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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Meeting Summary - CINRYZE

Date: August 21, 2007          Time: 2:30 PM

From: Nannette Cagungun

To: STN 125267/0

Re: First Committee Meeting for LevPharma’s C1 Esterase Inhibitor BLA
________________________________________________________________________

FDA Participants:

Nannette Cagungun
Paul Buehler
Omer Butt
Felice D’Agnillo
Dave Doleski - Absent
Mahmood Farshid
Elena Karnaukhova
Charles Maplethorpe
Lisa Stockbridge (Jean Mackie)
Robert Wesley
Boris Zaslavsky - Absent

Background:

The sponsor will be using US source plasma to manufacture the product. The product is manufactured under contract by Sanguin Blood Supply Foundation in The Netherlands. The sponsor has performed a pivotal Phase III study investigating the safety and efficacy of the product for the prevention and treatment of HAE attacks. The acute therapy portion of that study forms the basis of the efficacy data included in the application. The sponsor has indicated that they would submit the prophylaxis portion of the study as an amendment to the BLA within 90 days from submission of the BLA. According to the sponsor, to meet the anticipated market demand for the product, certain early stage manufacturing processes will be moved to a new manufacturing location, --(b)(4)---, in ----(b)(4)----------. A comparative study of the intermediates manufactured from both locations and final products made at Amsterdam from both intermediates including a ----------------------(b)(4)--------------------------------------.

 Discussion:

The review committee members introduced themselves. Charles Maplethorpe suggested that the review committee familiarize themselves with the pre-BLA correspondence between FDA and the sponsor. FDA sent four sets of responses and clarifications to the sponsor prior to the submission of the BLA. (Correspondence dates: May 21, 2007, June 6, 2007, June 13, 2007 and June 21, 2007)

  • The RPM informed the group that the sponsor had submitted another dataset upon request from the statistician who could not open the SAS dataset. Charles Maplethorpe and Robert Wesley indicated that they could access the contents of the SAS transport file in the EDR. The committee agreed that the reviewers should look at the same dataset. The existence of two datasets in the EDR would only confuse the reviewers. It was agreed to ask the sponsor to indicate which dataset to review.
  • The sponsor has not requested a proprietary name review.
  • The RPM will request a clinical pharmacology reviewer for the BLA.
  • BIMO has some inspectional issues related to the short review schedule. We need to see the prophylaxis data; however, we do not know when that will arrive at CBER.
  • Section 16.1.4 of the submission indicates 6 clinical sites and investigators do not match up with the 21 sites that treated subjects and the dataset. The submission is missing information on study subjects. The sponsor should provide an accurate list of the number of subjects enrolled and treated for both the LevP 2005-1/Part A & B studies.
  • The CMC reviewers must look at the C4 assay validation carefully. The sponsor changed labs midway into the trial and results of the C4 assay were used as basis for the inclusion or confirmatory criteria. (23 subjects were adjudicated as protocol violators based on the results of the C4 assay).
  • Because the DMPQ reviewer could not participate, RPM will contact him to find out his inspection plans for this BLA.
  • The committee members will send their filing memo to the RPM and the SL prior to the filing meeting.

Action Items:

  1. LevPharma will be asked to submit a proprietary name review request.
  2. We need to ensure that there is only one database in the system. We will ask LevPharma to inform us which dataset to use. We will ensure that the biostatistician can open the dataset.
  3. Charles Maplethorpe and Robert Wesley will ensure that the clinical information is complete for the BIMO inspection.
  4. We will request a clinical pharmacology reviewer from Susan Abbondanzo.
  5. We will obtain inspection information from Dave Doleski.

Post meeting note:

Robert Wesley (BIMO said the protocols as well as the list of clinical investigators have been located in the submission. However, the sponsor should submit a listing of the number of subjects at each clinical site.