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First Committee Post Resubmission Meeting Summary - Berinert, May 26, 2009
First Committee Post Resubmission Meeting Summary
Date: May 26, 2009 Time: 10:30 AM – 11:30 AM
From: Nannette Cagungun, CBER/OBRR/DBA, HFM-380
To: STN 125287/0
Subject: First Committee Meeting post resubmission for CSLB’s C1 Esterase Inhibitor BLA
Paul Buehler- absent
Dave Doleski – absent
Marion Michaelis – absent
Jean Makie- on the phone
Bhanu Kannan –on the phone
Joe Quander-on the phone
The clinical reviewer, Ross Pierce indicated there are several clinical and statistical issues that need to be conveyed to CSL Behring (CSLB). Several claims made in the cover letter of the resubmission do not seem accurate. The complete method of calculation of the primary endpoint using the various revised sponsor databases could not be located in the resubmission, only a rough outline of the process. Amendment 25 does not stand on its own in terms of containing the detailed methodology to validate the sponsor’s analyses of the primary endpoint using the revised databases (revisions based on review of hospital medication records). CSLB refers to an old amendment for some of the requisite -b(4)- code without naming the amendment number. Copies of medication records from the hospital medical records are for all subjects in the pivotal trial for whom discouraged or non-permitted/forbidden medications that are listed in the CRF as continuing following enrollment in the study are said to be provided in the submission. These formed the basis of database revisions. CBER needs to check the veracity of CSLB’s claims that the robustness analysis remains statistically significant for the comparison of high dose and placebo groups. CBER need to see raw data as well as clarify imputed data. The firm’s position regarding non-narcotic analgesic concomitant medications amounts to a post hoc analysis because the protocol definition of the primary endpoint called for imputation of a poor/failure value if analgesics (not restricted to narcotic analgesics) were taken during the time window of interest. The SAP version 2 was not submitted to the IND. This should have been submitted to the IND before the blind was broken and before the BLA was submitted. CBER does not yet know whether the SAP was finalized before the dataset was unblinded. Dr. Pierce said he does not agree with the sponsor’s analysis plan as described in version 2 of the SAP because not all of the discouraged/non-permitted medications were taken into account when imputing a poor/failure value of 24 hours for the primary endpoint. All such medications should be taken into account in the primary analysis that would go into the labeling. CSLB has indicated that they did not mean to include non-narcotic analgesics in the dataset; however, according to sponsor’s consultants’ letters included in amendment 25, there are no data in the literature to determine one way or the other whether the non-narcotic medications have any effect. The applicant should put both analyses (with and without taking into account non-narcotic analgesics) in the labeling. There are also the issues regarding differentiating the outcomes of facial and abdominal attacks that should be discussed with CSLB. All of these issues should be conveyed to the firm as soon as possible.
With regard to viral validation and additional step, Felice D’Agnillo stated that CSLB’s proposal appears adequate. He said that Dave Doleski recently indicated to him that the 483 items were on track. A telecon will most likely be conducted between DMPQ and CSL Behring soon.
There are no new BIMO issues at this point. Because there are no new sites and new investigators, Bhanu Kannan said no inspections will be scheduled.
Jean Makie stated that CSLB did not include any labeling for the carton, container and package insert in the resubmission. CSLB should resubmit a proprietary name review request soon. CBER sent the labeling recommendations for the PI to CSLB on November 5, 2008 and the labeling recommendations for the carton and container on October 15, 2009. Nannette Cagungun informed the review committee that a PNR letter must issue by July 9, 2009. She also noted that any PMR or safety labeling must be sent to the OBRR Safety Working Group representative by July 16, 2009.
Ross Pierce said that higher doses of the product could have a potential risk for thrombotic adverse events (AEs). The data on the Phase 4 study for facial attacks seem to be weaker that that of abdominal attacks. A recommendation for a patient registry will be considered as part of a PMR.
OBE did not have any comments regarding their review of the submission.
Nannette Cagungun said that the BPAC waiver justification should be signed by the CRB acting chief.
Jean Wang will work closely with Ross Pierce to analyze the datasets.
Joe Quander does not have any issues but pointed out that he will need to review the lot release protocol and receive lot release samples. Felice D’Agnillo indicated that the lot release testing plan has been signed.
The review committee will meet again at mid-cycle of the review.
In the meantime, a conference call will be scheduled with CSLB to convey comments regarding clinical, statistical and labeling issues.