In an article in the December 15 issue of the New England Journal of Medicine, regulators from the FDA’s Center for Drug Evaluation and Research (CDER), with Badhul Chowdhury, director of Division of Pulmonary, Allergy, and Rheumatology Products, as lead author, detail the decision making process that led to approval of a single 75 μg dose of Novartis’s Arcapta Neohaler indacaterol DPI for the treatment of COPD. “Since the European Medicines Agency (EMA) had approved indacaterol at doses of 150 μg and 300 μg in 2009,” they acknowledge, “one might question why the FDA selected a 75 μg dose.”
The article provides a comprehensive review of the history of Novartis’s NDA submissions and resubmissions for indacaterol and the FDA’s repeated questioning of differences in efficacy at higher doses. The rejection of the original NDA, which was submitted in 2009, the authors explain, resulted from safety concerns, including “a small numerical increase in serious asthma exacerbations and respiratory-related deaths” in asthma patients receiving doses of 300 μg and 600 μg in a dose ranging trial, events that they say are “typically very rare in preapproval LABA studies.” At the same time, they say, they saw no significant difference in efficacy between the 75 μg dose and higher doses, suggesting that higher doses were unnecessary.
When Novartis submitted its complete response in December 2010, the authors say, data from a new dose ranging study showed no greater improvement in quality of life as measured by the St. George’s Respiratory Questionnaire for higher doses compared to the 75 μg dose. Novartis submitted model-based analyses to back up its claim of increased efficacy for a 150 μg dose that the FDA decided “were insufficient to support approval of a second, higher dose of indacaterol and could not replace comparison of the two proposed doses in a clinical trial.”
Despite the fact that the data “did not show worrisome findings” for the 150 μg dose, and even though the adverse events seen at the higher doses in asthma patients did not appear to occur in COPD patients, the FDA was still concerned about minimizing the dose, the regulators explain. With no data to show superiority of the 150 μg dose over the 75 μg dose, they say, “the FDA emphasized dose selection and safety to ensure that the marketed dose would provide maximal benefit without posing unnecessary safety risks.”
As for the EMA decision, it might have considered other data such as comparisons with active controls or Mahler Transitional Dyspnea Index scores that may led to its approval of higher doses.
Read the NEJM article.
