Mid-Cycle Telecon, October 10, 2013 - Ruconest

Mid-Cycle Communication

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research




Application:
 
BL STN 125495/0
 


Product:
 
C1 Esterase Inhibitor (Recombinant)
 


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


Applicant:
 
Pharming Group NV
 


Chair:
 
Elena Karnaukhova, PhD, OBRR/DH/LBVB
 


RPM:
 
Nannette Cagungun, MS, PD, OBRR/DBA/RPMB
 


Meeting Date:
 
October 10, 2013, 11:30 – 11:45 am
 

FDA Attendees:
Nannette Cagungun, MS, PD, RAC, OBRR/DBA/RPMB
Felice D’Agnillo, PhD, OBRR/DH/LBVB
Elena Karnaukhova, PhD, OBRR/DH/LBVB
Kimberly Taylor, CDER/OPI/OPA/PES

Eastern Research Group attendees:
So Hyun Kim, Independent Assessor
Christopher Sese, Independent Assessor

Pharming/Santarus Attendees:
Mark Totoritis MD, Senior VP, Clinical Research
Michael Huang MD, Medical Director, Clinical Research
Mario Bedoya-Toro, PhD, MBA, Senior VP, Regulatory Affairs and Quality Assurances
Matt Moran, MS, Senior Director, Regulatory Affairs
Waren Hall, PhD, Senior VP, Manufacturing and Product Development
Bob Bagin PhD, Senior Director Biostatistics & Data Management
Yun Hardiman, MS, Director Biostatistics & Data Management
Wendell Wierenga, PhD, Executive VP Research and Development
Anurag Relan MD, Director, Clinical, Pharming
Edwin van Amersfoort PhD, Director Regulatory Affairs and Nonclinical, Pharming
Jos van der Lubbe, PhD, Quality Assurance, Pharming
Sander Mathôt PhD, Senior Director Supply Chain, Pharming

Discussion Summary:
1.Significant issues identified by the review committee to date

Clinical:
•Study 1310 failed to demonstrate efficacy in female subjects and in U.S. subjects.
•Development of neutralizing antibodies against your product may have led to lack of efficacy. Please submit the assay validation and results for detecting neutralizing antibody against rhC1INH. 

Statistical:
•The data reviewed so far shows lack of efficacy in the US subjects and in the female subjects in the confirmatory study 1310 with respect to the primary endpoint, time to beginning of relief based on TEQ question 1 and question 2 with persistence. This information was communicated to you in the FDA filing with deficiency letter dated June 14, 2013. Your July 29, 2013 response to the FDA cited a delay from time of attack onset to presentation for evaluation as the reason for a lack of demonstrated efficacy in the two subgroups. We find your analysis and the statement not convincing due to inclusion of three “outliers.” This issue was sent to you as an IR on September 25, 2013. 
2.Preliminary review committee thinking regarding risk management
The review committee (currently) does not think that a Risk Evaluation and Mitigation Strategy (REMS) is required.
3.Information requests sent with responses not yet received
September 17 & September 20, 2013 – response requested by October 15, 2013
September 25, 2013 – response requested by October 25, 2013
October 8, 2013 – response requested by October 31, 2013
4.Any new information requests to be communicated

Clinical issues
a.Development of neutralizing antibodies against your product may have led to lack of efficacy. Please submit the assay validation and results for detecting neutralizing antibody against rhC1INH.
b.Please submit an explanation for lack of efficacy in the two subgroups (females and US) in study 1310.

CMC issues
•Please submit the validations for the neutralizing antibody assays that must be used to determine whether the observed anti-rhC1INH antibodies neutralize activity of rhC1INH (in addition to that of plasma C1INH). As plasma C1INH and rhC11NH are not identical (e.g., glycosylation pattern), it is possible that those antibodies which show negative in the neutralization assay using plasma C1INH, may still neutralize activity of rhC1INH. All future studies should include measurement of antibodies that neutralize the activity of rhC1INH.
5.Proposed date for the late-cycle meeting 
The late-cycle meeting is scheduled for January 16, 2014, 2:30 – 4:00 pm
6.Updates regarding plans for the AC meeting 
The decision to present to the Blood Product Advisory Committee has not been made as yet.
7.Other projected milestones 
Labeling and PMC/PMR target date: March 17, 2014 
