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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Rockville, MD 20852-1448
June 10, 2005
Our STN: BL 125111/0
Luc Kuykens, M.D.
Aventis Pasteur Limited
Vice President, Regulatory Affairs North America
1755 Steeles Avenue West
Toronto, Ontario Canada M2R3T4
Dear Dr. Kuykens:
We have approved your Biologics License Application (BLA) for Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed, under your existing Department of Health and Human Services U.S. License No. 1280. Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed is indicated for booster immunization against tetanus, diphtheria and pertussis as a single dose in individuals 11 through 64 years of age.
Under this authorization, you are approved to manufacture Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed at your facility in Toronto, Ontario, Canada. You may label your product with the proprietary name, ADACEL. The vaccine will be marketed in 0.5 mL single dose vials.
The dating period for ADACEL vaccine shall be 36 months from the date of the manufacture of the final bulk when stored at
2- 8°C. The date of manufacture is defined as the date of final formulation of the final bulk.
Please submit final bulk samples of the 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 ADACELT vaccine, or in the manufacturing facilities.
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 waiver of pediatric studies for children 7 to less than 11 years is justified because such studies are highly impractical and because the number of eligible subjects in that age group is small and geographically dispersed. In addition, we agree that a waiver of pediatric studies for children less than 7 years of age is applicable because ADACEL vaccine does not represent a meaningful therapeutic benefit over existing therapies for pediatric subjects in this age group.
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70
We acknowledge your written commitments as described in your letter of June 9, 2005, as outlined below:
- To conduct an open label, descriptive, epidemiological safety surveillance study that enrolls at least 10,000 adolescents (ages 11-17 inclusive) and 6,000 adults (ages 18-64 inclusive) or enrolls for one year, whichever results in the larger enrollment. The study protocol/analysis plan will be submitted by September 2005. Subject accrual will begin no later than September 2005. The final study report will be submitted 1 year after the last subject has completed the study, by November 2008.
- To complete and submit the results from the ongoing randomized, modified double-blind, comparative study evaluating safety and immunogenicity when Menactra vaccine is given concomitantly with ADACEL vaccine. This study is being conducted in approximately 1400 adolescents aged 11-17 years. The study was initiated in April 2005. The statistical analysis plan, which will include analyses for fever and pain, will be submitted by June 2006. The final study report will be submitted by December 2006.
- To submit the results from the ongoing study evaluating the duration of the antibody response at 1, 3 and 5 years post-vaccination in participants who had received a single dose of ADACEL vaccine in the pivotal trial Td506. The 1-year serology study is complete; the study report will be submitted by September 2005. The 3-year field study is complete; the study report will be submitted by December 2006. The study report for the 5-year follow up will be submitted by July 2008. An amendment to the Td506 protocol to extend follow-up to 10 years post immunization will be submitted by October 2005.
- To implement the web site for the established Pregnancy Registry by the end of August 2005.
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.
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We request that you submit clinical protocols to your IND, with a cross-reference letter to this BLA, STN BL 125111/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125111/0. 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.
Adverse experience reports should be submitted 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 a 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 yours,
--- signature ---
Norman W. Baylor, Ph.D.
Director
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
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