Vaccines, Blood & Biologics

February 21, 2008 Approval Letter - XYNTHA

February 21, 2008

Our STN: BL 125264/0

Wyeth Pharmaceuticals, Inc.
Attention: Ms. Joyce Schwenk
P.O. Box 8299
Philadelphia, PA 19101-8299

Dear Ms. Schwenk:

We have approved your biologics license application for Antihemophilic Factor (Recombinant), Plasma/Albumin Free effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Antihemophilic Factor (Recombinant), Plasma/Albumin Free under your existing Department of Health and Human Services U.S. License No. 3. Antihemophilic Factor (Recombinant), Plasma/Albumin Free is indicated for control and prevention of bleeding episodes and for surgical prophylaxis in patients with hemophilia A.

Under this license, you are approved to manufacture Antihemophilic Factor (Recombinant), Plasma/Albumin Free drug substance at ---------------- in ---------------------. The final formulated product will be manufactured, filled, labeled, and packaged at ----------------------, ---., in ---------------. You may label your product with the proprietary name XYNTHATM and will market it in 250, 500, 1000 and 2000 IU/vial fill sizes.

The dating period for Antihemophilic Factor (Recombinant), Plasma/Albumin Free shall be 24 months from the date of manufacture when stored at 2oC to 8oC. 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.

The dating period for your drug substance shall be --- months when stored at --------. The expiration date for the packaged product XYNTHATM plus the 0.9 % sodium chloride diluent in a pre-filled syringe shall be dependent on the shortest expiration date of any component.

Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is exempt from the lot release requirement of 21 CFR 610.2.

Pediatric Research Equity Act (PREA) does not apply to orphan indications.

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 Antihemophilic Factor (Recombinant), Plasma/Albumin Free, or in the manufacturing facilities.

We acknowledge your written commitments as described in your submission of April 25, 2007 as outlined below:

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 Word and PDF-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: Moroctocog alfa (AF-CC) [XYNTHA] is a recombinant analog of coagulation factor VIII (FVIII). The mechanism of action and function of FVIII in the blood coagulation cascade are well studied and understood. XYNTHA is ------------------------------------------ and structurally similar to Wyeth's currently licensed recombinant FVIII product, ReFacto, licensed on 6 March 2000. In vitro and in vivo biochemical and functional characterization demonstrated that XYNTHA is structurally and functionally comparable to its predecessor product, Antihemophilic Factor (Recombinant, B domain deleted) [ReFacto]. Pharmacokinetic data show that XYNTHA and Baxter's ADVATE, Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method licensed in 2003, are pharmacokinetically equivalent. The results of the pivotal safety and efficacy study did not raise any concerns. Review of information submitted in the BLA for XYNTHA did not raise controversial issues or pose unanswered scientific questions which would have benefited from advisory committee discussion and recommendations. XYNTHA is considered to have a favorable safety profile related to known infectious agents and impurities.

Sincerely yours,

/Jay S. Epstein, M.D./
Jay S. Epstein, M.D.
Office of Blood Research and Review
Center for Biologics Evaluation and Research

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

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