On Thursday Feb 23, 2012, the FDA Pulmonary-Allergy Advisory Committee will discuss the Forest Laboratories, Inc./Almirall S.A. aclidinium NDA for the treatment of COPD.
I find it interesting when the FDA includes the regulatory history in the Briefing Document, probably because it usually focuses right in on the issues. In this case, it shows that the sponsor was given some advice on how to develop the drug by the FDA and chose to ignore it.
The FDA early on “suggested” that peak FEV and FEV AUC were the appropriate measures for a COPD trial. The sponsor chose FEV trough. Using this FEV trough, the sponsor provided an improvement of 60 ml vs the 150 ml they had offered in the Phase 2 trials. The sponsor offered 1800 patients for safety at the recommended dose which the FDA said might be ok if the data were robust. When the sponsor and FDA agreed that the 200 mcg dose was inadequate, the sponsor went back and did 2 more Phase 3 trials and then offered the FDA less than 1800 patients at the recommended dose of 400 mcg. In this meager data base, there were patients with cardiovascular problems.
Anticholinergic drugs carry a risk of cardiovascular problems. This is an anticholinergic drug. The data base was too small to evaluate the cardiovascular risk of patients taking the recommended dose as chronic therapy.
The sponsor has probably failed on the efficacy measure with the FEV trough measure, hence the question from the FDA on the “clinically meaningful benefit” of the 400 mcg dose. The sponsor failed to provide a data base that could adequately answer the question about cardiovascular risk for this anticholinergic drug. The sponsor will fail to gain the approval of the Advisory Committee.