Pharmaxis Ltd.: Bronchitol

The submitted data do not provide a favorable benefit-risk balance to support the use of inhaled mannitol in patients with cystic fibrosis 6 years of age and older.

The determination of efficacy based on the two submitted trials are not adequate because of the treatment-related frequent early dropouts in trial 301 for which the primary statistical analyses did not account and the lack of statistical significance in trial 302 for the primary endpoint.

Sensitivity analyses conducted on data from study 301 either fail to confirm a treatment effect on the primary efficacy or are problematic in that they attribute a good outcome to some patients who discontinue treatment or they impute a single score without accounting properly for variability.

Satisfactory resolution of these deficiencies is required before this application may be approved.

Your conclusions need to be supported by the dose performance data, including APSD and be adequately addressed in the labeling, especially in the instructions for patients.