Vaccines, Blood & Biologics

June 6, 2014 Approval Letter- Eloctate

June 6, 2014

Our STN:  BL 125487/0

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

Dear Dr. Cohen:

We have approved your biologics license application for Antihemophilic Factor (Recombinant), Fc Fusion Protein effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce, Antihemophilic Factor (Recombinant), Fc Fusion Protein under your existing Department of Health and Human Services U.S. License No. 1697.  Antihemophilic Factor (Recombinant), Fc Fusion Protein is indicated for the treatment of adults and children with Hemophilia A for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Under this license, you are approved to manufacture Antihemophilic Factor (Recombinant), Fc Fusion Protein drug substance at Biogen Idec facilities located in Cambridge, Massachusetts.  The final formulated product will be manufactured, filled, and lyophilized by ----b(4)------------------------------------------------------------------------------.  The Sterile Water for Injection (SWFI) pre-filled syringes will be manufactured by ----b(4)--------------------------------------------------------------------------------------.  The drug product and diluent are labeled and packaged at ---b(4)------------------------------------------------------------------------------------------------------------------------  You may label your product with the proprietary name ELOCTATE™.  The product will be marketed in nominal potencies of 250, 500, 750, 1000, 1500, 2000, and 3000 Factor VIII international units (IU) per vial.
We did not refer your application to the Food and Drug Administration Blood Products Advisory Committee because our review of information submitted in your biologics license application, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefitted from an advisory committee discussion.
The dating period for Antihemophilic Factor (Recombinant), Fc Fusion Protein shall be 24 months from the date of manufacture when stored at 2oC to 8oC (36oF to 46oF).  The product may be stored at room temperature, not to exceed 30°C (86°F), for a single period of up to 6 months within the 24 month time period.  The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product in accordance with 21 CFR 610.50.  Following the final sterile filtration, no reprocessing or reworking is allowed without prior approval from the Agency.  The dating period for your drug substance shall be –b(4)--- when stored at ---b(4)-----

You are not currently required to submit samples of future lots of Antihemophilic Factor (Recombinant), Fc Fusion Protein to the Center for Biologics Evaluation and Research (CBER) for release by the Director, CBER, under 21 CFR 610.2.  We will continue to monitor compliance with 21 CFR 610.1 requiring completion of tests for conformity with standards applicable to each product prior to release of each lot.

You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in the product, production process, quality controls, equipment, facilities, responsible personnel or labeling of Antihemophilic Factor (Recombinant), Fc Fusion Protein.

You must submit reports of biological product deviations under 21 CFR 600.14.  You should identify and investigate all manufacturing deviations promptly, including those associated with processing, testing, packing, labeling, storage, holding and distribution.  If the deviation involves a distributed product, may affect the safety, purity, or potency of the product, and meets the other criteria in the regulation, you must submit a report on Form FDA 3486 to the Director, Office of Compliance and Biologics Quality, at the following address:

Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Ave.
WO71-G112
Silver Spring, MD  20993-0002

Under 21 CFR 201.57(c)(18), patient labeling must be reprinted at the end of the package insert.  We request that the text of information distributed to patients be printed in a minimum of 10-point font.

Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels.  In addition, please submit three original paper copies for carton and container final printed labeling.  All final labeling should be submitted as Product Correspondence to this biologics license application at the time of use (prior to marketing) and include implementation information on Form FDA 356h.

In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.  Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As,” at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf.

You may submit two draft copies of the proposed introductory advertising and promotional labeling with a Form FDA 2253 to the Advertising and Promotional Labeling Branch, at the following address:

Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Ave.
WO71-G112
Silver Spring, MD  20993-0002

You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).  

All promotional claims must be consistent with and not contrary to approved labeling.  You should not make a comparative promotional claim or claim of superiority over other products unless you have substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).

ADVERSE EVENT REPORTING

You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products under 21 CFR 600.80, and you must submit distribution reports as described in 21 CFR 600.81.  You should submit postmarketing adverse experience reports and distribution reports to the Office of Biostatistics and Epidemiology, at following address:

Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Ave.
WO71-G112
Silver Spring, MD  20993-0002

Prominently identify all adverse experience reports as described in 21 CFR 600.80.

PEDIATRIC REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.

Because the biological product for this indication has an orphan drug designation, you are exempt from this requirement.

POSTMARKETING COMMITMENTS

We acknowledge your written commitments, which were conveyed in your letter received on November 27, 2013.

Postmarketing Studies Subject to Reporting Requirements under 21 CFR 601.70.

  • To complete the data analysis for trial 8HA02PED, An Open-Label, Multicenter Evaluation of Safety, Pharmacokinetics, and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein, BIIB031, in the Prevention and Treatment of Bleeding Episodes in Pediatric Subjects With Hemophilia A, and submit the final study report

    Final Report Submission date: September 30, 2014
  • To complete ongoing trial 8HA01EXT, An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Recombinant Human Coagulation Factor VIII Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects With Hemophilia A

Final protocol submission date:  Submitted in STN BL 125487/0
Trial completion date: December 31, 2018
Final Report Submission date: September 30, 2019

  • To complete trial 99HA306, An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia A.

Final protocol submission date:  October 31, 2014
Trial completion date: December 31, 2023
Final Report Submission date: December 31, 2024

Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application, STN BL 125487/0.  If the information in the final study report supports a change in the labeling, the final study report should be submitted as a supplement.  We may also request a supplement if we think labeling changes are needed.  Please use the following designators to prominently label all submissions, including supplements, relating to these postmarketing study commitments, as appropriate:

  • Postmarketing Study Commitment Protocol
  • Postmarketing Study Correspondence
  • Postmarketing Study Commitment – Final Study Report
  • Supplement Contains Postmarketing Study Commitment – Final Study Report

For each postmarketing study subject to the reporting requirements of 21 CFR 601.70, you must describe the status in an annual report on postmarketing studies for this product.  Label your annual report as an, “Annual Status Report of Postmarketing Study Commitments.”  The status report for each study should include:

  • information to identify and describe the postmarketing commitment,
  • the original schedule for the commitment,
  • the status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted), and
  • an explanation of the status including, for clinical studies, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment).

As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our web site: (http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm).  Please refer to, “Guidance for Industry: Reports on the Status of Postmarketing Studies – Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997,” publishedFebruary 2006, (see http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080569.pdf for further information). 

PDUFA V APPLICANT INTERVIEW

FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and original BLAs under PDUFA V (‘the Program’).  The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program.  For this purpose, first cycle actions include: approvals, complete responses, and withdrawals after filing.  The purpose of the interview is to better understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review.

ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about the interview process.  Your responses during the interview will be confidential with respect to the FDA review team.  ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside the project team.  ERG will report only collated, general results and findings in the interim and final assessments.  Members of the FDA review team will be interviewed by ERG separately.  While your participation in the interview is voluntary, your feedback will be helpful to these assessments.

Sincerely yours,

/signature/

Jay S. Epstein, MD
Director
Office of Blood Research and Review
Center for Biologics
Evaluation and Research

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