Our STN: BL 125020/322
MedImmune Vaccines, Inc.
Attn: 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 Virus Vaccine Live, Intranasal (FluMist®), to revise your indication to the following: For the active immunization of individuals 2-49 years of age against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.
All applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens must contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We note that you have fulfilled the pediatric study requirement for this application for the pediatric population older than six months of age. We waive the requirement for pediatric studies in infants six months of age and younger.
We acknowledge your written commitments as described in your letter of September 18, 2007, which are outlined below:
Postmarketing Commitments subject to reporting requirements of 21 CFR 601.70.
MedImmune agrees to conduct a large, multi-year clinical safety population-based study of FluMist® recipients vaccinated within a managed care organization (Study MI-MA162), submitted on September 14, 2007 to this supplement, to be initiated during the 2007-2008 influenza season. Appropriate comparison groups, including but not limited to TIV (trivalent influenza vaccine)-exposed and unvaccinated groups will be used. The study will be designed to have an 80% power to detect a statistically significant increase in relative risk if the true risk is >2 for events occurring at a rate of 1 in 1,000 in the age group of 24-59 months. At least one third of the total study population will be children <36 months of age. Safety outcomes for this study will include, but are not limited to:
- Asthma/reactive airway disease and wheezing, including exacerbations of these pre-existing conditions
- Serious adverse events (SAEs), including hospitalizations and deaths
- Acute severe hypersensitivity disorders
- Nervous system disorders including but not limited to Bell's palsy, GBS, encephalitis and convulsions
- Rare events potentially related to wild-type influenza virus infection
- Influenza and respiratory conditions among immunocompromised patients subsequent to FluMist administration
A subgroup analysis of those children 24-59 months of age who have had one or more prior vaccinations with inactivated influenza vaccine (TIV) will also be performed. Outcomes of interest of this evaluation will include but are not limited to wheezing-asthma.
The number of individuals to be vaccinated in this study will be approximately 25,000. Enrollment will be targeted at 10,000 vaccinees per season. Completion of enrollment is anticipated before 31 December 2012. Interim reports containing preliminary data will be submitted to BB-IND 9204 as soon as available, but before October 1 of each year following each influenza season. The final study report will be submitted to BB-IND 9204 before 30 June 2014.
- MedImmune will provide a summary analysis of the one dose group previously vaccinated with TIV from study MI-CP111. The analysis will be submitted to BB-IND 9204 before 30 September 2008.
- MedImmune agrees to continue to provide interim analyses annually for study FM025, initiated in 2003 (as a postmarketing commitment for the original BLA), and to provide a final study report to BB-IND 9204 by 31 December 2011.
MedImmune has submitted on 1 May 2007 a risk minimization action plan (RiskMAP) consisting of targeted education, outreach to parents/guardians and health care providers, and screening information in educational pamphlets for non-managed care and managed care settings. The effectiveness of this RiskMAP to prevent vaccination of certain persons for whom the vaccine was not indicated will be assessed within a managed care organization and may be part of the observational safety study described above (Study MI-MA162). RiskMAP effectiveness and safety outcomes will be assessed following separate protocols (Studies MI-MA164 and MI-MA172) as the two protocols contain different instructions and methods for capturing the data in the two settings. Vaccination errors of interest will include, among others, vaccination of persons with a history of asthma/reactive airway disease and of children <24 months of age. In addition, vaccination of immunocompromised persons will be identified and described. Analyses will include evaluation of rates of vaccination errors and their consequences, and available information regarding reasons for vaccination of people for whom the vaccine was not indicated. A similar study will also be conducted in a non-managed care setting (MI-MA163).
- MedImmune will submit protocols for studies MI-MA163, MI-MA164 and MI-MA172 to BB-IND 9204 by 31 October 2007 and initiate the studies during the 2007-2008 influenza season.
- Following each influenza season, interim reports will be submitted to BB-IND 9204 by June 30th of each year until 2012.
- The final study report will be submitted to BB-IND 9204 before 30 June 2014.
Postmarketing Commitments not subject to reporting requirements of 21 CFR 601.70.
- MedImmune agrees to report each adverse experience not reported under paragraph 21CFR 600.80(c)(1)(i) of this section for the newly indicated population (2 years to 59 months of age) at monthly intervals for the first three years following approval (accelerated reporting), and then at annual intervals. Reports of medical errors that are classified as serious events, including serious events among persons with a history of asthma/reactive airway disease or among persons with immunosuppressive conditions, will be sent to the VAERS contractor as "15-day" reports.
MedImmune has agreed to provide to CBER, a copy of the content of any abstract, public presentation, or manuscript submission based on data originated in any of aforementioned postmarketing studies in this letter, before either publication or presentation in a public forum.
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 final study reports to your BLA. If the information in the final study report supports a change in the labeling, the final study report should be submitted as a labeling 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 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 Internet site (http://www.fda.gov/cder/pmc/default.htm). For further information, 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 http://www.fda.gov/cber/gdlns/post040401.htm).
Please submit all final printed labeling at the time of use and include implementation information on FDA Form 356h. Please provide a PDF-format electronic copy as well as one original paper copy. In addition, you may wish to submit 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, MD 20852-1448. Please submit your final printed advertising and promotional labeling at the time of initial dissemination, accompanied by an FDA Form 2253.
We will include information contained in the above-referenced supplement in your biologics license application file.
Janice Soreth, M.D.
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
Attachment: Final Draft Labeling of Package Insert