FDA CRL - Medac Gesellschaft fur klinische Spezialpraparate M.B.H.

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to medac Gesellschaft fur klinische Spezialpraparate mbH regarding their New Drug Application (NDA 214759) for Grafapex (treosulfan), submitted on August 11, 2020. Operating under section 505(b) of the Federal Food, Drug, and Cosmetic Act, the FDA determined the application could not be approved due to a lack of substantial evidence of effectiveness.

The primary issues cited involve the absence of complete blood cell (CBC) and marrow results for Study MC-FLudT-14/L Trial II, which prevented independent verification of the primary endpoint, event-free survival (EFS), and assessment for both AML and MDS indications. Furthermore, overall survival (OS) data was deemed insufficient as a sole basis for approval because the statistical plan lacked control for Type 1 error and prespecified boundaries for interim analyses, making OS findings exploratory.

To address these deficiencies, medac is required to submit the missing CBC and marrow results from the specified trial. A new, adequate, and well-controlled trial comparing treosulfan to busulfan, with a prespecified OS analysis for each indication and control of Type 1 error, is also mandated. Additionally, the company must provide a comprehensive safety update and address clinical pharmacology concerns related to dosing for patients with moderate renal impairment. Other considerations, such as labeling and proprietary name, are contingent upon resolving these core clinical and safety deficiencies.