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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Filing Letter - Berinert, May 5, 2008

May 5, 2008

Our STN:  BL 125287/0

CSL Behring LLC
Attention:  Paul Hartmann, R.Ph.
1020 First Avenue
P.O. Box 61501
King of Prussia, PA 19406-0901

Dear Mr. Hartmann:

This letter is in regard to your biologics license application (BLA) submitted under section 351 of the Public Health Service Act.

We have completed an initial review of your application dated 06 March 2008 for C1 Esterase Inhibitor (Human) to determine its acceptability for filing.  Under 21 CFR 601.2(a), we have filed your application today.  The review goal date is 06 September 2008.  This acknowledgment of filing does not mean that we have issued a license nor does it represent any evaluation of the adequacy of the data submitted.

We will contact you regarding your proposed labeling no later than 08 August 2008.  If post marketing study commitments (506B) are required, we will contact you no later than 08 August 2008.

While conducting our filing review, we identified the following potential review issues:

  1. Please explain how the PK study was conducted and audited.  Please provide supporting documentation to establish robustness of the data, namely, SOPs that were followed in generating PK data, sample handling, data collection, and handling and analysis.
  2. Please submit the details of analytical methods (both functional and antigenic) for the determination of C1 esterase inhibitor concentrations in blood or plasma.
  3. Please note that your current analysis of PK data for functional C1INH is not acceptable.  In       addition, you have not submitted the PK analysis of your antigenic data.  Please contact FDA’s pharmacokineticist in the Division of Hematology for further information on the required PK analyses.
  4. Please provide complete validation and/or qualification packages for all central laboratory non-routine clinical assays.
  5. Please provide analysis-ready dataset in -b(4)- transport files for each summary table   presented for Efficacy and Safety Findings (i.e., Tables 5, 6, 7, and 8 in the Clinical Overview section).
  6. Please provide a complete assay validation package for the anti-C1INH antibody assay performed by the central laboratory.
  7. Please submit an amendment to your ongoing U.S. extension study to provide for measurement of anti-C1INH antibodies.  If positive samples are obtained, it will be necessary to determine whether the antibodies are inhibitory.  If positive samples are obtained, testing of baseline stored specimens may be explored to determine whether the test results were “treatment-emergent.”
  8. We have not yet received your formal request for a proprietary name review (PNR).  We remind you to refer to CBER SOPP 8801.4, Review of CBER Regulated Product Proprietary Names, Appendix 1: Request for Proprietary Name Review available at http://www.fda.gov/cber/regsopp/80014app1.htm).

We are providing the above comments to give you preliminary notice of potential review issues.  Our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our complete review.  Issues may be added, deleted, expanded upon, or modified as we review the application.  If you respond to these issues during this review cycle, we may not consider your response before we take an action on your application.  Following a review of the application, we shall advise you in writing of any action we have taken and request additional information if needed.

If you have any questions, please contact the Regulatory Project Manager, Ms. Nannette Cagungun, at (301) 827-6174.

Sincerely yours,

            J. Anderson     for

Elizabeth G. Callaghan, M.S.
Acting Director
Division of Blood Applications
Office of Blood Research and Review
Center for Biologics Evaluation and Research