Late Cycle Meeting Package, January 16, 2014 - Ruconest

DEPARTMENT OF HEALTH & HUMAN SERVICES
 Public Health Service

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

                                           
 BLA 125495/0                                            LATE CYCLE MEETING
 BACKGROUND PACKAGE
 Pharming Group, NV 
 Attention:  Mr. Matthew E. Moran
 Santarus, Inc.
 3611 Valley Centre Drive, Suite 400
 San Diego, CA  92130

Dear Mr. Moran:

Please refer to your Biologics License Application (BLA) submitted under section 351 of the Public Health Service Act for C1 Esterase Inhibitor (Recombinant) [RUCONEST] for the treatment of acute attacks of hereditary angioedema (HAE) in adult and adolescent patients.

We also refer to the Late-Cycle meeting (LCM) scheduled for January 16, 2013.  Attached is our background package, to include a review status update and an agenda for this meeting.

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

Sincerely,

 

Basil Golding, MD
 Director
 Division of Hematology
 Office of Blood Research and Review   
 Center for Biologics
   Evaluation and Research

ENCLOSURE:
             Late-Cycle Meeting Background Package

LATE-CYCLE MEETING BACKGROUND PACKAGE

Meeting Date and Time:       Thursday, January 16, 2014; 2:30 p.m. – 4:00 p.m. EST

Meeting Location:                 Woodmont Office Complex I
                                                 CBER Conf. WOC-1
                                                 1401 Rockville Pike
                                                 Rockville, MD  20852

Application Number:             STN 125495/0

Product Name:                       C1 Esterase Inhibitor (Recombinant) [RUCONEST]

Indication:                              Treatment of acute attacks of hereditary angioedema (HAE) in                                                         adult and adolescent patients

Applicant Name:                    Pharming Group, NV

INTRODUCTION

The purpose of a Late-Cycle meeting (LCM) is to share information and to discuss any substantive review issues that we have identified to date, Advisory Committee (AC) meeting plans (if scheduled), and our objectives for the remainder of the review.  The application has not yet been fully reviewed by the signatory authority, division director, or chairperson and therefore, the meeting will not address the final regulatory decision for the application.  We are sharing this material to promote a collaborative and successful discussion at the meeting.

During the meeting, we may discuss additional information that may be needed to address the identified issues, whether it will be reviewed by the Agency in the current review cycle, and, if so, whether the submission would constitute a major amendment and trigger an extension of the PDUFA goal date.  If you submit any new information in response to the issues identified in this background package before this LCM or the Advisory Committee meeting, if an AC is planned, we may not be prepared to discuss that new information at this meeting.

Substantive Issues to be discussed at the Late Cycle Meeting:

Chemistry, Manufacturing and Controls
1.Specifications

There are no substantive review issues at this time.
2.Stability

There are no substantive review issues at this time.
3.Adventitious Agents Safety Evaluation

There are no substantive review issues at this time.
4.Analytical Methodology

Section 5.3.1 that addresses the methods/assay validation studies section is lacking a neutralizing assay for the rhC1INH, and is also lacking a method for the assay of rhC1INH antibodies that has been validated using a standard rhC1INH antibody with proven specificity to the recombinant form of the C1 esterase inhibitor.  In both cases Pharming uses antibodies that have been validated for C1INH and have been demonstrated to cross react with rhC1INH.  The antibodies used for validation are -------------------------------------------------------------------(b)(4)-----------------------------------------------------------------------------. This was previously the subject of an information request that was submitted on Oct 23, 2013 regarding validation report VAL-R-03-137.
5.Facilities and Equipment

The pre-license inspection was postponed pending resolution of substantive critical review issues in the application.  When these issues are resolved, the inspections will be rescheduled.

Non-clinical pharmacology / toxicology
 There are no substantive review issues at this time.

Clinical pharmacology
 There are no substantive review issues at this time.

Clinical
 The Phase 3 study 1310 suggests a lack of efficacy in the primary endpoint of time to beginning of relief in the pre-specified subgroups of “US subjects” and “female subjects.” FDA has communicated to you our concern over these study outcomes and reviewed your responses to these communications. Your responses to our informational requests, including post hoc analyses have not alleviated our concerns regarding efficacy of rhC1INH in these subgroups.

Bioresearch Monitoring
 There are no substantive review issues at this time.

Pharmacovigilance
 We agree with the Risk Management Plan as proposed by Pharming with the additional recommendation to submit a final list of MedDRA Preferred Terms (PTs) and other non-MedDRA terms that will be used in signal detection to identify the rhC1INH identified and potential risks (i.e., hypersensitivity reactions and thromboembolic complications), as well as identify pregnant and nursing women, to then apply the Data Capture Aids to.  On December 18, 2013, FDA sent Pharming a list of the 29 most important PTs, as well as a more comprehensive list (that included these 29 PTs), and Pharming was asked to submit their final list for use in signal detection activities.

REMS or other risk management actions
 No issues were identified that would require a Risk Evaluation Mitigation Strategy (REMS).

Labeling
 There are no substantive review issues at this time.

Advisory committee meeting
 Presentation of the BLA at the Blood Products Advisory Committee meeting is not planned.

PMC/PMR
 No Post-Marketing Commitment was proposed by the Applicant and no issues have been identified at this time that would require a Post-Marketing Requirement.

LCM AGENDA
1.Introductory Comments – 5 minutes (RPM/Chair)

Welcome, Introductions, Ground rules, Objectives of the Meeting
2.Discussion of Substantive Review Issues – 50 minutes
a.The Phase 3 study 1310 suggests a lack of efficacy in the primary endpoint of time to beginning of relief in the pre-specified subgroups of “US subjects” and “female subjects.”  
b.Lack of  a neutralizing assay for the rhC1INH
3.Potential questions from Pharming – 5 minutes
4.Wrap up and Action Items – 10 minutes
