy for asthma and chronic obstructive bronchitis (COPD) since the introduction of albuterol many years ago. For almost as long, they have been surrounded by controversy, especially when used to treat asthma. Growing evidence suggests that, along with their many benefits, they also increase the risk of sudden, worsening bronchospasm that can lead to hospitalization, intubation, and even death. As that realization has grown, FDA has called numerous advisory panels to discuss the risk and the best way to minimize it. Most recently, the agency issued a statement outlining even more restrictive labeling language and its plans to mandate conduct of large safety trials. It then called yet another Advisory Panel meeting to discuss the optimal design for such a trial.

Into this context, Novartis developed an ultra-long-acting (once- instead of twice-daily) agent –  indacaterol – and filed an NDA seeking approval for use in the treatment of COPD. This decision to limit the initial application to COPD was most likely motivated by FDA’s assertion that the safety concerns do not apply to use in COPD – only to the asthma setting. In spite of those FDA statements and indacaterol’s approval in Europe, FDA issued a Complete Response Letter last October. In a recently issued report, we attempt to ‘read between the lines’ of Novartis’s limited disclosures relative to the content of that letter in an effort to determine the nature of FDA’s concerns, the path forward, the probability of eventual approval, and ultimately of market success.