1. FDA/Industry Statistics Workshop 2005 Parallel Session 6: Vaccine Trials 10:10 am – 11:30 am, Sept. 16, 2005

2. Co-Chairs: Jingyee Kou (CBER), William Wang (Merck) Panelists: FDA Statistician: Dale Horne (CBER) Academia Statistician: Lawrence Moulton (Johns Hopkins) Industry Statistician: Joseph Heyse (Merck) FDA Clinician: Douglas Pratt (CBER) Industry Clinician: Jill Hackell (Wyeth)

3. 3 Outline Vaccine Safety (1 topic) Vaccine Efficacy (3 topics) Vaccine Immunogenicity (3 topics) Other (1 topic)

4. 4 Vaccine Safety Topic Trial design for pre-licensure and post-licensure study Large safety trial to detect rare adverse reaction. How rare should the event be in the interest of the public health: e.g., 1/1,000 or 1/10,000? Long term safety trial to evaluate potential events with a long-latency pre-licensure (active reporting) versus post-licensure (voluntarily reporting, e.g VAERS )

5. 5 Vaccine Efficacy Topic 1 Estimation of indirect and total effects of vaccine Simple randomization vs Group randomization How should group randomization be used in vaccine development?

6. 6 Vaccine Efficacy Topic 2 Superiority vs super-superiority Study Hypothesis on Vaccine Efficacy (VE) is H 0 : VE 0 When is it enough for the lower limit 0 of the 95% CI to be 0 or close to 0, and when should it be set higher?

7. 7 Vaccine Efficacy Topic 3 How to evaluate vaccine effect on the incidence (randomized comparison) and severity (non- randomized comparison)? Vaccine might reduce the incidence of disease moderately, while reducing severity of the disease among breakthrough cases How should one assess the vaccine efficacy on both the incidence and the severity?

8. 8 Vaccine Immunogenicity Topic 1 Vaccine approval based only on immunogenicity Vaccine may induce strong immune responses that have not been demonstrated as correlates of protection Under what conditions is it appropriate to approve a vaccine based solely on immunogenicity?

9. 9 Vaccine Immunogenicity Topic 2 Selection of immunologic markers and non-inferiority margins Whats proper methodologies to establish immune responses (e.g, antibody level) as correlates of vaccine efficacy? Regression Analysis Proportion Explained Discriminant Analysis What factors should be considered in choosing delta (e.g. 10% vs 15% percentage difference on sero- response rate)?

10. 10 Vaccine Immunogenicity Topic 3 Immunogenicity evaluation with multiple serotypes Combination vaccine containing multiple serotypes How should one evaluate non-inferiority for all components?

11. 11 Other Topic Accelerated development strategy in vaccine development Critical path initiative for vaccine development How should one apply adaptive designs and Bayesian techniques in vaccine development?