medac Gesellschaft fur klinische Spezialpraparate mbH: Grafapex

1. You have not provided substantial evidence of effectiveness of treosulfan as a part of a preparative regimen for allogeneic hematopoietic stem cell transplantation for adult and pediatric patients with AML or MDS for the following reasons:

Because all complete blood cell (CBC) and marrow results were not submitted, we were unable to independently confirm the results of the analysis of the primary endpoint of EFS for Study MC-FLudT-14/L Trial Il.

Whether the results would be adequate to support approval of both indications will be a review issue.

To address this issue, submit data from an adequate and well-controlled trial of treosulfan vs busulfan with a prespecified analysis of OS for each indication with control of Type 1 error.

We reserve comment on the proposed carton and container until the application is otherwise adequate.

In order to obtain approval for both indications, you would need to demonstrate substantial evidence of effectiveness for each individually.

2. Your subgroup analyses of EFS and OS suggest a substantial difference in treatment effect by donor type.

Clarify how the results support your claim of noninferiority of treosulfan for HSCT from both related and unrelated donors (with the latter using ATG).

3. You conducted your efficacy analyses in the Full Analysis Set (FAS).

Fora randomized trial with EFS and/or OS endpoints, the analyses should be conducted on the intent-to-treat (ITT) population.

Include subgroup analyses by race and ethnicity for overall survival, nonrelapse mortality and relapse-free survival with at least 3 years of follow-up.

6. Address the following in the NDA resubmission:

7. We recommend that prior to the resubmission of the NDA, you conduct an in vitro study demonstrating DNA alkylation and breakage with treosulfan to adequately characterize the alkylating and genotoxicity properties and determine the potential serious risk of reproductive and developmental toxicity and carcinogenicity with treosulfan.

This study should be submitted to the NDA with the resubmission.