November 27, 2009
Our STN: BL 125297/0
Novartis Vaccines and Diagnostics, Inc.
Attention: Joanne Totosy de Zepetnek, Ph.D.
Vaccine Regulatory Affairs
350 Massachusetts Avenue
Cambridge, MA 02139-4182
Dear Dr. Totosy de Zepetnek:
We have approved your biologics license application for Influenza Virus Vaccine according to the regulations for accelerated approval effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce Influenza Virus Vaccine under your Department of Health and Human Services U.S. License No. 1751.
Under this license, you are approved to manufacture Influenza Virus Vaccine, at Novartis Vaccines and Diagnostics, Via Fiorentina 1, 53100 Siena, Italy. The final formulated product will be filled, labeled, and packaged by Novartis Vaccines and Diagnostics -------b(4)---------- ------------b(4)---------------. You may label your product with the proprietary name AGRIFLU and market it in 0.5 mL preservative-free single dose syringes.
AGRIFLU is an inactivated influenza virus vaccine, indicated for active immunization of adults 18 years of age and older against influenza disease caused by influenza virus subtypes A and type B present in the vaccine. This indication is based on the immune response elicited by AGRIFLU. There have been no controlled clinical studies demonstrating a decrease in influenza disease after vaccination with AGRIFLU.
We did not refer your application to the Vaccines and Related Biological Products Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues that would have benefited from an advisory committee discussion.
The dating period for AGRIFLU shall be no more than 12 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. 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.
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 AGRIFLU, 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 content of labeling in Structured Product Labeling format.
Please note that the accelerated approval regulation concerning promotional materials (21 CFR 601.45) stipulates that all advertising and promotional labeling items that Novartis wishes to distribute in the first 120 days following approval, must have been received by FDA prior to the approval date. After approval, promotional items intended for dissemination after the first 120 days following approval should be submitted to the FDA 30 days prior to the anticipated distribution date. Please submit these materials with 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 all final advertising and promotional labeling materials 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 substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).
ADVERSE EVENT REPORTING
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 (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/Vaccines/UCM164319.pdf).
Per 21 CFR 600.2(f), please refer to http://www.fda.gov/AboutFDA/CentersOffices/CBER/ ucm106001.htm for updated mailing address information.
ACCELERATED APPROVAL REQUIRED STUDY
Products approved under the accelerated approval regulations, 21 CFR 601.41, require further adequate and well-controlled confirmatory clinical studies to verify and describe clinical benefit. We remind you of your postmarketing study commitments specified in your submission dated November 23, 2009. This commitment, along with any completion dates agreed upon, is listed below.
- Novartis Vaccines and Diagnostics agrees to submit the results of Study No. V58P13, a placebo-controlled clinical endpoint efficacy and safety study of Novartis’s AGRIFLU in healthy adults 18 to 49 years of age. The final study report for the study will be submitted by January 31, 2010.
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 the necessary studies are impossible or highly impracticable to conduct and there is evidence strongly suggesting that the product would be ineffective in this age group.
We are deferring submission of your study for ages 6 months to 17 years for this application because this product is ready for approval for use in adults.
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:
- Novartis Vaccines and Diagnostics agrees to conduct Study No. V71_18, a randomized, observer-blind, non-inferiority immunogenicity and safety study with Novartis’s AGRIFLU and a US licensed trivalent inactivated Influenza Vaccine in a pediatric population from 3 years to 17 years of age. A protocol for this study will be submitted by December 31, 2009. The study will begin in September 2010. The final study report will be submitted in January, 2012.
- Novartis Vaccines and Diagnostics agrees to conduct Study No. V71_20, a randomized, observer-blind, immunogenicity and safety study with Novartis’s AGRIFLU and a US licensed trivalent inactivated Influenza Vaccine in a pediatric population from 6 months to less than 3 years of age. The final protocol for this study will be submitted by December 31, 2010. The study will begin in September 2011. The final study report will be submitted in January 2013.
Please submit the 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 ---b(4)---, 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 60.70 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.
AGREED UPON POSTMARKETING COMMITMENTS
We acknowledge your written commitments as described in your letter of September 4, 2009 as outlined below:
- Novartis Vaccines and Diagnostics agrees to establish a pregnancy registry to prospectively collect data on spontaneously-reported exposures to AGRIFLU during pregnancy. A protocol for this pregnancy registry will be submitted by June 30, 2010. This protocol will address elements found in FDA’s guidance for Industry on Establishing Pregnancy Exposure Registries (9/2/2002) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM071639.pdf). The pregnancy registry will be established by
June 30, 2011.
Based on your letter of November 25, 2009:
- Novartis Vaccines and Diagnostics agrees to conduct a non-inferiority immunogenicity study with AGRIFLU and a US-licensed trivalent inactivated seasonal influenza vaccine in a population of adults 50 years of age and older. The final study protocol for this study will be submitted by June, 2010. This study will start by March 2013. The final study report will be submitted by November 2014.
We request that you submit clinical protocols to your IND ---b(4)---, with a cross-reference letter to this BLA, STN BL 125297. 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.
If you have any questions please contact Dr. Bernard J.P. McWatters at 301-827-3070.
Norman W. Baylor, Ph.D.
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research