Our STN: BL 125398/0
Novo Nordisk Inc.
Attention: Lewis Pollack, PhD
P.O. Box 846
Plainsboro, NJ 08536
Dear Dr. Pollack:
We have approved your biologics license application for Coagulation Factor XIII A-Subunit (Recombinant) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Coagulation Factor XIII A-Subunit (Recombinant) under your existing Department of Health and Human Services U.S. License No. 1261. Coagulation Factor XIII A-Subunit (Recombinant) is indicated for routine prophylaxis of bleeding in patients with congenital Factor XIII A-subunit deficiency.
Under this license, you are approved to manufacture Coagulation Factor XIII A-Subunit (Recombinant) drug substance at your Bagsvaerd, Denmark facility. The final formulated product will be manufactured, filled, labeled, and packaged at the -------(b)(4)--------- facility. You may label your product with the proprietary name, TRETTEN, and will market it as a lyophilized powder in a single-use vial containing nominally 2500 IU per vial (2000-3125 IU) of Coagulation Factor XIII A-Subunit (Recombinant). The actual amount of Coagulation Factor XIII A-Subunit (Recombinant) in each vial will be stated on each carton and vial.
We did not refer your application to the Blood Products Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion.
The dating period for Coagulation Factor XIII A-Subunit (Recombinant) shall be 24 months from the date of manufacture when stored at 5 °C ± 3 °C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency.
You currently are not required to submit samples of future lots of Coagulation Factor XIII A-Subunit (Recombinant) 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.
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 BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h [OPTION: and FDA Form 2567 as appropriate].
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 an FDA Form 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. 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 (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 Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology, HFM-210, Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448. Prominently identify all adverse experience reports as described in 21 CFR 600.80.
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.
AGREED UPON POSTMARKETING COMMITMENTS
We acknowledge your written commitments as described in your letter of December 13, 2013, as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
1. Post Approval Safety Study (PASS) NN1841-3868: “Use of rFXIII in treatment of congenital FXIII deficiency, a prospective multi-center observational study.”
Final protocol submission date: December 27, 2012 (submitted in Module 1.16, Seq 0033)
Study completion date: June 30, 2018
Final Report Submission date: December 31, 2018
Please submit clinical protocols to your IND 10674, with a cross-reference letter to this biologics license application (BLA), STN BL 125398. Submit all study final reports to your BLA, STN BL 125398. 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 label prominently 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 Commitments – 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 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 the February 2006 Guidance for Industry: Reports on the Status of Postmarketing Studies – Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (see http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation
/Guidances/UCM080569.pdf for further information).
Jay S. Epstein, MD
Office of Blood Research and Review
Center for Biologics Evaluation and Research