1. 1 Licensure of Pandemic Influenza Vaccines: Demonstration of Effectiveness Vaccines and Related Biological Products Advisory Committee Meeting February 29, 2012 Theresa M. Finn, OVRR, CBER, FDA

2. 2 Outline Background –Pandemic influenza Pandemic Planning –2007 Guidance for Industry –H1N1 2009 experience –U.S.-licensed pandemic influenza vaccines: H1N1 vaccines H5N1 vaccine Effectiveness of pandemic vaccine inferred from efficacy of seasonal Pandemic influenza vaccines in development –Made by the same process as a seasonal influenza vaccine but w/adjuvant –Made by a process that is not U.S-licensed w/wo adjuvant –Approaches to infer effectiveness

3. 3 Influenza A Pandemics 1918/1919: “Spanish Influenza” H1N1 1957: “Asian Influenza” H2N2 1968: “Hong Kong Influenza” H3N2 2009: H1N1

4. 4 Influenza A Subtypes of Pandemic Potential H1: H1N1 1918, 2009 H2: H2N2 1957 H3: H3N2 1968 H5: Highly Pathogenic Avian Influenza (HPAI) H5N1 virus currently circulating in poultry in parts of Asia and NE Africa, since 1997 human disease and death H7: infection in humans is rare but can occur among persons who have direct contact with infected birds. Mild to severe and fatal illness in humans. H9: Low Pathogenic Avian influenza (LPAI) H9N2 virus endemic in poultry in Middle East and Asia, since 1997 multiple (mild) human infections

5. 5 Areas with confirmed human cases of H5N1 avian influenza since 2003. Status as of 16, March 2011 latest available update.

6. 6 Areas with confirmed human cases of H5N1 avian influenza since 2003*

7. 7 FDA Guidance For Industry Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines (2007)

8. 88 Pandemic Influenza Vaccine Licensure Pathways “Traditional” Approval – 21 CFR 601 Subpart A and C Approval “…based on data… which demonstrate that the manufactured product meets prescribed requirements of safety, purity and potency…” Accelerated Approval –21 CFR 601 Subpart E Approval “…on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint …reasonably likely…to predict clinical benefit…” Approval “..subject to the requirement that the applicant study the biological product further to verify and describe its clinical benefit…[such] studies would usually be already underway…such studies must also be adequate and well controlled. The applicant shall carry out such studies with due diligence”

9. 9 Pandemic Influenza Vaccine Licensure Pathways, 2007 Guidance Pandemic vaccine made by the same process as a manufacturer’s U.S.-licensed seasonal vaccine: –Traditional approval: Effectiveness of the pandemic vaccine inferred from efficacy of the seasonal Pandemic vaccine made by manufacturers without U.S.- licensed seasonal licensed vaccine or for adjuvanted pandemic vaccines: –Accelerated Approval: Prelicensure safety and immunogenicity data required to support dose and dosing regimen –Manufacturer must verify clinical benefit during the pandemic

10. 10 A(H1N1) 2009 Pandemic Experience U.S.- manufacturers had no control over distribution and use of vaccines Manufacturer’s ability to conduct with due diligence adequate and well controlled studies to verify benefit not guaranteed

11. 11 Pandemic Planning Vaccine: Well matched to circulating strain Available in a timely manner –Strain change supplement to an existing license –Pre-requisite: Licensed vaccine against influenza A subtype of pandemic potential (“prototype” vaccine) Safe and effective

12. 12 “Effectiveness” 21 CFR 201.57(c)(2)(v) For biological products, all indications...must be supported by substantial evidence of effectiveness…” Regulatory determination that the vaccine will prevent disease in the target population when used appropriately: –Clinical endpoint efficacy data (e.g. Prevnar) –Serological data using an established correlate of protection (e.g. HepB) –Serological data to “bridge” populations and formulations (e.g. pertussis antigens in Tdap)

13. 13 Effectiveness of Seasonal Inactivated Influenza Vaccines Immunogenicity data: –Antibody to HA (Hemagglutination inhibition, HAI) correlates with protection –HAI assays not standardized and subject to inter- laboratory variability Immunogenicity (GMTs, rates of sero-conversion) used as immunogenicity bridge and as endpoint to support accelerated approval –For traditional approval, vaccine efficacy against influenza illness demonstrated in an adequate and well-controlled clinical study

14. 14 Pandemic Influenza Vaccines

15. 15 U.S.-licensed Influenza A (H1N1) 2009 Vaccines

16. 16 Pandemic (H1N1) 2009. Countries, territories and areas with lab confirmed cases and number of deaths as reported to WHO http://www.who.int/csr/don/GlobalSubnationalMasterGradcolour_20090806_weekly.png

17. 17 U.S.-Licensed Influenza A (H1N1) 2009 Vaccines Sanofi pasteur > 6 months of age Novartis > 4 years of age CSL >18 years of age (>6m Nov. 2009) IDB/GSK >18 years of age MedImmune 2-49 years of age

18. 18 Influenza A (H1N1) 2009 Vaccines Approved as strain change supplements to the seasonal influenza virus vaccine BLAs –Consistent with licensure of seasonal vaccines –Consistent with past regulatory actions: 1986 - Influenza A/Taiwan/1/86 H1N1 Monovalent vaccines licensed as strain change supplements No clinical data –Supported by VRBPAC 7/2009 Strain change supplement Influenza A (H1N1) 2009 vaccines U.S. Licensed Seasonal Influenza Vaccine H1, H3, B

19. 19 Influenza A (H1N1) 2009 Vaccines - Strain Change Supplements Manufacturers utilized same egg based manufacturing process as used for their seasonal vaccines Vaccines contained the same quantity of antigen as a single strain in seasonal vaccine Same population usage as the licensed seasonal vaccine Same clinical data requirements as for seasonal influenza vaccine strain change supplements: –Inactivated vaccines: No clinical data –Live attenuated: Limited clinical data to verify attenuation Pre-licensure clinical studies not required but manufacturers and N.I.H. conducted studies to verify dose and vaccination regimen Effectiveness inferred from efficacy of the seasonal

20. 20 U.S.-licensed Influenza Virus Vaccine, H5N1

21. 21 Influenza Virus Vaccine, H5N1 Manufactured by Sanofi Pasteur, Inc. using same egg based manufacturing process as the seasonal influenza vaccine, Fluzone Safety and immunogenicity data generated to support the dose (90ug HA/1mL dose) and regimen (2 doses, 28 days part) For use in persons 18-64 years of age VRBPAC February 2007 Approved April 2007 Effectiveness inferred from efficacy of the seasonal

22. 22 U.S.-licensed Influenza Virus Vaccine, H5N1 U.S. Licensed Seasonal Influenza Vaccine Fluzone A, subtype: H1, H3 H5N1 “Prototype” pandemic vaccine: unadjuvanted Licensure approach:  safety  immunogenicity  effectiveness Efficacy Effectiveness inferred from efficacy of the seasonal

23. 23 Influenza Virus Vaccine, H5N1 Strain change supplements Licensure of the “prototype” H5N1 vaccine would permit use of a strain change supplement to approve a vaccine “matched” to a pandemic virus strain change supplement Pandemic H5N1 vaccine Influenza Virus Vaccine, H5N1

24. 24 Pandemic Influenza Vaccines in Development

25. 25 Pandemic Influenza Vaccines in Development Inactivated H5N1 vaccines Principles apply to other inactivated influenza A subtype (H7, H9) vaccines Live attenuated influenza vaccines: additional considerations regarding clinical studies prior to a pandemic (e.g. safety assessment).

26. 26 H5N1 Vaccines in Development

27. 27 Adjuvanted H5N1 Vaccines in Development Manufactured using the same process as a U.S.-licensed seasonal influenza vaccine but includes a novel adjuvant –In advanced clinical development –Safety data and immunogenicity data required to define HA dose, adjuvant content and dosing regimen

28. 28 Adjuvanted H5N1 Vaccines Same manufacturing process as U.S-licensed seasonal influenza vaccine Category 1: Efficacy of unadjuvanted seasonal vaccine made by same manufacturer has been demonstrated (i.e. traditional approval) Category 2: Efficacy of unadjuvanted seasonal vaccine made by same manufacturer not yet verified (i.e. accelerated approval regulations)

29. 29 Adjuvanted H5N1 Vaccines in Development Category 1: Efficacy of unadjuvanted seasonal vaccine made by same manufacturer has been demonstrated Approach to demonstrate of effectiveness of adjuvanted H5N1 vaccine: –Effectiveness of the adjuvanted H5N1 vaccine is inferred from efficacy of the manufacturer’s seasonal vaccine

30. 30 Adjuvanted Influenza Virus Vaccine, H5N1: Efficacy of Seasonal Vaccine Demonstrated U.S. Licensed Seasonal influenza Vaccine H5N1 “Prototype” pandemic vaccine:  adjuvanted Licensure approach:  safety  immunogenicity  effectiveness efficacy strain change supplement pandemic H5N1 vaccine Pandemic vaccine adjuvanted Pandemic Pre-pandemic period Effectiveness inferred from efficacy of the seasonal

31. 31 Adjuvanted H5N1 Vaccines in Development Category 2: Efficacy of unadjuvanted seasonal vaccine made by same manufacturer and process not yet verified (i.e. accelerated approval) Approach to demonstrate effectiveness of adjuvanted H5N1 vaccine: a) Accelerated approval: Effectiveness will be inferred from the efficacy of the unadjuvanted seasonal vaccine when clinical benefit is verified b) Traditional approval: Effectiveness is inferred from observational effectiveness data using a non-U.S.-licensed adjuvanted influenza A(H1N1) 2009 pandemic vaccine made by the same process (e.g. case control study)

32. 32 U.S. Licensed Seasonal influenza Vaccine Accelerated Approval  strain change  supplement Efficacy not yet confirmed A, subtype: H5 Licensure of “Prototype” pandemic vaccine:  adjuvanted Pandemic vaccine update:  adjuvanted pandemic H5N1 Licensure approach: Accelerated Approval  safety  Immunogenicity  effectiveness Adjuvanted Influenza Virus Vaccine, H5N1: Efficacy of Seasonal Vaccine Pending, Approach A Efficacy confirmed Effectiveness inferred when the efficacy of the seasonal confirmed PandemicPre-pandemic period Traditional Approval

33. 33 U.S. Licensed Seasonal influenza vaccine  strain change  supplement Efficacy not yet confirmed A, subtype: H5 Licensure of “Prototype” pandemic vaccine:  adjuvanted Pandemic vaccine update:  adjuvanted Pandemic H5N1 Licensure approach: Traditional Approval  safety  Immunogenicity  effectiveness Non-U.S. Licensed Adjuvanted H1N1 influenza vaccine Same manufacturer/process Effectiveness data Adjuvanted Influenza Virus Vaccine, H5N1: Efficacy of Seasonal Vaccine Pending, Approach B Effectiveness is inferred from observational effectiveness data with adjuvanted H1N1 vaccine PandemicPre-pandemic period

34. 34 H5N1 Vaccines in Development Manufactured using a process that is not U.S.-licensed (with or without adjuvant) Protective mechanisms dependent on HA antibody response –Safety data and immunogenicity data (HAI) required to define antigen dose, adjuvant content ( if used) and dosing regimen Protective mechanisms not dependent HA antibody response –Safety data and immunogenicity data required to define antigen dose, adjuvant content (if used) and dosing regimen

35. 35 H5N1 Vaccines in Development Manufactured using a process that is not U.S.- licensed (with or without adjuvant) Demonstration of effectiveness: –If the manufacturer develops a seasonal influenza vaccine: Infer effectiveness of the H5N1 vaccine from the efficacy of the seasonal made by the same process –If the manufacturer does not develop a seasonal vaccine Other approaches to demonstrate effectiveness prior to a pandemic needed.

36. 36 Summary U.S.-licensed influenza A (H1N1) 2009 vaccines and an influenza A (H5N1) vaccine manufactured using the same process as the seasonal vaccine: –Efficacy data accrued with a U.S.-licensed seasonal influenza vaccine has been used by FDA to infer effectiveness Adjuvanted influenza A subtype (e.g. H5) vaccines in development manufactured using the same process as the seasonal vaccine: Infer effectiveness from: –Efficacy data accrued with a U.S.-licensed seasonal influenza vaccine –Observational effectiveness data accrued with a non-U.S.-licensed adjuvanted H1N1 vaccine (same manufacturer and process) Influenza A subtype vaccines in development manufactured by a process that is not U.S.-licensed: –Pursue licensure of a seasonal vaccine: Use efficacy data accrued with licensed seasonal influenza vaccine to infer effectiveness –Do not pursue licensure of seasonal vaccine: Discussion needed regarding approaches to demonstrate effectiveness

37. 37 Discussion Items 1. To infer effectiveness of an adjuvanted pandemic influenza A subtype vaccine, please discuss the use of: a) clinical endpoint efficacy data accrued with a U.S.-licensed unadjuvanted seasonal vaccine made by the same manufacturer and process, and b) observational effectiveness data accrued during the H1N1 2009 pandemic for a non-U.S.-licensed adjuvanted monovalent vaccine made by the same manufacturer and process. 2. Please discuss approaches to infer effectiveness for pandemic influenza vaccines that are manufactured using a process not licensed in the U.S.: a) pandemic influenza vaccines dependent on an HA antibody response b) pandemic influenza vaccines with protective mechanisms that are not dependent on an HA antibody response

38. 38 Acknowledgements Marion Gruber Karen Farizo Carmen Collazo Brenda Baldwin Andrea James Melisse Baylor Lew Schrager Phil Krause Wellington Sun Sara Gagneten Hana Golding Douglas Pratt Jerry Weir Liz Sutkowski Deanna Shone Zhiping Ye Rakesh Pandey Bob Ball Michael Nguyen