Vaccines, Blood & Biologics

April 17, 2007 Approval Letter - Influenza Virus Vaccine, H5N1

Our STN: BL 125244/0

Sanofi Pasteur Inc.
Attention: Gary K. Chikami, MD
Director, Vaccines Establishment
U.S. Regulatory Affairs
Discovery Drive
Swiftwater, PA 18370

Dear Dr. Chikami:

We have approved your Biologics License Application (BLA) for Influenza Virus Vaccine, H5N1, effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Influenza Virus Vaccine, H5N1, under your existing Department of Health and Human Services U.S. License No. 1725; however, we acknowledge your statement provided in your submission of April 5, 2007, that Sanofi Pasteur Inc. does not intend to license this product for commercial distribution, since it was produced under contract to the U.S. Department of Health and Human Services as part of national pandemic preparedness initiatives. Influenza Virus Vaccine, H5N1, is indicated for active immunization of persons 18 through 64 years of age at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine.

Under this authorization you are approved to manufacture Influenza Virus Vaccine, H5N1 at your Swiftwater, PA facility. Final product filling, labeling, and packaging will be performed at your above facility. The vaccine will be supplied as a suspension in 5 mL multi-dose vials.

The dating period for Influenza Virus Vaccine, H5N1 shall be 18 months from the date of manufacture of the final container vaccine. The date of manufacture shall be defined as the date on which this monovalent vaccine is filled; thus, the 18-month shelf life is inclusive of the time that the product is held in filled final containers at 2-8oC prior to packaging.

We note that you have submitted samples and Batch Release Protocols for Influenza Virus Vaccine, H5N1, bulk Lots U2148, U2149, and U2150. For any other bulk lots that you may have produced or will produce in the future, please submit final bulk samples of the product together with lot release protocols in the proper format 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 Influenza Virus Vaccine, H5N1, 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 dated February 9, 2007, and we deny your full waiver request for pediatric assessment. However, we grant a deferral of your pediatric studies for Influenza Virus Vaccine, H5N1, in children less than or equal to 16 years of age.

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70

We acknowledge the postmarketing clinical commitments outlined in your submission of April 5, 2007. These commitments, along with any completion dates agreed upon, are listed below and will provide additional clinical data for the Influenza Virus Vaccine, H5N1.

  1. You agreed to submit data to assess safety, reactogenicity and immunogenicity of Influenza Virus Vaccine, H5N1 administered in children.

    Protocol submission: Study DMID 04-077: "A randomized, double-blinded, phase I/II, study of the safety, reactogenicity, and immunogenicity of intramuscular inactivated influenza A/H5N1 vaccine in healthy children aged 2 years through 9 years."

    Final study report submission: September 30, 2008.

    Please note that although your pediatric studies required under section 2 of the Pediatric Research Equity Act (PREA) are deferred, the deferred status of these required postmarketing studies should be reported as such annually according to 21 CFR 314.81. We will reassess the deferred status of your pediatric studies upon review of the data from the completed pediatric study which you have agreed to submit as a postmarketing commitment listed above.

  2. You agreed to provide the final study reports on or before June 30, 2008, as additional data to support immune responses and safety of the Influenza Virus Vaccine, H5N1.
    1. Study DMID 04-076: "A randomized double-blinded, placebo-controlled, phase I/II, dose-ranging study of the safety, reactogenicity, and immunogenicity of intramuscular inactivated influenza A/H5N1 vaccine in healthy elderly adults."
    2. Study DMID 05-0043: "Revaccination of healthy subjects with intramuscular inactivated subunit influenza A/Vietnam/1203/2004 (H5N1) vaccine representing a drifted variant."
    3. Study DMID 05-0090: "Evaluation of a booster dose of A/Vietnam/1203/04 (H5N1) vaccine administered at 6 months to healthy adult subjects after a two dose schedule at 0 and 1 month."
    4. Study DMID 05-0129: "Open label evaluation of H5N1 vaccine at vaccine manufacturing facilities."
    5. Study DMID 05-0130: "A single center, open label, phase I/II study of the safety and immunogenicity of two 90 µg doses of intramuscular inactivated influenza A/H5N1 vaccine in healthy adult subjects."

Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70

We acknowledge the postmarketing commitments outlined in your submission of April 5, 2007 to submit updated stability data as follows.




Please submit non-clinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125244. 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 ( 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 for further information.

Please 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, you must also submit these reports to the Vaccine Adverse Event Reporting System (VAERS) using the pre-addressed form VAERS-1. Furthermore, we acknowledge your agreement stated in your pharmacovigilance plan and submitted on April 5, 2007, to work with U.S. federal government agencies to design epidemiological studies to assess safety and efficacy of the vaccine and to collaborate to fill gaps in the collection and analysis of important safety, and possibly effectiveness, data in a pandemic situation.

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 and implementation information on FDA Form 356h. Please provide a PDF-format electronic copy as well as one original paper copy.

Since, as stated in your April 5, 2007, submission, you do not intend to market this product for commercial distribution, we understand that you will not be distributing promotional advertising or promotional labeling materials. However, should you develop any advertising and/or promotional labeling related to this product (for example, educational brochures), we request that you submit two draft copies 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.

If you have any questions, please contact Dr. Rakesh Pandey at 301-827-3070.

Sincerely yours,

--- signature ---

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

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