Initial Review Letter - RUCONEST

DEPARTMENT OF HEALTH & HUMAN SERVICES
 Public Health Service

Food and Drug Administration
 1401 Rockville Pike
 Rockville, MD 20852-1448

Our STN:  BL 125495/0 

Pharming Group N.V.
 Attention: Matthew E. Moran
 Santarus, Inc.
 3611 Valley Centre Drive, Suite 400
 San Diego, CA  92130

Dear Mr. Moran:

This letter is in regard to your biologics license application (BLA) submitted under section 351 of the Public Health Service Act.

We have completed an initial review of your application dated April 15, 2013 for C1 Esterase Inhibitor (Recombinant) to determine its acceptability for filing.  Under 21 CFR 601.2(a) we have filed your application today.  The review classification for this application is Standard.  Therefore, the review goal date is April 16, 2014.  This acknowledgment of filing does not mean that we have issued a license nor does it represent any evaluation of the adequacy of the data submitted. 

We are reviewing your application according to the processes described in the Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA Products.  Therefore, we have established internal review timelines as described in the guidance, which include the timeframes for FDA internal milestone meetings.  We plan to hold our internal mid-cycle review meeting on September 26, 2013.  Please be aware that the timelines described in the guidance are flexible and subject to change based on workload and other potential review issues (e.g., submission of amendments).  We will inform you of any necessary information requests or status updates following the milestone meetings or at other times, as needed, during the process. 

We will contact you regarding your proposed labeling no later than March 17, 2014.  If post marketing study commitments (506B) are required, we will contact you no later than March 17, 2014.

We plan to present this application to the Blood Products Advisory Committee (BPAC).

While conducting our filing review, we identified the following potential review issues:

1.   Our preliminary review of the results of the pivotal study has identified the following deficiencies: 
•As shown in Table 15 (clinical study report, page 91), the pivotal study 1310 did not demonstrate efficacy at sites in the U.S., which accounted for one-half of the total enrollment.
•As shown in Table 15 (clinical study report, page 91), the pivotal study 1310 did not demonstrate efficacy for female subjects, who accounted for 63% of the enrollment.

Both subgroup analyses were pre-specified in the plan for statistical analysis. 

Please note in the November 30, 2012, pre-BLA meeting briefing package intended for the January 8, 2013, pre-BLA meeting (which was not held) you did not inform CBER of the failure to demonstrate efficacy for subjects enrolled at U.S. sites in pivotal study 1310, and you did not inform CBER of the failure to demonstrate efficacy for female subjects in pivotal study 1310.  The pre-BLA meeting package only presented outcomes for pivotal study 1310 for secondary endpoints or subgroups that were favorable for licensure.

Please submit additional data from a randomized controlled study that can provide robust evidence for efficacy of the product.

2.   Please compare and submit the outcomes for the primary endpoint in study 1310 for the two groups 1) placebo subjects enrolled at U.S. sites, and 2) placebo subjects enrolled at European sites, using the procedures for the primary efficacy analysis described in section 6.11.1 of the statistical analysis plan for study 1310, and submit the results to STN 125495.

3.   Some subjects were enrolled in multiple studies.  Please submit a unique subject identifier mapping that identifies unique subjects across all studies.

We are providing the above comments to give you preliminary notice of potential review issues. Our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our complete review.  Issues may be added, deleted, expanded upon, or modified as we review the application.  If you respond to these issues during this review cycle, we may not consider your response before we take an action on your application.  Following a review of the application, we shall advise you in writing of any action we have taken and request additional information if needed.

If you have any questions, please contact the Regulatory Project Manager, Nannette Cagungun, at (301) 827-6174.

Sincerely yours,

 

Iliana Valencia, MS
 Chief
 Regulatory Project Management Branch
 Division of Blood Applications
 Office of Blood Research and Review
 Center for Biologics 
   Evaluation and Research
