EMD Serono, Inc.: cladribine

Please refer to your New Drug Application (NDA) dated May 27, 2010, received May 28, 2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for a (cladribine) Tablets.

Although we have concluded that cladribine is effective as a treatment for patients with relapsing remitting multiple sclerosis (RRMS), safety concerns associated with its use preclude its approval at this time.

Substantial evidence of cladribine's effectiveness was provided by the CLARITY study.

The effect of cladribine was demonstrated by effects on relapse rate, disability progression, and various imaging markers of disease activity.

We believe that the data, taken as a whole, meet the standard for substantial evidence of effectiveness, as provided by one adequate and well controlled clinical trial and confirmatory evidence.

When considering the entire safety database, in completed studies of cladribine and ongoing controlled studies of cladribine, there were 33 cases of malignancy in cladribine-treated subjects and two in placebo-treated subjects.

In trials of oral cladribine in the U.S. the incidence was even higher with 18.3 cases of malignancy per 1000 subjects in cladribine treated subjects (3 cases in 164 subjects) and no cases in placebo.

You must provide an improved understanding of this risk, either through additional analyses or by conducting additional studies, before we could consider approving this application.

We remain concerned, because an increased risk of malignancy in cladribine-treated subjects compared to placebo-treated subjects persists after excluding these cases.

Although we agree that there is considerably more long-term experience under treatment, compared to placebo, conditions, we note that there is still a worrisome signal for malignancy in CLARITY.

Although the maximum duration of observation in CLARITY is 2 years, we believe that this is a sufficient duration of exposure to cladribine to consider any malignancies occurring then to be biologically plausible.

Given our significant concerns about cladribine-induced malignancies, we have not included draft labeling with this letter.

However, we have the following comments related to carton and container labeling.

Please submit draft carton and container labeling revised as follows:

We reserve comment on the remainder of your proposed labeling until the application is otherwise adequate.

For subgroups stratified by location (U.S. versus non-U.S. sites) and by route of administration (oral vs. parenteral), we request tables with the number of reported malignancies, number of subjects, incidence proportions, subject-years of exposure, and incidence rates for cases of malignancy in completed and ongoing trials for placebo-treated and cladribine-treated subjects.

V.2. We request additional information about (1) a 26 year old male from the Ukraine who was diagnosed with tuberculosis of the right upper lung (MFR Control No. 7014989; initial report submitted 02 Sep 2010) and (2) me 445 year old female from Lebanon who was found to have conversion to a positive PPD.

Level Group Term in completed placebo-controlled trials.

We request the number of cases, the number of subjects, incidence proportions, subject-time of exposure in subject-years, and incidence rates for cladribine-treated and placebo-treated study subjects.

X.1. We request a narrative that includes the details of the SAEs of angioedema and urticaria, which led to treatment discontinuation, for Subject © in the ONWARD Study.

XVI.2. We request the following additional information regarding Case 7023305, a 21 year old male subject from Poland in the ORACLE MS trial with elevated amylase and lipase levels (information submitted 22 Nov 2010):