【正文】 ts Finnish OM Study: Safety Analysis, Local and Systemic Reactions, First 3 Doses D o s e 1 D o s e 2 D o s e 3 Pn c C R M N = 8 2 5? % H BV N = 8 2 5? % p v a l u e1 Pn c C R M N = 8 1 8? % H BV N = 8 2 6? % p v a l u e1 Pn c C R M N = 8 1 7? % H BV N = 8 1 6? % p v a l u e1 F e v e r ? 38 ? C 1 4 . 3 9 . 3 0 . 0 1 1 8 . 4 1 2 . 7 0 . 0 1 2 3 . 5 1 3 . 3 0 . 0 1 F e v e r ? 39 ? C 0 . 4 0 . 2 1 1 . 0 0 . 5 0 . 3 8 2 . 0 0 . 5 0 . 0 1 C ry i n g i n c r e a s e d 4 1 . 6 3 6 . 4 0 . 0 3 4 2 . 0 3 2 . 9 0 . 0 1 3 9 . 6 3 0 . 6 0 . 0 1 C ry i n g 4 h rs 0 . 6 0 . 4 0 . 7 2 0 . 5 0 . 1 0 . 3 7 0 . 4 0 . 1 0 . 6 2 Pa i n 3 . 4 1 . 9 0 . 0 9 3 . 7 0 . 7 0 . 0 2 5 . 1 2 . 8 0 . 0 2 R e d n e s s (An y ) 1 4 . 2 9 . 3 0 . 0 1 1 6 . 0 1 2 . 6 0 . 0 6 2 0 . 0 1 5 . 9 0 . 0 2 ? 2 . 5 c m 0 0 . 1 1 0 . 2 0 . 2 0 . 6 2 0 . 4 0 . 0 0 . 2 5 Sw e l l i n g ( An y ) 4 . 7 1 . 7 0 . 0 1 4 . 0 3 . 0 0 . 1 6 4 . 8 3 . 6 0 . 1 9 ? 2 . 5 c m 1 . 0 0 . 1 1 0 . 9 0 . 4 0 . 3 3 0 . 5 0 . 2 0 . 6 8 ? N u m b e r o f s u b j e c t s m a y v a ry s l i g h t l y d e p e n d i n g o n r e p o rt s re c e i v e d . 1 P v a l u e b a s e d o n C h i s q u a r e t e s t . Finnish OM Study: Safety Analysis, Local and Systemic Reactions, 4th Dose D o s e 4 ( 1 2 m o n t h s ) P n c C R M N = 79 8? % HBV N = 79 8? % p v a l u e1 1 1 . 5 6 . 9 0 . 0 1 F e v e r ? 38 ? C ? 39 ? C 1 . 6 1 . 7 0 . 9 7 2 8 . 2 1 9 . 3 0 . 0 1 C r y i n g i n c r e a s e d C r y i n g 4 h o u r s 0 0 NA P a i n 7 . 5 2 . 3 0 . 0 1 1 4 . 7 1 4 . 4 0 . 6 0 R e d n e s s ( A n y ) ? 2 . 5 c m 0 . 8 0 . 0 0 . 0 4 4 . 9 5 . 4 0 . 8 3 S w e l l i n g ( A n y ) ? 2 . 5 c m 1 . 3 0 . 4 0 . 0 9 1 p v a l u s d e r i v e d f r o m C h sq u a r e t e st . ? To t a l n u m b e r m o n i t o r e d v a r i e d f r o m 7 7 1 7 9 8 , d e p e n d i n g o n n u m b e r o f co m p l e t e d r e p o r t s r e c e i v e d . Finnish OM Study: Safety Analysis, Conclusions ? Safety data are consistent with earlier observations regarding the safety of Prevnar ? Increased rate of lowgrade fever ? Complications of postvaccination fever were unmon ? No new safety concerns were identified Considerations Required Level of Efficacy The minimum level of efficacy required for licensure of a preventive vaccine is not specifically addressed by FDA regulations or published guidance. Considerations: Licensure of Other Pneumococcal Vaccines for Otitis Media ? AOM indication should stand on its own. ? License applications for new pneumococcal vaccines for prevention of AOM may not include evidence of efficacy for prevention of invasive disease. ? If approved, a level of efficacy, preferred endpoints, and type of data (number of trials) sufficient for approval for AOM would be established. ? Prevention of more AOM episodes with less vaccine serotypespecific efficacy is a possible scenario. Considerations: Description of the treatment effect ? Primary outes in NCKP study and Finnish OM study differ ? Prevention of AOM due to vaccine serotypes does not capture: ? Positive treatment effect on vaccinerelated pneumococcal serotypes ? Negative efficacy for unrelated pneumococcal serotypes ? Efficacy estimates relatively low for some outes ? Confidence intervals wide for some outes Considerations: Clinical benefit vs. economic benefit ? Substantial evidence of clinical benefit must be provided from adequate and wellcontrolled studies. ? Economic benefit is not considered in the efficacy evaluation by FDA. Considerations: Marketing Implications ? Promotional materials based on approved labeling ? Potential for unrealistic expectations ? FDA is empowered to restrict marketing claims: ? Advertisements and promotional labeling are reviewed by CBER ? Advertisements that are misleading (defined in 21 CFR ) can result in a product being misbranded. If a pany fails to correct such violations, CBER is empowered to take multiple corrective actions (21 CFR and ). Questions to the Committee 1. Are the data adequate to support the efficacy of Prevnar in infants and toddlers for prevention of otitis media caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F)? 2. If not, would additional analyses from the Finnish otitis media study, the Northern California Kaiser Permanente efficacy study, or additional clinical trials be useful in establishing efficacy? Questions to the Committee (cont.) 2. Please discuss the strength of the data with respect to secondary otitis media outes: a. Acute otitis media episodes caused by S. pneumoniae, regardless of serotype b. Overall reduction in acute otitis media episodes c. Frequent otitis media d. 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