Pharmaxis Ltd – FDA CRL

Pharmaxis Ltd. received a Complete Response Letter (CRL) from the FDA for its New Drug Application (NDA 202049) for Bronchitol (mannitol) Inhalation Powder. The FDA determined that the application cannot be approved in its current form due to significant clinical, product quality, and manufacturing deficiencies.

Clinically, the data did not demonstrate a favorable benefit-risk balance for inhaled mannitol in cystic fibrosis patients aged 6 and older. Efficacy trials were deemed inadequate due to high early dropouts in one study and a lack of statistical significance in another. Safety concerns included a high occurrence of hemoptysis, particularly in pediatric patients, which outweighed the presented efficacy. To address this, Pharmaxis must conduct at least one new clinical trial showing substantial efficacy and balancing safety. Recommendations include a more conservative mannitol tolerance test, exploring lower doses, and initially testing adults before children, with specific criteria for hemoptysis.

Regarding product quality and manufacturing, an inspection of the packaging and labeling facility revealed current Good Manufacturing Practices (CGMP) deficiencies that require satisfactory resolution. Additionally, the FDA requested revisions to drug product delivered dose uniformity (DDU) specifications, investigation into physicochemical changes in the manufacturing process, and a study demonstrating the ruggedness of the delivery device. The company also needs to evaluate and ensure an adequate supply of inhalers, given issues with intermittent high drug delivery from individual capsules. Labeling comments are reserved until other issues are resolved. A comprehensive safety update is also required.

This outlines the key hurdles Pharmaxis must overcome under the Federal Food, Drug, and Cosmetic Act before their application can be reconsidered for approval.