Clinical Evaluation of Pandemic Influenza Vaccines in Children

1. Clinical Evaluation of Pandemic Influenza Vaccines in Children Vaccines and Related Biological Products Advisory Committee February 19, 2009

2. Agenda • Introduction and Background: Douglas Pratt • European Perspective: Bettie Voordouw • Subpart D: Additional Safeguards Skip Nelson for Children in Clinical Studies • Sponsor Presentations: • GlaxoSmithKline David Vaughn • Novartis Theodore Tsai • NIAID Richard Gorman • Discussion Points to the Committee

3. Overview • Background • Epidemiology of H5N1 • Definitions: Pandemic & Pre-Pandemic Vaccines • Pediatric Research Equity Act (PREA) • 21 CFR 50 Sub-part D • Age considerations for pandemic vaccines • Allocation priority in DHHS/DHS Guidance • Seasonal influenza recommendations • Summary of H5N1 vaccine studies in children • Safety considerations • Existing FDA Guidance • Preview of Discussion Points

4. H5N1: Epidemiology • Since 2003 World Health Organization (WHO) • 404 human cases of H5N1 (Feb 2, 2009) • 63% have been fatal • Most cases among people in contact with domestic poultry • All human cases have been in Asia or Africa • No avian or human cases of highly pathogenic H5N1 reported in Western Hemisphere

5. H5N1 Human Cases by Age(WHO: Weekly Epidemiological Record (WER) vol. 81; June 2006)

6. H5N1 Case Fatality Rate by Age(WHO: Weekly Epidemiological Record (WER) vol. 81; June 2006)

7. Pandemic Vaccine Indication • For the active immunization of persons: • at increased risk of exposure to an influenza virus that has the potential to cause an influenza pandemic, and • during a pandemic caused by the influenza virus subtype contained in the vaccine To be used under an emergency declared by the U.S. Secretary of HHS under Section 319 of the PHS Act

8. Pre-Pandemic Vaccine Indication • For active immunization of persons against an influenza virus subtype(s) that has the potential to cause a pandemic as a strategy for pandemic influenza preparedness. • for use in the inter-pandemic period before a pandemic is declared • for population priming and boosting

9. Pediatric Research Equity Act (PREA) • Enacted 2003, renewed in 2007 with FDAAA • To assure children have access to safe and effective drugs through proper testing for pediatric use • Pediatric assessment for all relevant pediatric populations required in applications or supplements for new: • active ingredient, indication, dosage form, dosing regimen, or route of administration

10. Pediatric Research Equity Act (PREA) • Pediatric assessment should contain data from pediatric studies for each age group for which the assessment is required • Data should be adequate to assess: • safety and effectiveness for claimed indications in all relevant pediatric subpopulations • dosing and administration

11. Pediatric Research Equity Act (PREA) FDA reviews assessments and determines if additional studies in children are needed. Based on specific provisions in the law, FDA may conclude that: • The assessment is adequate to support safety and effectiveness in all age groups; • Findings in the assessment can be extrapolated from adults or between age groups, if the course of the disease and the effects of the drug (vaccine) are sufficiently similar; • Additional studies are deferred, and provided at an agreed upon date; • Additional studies are waived, and will never be requested • necessary studies are impossible or highly impracticable • evidence that product is unsafe or likely ineffective in children

12. U.S. Licensed Pandemic Vaccine: Sanofi Pasteur Influenza Virus Vaccine, H5N1(for National Stockpile) • INDICATION: Active immunization of persons 18 through 64 years of age at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine • DOSAGE AND ADMINISTRATION:Two 1 mL (90 μg) intramuscular injections, a 1 mL dose given on day 1 followed by another 1 mL dose given approximately 28 days later (window 21 to 35 days)

13. U.S. Licensed Pandemic Vaccine: Sanofi Pasteur Influenza Virus Vaccine, H5N1(for National Stockpile) • Pediatric studies required under PREA were deferred • Deferred status to be reassessed upon review of the data from a completed pediatric study • Commitment to submit data to assess safety, reactogenicity and immunogenicity of Influenza Virus Vaccine, H5N1 administered in children • Protocol submission: randomized, double-blinded, phase I/II, study of the safety, reactogenicity, and immunogenicity of H5N1 vaccine in healthy children aged 2 years through 9 years

14. Additional Safeguards for Children in Clinical Investigations • 45 CFR part 46 (Subpart D) • Adopted in 1983 • Applies to federally funded research • 21 CFR part 50 (Subpart D) • Adopted in 2001 • Applies to all FDA regulated research

15. Additional Safeguards for Children in Clinical Investigations Subpart D: Clinical investigations involving children can be approved by an Institutional Review Board (IRB) only if the clinical investigation: 50.51 Does not involve more than minimal risk, or 50.52 Presents the prospect of direct benefit for the individual subject, or 50.53 The risk represents a minor increase over minimal risk, and Is likely to yield generalizable knowledge about the subject’s disorder or condition

16. Additional Safeguards for Children in Clinical Investigations Subpart D: Clinical investigations involving children not otherwise approvable, but 50.54 Present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children An IRB cannot approve research under this provision but must refer it to the FDA Commissioner for panel review. The Pediatric Advisory Committee serves as the reviewing panel if studies are referred under 50.54.

17. Historical Perspective:Smallpox Vaccine Study in Children • In 2002 a clinical trial of a live vaccinia smallpox vaccine in children 2-5 years of age was sponsored by NIAID • 2 IRBs approved the trial • I IRB referred the trial for panel review under Subpart D • Lack of prospect of direct benefit cited • Panel of 10 experts organized by OHRP provided written opinions regarding approvability of the study • Panel found that the research was approvable • Most agreed that the research provided opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (i.e., approvable under 21 CFR 50.54). • Ultimately, study not conducted • other means of addressing vaccine availability pursued by HHS

19. DHHS & DHS: Guidance on Allocation and Targeting Use of Pandemic Influenza Vaccine during a Severe Pandemic • Tier 1 • Pregnant women • Infants & toddlers 6-35 months of age • Tier 2 • Children 3-18 years with high risk medical condition • Household contacts of infants < 6 months of age • Tier 3 • Children 3-18 years without high risk medical condition

20. ACIP: Seasonal Influenza Vaccine Recommendations 2009MMWR: January 2, 2009 / 57(51);Q-1-Q-4 • Minimum age • 6 months for trivalent inactivated influenza vaccine • 2 years for live, attenuated influenza vaccine • Administer annually to children aged 6 months-18 years. • Children receiving TIV should receive • 0.25 mL if aged 6-35 months, or • 0.5 mL if aged 3 years or older. • Administer 2 doses (separated by at least 4 weeks) to children aged younger than 9 years who: • are receiving influenza vaccine for the first time, or • were vaccinated for the first time during the previous influenza season but only received 1 dose.

21. Summary of Pandemic Influenza Vaccine Studies in Children

22. Pandemic Influenza Vaccines: Safety Considerations for Pediatric Trials • Larger antigen doses may be required than for seasonal inactivated influenza vaccines • May contain a novel adjuvant • e.g., MF-59 or ASO3 • Not components of any US-licensed vaccine (though in some vaccines approved in Europe) • No long term, extensive record of safe use in US • Theoretical concern: non-specific, self-directed immune responses might be stimulated • No serious safety issue identified based on published data • Live pandemic influenza vaccines pose risks associated with replication, shedding, transmission, reassortants

23. “It is anticipated that data will be collected in adults and in the pediatric population in a step-wise fashion. We assume that approval for use in the adult population, including the geriatric population, would be sought with the initial application…

24. …The amount of data needed for a particular sponsor’s pandemic influenza vaccine to support approval for use in the pediatric population will depend on available clinical data for that sponsor’s U.S. licensed seasonal influenza vaccine…

25. …The timing of the clinical development in the pediatric population warrants discussion with CBER.”

26. Summary (1) • Children of all ages are at risk for pandemic influenza • Avian influenza (H5N1) has infected and killed children in Asia and Africa • The timing, subtype, and clade/strain of the next influenza pandemic are not known • PREA promotes proper testing to assure products are safe and effective for pediatric use • extrapolation of data from adults, and across age groups, can address PREA requirements, if disease and effects of vaccine are similar • Subpart D provides an ethical framework for conducting clinical investigations in children

27. Summary (2) • Seasonal influenza vaccine recommended dose and schedule depend on age of child • DHHS/DHS Guidance on allocation of Pandemic Vaccine during a severe pandemic place: • infants and toddlers (6 - 35 mos of age) in Tier 1 • children 3-18 years in Tier 3. • Multiple manufacturers are investigating H5N1 vaccines in children • Age groups being evaluated vary among manufacturers

28. Summary (3) • Novel adjuvants used in some pandemic vaccine candidates lack extensive safety experience in children • Existing FDA Guidance regarding pandemic influenza vaccine development for children does not address: • vaccines without a corresponding licensed seasonal vaccine • specific age groups to be studied • live, attenuated vaccines

29. Discussion 1. Please discuss whether clinical studies in one or more pediatric age group should be conducted using inactivated pandemic influenza vaccine candidates as part of pandemic preparedness. a. If your recommendation is that no clinical studies in any pediatric age group should be conducted prior to use of an inactivated pandemic influenza vaccine in children, please discuss whether other data, if any, would be needed to support immunizing children in the event of an influenza pandemic.

30. Discussion 1. (continued) b. If your recommendation is that clinical studies should be conducted in one or more pediatric age groups prior to use of an inactivated pandemic influenza vaccine in children, please discuss your recommendations regarding: • Which pediatric sub-population(s) should be studied? • The adult safety and immunogenicity data needed to support proceeding to pediatric studies with inactivated pandemic influenza vaccine candidates. In your deliberations please consider: • Use of novel adjuvants • Additional viral subtypes other than H5N1

31. Discussion • Please discuss what pediatric safety and immunogenicity data you would consider adequate to support licensure of an inactivated pandemic influenza vaccine candidate for use in one or more pediatric populations. In your deliberations please consider: • Use of novel adjuvants • Other influenza viral subtypes in addition to H5N1