Vaccines, Blood & Biologics

November 20, 2012 Approval Letter- Flucelvax

Our STN: BL 125408/0

Novartis Vaccines and Diagnostics, Inc.
Attention: Matthew Gollwitzer
350 Massachusetts Avenue
Cambridge, MA 02139
Dear Mr. Gollwitzer:
We have approved your biologics license application for Influenza Virus Vaccine effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Influenza Virus Vaccine under your existing Department of Health and Human Services U.S. License No. 1751. Influenza Virus Vaccine is indicated for active immunization of persons 18 years of age and older for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.
The review of this product was associated with the following National Clinical Trial (NCT) number(s): NCT00264576, NCT00310804, NCT00306527, NCT00492063, NCT00511914, NCT00560066, NCT00630331, and NCT00645411.
Under this license, you are approved to manufacture Influenza Virus Vaccine drug substance at Novartis Vaccines and Diagnostics GmbH, Emil-von-Behring-Str. 76, 35041 Marburg, Germany. The final formulated product will be (b)(4)-, filled, labeled, and packaged at Novartis Vaccines and Diagnostics -----------(b)(4)-----------------------------. You may label your product with the proprietary name FLUCELVAX and market it in 0.5 mL single dose syringes.
We did not refer your application to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion. In addition, issues associated with the use of MDCK cells in vaccine manufacture were discussed in the November 2005 VRBPAC.

The dating period for Influenza Virus Vaccine shall be no more than 11 months from the date of manufacture of the final container vaccine, but not to exceed June 30th of the influenza season for which it was formulated when stored at 2-8°C (36-46°F). The date of manufacture shall be defined as the date on which this vaccine is filled. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency. 

Any extension of the dating period will require the submission and approval of supportive data as a prior approval supplement to your BLA; ongoing stability data may be submitted as product correspondence as it becomes available.
Each influenza season, please submit the first five monovalent concentrates of each strain to CBER for potency testing, along with the protocol for each submitted lot. CBER will not release monovalent lots; however, results of potency testing will be provided for your information only. For the lots to be released, please submit your final trivalent 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 the product until you receive a notification of release from the Director, Center for Biologics Evaluation and Research (CBER).
You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing, packaging or labeling of Influenza Virus Vaccine, 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 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 and FDA Form 2567 as appropriate.
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 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
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)).
You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports as described in (21 CFR 600.81). You should submit these reports to the Vaccine Adverse Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100, using the pre-addressed form VAERS-1 (
). Per 21 CFR 600.2(f), please refer to for updated mailing address information.
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 in infants from 0 to < 6 months of age, because this product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients and is not likely to be used in a substantial number of infants < 6 months of age. Available data indicate that serum antibody responses to inactivated influenza vaccines in infants < 6 months of age are not as robust as in older children due to inherent immaturity of the immune system and interference from maternal antibody.
We are deferring submission of your studies for ages 6 months to 17 years for this application because this product is ready for approval for use in adults and the pediatric studies have not been completed.
Your deferred pediatric studies required under 505B(a) of the Federal Food, Drug, and Cosmetic Act are required postmarketing studies. The status of these postmarketing studies must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act. These required studies are listed below:
  1. Deferred completed pediatric study (Study V58P12) under PREA to evaluate the safety and immunogenicity of FLUCELVAX in children ages 4 years to < 18 years.
Final Report Submission: May 2014

  1. Deferred pediatric study (Study V58_31) under PREA to evaluate the safety of FLUCELVAX in children ages 4 years to < 18 years.
Final Protocol Submission: November 30, 2012
Study Completion Date: May 2014
Final Report Submission: November 2014
3.   Deferred pediatric dose ranging, immunogenicity and safety study (Study V58P16) under PREA in children ages 6 months to < 4 years.
Final Protocol Submission: October 2014
Study Completion Date: May 2016
Final Report Submission: November 2016
  1. Deferred pediatric study (Study V58_35) under PREA to evaluate the safety and immunogenicity of FLUCELVAX in children ages 6 months to < 4 years.
Final Protocol Submission: August 31, 2016
Study Completion Date: May 2018
Final Report Submission: November 2018
Submit final study reports to this BLA. For administrative purposes, all submissions related to these required pediatric postmarketing studies must be clearly designated “Required Pediatric Assessment(s).”
Please submit the protocol(s) to your IND 11580 with a cross-reference letter to this BLA. Submit all final reports to this BLA and prominently identify them as appropriate: 
  • Required Postmarketing Protocol under 505(o)
  • Required Postmarketing Final Report under 505(o)
  • Required Postmarketing Correspondence under 505(o)
Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 601.70, requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials.
We will consider the submission of your annual report under section 506B and 21 CFR 601.70 to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 601.70. We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
We acknowledge your written commitments as described in your letter of November 1, 2012 as outlined below:
  1. To establish a pregnancy registry to prospectively collect data on spontaneously-reported exposures to FLUCELVAX during pregnancy.  A protocol for this pregnancy registry will be submitted by June 30, 2013.  The pregnancy registry will be established by September 30, 2014.  When the registry has enrolled a minimum of 600 evaluable subjects and collected data on the outcomes specified in the protocol, Novartis will submit a full study report and continue enrolling in the registry pending CBER review and discussion of registry results with Novartis.
  1. To conduct a randomized, controlled, observer-blind, immunogenicity and safety study in adults comparing three lots of FLUCELVAX produced under manufacturing process 1.1 at the Holly Springs facility. 
Final study protocol submission date: December 1, 2013
Study completion date: January 29, 2015
Final study report submission date: June 30, 2015
Please submit clinical protocols to your IND 11580, with a cross-reference letter to this biologics license application (BLA), STN BL 125408/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL 125408. 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:
o        information to identify and describe the postmarketing commitment,
o        the original schedule for the commitment,
o        the status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted), and
o        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 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 for further information.
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.  
7.      -----------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------
8.      --------------------------------------------------------(b)(4)-----------------------------------------------------------------------------------------------------------------------------------------------------.
For each postmarketing commitment not subject to the reporting requirements of 21 CFR 601.70, 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.
If you have any questions regarding the above, please contact the Regulatory Project Managers, Timothy Fritz, Ph.D. or Brenda Baldwin, Ph.D., at (301) 796-2640.
Sincerely yours,
Marion Gruber, Ph.D.
Office of Vaccines
 Research and Review
Center for Biologics
 Evaluation and Research

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