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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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December 5, 2012 Approval Letter - EVARREST

 

Our STN: BL 125392/0
 
Ethicon, Inc
Attention: Jessica Chung
G-106-10
P.O. Box 151, Route 22 West
Somerville, NJ 08876-0151
 
Dear Ms. Chung:
 
We are issuing Department of Health and Human Services U.S. License No. 1879 to Ethicon, Inc., Somerville, NJ, USA, under the provisions of section 351(a) of the Public Health Service Act controlling the manufacture and sale of biological products. The license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with establishment and product standards.
 
Under this license, you are authorized to manufacture the product Fibrin Sealant Patch. Fibrin Sealant Patch is indicated for use with manual compression as an adjunct to hemostasis for soft tissue bleeding during open retroperitoneal, intra-abdominal, pelvic, and non-cardiac thoracic surgery when control of bleeding by standard surgical methods of hemostasis (e.g., suture, ligature, cautery) is ineffective or impractical.
 
The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT00658723, NCT00598130, NCT00977925, and NCT01166243.
 
Under this license, you are approved to manufacture Fibrin Sealant Patch at the Omrix Biopharmaceuticals, Ltd Fibrin Pad Production Facility in 14 Einstein Street, Weismann Science Park, Nes Ziona, Israel.   You are approved to manufacture drug substances for Fibrin Sealant Patch – Human Fibrinogen and Human Thrombin – at the ---------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------. You may label your product with the proprietary name EVARREST and market it in one 4 x 4 inch (10.2 x 10.2 cm) patch size.
 
We did not refer your application to the Blood Products Advisory Committee because our review of information submitted in your BLA, including the overall clinical program and trial results, did not raise concerns or controversial issues which would have benefited from an Advisory Committee discussion.
 
The dating period for Fibrin Sealant Patch shall be 24 months from the date of manufacture when stored at 2 to 25 °C.  The date of manufacture for EVARREST Fibrin Sealant Patch shall be defined as the date of the application of the biological substances onto the backing layer by    -------------------(b)(4)------------------- method.  The dating period for your drug substances          ----(b)(4)---- shall be up to ---(b)(4)--- from the date of manufacture when stored at --(b)(4)-- before further processing; the dating period for the (b)(4) drug substances shall be up to ---(b)(4)--- when stored at --(b)(4)-- before the application procedure.
 
Please submit samples of the product in final containers together with protocols showing results of all applicable tests.  You may not distribute any lots of product until you receive a notification of release from the Director, Center for Biologics Evaluation and Research (CBER).
 
You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing, packaging or labeling of Fibrin Sealant Patch, or in the manufacturing facilities.
 
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, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, MD 20852-1448.
 
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 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)].
 
Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes these changes.
 
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. 
 
You must also submit adverse experience reports in accordance with the Medical Device Reporting requirements for medical devices (21 CFR 803) as required by 21 CFR 600.80(k)(2). Since your product is characterized as a device as well as a biologic, submit these reports to the MedWatch System using MedWatch Reporting Form 3500A.  Required reports should be submitted to the Food and Drug Administration, Center for Devices and Radiological Health, Medical Device Reporting, P.O. Box 3002, Rockville, Maryland 20847-3002.
 
Per 21 CFR 600.2(f), please refer to http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm for updated mailing address information.
 
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.
 
We are deferring submission of your pediatric study until December 2013 because this product is ready for approval for use in adults and the pediatric study has not been completed.
 
Your deferred pediatric study required under 505B(a) of the Federal Food, Drug, and Cosmetic Act is a required postmarketing study.  The status of this postmarketing study must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act.  This required study is listed below:
 
1.     Deferred pediatric study under PREA for use of EVARREST as an adjunct to hemostasis
in patients 1 month to 17 years undergoing intra-abdominal, retroperitoneal, pelvic, and non-cardiac thoracic surgical procedures.
 
Final Protocol Submission: December 2013
 
Study Completion Date: December 2016
 
Final Report Submission: March 2017
 
We are partially waiving the pediatric study requirement for ages 0-28 days old because: Use of EVARREST in children under the age of one month may be unsafe or ineffective due to small size and limited ability to apply the patch as recommended.  Slow absorption and possibility of adhesions can further complicate use of EVARREST in the neonates.
 
AGREED-UPON POSTMARKETING COMMITMENTS
 
We acknowledge your written commitments as described in your letters dated September 17, 2012 (commitments 1-3), and September 6, 2012 (commitments 4-5) as outlined below:
 
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.
 
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We request that you submit information concerning nonclinical and chemistry, manufacturing, and controls postmarketing commitments and final reports to your BLA, STN BL 125392/0.For each postmarketing commitment not subject to the reporting requirements of 21 CFR 601.70, you may report the status to FDA as a “PMC Submission – Status Update.” The status report for each commitment should include:
 
  • The original schedule for the commitment, and
  • The status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted).
 
When you have fulfilled your commitment, submit your final report as PMC Submission – Final Study Report or Supplement Contains Postmarketing Study Commitment – Final Study Report.
 
 
Sincerely yours,
 
              /s/                                                                     /s/
 
        Mary A. Malarkey                                              Jay S. Epstein, MD                
        Director                                                               Director                                                         
        Office of Compliance and                                  Office of Blood Research and Review
         Biologics Quality                                              Center for Biologics                           
        Center for Biologics                                            Evaluation and Research
         Evaluation and Research