Late-Cycle Meeting Summary, September 12, 2013-ALPROLIX

DEPARTMENT OF HEALTH & HUMAN SERVICES
 Public Health Service


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

Late-Cycle Meeting Summary 

Application type and number: STN BL 125444/0 
Product name: Coagulation Factor IX (Recombinant), Fc Fusion Protein 
Applicant: Biogen Idec, Inc.
Meeting category: Late-Cycle Meeting (LCM)
Meeting date & time: September 12, 2013, 10 a.m. to 11 a.m.
Meeting format: Face-to-face 
Meeting Chair/Leader: Paul D. Mintz, MD
Meeting Recorder: Edward Thompson

LCM package sent: August 28, 2013

FDA Participants: 
 Bethany Baer, MD, Medical Officer, Division of Epidemiology, OBE
 Lokesh Bhattacharyya, PhD, Chief, Laboratory of Analytical Chemistry and Blood Related Products, Division of Biological Standards and Quality Control, OCBQ
 La’Nissa Brown-Baker, PhD, Pharmacologist, Division of Hematology, OBRR
 John Eltermann, RPh, MS, Director, Division of Manufacturing and Product Quality, OCBQ
 Mahmood Farshid, PhD, Deputy Director for CMC Policy and Review, Division of Hematology, OBRR
 Basil Golding, MD, Director, Division of Hematology, OBRR 
 Anthony Hawkins, MS, Consumer Safety Officer, Division of Inspections and Surveillance, OCBQ
 Jie He, MS, Consumer Safety Officer, Division of Manufacturing and Product Quality, OCBQ
 Ellen Huang, Consumer Safety Officer, Division of Manufacturing and Product Quality, OCBQ
 Nisha Jain, MD, Chief, Clinical Review Branch, Division of Hematology, OBRR
 Betsy Jett, Deputy Associate Director for Regulatory Affairs, OBRR
 Chris Joneckis, PhD, Senior Advisor, Office of the Director, CBER
 So Hyun Kim, Independent Assessor, Eastern Research Group, Inc.
 Nancy Kirschbaum, PhD, Chemist, Division of Hematology, OBRR
 Judy Li, PhD, Mathematical Statistician, Division of Biostatistics, OBE 
 Marion Michaelis, Chief, Review Branch II, Division of Manufacturing and Product Quality, OCBQ 
 Ginette Y. Michaud, MD, Deputy Director, OBRR
 Paul D. Mintz, MD, Deputy Director of Medical Affairs, Division of Hematology, OBRR
 Loan Nguyen, PharmD, Consumer Safety Officer, Division of Case Management, OCBQ
 Ze Peng, PhD, Staff Fellow, Division of Hematology, OBRR
 Anne M. Pilaro, PhD, Acting Chief, Pharmacology and Toxicology Branch, Division of Hematology, OBRR
 Catherine Poole, MS, Regulatory Coordinator, Division of Biological Standards and Quality Control, OCBQ
 Renee Rees, PhD, Mathematical Statistician, Division of Biostatistics, OBE 
 Andrey Sarafanov, PhD, Chemist, Division of Hematology, OBRR
 Christopher Sese, Independent Assessor, Eastern Research Group, Inc.
 Destry Sillivan, MS, Team Lead, Division of Manufacturing and Product Quality, OCBQ
 Carl-Michael Staschen, MD, PhD, Pharmacologist, Division of Hematology, OBRR
 Kimberly Taylor, MBA, MPH, Operations Research Analyst, Office of Program & Strategic Analysis, OSP/CDER
 Edward Thompson, Regulatory Project Manager, Division of Blood Applications, OBRR

Biogen Idec Inc Attendees:
 Amin Abujoub, Vice President, Global Quality Control
 Aoife Brennan, Senior Director, Medical Research
 Doug Cecchini, Director, Technical Development
 Paula Cobb, Vice President, Program Management
 Lynda Cristiano, Director, Drug Safety and Risk Management
 Steve Doares, Associate Director, Manufacturing Sciences
 Sofi Fexby, Manager, CMC Regulatory Affairs
 Kim Hocknell, CMC Team Director
 Helen Lockett, Senior Manager, Regulatory Affairs
 Justin McCue, CMC Team Director
 Joseph Molon, Director, Quality Control
 Ivan Nestorov, Senior Director, Clin Pharmacology & Pharmacometrics
 Clive Patience, Vice President, Global Quality Assurance
 Glenn Pierce, Senior Vice President, Global Medical Affairs
 Heidi Reichert, CMC Team Director
 Denise Schultz, Associate Director, CMC Regulatory Affairs
 Debra Segal, Director, Regulatory Affairs
 Ketan Shah, Director, Quality Control
 Daniel Soroko, Associate Director, Regulatory Affairs
 Suzanne Stella, Director, CMC Regulatory Affairs

Background and Objectives: 

FDA contacted Biogen Idec, Inc. (Biogen) on June 19, 2013, to provide the date for the late-cycle meeting. The purpose of the meeting is to share information, to discuss substantive review issues, and to communicate our objectives for the review cycle of STN BL 125444/0 for Coagulation Factor IX (Recombinant), Fc Fusion Protein for the proposed indication of:

• Control and prevention of bleeding episodes
• Perioperative management for surgical prophylaxis
• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes

FDA conveyed the Late-Cycle Meeting package to Biogen on August 28, 2013.

DISCUSSION SUMMARY:

Introductory Comments:

FDA introduced the agenda items, which are listed herein.
1.Chemistry, Manufacturing and Controls: specifications, stability, adventitious agents safety, analytical methodology, process intermediate hold times, one-time exception notification, process validation and facilities/equipment
2.Labeling
3.Outstanding Information Requests
4.Post-marketing Commitments
5.Summarization by Biogen Idec
6.Noted action items

FDA explained that the meeting is not intended to discuss the pending regulatory decision on the application. After the meeting discussion, FDA may request Biogen to submit additional data or analysis. Submission of significant additional information may be considered a major amendment, and therefore could extend the user fee goal date 3 months beyond the current date of December 27, 2013.

Chemistry, Manufacturing and Controls
1.Specifications
•Revised drug substance (DS) and drug product (DP) release specifications appear acceptable. We note, however, that the tests for ---(b)(4)--- and excipients are projected for implementation in January 2014. All analytical method validation must be completed and submitted to the Agency for review prior to approval.


Additional discussion:
 Biogen intends to submit the requested information by November 1, 2013.
•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)-----------------------------------------.


Additional discussion:
 Biogen agreed to revise the IPS for bioburden and endotoxin, accordingly. Relevant quality documents will be updated.
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).


Additional discussion:
 Biogen agreed to add the test for (b)(4) to the stability monitoring program for the diluent. Biogen will establish a provisional specification of, “Report Results,” until sufficient data have been generated and analyzed to establish a numerical range. FDA accepted Biogen’s proposal.
•In order to support the label claim of 6 month storage at room temperature (not to exceed 30 oC) within a 24 month shelf life, please monitor all conformance lots at room temperature after storage at 2 – 8 oC for 18 months.


Additional discussion:
 Biogen will submit updated stability data by September 27, 2013. Biogen seeks to claim a 36 month product shelf life. FDA commented that the product shelf life assigned at approval will be based directly on analysis of the submitted stability data.
3.Adventitious Agents Safety 
•Please provide, in writing, a postmarketing 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.


Additional discussion:
 Biogen will provide the postmarketing commitment and time line. Biogen is developing ----------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------- step. Biogen plans to request a Type C meeting to discuss the data package prior to initiating process validation and comparability studies.
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 DP shelf life and (b) the study did not include (b)(4) IU and 3000 IU dosage presentations.


Additional discussion:
 Biogen agreed to conduct the additional validation and submit an amendment to the method validation report by November 1, 2013.
5.Process Intermediate Hold Times
•Please establish shorter process intermediate hold times based on conformance batch manufacturing experience, e.g.,


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

Additional discussion:
 Biogen has established -(b)(4)- process intermediate hold times from analysis of manufacturing data for -(b)(4)- batches produced with the validated, commercial process.
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).


Additional discussion:
 Biogen concurred with the Agency’s request. In response to Biogen’s inquiry, the Agency clarified that its intent was to include all process parameters controlling the ----(b)(4)---- virus filtration step (including non-critical parameters) since this was considered a critical process step.
7.Process Validation
•There is a concern about your process validation conformance lots for the following reasons:


There are insufficient data to support manufacturing on ------(b)(4)--------. Specifically, the conformance lot for which data were submitted was not manufactured under prospective validation and was not carried on beyond the ---(b)(4)--- process.

Additional discussion:
 Biogen stated that lot ------(b)(4)-------, which was manufactured on --------(b)(4)---------, was manufactured under prospective validation during the --(b)(4)--- process. Lot (b)(4)---------------- was carried on beyond the ---(b)(4)---- process (all the way through DS and DP manufacturing). Biogen stated they had data to support that -------(b)(4)-------- are comparable. Biogen will submit the -(b)(4)- data for review to the FDA by September 27, 2013.
•DS batches ------------------(b)(4)---------------------- were not manufactured as part of the DS conformance batches and were used for the 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.


Additional discussion:
 FDA received the amendment for this information and found the responses adequate.
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)------. Form FDA 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. FDA expects Biogen to establish, document and follow a procedure to qualify each new lot of -------------------------------------------(b)(4)---------- (aPTT) reagent. Therefore, your response is considered inadequate.

Additional discussion:
 Item not discussed in the meeting.
?Observation 4b cited, “Instruction 4.6.2.4 permits storage of -----------(b)(4)------------------------------------ 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 FDA. Please commit to one of the following options, as applicable: (1) submission of a revised procedure prior to the action due, instructing a ------------(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 STN BL 125444.

Additional discussion:
 Item not discussed in the meeting.
•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.

Additional discussion:
 Item not discussed in the meeting.
•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. FDA does not concur; therefore, your response is considered inadequate.

Additional discussion:
 Biogen presented their ---(b)(4)--- approach for repeat testing: (1) any control failure on ---(b)(4)--- results in repeat of the entire assay and an investigation; (2) a confirmed sample failure may be repeated in a different assay. FDA concurred with this approach.

•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.

Additional discussion:
 Item not discussed in the meeting.

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. FDA does not concur; therefore, your response is considered inadequate.

Additional discussion:
 Biogen concurred with FDA’s request.
•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)---------------------------,” 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.

Additional discussion:
 Biogen concurred with FDA’s request.
•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. FDA 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.

Additional discussion:
 Biogen reiterated its statistically justified approach to long term collection of (b)(4) data points prior to establishing control limits. FDA explained that long term collection of data and incorporation of such data into control ranges would defeat the purpose of analytical control monitoring for potential assay bias or drift. Biogen and FDA agreed to further discussion of the issue.

Labeling
•APLB will perform a secondary review of the proprietary name within 90 days of the Action Due Date.

Additional discussion:
 Item not discussed in the meeting.
•Recommendations to the Prescribing Information and the vial and carton labels will be provided as part of the labeling review.

Additional discussion:
 Item not discussed in the meeting.

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.

Additional discussion:
 FDA communicated that Biogen’s responses regarding lyophilization were received and FDA needs additional data to support Biogen’s final lyophilization cycle. The process validation lots did not have adequate sampling to demonstrate batch to batch uniformity and consistency. Additionally, the technical runs and operating range studies did not have adequate sampling and did not represent the final lyophilization production cycle. Furthermore, the equipment qualification did not demonstrate tight temperature control. Thus, the data provided at this time do not verify that the final production cycle is in control, reproducible, and capable of manufacturing uniform product. FDA requested a teleconference for Monday, September 16, 2013, with the lyophilization experts from Biogen and ------(b)(4)---- to discuss FDA’s concerns.
•Clarification of defined sterilization loads and validation 


Additional discussion:
 FDA communicated that Biogen’s responses regarding sterilization were received and FDA has additional questions regarding sterilization. Biogen stated that additional responses regarding sterilization would be submitted later that day (September 12, 2013).
•Comparison of --------(b)(4)------- vials

Additional discussion:
 FDA communicated that Biogen’s responses regarding the vials were received and FDA may have additional questions regarding the vials.

Post-marketing Commitments (PMC)

We request that you qualify the following ongoing study as a 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.” 

Additional discussion:
 FDA clarified that FDA was not asking for additional postmarketing studies. Biogen agreed.

Please revise the protocol to include:
•Evaluation of the 14 day dosing frequency as a stand-alone regimen

Additional discussion:
 FDA clarified that the protocol of the ongoing study should be revised to include evaluation of efficacy in patients on the 14 day dosing frequency.
•Monitoring of inhibitor and anti-drug binding antibody formation in all subjects receiving Alprolix

Additional discussion:
 Biogen agreed.
•Evaluation of blood pressure and transaminase deviations in “at risk” populations such as patients with heart disease and liver disease, respectively.

Additional discussion:
 Biogen agreed.

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

Additional discussion:
 Biogen agreed.

Decisions made and/or agreements reached:
•Biogen understood the significance of submitting the additional data and information prior to September 27, 2013. Additional information sent after that date may be classified as a major amendment and extend the application action due date beyond 3 months from December 27, 2013.

Issues requiring further discussion:
•The details regarding DMPQ/facility reviewer’s concerns about lyophilization will be discussed during the Monday, September 16, 2013 teleconference.

Action items:
•Biogen agreed to submit method validation and laboratory control reports by November 1, 2013.
•Biogen agreed to submit updated stability data by September 27, 2013.
•Biogen agreed to provide the post-marketing commitment to incorporate a ------(b)(4)-------- step into the rFIXFc manufacturing process.
•Biogen and FDA agreed to have an informal teleconference to discuss Biogen’s approach to establishing limits for analytical control preparations.
•Biogen and FDA agreed to have another teleconference to discuss lyophilization and sterilization validation.
•Biogen agreed to submit a post-marketing commitment to qualify the following ongoing study as a 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.” 

End
