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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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November 3, 2003 Approval Letter

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville MD 20852-­1448

November 3, 2003

Our STN: BL 103171/0

Luc Kuykens, M.D.
Aventis Pasteur Limited
1755 Steeles Avenue West
Toronto, Ontario
Canada M2R 3T4

Dear Dr. Kuykens:

We have approved your Biologics License Application (BLA) for Tetanus and Diphtheria Toxoids Adsorbed For Adult Use effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Tetanus and Diphtheria Toxoids Adsorbed For Adult Use under your existing Department of Health and Human Services U.S. License No. 1280. Tetanus and Diphtheria Toxoids Adsorbed For Adult Use is indicated for primary and booster immunization of persons 7 - 59 years of age against tetanus and diphtheria.

Under this authorization, you are approved to manufacture Tetanus and Diphtheria Toxoids Adsorbed For Adult Use at your facility in Toronto, Ontario, Canada. You will market your product in 0.5 mL single dose vials and 5.0 mL multi-dose vials.

The dating period for Tetanus and Diphtheria Toxoids Adsorbed For Adult Use shall be 18 months from the date of manufacture when stored at 2-8°C. The date of manufacture shall be defined as the date of initiation of the last valid potency test of either the diphtheria or tetanus component of the final formulated bulk vaccine, whichever is earliest. The dating period for each individual --------- concentrate of diphtheria and tetanus toxoid shall be -------- from the date of preparation when stored at ----. We have approved the stability protocols in your license application for the purpose of extending the expiration dating period of your adsorbed tetanus and diphtheria toxoid concentrates and your Tetanus and Diphtheria Toxoids Adsorbed For Adult Use final product under 21 CFR 601.12.

Any request for extension of dating of final product up to the ------ covered by these protocols or extension of dating of individual ------- concentrates up to ------------ covered by these protocols may be submitted as a "Supplement-Changes Being Effected in 30 Days."

Please submit samples of the bulk product 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 BLA for our review and written approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging or labeling of Tetanus and Diphtheria Toxoids Adsorbed For Adult Use or in the manufacturing facilities.

We acknowledge your written commitments as described in your letter of October 30, 2003, as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

  1. You have agreed to conduct a safety and immunogenicity postmarketing study in approximately 3000 subjects receiving your Tetanus and Diphtheria Toxoids Adsorbed For Adult Use vaccine under IND, to include a subset of subjects 60 years of age and older. You have agreed to submit a final study protocol by December 2003, and to initiate this study by April 2004 or 2 weeks after CBER releases the first commercial batch of Tetanus and Diphtheria Toxoids Adsorbed For Adult Use, whichever is later. In addition, you have agreed to complete patient accrual 20 months after the first patient is enrolled in the study and to complete the study 6 months after the last patient has been enrolled in the study. The final study report will be submitted 1 year after the last patient has completed the study.
  2. You have agreed to provide the final data report from your ongoing non-clinical reproductive toxicology study to CBER for our review by the end of May 2004. Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.
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We request that you submit clinical protocols to an IND, with a cross-reference letter to this BLA, STN 103171. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN 103171. 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);
  • 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.

Submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and distribution reports as described in 21 CFR 600.81. Under 21 CFR 600.80(c)(2) [Periodic Adverse Experience Reports], you must report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals for the first 3 years following approval, and then at annual intervals. Since your product is characterized as a vaccine, submit these reports to the Vaccine Adverse Event Reporting System (VAERS) using the pre-addressed form VAERS-1.

You must submit reports of biological product deviations under 21 CFR 600.14. You should promptly 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-format electronic copy as well as original paper copies (ten for circulars and five for other labels). In addition, you may wish to 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. Two copies of final printed advertising and promotional labeling should be submitted at the time of initial dissemination, accompanied by FDA Form 2253.

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 had them approved.

Sincerely,

--- signature ---

William M. Egan, Ph.D.
Acting Director
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research