FDA CRL - EMD Serono, Inc.

The FDA issued a Complete Response Letter to EMD Serono, Inc. regarding its New Drug Application (NDA 022561) for cladribine tablets, submitted on May 27, 2010, under section 505(b) of the Federal Food, Drug, and Cosmetic Act. While the FDA deemed cladribine effective for relapsing remitting multiple sclerosis, the application could not be approved due to significant safety concerns. The primary issue was an unacceptable increased risk of malignancy associated with cladribine. Clinical trials, including the CLARITY study, demonstrated a disproportionately higher number of cancer cases in cladribine-treated subjects compared to placebo. For instance, the broader safety database revealed 33 cases in cladribine subjects versus two in placebo. The FDA found the company's counter-arguments, such as comparisons to general population malignancy rates, unconvincing. To address these concerns, EMD Serono, Inc. must provide a better understanding of this malignancy risk through additional analyses or studies. Specific requests included more information on methods for calculating standardized incidence ratios, clarification on documented pre-existing malignancy risk factors across all study subjects, and further details regarding the planned PREMIERE long-term safety registry. Additionally, the FDA noted that a sustained decrease in lymphocyte count observed with cladribine would also require attention once the primary malignancy concerns are resolved.