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U.S. Department of Health and Human Services

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February 29, 2012 Approval Letter - FluMist® Quadrivalent

Our STN:  BL 125020/1668        

MedImmune, LLC
Attention:  Nancy R. Kavanaugh, Ph.D
One MedImmune Way
Gaithersburg, MD  20878

Dear Dr. Kavanaugh:

We have approved your request to supplement your biologics license application for Influenza Vaccine Live, Intranasal, to include a quadrivalent formulation containing two influenza A subtype viruses and two type B viruses.

Under license 1799, you are approved to manufacture this quadrivalent formulation of Influenza Vaccine Live, Intranasal at your facility in -----------------------------------------(b)(4)------------------------------------------------------. You may label this formulation of your product with the proprietary name FluMist® Quadrivalent and market it in the Accuspray™ (Becton Dickinson) Nasal Spray System. The expiry dating period for final container vaccine is not to exceed ----(b)(4)-- from date of manufacture, which is defined as the date of fill. The dating period will include ----------------------------------------(b)(4)--------------------------------------------- refrigerated storage at 2 to 8°C not to exceed 18 weeks -------------------------------------(b)(4)----------------------------.

FluMist Quadrivalent is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FluMist Quadrivalent is approved for use in persons 2 through 49 years of age.

We did not refer your supplement to the Vaccines and Related Biological Products Advisory Committee because our review of information submitted in your supplement, including the design and results of the clinical trials, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion.

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, or electronically to http://www.fda.gov/cber/biodev/biodev.htm.

The review of this product was associated with the following National Clinical Trial (NCT) number(s): NCT00860067, NCT00952705, and NCT01091246.

Under 21 CFR 201.57(c)(18), patient labeling must be reprinted at the end of the package insert.  We request that the text of information distributed to patients be printed in a minimum of 10-point font.

Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels.  In addition, please submit three original paper copies for carton and container final printed labeling.  All final labeling should be submitted as Product Correspondence to this BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h.

In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.  Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf.

You may 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. You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).

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 substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).

Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes [this/these] change(s).

ADVERSE EVENT REPORTING

As required under 21 CFR 600.80(c)(2) you must provide Periodic Adverse Experience Reports to the VAERS contractor.  Please report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals for the first year following the approval of your supplement 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, please 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 in pediatric patients unless this requirement is waived, deferred, or inapplicable.

We are waiving the pediatric study requirement for ages 0 months through 23 months because there is evidence strongly suggesting that the biological product would be unsafe in this pediatric group. In clinical trials, use of FluMist (Influenza Vaccine Live, Intranasal) in children 6 months through 23 months of age was associated with increased risks of hospitalization and wheezing.

We note that you have fulfilled the pediatric study requirement for ages 2 years through 17 years for this application.

AGREED UPON POSTMARKETING COMMITMENTS

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

We acknowledge your written commitments as described in your letter of February 8, 2012, as outlined below:

1.   You have agreed to conduct an observational postmarketing safety surveillance study of FluMist Quadrivalent in children 2 years through 8 years of age. The study is designed to evaluate rates of medically attended events in a minimum of 10,000 FluMist Quadrivalent recipients, compared to non-randomized comparison groups. The final protocol will be submitted by April 30, 2013. The study will be completed by
June 30, 2018 and the final study report will be submitted by June 30, 2019.

2.   You have agreed to conduct an observational postmarketing case-control study of the effectiveness of FluMist Quadrivalent in children 2 years through 17 years of age. The study is designed to compare the effectiveness of vaccination with FluMist Quadrivalent to no vaccination and to vaccination with an inactivated influenza vaccine over four influenza seasons.  The final protocol submission date will be April 30, 2013. The study will be completed by December 31, 2017 and the final report will be submitted by December 31, 2018.

Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125020.  Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL 125020.  If the information in the final study report supports a change in the labeling, the final study report should be submitted as a supplement.  We may also request a supplement if we think labeling changes are needed.  Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

  • Postmarketing Study Commitment Protocol
  • Postmarketing Study Correspondence
  • 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 an “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), 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/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm).  Please refer to the February 2006 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/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080569.pdf) for further information. 

Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.  

We acknowledge your written commitment as described in your submission dated
February 28, 2012, as outlined below:

3.   -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

4.   ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.
We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to STN BL 125020.

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

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

We will include information contained in the above-referenced supplement in your biologics license application file.

Sincerely yours,

 

Wellington Sun, M.D.
Director
Division of Vaccines and
Related Products Applications
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research

Attachment:  Approved Final Draft Labeling