Mid-cycle Meeting Summary - Berinert, June 4, 2008
Mid-cycle Meeting Summary
Date: June 4, 2008 Time: 10:30 AM – 11:30 AM
From: Nannette Cagungun, CBER/OBRR/DBA, HFM-380
To: STN 125287/0
Subject: Mid-cycle Meeting for CSL Behring’s C1 Esterase Inhibitor BLA
Paul Buehler- on the phone
Dave Doleski – on inspection
Marion Michaelis – on inspection
Mahmood Farshid – on travel
Jean Mackie- on the phone
The RPM and the Scientific Lead gave an update on the status of this BLA.
This BLA was filed on May 5, 2008. Several information requests have been faxed to the applicant since receipt of the submission. Responses to several of those Information Requests are still pending.
On May 28, 2008, OBRR informed CSL Behring that it was considering the possibility of presenting the BLA to the BPAC in September and requested the firm to submit all information requested by June 13, 2008.
CSL Behring submitted the list of definitions of the field variable names for each of the datasets as well as the analysis-ready datasets on May 30, 2008.
The clinical reviewer stated that the BLA was submitted prematurely because the firm did not submit the three-month viral follow-up safety data (as called for in the protocol) prior to submitting the application.
The submission does not contain any data from laboratory safety and immunogenicity testing. FDA has asked the firm to submit it on their ongoing US extension study (i.e., measurement of anti-C1INH antibodies, routine chemistry and CBC follow-up testing post product exposure). If positive anti-C1-INH antibody samples are obtained, it will be necessary to determine if the antibodies are inhibitory. The firm should also provide baseline measurements before subjects are exposed to the product.
FDA is also waiting to receive additional information on adverse events analyses (i.e., subjects randomized to placebo vs. subjects randomized to treatment) to help with writing the adverse reactions section of the package insert.
The product met the primary endpoint and works in the higher dose. The lower dose appears to have a definite trend.
There seems to be a gender effect. In a spot-check CRF review, subject individual symptoms scores appeared to be inconsistent with the subject’s subjective assessment of time to initial relief of symptoms (the primary endpoint). The firm has been asked to present a single page for each subject that permits the results of individual HAE symptoms scores over time to be compared to the responses to the question that determines the primary endpoint. Should the primary endpoint prove to be inconsistent with the individual symptom scores, it would tend to undermine the validity of the primary endpoint.
FDA has asked the sponsor to validate their analytical method. When their response arrives, CMC reviewers will evaluate it for completeness and acceptability. FDA needs to confirm whether the firm did an audit of the laboratory. It was noted that CSL Behring has not yet informed the Agency whether its inspectors can go to the laboratory where the PK assays were done. FDA is also still waiting for the SOPPs and informed consent requested on April 15, 2008.
The sponsor has submitted information on the functional assay (---b(4)---------). However, CSL Behring needs to qualify this assay.
The population PK that the firm conducted is problematic because the analysis was done using -b(4)-. In addition, the sponsor should make appropriate assumptions for the study.
CSL Behring submitted the analytical validation in amendment 6. However, further clarification and/or justification of major parameters are required. The firm should be advised that endotoxin testing must be part of the final product release specifications with a justified acceptance criterion for endotoxin level. The firm should clarify whether --b(4)-- testing is part of the release specifications. As in validation study reports some data are missing, the CMC reviewers request (a) several actual ---b(4)---------------------- that address the ---b(4)--------- testing, and (b) some typical (actual) --b(4)---------- data for both release and dating period.
The sponsor has not yet submitted any data on the conformance lots. They are requesting a 30 month dating period. The application also does not contain post-marketing commitments regarding stability.
Dr. Golding stated that it is more important for the firm to provide information on lots used in the clinical study. If there are no changes in the manufacturing and specifications, then the lots should be acceptable.
The sponsor used two viral validation methods: heat treatment and ---b(4)---------------------------------------. The kinetics of inactivation of HIV is much slower in these methods than what has been reported by other sponsors of other products. The interaction between HIV and C1 Esterase Inhibitor appears to extend the viral inactivation kinetics. This observation, which can be attributed to the ---b(4)---------------------------- has also been seen with PRV. The
----b(4)------------------------ step is not robust for non-enveloped viruses. --b(4)------------ is deemed better.
Missing information has just been submitted by the firm in Amendment 7 (submitted on May 30, 2008).
According to the scientific lead, the 483 items can be corrected in a reasonable amount of time.
The pre-clinical reviewer will provide some labeling recommendations.
Inspection has not yet begun in two U.S. sites.
Labeling considerations will be made available soon.
Pharmacovigilance planning. The epidemiologist will pay attention to lack of effect, thromboembolic events, and additional analysis (e.g. children with cardiac surgeries).
Labeling should be made as broad in the US as to what is being used in Europe.
The contraindication section will be expanded.
FDA will require a Phase 4 commitment.
CDER Pulmonary consult will be sought.
The meeting ended.