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Vaccines

June 20, 2008 Approval Letter - Pentacel

June 20, 2008

Our STN: BL 125145/0

Sanofi Pasteur Limited
Attention: Gary K. Chikami, M.D.
Associate Vice President, Regulatory Affairs, North America
Sanofi Pasteur. Inc.
Discovery Drive
Swiftwater , PA 18370-0187

Dear Dr. Chikami:

We have approved your biologics license application (BLA) for Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine, effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine under your existing Department of Health and Human Services U.S. License No. 1726. Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine is indicated for active immunization against diphtheria, tetanus, pertussis, poliomyelitis and invasive disease caused by Haemophilus influenzae type b when administered to infants and children 6 weeks through 4 years of age (prior to fifth birthday).

Under this license, you are approved to manufacture and fill the Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus (DTaP-IPV) component at Sanofi Pasteur, Limited, in Toronto, Canada. The Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), ActHIB® component, is manufactured, filled and lyophilized at Sanofi Pasteur, S.A., France. Vials are labeled and packaged at Sanofi Pasteur, Limited, in Toronto, Canada. You may label your product with the proprietary name Pentacel®. The vaccine will be supplied as five dose packages containing five single dose vials of the DTaP-IPV component to be used to reconstitute five single dose vials of the lyophilized ActHIB® vaccine component.

The dating period for the DTaP-IPV component is no more than 30 months from the date of formulation of the final bulk when stored at 2 to 8 °C (35 to 46 °F) . The dating period for the lyophilized ActHIB® component is 36 months when stored at 2 to 8 °C (35 to 46 °F). The dating period for the co-packaged DTaP-IPV component and lyophilized ActHIB® component shall be no more than 30 months or whichever vial has the earliest expiration date when stored at 2 to 8 °C (35 to 46 °F).

Please submit final container 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 BLA for our review and written approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging or labeling of Pentacel ®, or in the manufacturing facilities.

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 version of the label.

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 have received CBER approval for such claims.

ADVERSE EVENT REPORTING

As required under 21 CFR 600.80(c)(2) you must provide a Quarterly Periodic Adverse Experience Report to the VAERS contractor. We have granted your waiver (21 CFR 600.90) to replace the Periodic Adverse Experience Reports format with the Periodic Safety Update Report (PSUR) format as specified in the International Conference on Harmonisation (ICH) E2C guideline using the international birth date (IBD) for the product (May 12, 1997) in lieu of the date of issuance of this biologics license. As described under 21 CFR 600.80(c)(2) you must report each adverse experience not reported under paragraph (c)(1)(i) of this section in PSUR format at quarterly intervals for the first 3 years following May 12, 2008, and then at annual intervals. In addition, distribution reports are also required as described in 21 CFR 600.81. 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.

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(s) in pediatric patients unless this requirement is waived, deferred or inapplicable.

We are waiving the pediatric study requirement for this application for ages 0-5 weeks (i.e., before age 6 weeks) and 5-16 years (i.e., 5 years to prior to 17 th birthday) because:

A) In the pediatric population 0-5 weeks of age, necessary studies are impossible or highly impracticable because neither diphtheria, tetanus, nor poliomyelitis occur in U.S. infants too young to be protected from vaccination beginning at 6 weeks of age.

B) In the pediatric population 0-5 weeks of age, Pentacel® does not represent a meaningful therapeutic benefit over initiating vaccination against diphtheria, tetanus, and poliomyelitis at 6 weeks of age and is not likely to be used in a substantial number of pediatric patients ages 0-5 weeks.

C) In the pediatric population 5-16 years of age, necessary studies are impossible or highly impracticable because too few children, geographically dispersed, would need vaccination with all of the antigens contained in Pentacel®.

D) In the pediatric population 10-16 years of age, Pentacel® does not represent a meaningful therapeutic benefit over vaccination with existing vaccines (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed; and Poliovirus Vaccine Inactivated) and is not likely to be used in a substantial number of patients.

We note that you have fulfilled the pediatric study requirement for infants and children 6 weeks through 4 years of age (prior to fifth birthday).

POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS OF 21 CFR 601.70

We acknowledge your written commitment to provide the following information as described in your May 27, 2008, letter as outlined below:

1. To submit clinical data to support use of DAPTACEL® to complete the DTaP series following four previous doses of Pentacel®.
Final report submission (P3T10): July 31, 2008

We request that you submit clinical protocols and nonclinical toxicology protocols to your IND, with a cross-reference letter to this BLA, STN BL 125145/0.

Please use the following designators to label prominently all submissions, including supplements, relating to this postmarketing study commitment as appropriate:

  • Postmarketing Study Commitment Protocol
  • Postmarketing Study Correspondence/Status Update
  • Postmarketing Study Commitment – Final Study Report
  • Supplement Contains Postmarketing Study Commitments – Final Study Report

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. Label your annual report “Annual Status Report of Postmarketing Study Commitments.” 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), and
  • a revised schedule if the study schedule has changed and an explanation of the basis for the revision.

As described in 21 CFR 601.70(e), we may publicly disclose information regarding this postmarketing commitment on our Web site ( http://www.fda.gov/cder/pmc/default.htm).

Please refer to the February 2006 Guidance for Industry: Reports on the Status of Postmarketing Study Commitments – Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (see http://www.fda.gov/cber/gdlns/post130.htm ) for further information.

POSTMARKETING COMMITMENTS NOT SUBJECT TO REPORTING REQUIREMENTS OF 21 CFR 601.70

We also acknowledge your written commitments as described in your submission of May 27, 2008, and June 19, 2008, as outlined below:

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We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL125145/0.

Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

  • Postmarketing Correspondence
  • Postmarketing Commitment – Final Study Report
  • Supplement Contains Postmarketing Commitment – Final Study Report

For each postmarketing commitment not subject to the reporting requirements of 21 CFR 610.70, you may report the status to FDA as a “PMC Submission – Correspondence/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 Report or Supplement Contains Postmarketing Commitment – Final Report.

If you have any questions, please contact LCDR Edward Wolfgang, at (301)-827-3070.

Sincerely yours,

/Norman W. Baylor/

Norman W. Baylor, Ph.D.
Director
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research

 

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