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U.S. Department of Health and Human Services

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January 17, 2008 Approval Letter - RECOTHROM

January 17, 2008

Our STN: BL 125248/0

ZymoGenetics, Inc.
Attention: Mr. Mark W. Gauthier
1201 Eastlake Avenue East
Seattle, WA 98102

Dear Mr. Gauthier:

We are issuing Department of Health and Human Services U.S. License No. 1758 to ZymoGenetics Inc., Seattle, Washington, 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 Thrombin topical (Recombinant). Thrombin topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. Thrombin topical (Recombinant) may be used in conjunction with an absorbable gelatin sponge, USP.

Under this license, you are approved to manufacture Thrombin topical (Recombinant) drug substance at -------------------------------------------------. The final formulated product will be ------------------------------------------------------------------------------------. ------------------------- ------------------------------------------------------------------------------------------------You may label your product with the proprietary name "RECOTHROMT" and will market it in 5000 IU fill size.

The dating period for Thrombin topical (Recombinant) shall be 24 months from the date of manufacture when stored at 2 to 25 °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.

Thrombin topical (Recombinant) is exempt from the lot release requirement of 21 CFR 610.2. ------------------------------------------------------------------------------------------------------------------ ----------------------------------------------------------------------------

All applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We have reviewed your submission and agree that a deferral of your pediatric studies for Thrombin topical (Recombinant) for all ages until June 2008 for the submission of the study protocol and until December 2010 for the final study report is justified because adult studies are completed and ready for approval.

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 manufacturing, testing, packaging or labeling of Thrombin topical (Recombinant), or in the manufacturing facilities.

We acknowledge your written commitments as described in your letter of December 4, 2007 and as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70

  1. Your deferred pediatric studies required under section 2 of the Pediatric Research Equity Act (PREA) are considered required postmarketing study commitments. The status of these postmarketing studies shall be reported annually according to 21 CFR 601.70. These commitments are listed below.
    1. Deferred pediatric study under PREA as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical in all age groups.
    2. Study Protocol by: June 2008
    3. Final Report Submission by: December 2010
    4. Please submit final study reports to this BLA. For administrative purposes, all submissions related to this pediatric postmarketing study commitment must be clearly designated "Required Pediatric Study Commitments".
  2. ZymoGenetics will conduct a postmarketing study to evaluate immunogenicity and safety of re-exposure to RECOTHROMT. The clinical study protocol will be submitted 90 days following approval, with first patient first visit (FPFV) approximately 6 months following approval of the protocol and last patient last visit no later than 25 months after FPFV.

We request that you submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125248/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125248/0. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

  • Postmarketing Study Protocol
  • Postmarketing Study Final Report
  • Postmarketing Study Correspondence
  • Annual Report on Postmarketing Studies

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. 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/cder/pmc/default.htm). Please refer to the April 2001 Draft 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/cber/gdlns/post040401.htm) for further information.

Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70

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In addition, pursuant to 21 CFR 600.80(c)(2) (Periodic Adverse Experience Reports), the Agency is requiring that manufacturers report on a monthly basis any infectious disease transmission associated or possibly associated with any licensed biological product that is not reportable under 21 CFR 600.80 (c)(1)(Fifteen-day Alert Reports). The timing of this monthly periodic reporting requirement was selected, among other reasons, to permit the acquisition of patient information, including clinical evaluation, sufficient to help in the timely assessment of a causal connection between the biological product and possible or documented infectious disease transmission. This new reporting requirement was also based on the observation of inconsistent practices by some manufacturers in submitting reports of possible infectious diseases.

Please note that this monthly reporting requirement applies only to infectious disease transmission. Other periodic reports should continue to be submitted on the quarterly or annual basis that is appropriate to each licensed biological product for all other adverse experiences not reportable under 21 CFR 600.80(c)(1). You should submit these monthly reports to the Center for Biologics Evaluation and Research, Division of Epidemiology, HFM-210, 1401 Rockville Pike, Rockville, MD, 20852-1448. Please contact the Division of Epidemiology (301-827-3974) if you have any questions about these periodic adverse event reporting requirements.

You must submit adverse experience reports under the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports under 21 CFR 600.81. You should submit postmarketing adverse experience reports and distribution reports to the Center for Biologics Evaluation and Research, HFM-210, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448. Prominently identify all adverse experience reports as described in 21 CFR 600.80.

You must submit reports of biological product deviations under 21 CFR 600.14. You promptly should identify and investigate all manufacturing deviations, 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 submit all final printed labeling at the time of use and include implementation information on FDA Form 356h and FDA Form 2567 as appropriate. Please provide a PDF and Word-format electronic copy as well as original paper copies (five for circulars and five for other labels).

Two copies of final printed advertising and promotional labeling should be submitted at the time of initial dissemination with a 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. 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 submitted data to support such claims to us and received CBER approval for such claims.

FDA has determined that referral of this application to the Blood Products Advisory Committee (BPAC) prior to approval (FDAAA [HR 3580-138 SEC. 918: REFERRAL TO ADVISORY COMMITTEE]) was not needed for the following reasons: Thrombin's mechanism of action and function in the blood coagulation cascade are well studied and understood. RECOTHROMT is identical in amino acid sequence and structurally similar to plasma-derived human thrombin. In vitro and in vivo biochemical and functional characterization of RECOTHROMT demonstrated that its hemostatic activities are comparable (non-inferior) to those of human plasma-derived thrombin. Currently two thrombin products, one purified from human blood and one purified from bovine blood, are licensed in the U.S. The proposed indication for the topical use of RECOTHROMT is the same as that for both currently licensed thrombin products. In addition, human plasma-derived thrombin is an active ingredient in two U.S. licensed fibrin sealant products. Evaluation of the safety data in RECOTHROMT clinical studies (~ 270 subjects) did not reveal unexpected issues in this class of products. The study design to evaluate efficacy of RECOTHROMT was adequate and well controlled and the results of the study did not raise any concerns related to safety and efficacy. In particular, RECOTHROMT was non-inferior to a licensed bovine thrombin product. Monitoring of potential immunogenic responses to RECOTHROMT will continue after the approval of the BLA in a Phase IV, repeat-exposure study. Products manufactured by recombinant DNA technology may provide additional safety assurance regarding adventitious agents. RECOTHROMT is subjected to solvent/detergent treatment and nanofiltration viral reduction steps. Review of information submitted in the BLA for RECOTHROMT did not raise any controversial issues or pose unanswered scientific questions which would have benefited from advisory committee discussion and recommendations.

Sincerely yours,

/Mary A. Malarkey/
Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
/Jay S. Epstein, M.D./
Jay S. Epstein, M.D.
Director
Office of Blood Research and Review
Center for Biologics Evaluation and Research
 

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