DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
June 17, 2003
Our STN: BL 125020 / 0
Mr. William Turner
MedImmune Vaccines, Inc.
297 North Bernardo Avenue
Mountain View, CA 94043
Dear Mr. Turner:
Your Biologics License Application (BLA) for Influenza Virus Vaccine, Live, Intranasal (FluMist), for active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age, is approved effective this date. MedImmune Vaccines, Inc., Gaithersburg, Maryland is hereby authorized to introduce or deliver for introduction into interstate commerce, Influenza Virus Vaccine, Live, Intranasal, under U.S. Department of Health and Human Services License No 1652.
In accordance with approved labeling, your product will bear the proprietary name FluMist, and will be marketed in a 0.5 mL single dose, prefilled ------------ Nasal Spray System (manufactured by ------------------) consisting of a glass syringe barrel and a Teflon sprayer nozzle. Final trivalent bulk product is formulated and filled by MedImmune Vaccines, Inc., ------------------ and is packaged by ----------------------- -----------------------. MedImmune Vaccines, Inc. (Gaithersburg, MD) and Wyeth (Philadelphia, PA) will distribute packaged FluMist in the United States.
The dating period for the final container for FluMist shall be 9 months from the date of manufacture, but not beyond June 30th of the given influenza season, when stored continuously frozen at a temperature of -15°C or lower. The date of manufacture shall be defined as the date on which the trivalent vaccine is blended and filled. Potency testing performed on the final filled container must commence within ------ after filling. Any extension of the dating period will require the submission and approval of supporting data as a prior approval supplement to your BLA. Alternatively, you may submit, as a prior approval supplement to your BLA, a stability protocol to support the extension of dating.
You are requested to submit to the Center for Biologics Evaluation and Research (CBER) samples of each future final filled container lot of FluMist together with protocols showing the results of all applicable tests. No final container lots of product shall be distributed until notification of release is received from the Director, CBER.
Any changes in the manufacturing, testing, packaging or labeling of Influenza Virus Vaccine, Live, Intranasal, or in the manufacturing facilities will require the submission of information to your biologics license application for our review and written approval consistent with 21 CFR 601.12.
We acknowledge the post-marketing clinical commitments outlined in your submission of May 7, 2003, as follows:
You have agreed to conduct a large, open-label multi-year clinical safety trial in a total of 60,000 FluMist recipients receiving vaccine within the Kaiser Permanente (KP) system. Safety outcomes for this study will include, but are not limited to, asthma/wheezing; all medically attended adverse events (MAEs); serious adverse events (SAEs), including deaths; and rare events potentially related to wild-type influenza virus infection. FluMist will be administered to 20,000 individuals in each of the following age groups: 5-8 years, 9-17 years, and 18-49 years.
You have committed to submit the final clinical study protocol to your IND by July 31, 2003, and initiate the study on or about September 30, 2003, (depending on the availability of vaccine). The number of individuals expected to be vaccinated in this study is ~60,000 (~10,000 to 20,000 in the first season). For individuals age 5-8 years, enrollment is anticipated to be ~4000 per season, for individuals age 9-17 years enrollment is anticipated to be ~5000 per season, and for individuals 18-49 years enrollment is anticipated to be ~6,700 per season. You have indicated that the interim reports will be submitted annually and the final report for each age group will be available 1 year after complete follow-up data are available for each age group per final clinical study protocol.
You have agreed to collect solicited adverse experience monitoring data for individuals in a subset of subjects enrolled in the KP study. Data will be collected in the following age groups: 5-8 years, 9-17 years, and 18-49 years of age.
You have indicated that the protocol for this study will be submitted to CBER by July 31, 2003, and the study will be initiated on or about September 30, 2003. This study will be conducted within the large safety trial noted above and about 1500 subjects (500 in each age group enrolled in the large safety trial) will be analyzed. We note that you expect the subject accrual to be completed by December 31, 2003. You have agreed to provide a descriptive summary of results for the three age groups by September 30, 2004.
You have agreed to conduct a clinical study to investigate shedding of vaccine virus and immune responses to FluMist. As outlined in Attachment 2 of the revised proposal in your submission of May 7, 2003, you intend to conduct an off-season, open-label study to describe the occurrence and duration of shedding of vaccine virus in 100 subjects in each of the following age groups: 5-8 years, 9-17 years, and 18-49 years. You have indicated that serum HAI antibody responses will be evaluated in each age group. In addition, appropriate specimens will be obtained and banked for assessment of cellular immune response and mucosal antibody assays when validated assays become available. You have agreed to submit the protocol for this study by September 30, 2003, and initiate the study by June 30, 2004, (i.e., after the 2003-2004 influenza season). You have indicated that accrual of 300 subjects in this study will be completed by October 1, 2004, for adults and October 1, 2005, for children.
You have also indicated that the final clinical study report will be submitted by December 31, 2006. A supplemental report with results of the cellular and mucosal immune response will be submitted at a later date.
You have agreed to provide additional revaccination data from ongoing studies at completion. As noted previously in your February 5, 2003, submission, you have also committed to provide additional data pertaining to the safety of annual revaccination with FluMist for the following studies:
Submission of final clinical study report: by January 31, 2004
AV012, Year 3:
Submission of final clinical study report: by December 31, 2004
AV012, Year 4:
Submission of final clinical report: by December 31, 2005
With regard to non-clinical commitments:
- We also acknowledge your May 8, 2003, submission of a revised reproductive non-clinical toxicology protocol in response to our August 31, 2001, CR letter. You have agreed to initiate this study by July 2003 and complete the study and provide the final data report to CBER for our review by March 2004.
You are required to submit reports of biological product deviations in accordance with 21 CFR 600.14. All manufacturing deviations, including those associated with processing, testing, packaging, labeling, storage, holding and distribution, should be promptly identified and investigated. 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, a report must be submitted 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.
It is required that adverse experience reports be submitted in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and that distribution reports be submitted as described (21 CFR 600.81). According to 21 CFR 600.80(c)(2) [Periodic Adverse Experience Reports], the licensed manufacturer shall report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals for the first 3 years following approval. Since your product is characterized as a vaccine, these reports should be submitted to the Vaccine Adverse Event Reporting System (VAERS) using the pre-addressed form VAERS-1.
Please submit four copies of final printed labeling, under STN 125020/0, at the time of use and include Form FDA 2567 (09/02) with completed implementation information.
We recommend that you submit two draft copies of representative samples of your proposed introductory advertising and promotional labeling for advisory comment with a Form FDA 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. Final printed advertising and promotional labeling should be submitted at the time of initial dissemination, accompanied by a Form FDA 2253.
All promotional claims must be consistent with and not contrary to approved labeling. No comparative claims or claims of superiority over other products should be made unless data to support such claims are submitted to and approved by CBER.
Please acknowledge receipt of this letter, in writing, to the Director, Division of Vaccines and Related Products Applications, HFM-475, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research.
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Karen Midthun, M.D.
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
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Steven A. Masiello
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research