VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE CBER Regulatory Approaches & Activities To Support Licensure of Pandemic (H1N1) 2009 Vaccine Wellington Sun, MD Director, Division of Vaccines and Related Products Applications CBER/FDA July 23, 2009

Presentation Outline Background Vaccine licensure pathways Clinical trial design Emergency use authorization (EUA) Summary

Pandemic (H1N1) 2009 Vaccine Considerations New triple human, swine, avian reassortant Sustained transmission outside normal flu season Low antibody level and higher attack rate among children/adolescents Cross-reactive antibody in >60 yo suggesting the older population may be primed Recent seasonal vaccines unlikely to afford protection Multiple vaccine options available

Currently Licensed Influenza Vaccines in U.S. Seasonal Afluria (CSL)Inactivated≥ 18 yo Fluarix (GSK)Inactivated≥ 18 yo FluLaval (ID Biomed)Inactivated≥ 18 yo Fluvirin (Novartis)Inactivated ≥ 4 yo Fluzone (SP)Inactivated≥ 6 mo FluMist (MedImmune)LAIV2-49 yo PandemicH5N1 (SP)(Inactivated)18-64 yo

Available Regulatory Pathways for use of Pandemic (H1N1) 2009 Influenza Vaccine New BLA Supplement to seasonal license Emergency Use Authorization (EUA) Treatment IND

Licensure of Seasonal Influenza Vaccine - Strain Change Supplement Inactivated –Supplement under existing license –Chemistry, manufacturing, and controls (CMC) –No new clinical data LAIV –Supplement under existing license –CMC –Limited clinical safety data

Licensure of Unadjuvanted Monovalent Pandemic (H1N1) 2009 Vaccines Made by Licensed Process Manufacturers will submit a supplement to their seasonal influenza biologics license for the pandemic (H1N1) 2009 vaccine analogous to seasonal strain change supplement.

Licensure of Unadjuvanted Monovalent Pandemic (H1N1) 2009 Vaccines Made by Licensed Process Strain change supplement without new clinical data at the time of licensure relies on: –Nonclinical, CMC information –Clinical data in the BLA for seasonal influenza vaccine Age range, dose and dosing regimen for the pandemic (H1N1) 2009 vaccine will be the same as for each licensed seasonal vaccine –Vaccine will be formulated at 15 mcg/dose of HA for inactivated, FFU/dose for LAIV Applicable to non-adjuvanted vaccines only, when manufactured by the licensed egg-based manufacturing process

Pandemic (H1N1) 2009 Vaccine Licensure – Considerations In case of urgent public health need this pathway provides the most direct regulatory pathway to licensure Historical data suggests that vaccines containing 15 µg/dose of H1N1 antigens or FFU/dose of LAIV would be immunogenic Complete data from proposed clinical trials of inactivated monovalent H1N1 vaccine and post-dose 2 data of LAIV will be submitted post-licensure Modifications can be made if indicated by data from post licensure clinical trials.

Licensure of monovalent Pandemic (H1N1) 2009 Vaccine based on historical precedent Strain A/Taiwan/1/86 Influenza A/Taiwan/1/86 H1N1 virus represented a new antigenic variant of influenza A (H1N1) circulating in 1986 Monovalent influenza A/Taiwan/1/86 H1N1 virus vaccine licensure was considered a strain change Monovalent influenza A H1N1 subtype (A/Taiwan/1/86) vaccine was licensed as a supplemental vaccine to each manufacturer’s license application for seasonal trivalent vaccine with no new clinical data

Clinical Trial Basic Design Concepts Licensed Manufacturers Monovalent vaccine Designed to inform dose, dosing regimen and safety Common design communicated to license manufacturers Randomized, double or observer-blind, controlled, dose ranging 2 doses (0,21d) with post-dose 1 immunogenicity assessment Age stratification (6m-35m, ≥3-9yo, ≥18-64yo, ≥65yo) Adult and pediatric studies concurrent Unadjuvanted and adjuvanted arms Target for earliest possible clinical trial start Clinical trials conducted under IND

Clinical Trial Basic Design Age range 7.5 µg HA N 15 µg HA N 30 µg HA N 3.8 /7.5/15 µg HA + adjuvant N 6m-3y /antigen dose ≥3-9yo /antigen dose ≥18-64yo /antigen dose ≥65yo /antigen dose

Clinical Trial Endpoints Immunogenicity: 21 days post each vaccination Proportion seronegatives with HAI ≥ 1:40 Proportion seropositives with ≥4-fold rise in HAI (seroconversion rate) GMT Others: GMT, immunogenicity at earlier time points (e.g. 14 days after vaccination); microneutralization titers Safety solicited local and systemic events within 7 days of vaccination unsolicited adverse events, serious adverse events (SAEs) new onset medical conditions 6-12 month follow-up period after the last dose of vaccine Guidance for Industry, Clinical data needed to support the licensure of pandemic influenza vaccines, May 2007

Emergency Use Authorization Section 564 of the Federal Food, Drug and Cosmetic Act 1. Declaration of national emergency by HHS Secretary (25 April 2009) 2. FDA Commissioner in consultation with Directors of NIH and CDC: - serious or life-threatening condition or disease - based on scientific evidence, product may be effective - known and potential benefit outweighs risks - no adequate, approved, available alternative

Emergency Use Authorization Unapproved Products - vaccines with adjuvants Unapproved Use of Approved Products - approved vaccines for unapproved age

Summary 2009 H1N1 pandemic a declared national emergency Severity of ongoing disease in U.S. so far comparable to seasonal, but course and severity of pandemic in the fall are unpredictable Unadjuvanted inactivated and LAIV manufactured using licensed egg-based processes have a proven track record of safety and effectiveness with current formulations Licensure of a supplemental monovalent pandemic (H1N1) 2009 vaccine as a strain change is consistent with past regulatory actions

Summary (cont’d) A strain change BLA supplement formulated at 15 µg/dose of HA or 10 7 FFU/dose will allow for earliest availability of licensed vaccines Clinical trial design is for developing early immunogenicity data to inform dose and schedule modifications Regulatory pathways developed for all vaccine options in case of population immunization program Post-marketing surveillance of safety and assesment of vaccine effectiveness

FDA is committed to protecting the public’s health and ensuring the availability of safe and effective vaccines for our nation against the pandemic H1N virus as quickly as possible.

Acknowledgment Office of Vaccines Research and Review Melisse Baylor Brenda Baldwin Carmen Collazo Therese Cvetkovich Theresa Finn Timothy Fritz Sara Gagneten Marion Gruber Maureen Hess Andrea James Phil Krause Valerie Marshall Bernard McWatters Loris McVittie Cynthia Nolletti Rakesh Pandey Douglas Pratt Loren Rodgers Lewis Schrager Elizabeth Sutkowski