Late Cycle Meeting Package, September 12, 2013 - Alprolix

DEPARTMENT OF HEALTH & HUMAN SERVICES
 Public Health Service 

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

Our Reference: BL 125444/0

LATE CYCLE MEETING
BACKGROUND PACKAGE 

Biogen Idec, Inc.
 Attention: Nadine Cohen, PhD
 14 Cambridge Center
 Cambridge, MA 02142

Dear Dr. Cohen:

Please refer to your biologics license application (BLA), submitted under section 351(a) of the Public Health Service Act, for Coagulation Factor IX (Recombinant), Fc Fusion Protein.

We also refer to the Late Cycle meeting (LCM) scheduled for September 12, 2013. Attached is our background package, to include a review status update and an agenda for the meeting.

If you have any questions, please contact Edward Thompson at (301)827-9167.

Sincerely,


Basil Golding, MD
 Director
 Division of Hematology
 Office of Blood Research and Review 
 Center for Biologics
 Evaluation and Research


ENCLOSURE:
 Late Cycle Meeting Background Package




LATE CYCLE MEETING BACKGROUND PACKAGE



Meeting Date and Time: Thursday, September 12, 2013; 10 a.m. - 11:30 a.m. EDT

Meeting Location: Woodmont Office Complex I
 Conference Room 1
 1401 Rockville Pike
 Rockville, MD 20852

Application Number: STN 125444/0

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

Indication: For the control and prevention of bleeding episodes, routine prophylaxis and perioperative management (surgical prophylaxis) in individuals with hemophilia B

Applicant Name: Biogen Idec, Inc.

INTRODUCTION
 The purpose of this Late Cycle meeting (LCM) is to share information, to discuss substantive review issues identified to date, and to communicate our objectives for the remainder of the review cycle. The application has not yet been fully reviewed by the signatory authority, division director or chairperson; therefore, the meeting will not address the final regulatory decision for the application. We are sharing this information to promote collaborative and successful discussion.

Please be advised that any new information submitted before the LCM that had not been requested by the Agency will not be addressed during the meeting. Furthermore, during the meeting, we may request the submission of additional information, as necessary, to address identified issues. Our planned review timelines for any requested additional information will be communicated to you during the meeting. 

Substantive Issues to be discussed at the Late Cycle Meeting:

Chemistry, Manufacturing and Controls
1.Specifications
•Revised drug substance and drug product release specifications appear acceptable. We note, however, that the tests for --(b)(4)-- and excipients are projected for implementation in January 2014. Please be advised that product may not be released for commercial distribution until these tests have been adequately validated and implemented and reported to the Agency as a Changes Being Effected in 30 days (CBE-30) supplement to STN BL 125444.
•Further revisions to in-process specifications (IPS) for bioburden and endotoxin are required. You may establish bioburden IPS -----------------------(b)(4)----------------------------------------------. You may establish endotoxin IPS ------------------(b)(4)----------------------------------------.
2.Stability
•Please add the test for -(b)(4)- to the stability monitoring program for the diluent (even though it is not a ---(b)(4)--- solution).
•In order to support the label claim of 6 month storage at room temperature (not to exceed 30oC) within a 24 month shelf life, please monitor all conformance lots at room temperature after storage at 2 – 8 oC for 18 months.
3.Adventitious Agents Safety 

Please provide in writing, a post-marketing commitment to incorporate a -------(b)(4)------- step into the manufacturing process for rFIXFc. Please provide a timeline for completion and reporting of the manufacturing change in a prior approval supplement (PAS) to STN BL 125444.
4.Analytical Methodology
•Validation of the -------------(b)(4)------------- method against the ----(b)(4)---- method for determination of residual moisture was not adequate in that: (a) the validation study did not cover the full acceptance range of up to (b)(4), specified for rFIXFc drug product shelf life and (b) the study did not include (b)(4) IU and 3000 IU dosage presentations.
5.Process Intermediate Hold Times

Please establish shorter process intermediate hold times based on conformance batch manufacturing experience, e.g., 
 [--(b)(4)--]




[--(b)(4)--]
6.Notification to FDA for one time exception to release lots exhibiting excursions to critical controls

Please add the following to your commitments regarding notification to FDA for a one time exception [21 CFR 640.120(a)]: (a) excursion beyond any parameter controlling ----(b)(4)---- virus filtration and (b) exceeding any established process intermediate hold time (see item 5).
7.Process Validation

There is a concern about your process validation conformance lots for the following reasons:
•There is insufficient data to support manufacturing on --------(b)(4)-------. Specifically, the conformance lot data submitted was not manufactured under prospective validation and was not carried on beyond the ----(b)(4)---- process.
•Drug substance (DS) batches ------(b)(4)-------------------(b)(4)------- were not manufactured as part of the DS conformance batches and were used for the drug product (DP) conformance lots in support of this BLA. Additionally, it is not clear if these batches were manufactured under the process validation master plan or under prospective validation.

These items were discussed during an August 20, 2013 teleconference.
8.Facilities and Equipment

CBER performed a pre-license inspection at Biogen Idec’s Large Scale Manufacturing (LSM) facility in ---------------------(b)(4)-----------------------, from -------(b)(4)-------. FDA Form 483 containing six observations was issued to Biogen Idec on ----(b)(4)---. Biogen Idec responded to Form 483 observations in amendment 23, submitted August 15, 2013. The following observations have not yet been satisfactorily addressed:

Regarding Observation #4 pertaining to cited deficiencies in control of PRCD-19185, “Factor IX Fc Activity One Stage Activated Partial Thromboplastin Time (aPTT) Assay On --(b)(4)------------------”:
•Observation 4a cited, “There is no documented procedure for in-house qualification of critical reagents, --------(b)(4)-----------------aPTT reagent.” Biogen responded by presenting a justification for why this was not necessary. The Agency expects Biogen to establish, document and follow a procedure to qualify each new lot of ----(b)(4)-------------------------(b)(4)------------ (aPTT) reagent. Therefore, your response is considered inadequate.
•Observation 4b cited, “Instruction 4.6.2.4 permits storage of -----------(b)(4)-------------------------- plasma for up to --------------(b)(4)---------------, which is not supported by method validation.” Although you committed to performing a robustness study, you did not provide a timeline for study completion and submission of study results to the Agency. Please commit to one of the following options, as applicable: (1) submission of a revised procedure prior to the action due, instructing a shorter -------(b)(4)------- storage time for ---------------(b)(4)--------------------consistent with method validation or (2) conduct of a robustness study and submission of the associated study report either prior to the action due date or as a post-marketing commitment specifying timeline for completion and submission of the study report as a Changes Being Effected (CBE) supplement to BL STN 125444.
•Observation 4c cited, “There is no replicate analysis of the control preparation.” Biogen responded that the control is assayed in --(b)(4)-- and presented an illustration of the ---(b)(4)--- scheme showing --------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. The expectation is that ---(b)(4)--- of control be analyzed for each assay and that the samples be placed on the -(b)(4)- to control for location/time dependent effects. Therefore, your response is considered inadequate.
•Observation 4d cited, “Instruction 4.6 permits repeat testing of --------------(b)(4)--------------------- in the event of failure to meet any assay acceptance criterion.” Biogen responded by presenting a justification for why this practice was acceptable. The Agency does not concur; therefore, your response is considered inadequate.
•Observation 4e cited, “Instruction 4.9 for system suitability permits the exclusion of --(b)(4)-- sample clotting times in the event of failure to meet the acceptance criteria for %CV agreement or ---(b)(4)---- assay.” Biogen committed to revision of PRCD 19185 to eliminate this practice. Biogen committed to completing the revisions by October 30, 2013. Please submit the revised analytical procedure.

Regarding Observation #5 pertaining to cited deficiencies in the current program for qualification and use of analytical control preparations in the routine performance of PRCD-19185 and PRCD-22646, “Activated Factor IX (FIXa) -(b)(4)- for Determination of FIXa Impurity in Factor IX Fc ---------(b)(4)-------- Drug Product”:
•Observation 5a cited, “Control preparations may be prepared from rejected batches.” Biogen responded by presenting a justification for when this practice is acceptable. The Agency does not concur; therefore, your response is considered inadequate.
•Observation 5b cited, “Qualification of control preparations do not establish 2s limits,” and Observation 5d cited, “There are no documented procedures for statistical process control rules e.g., 1(3s), 2(2s) or 10x designed to initiate laboratory investigations into potential systematic bias or assay drift.” Biogen committed to revision of applicable procedure, PRCD 24655, “Commercial/Clinical Data Trending Using ---(b)(4)---

--------------------------(b)(4)-------------------------” such that appropriate statistical process control limits and defined actions in response to out of control situations will be defined for all commercial product QC methods globally, including bioassays. Please complete revisions and submit the revised procedure prior to the action due date.
•Observation 5c cited, “Pooled data may be used to widen analytical control limits.” Biogen committed to limiting the use of historical pooled data to -(b)(4)- data points. The Agency does not concur with the use of historical data to set control limits or to justify widening of initially set control limits. Therefore, your response is considered inadequate.

Responses to the remaining observations are under review.

Non-clinical pharmacology / toxicology

There are no substantive review issues at this time.

Clinical pharmacology

There are no substantive review issues at this time.

Clinical

There are no substantive review issues at this time.

Bioresearch Monitoring

There are no substantive review issues at this time.

Pharmacovigilance

There are no substantive review issues at this time.

Labeling
•APLB will perform a secondary review of the proprietary name within 90 days of the Action Due Date.
•Recommendations to the Prescribing Information and the vial and carton labels will be provided as part of the labeling review.

Advisory committee meeting

Presentation of the BLA at the Blood Products Advisory Committee meeting is not planned.

REMS or other risk management actions

No issues were identified that would require a Risk Evaluation and Mitigation Strategy (REMS).

Outstanding Information Requests
•Additional information was requested during a teleconference held on August 20, 2013. The important outstanding issues / questions were regarding the following:
•Lyophilization final cycle validation information is inadequate in that Biogen has not completely described its validation program and has not provided validation data
•Clarification of defined sterilization loads and validation
•Comparison of -------(b)(4)------ vials

PMR/PMC

We request that you qualify the following ongoing study as post-marketing commitment study: 
“Evaluation of long-term efficacy and safety of Alprolix in 100 subjects of all age groups with hemophilia B, of which at least 25 will be subjects naïve to Alprolix.”

Please revise the protocol to include:
•Evaluation of the 14 day dosing frequency as a stand-alone regimen;
•Monitoring of inhibitor and anti-drug binding antibody formation in all subjects receiving Alprolix;
•Evaluation of blood pressure and transaminase deviations in at risk populations such as patients with heart disease and liver disease, respectively.

Please submit the appropriate timeline for the above post-marketing commitment study. 


LCM AGENDA
1.Introductory Comments – 5 minutes (RPM/Chair)

Welcome, Introductions, Ground rules, Objectives of the Meeting
2.Discussion of Substantive Review Issues – 55 minutes
a.Biogen Idec’s responses to FDA Form 483 observations
b.Other noted issues
c.Outstanding information requests
3.Post-marketing commitments and risk management – 10 minutes
4.Questions from Biogen Idec – 10 minutes
5.Wrap up and Action Items – 10 minutes
