Committee Meeting Minutes, February 11, 2013 Alprolix

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration
 1401 Rockville Pike
 Rockville, MD 20852-1448 

Committee Meeting Minutes

Our Reference:     BL STN 125444/0

MEETING DATE: February 11, 2013, 3:30  4:15 p.m., Rm. 200S

SUBJECT:     Filing Meeting
FROM:           Edward Thompson (RPM) and Nancy Kirschbaum (Committee chair)

PRODUCT:  Coagulation Factor IX (Recombinant), Fc Fusion Protein [rFIXFc]

INDICATION: For control and prevention of bleeding episodes; routine prophylaxis to prevent or reduce the frequency of bleeding episodes; perioperative management (surgical prophylaxis) in patients with Hemophilia B

Summary of the Meeting 
 The filing meeting for BL STN 125444/0, original biologics license application (BLA) from Biogen Idec for Coagulation Factor IX (Recombinant), Fc Fusion Protein, was held on February 11, 2013, from 3:30  4:15 p.m.  The following issues were addressed.

1.   Refuse to File (RTF) issues or if a Deficiencies Identified letter is required
 Discussion: One potential RTF issue was discussed.  The manufacturing process for rFIXFc does not include a -----(b)(4)----- step.  The proposed commercial manufacturing process for rFIXFc incorporates a ----(b)(4)---- virus filtration step and a validated chromatography step,       -------------------(b)(4)------------------------.  In order to ensure viral safety, plasma derived ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------         --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------     --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.  The manufacturing process used to produce rFIXFc clinical material for phase 1 trials had incorporated a -(b)(4)- step, which was removed prior to manufacture of the phase 3 clinical trial product.  An information request was sent to Biogen Idec on 15 January 2013 requesting further information

---------------------------------------------------(b)(4)--------------------------------------------------           --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

---------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------             ----------------------------------------------------------------------------------------------------------               -----------------------------------------------------------------------------------------------------------------     -------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------         -----------------------------------------------------------------------------------------------------------------     ---------------------------------------------------------------------------------------------------------------        ----------------------------------------------------------------------------------------------------------------       ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
 -------------------------------------------------------------------------------------------------------------------   --------------------------------------------------------------------------------------------------------------         ---------------------------------------------------------------------------------------------------------------        ----------------------------------------------------------------------------------------------------------------       -------------------------------------------------------------------------------------------------------------------   -------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------       -------------------------------------------------------------------------------------------------------------------- -------------------------------------                                                                                                          -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------                                                                              --------------------------------------------------------------------------------------------------------------         ---------------------------------------------------------------------------------

The committee also considered the proposal to continue review of Biogen Idecs submitted commercial manufacturing process with the following two options: (1) licensure of the proposed manufacturing process, if data in the BLA are adequately supportive, without the requirement to incorporate a ------(b)(4)------- step post-licensure or (2) requirement to incorporate a ---(b)(4)---------------------- step as a post-marketing commitment.  The following information and data were discussed.
 i.    Viral contamination risk mitigation strategies incorporated into the rFIXFc process
  Extensive cell bank characterization
     Raw materials management  no animal derived raw materials used; receipt, handling and storage controls to prevent contamination and cross-contamination
     Facility design and production controls to prevent contamination and cross- contamination
     Adventitious virus detection in -----------(b)(4)--------------- cell lines for each         -----------(b)(4)------------ (cytopathic effect; hemadsorption)
     -------(b)(4)-------chromatography  validated virus reduction factors

[--(b)(4)--]

-----------------------------(b)(4)---------------------------------
 [--(b)(4)--] 

-----------------------------------(b)(4)--------------------------------
 --------------------------------------------------------------------------------------------------------------  -------------------                                                                                                                            -----------------------------------------------------------------------------------------------------------      -----------------------------------------------------------------                                                              -------------------------------------------------------------------------------------------------------------    -----------------------------------------------------------------------------------------                              --------------------------------------------------------------------------------------------------------------------------------------------------------                                                                                                ----------------------------------------------------------------------------------------------------------------------------------------------------

------------------------------(b)(4)---------------------------
 ------------------------------------------------------------------------------------------------                     -------------------------------------------------------------------------------------------------------            -------------------------------------------------------------------------------------------                            --------------------------------                                                                                                          ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------                                             ---------------------------                                                                                                                 ----------------------------------------                                                                                                -----------------------------------------------------------------------------------------------------------      ---------

iv. Currently licensed recombinant coagulation factor concentrates with -------(b)(4)----------- steps



 a.   BeneFIX  Coagulation Factor IX (Recombinant), approved in 1997
 b.   Recombinate  Coagulation Factor VIII (Recombinant), approved in 2000. The third generation of this product, Advate, approved in 2003, incorporated -------(b)(4)-------------------- step in the manufacturing process

v.   Viral transmission from recombinant products
To date, there have been no reported viral transmissions caused by recombinant therapeutic products
Recombinant products have been licensed since 1992

vi. Manufacturing processes for recombinant therapeutic proteins and monoclonal antibody therapeutics regulated by CDER
We will look to see if products incorporate a ------(b)(4)--------- step

The committee concurred that this issue would not prevent filing of the BLA.  This issue will be discussed further at the 12 March 2013 CBER Blood meeting.

2.   Identify any required material that may have been omitted from the submission
 Discussion: Information requests for missing information have been previously conveyed.

3.   Suitability for Filing
 The committee concurred that BL STN 125444/0 can be filed.  This item of the filing meeting minutes constitutes the memo documenting the committees filing decision.

4.   APLB reviewer comments on Proprietary Name Review
 Discussion: Loan Nguyen (OCBQ/DCM/APLB) reviewed the request submitted by Biogen Idec on 11 January 2013 to re-evaluate the proprietary name, ALPROIX.  Dr. Nguyen found the proprietary name, ALPROIX, to be acceptable.  Dr. Nguyen will re-evaluate the name 90 days prior to the 28 December 2013 action due date for this BLA.

5.   Lot Release
 Discussion: rFIXFc is exempt from Lot Release

END

Footnotes

1Guidance for Industry: Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin, September 1998
