1. CLINICAL EFFICACY Oral Telithromycin George Rochester, PhD, CCRN Statistical Reviewer Division of Biometrics III Division of Anti-infective Drug Products rochesterg@cder.fda.gov

2. 2 Outline Phase III clinical database Censored data Clinical or bacteriologic efficacy by indication Overall conclusion

3. 3 Phase III Clinical Database by Type of Study and Indication

4. 4 Censored Data Four investigators were censored by the FDA. Total number of patients excluded were 186. Patients were excluded from all indications except T/P. Both FDA’s and Sponsor’s analyses excluded all subjects from the censored sites.

5. 5 Phase III Clinical Data Dosing of interest was for 5 days for AECB, AMS and T/P, and 7-10 days for CAP. All studies had a designated test-of-cure (TOC) window for assessing the clinical or bacteriologic response. TOC varied by indication but was always specified in the study protocol.

6. 6 Definition of Populations The primary efficacy populations for CAP, AECB and AMS are mITT and PPc. mITT: All randomized subjects who met disease definition and received at least one dose of study drug. PPc: mITT subjects minus those with major protocol violations.

7. Community Acquired Pneumonia

8. 8 CAP: Clinical Response -TOC TelithromycinComparators95% C.I. %(N)% (%) PPc 3001 1 95(149)90(152) (-2.1, 11.1) 3006 2 88(162)88(156) (-7.9, 7.5) 3009 3 90(80)94(86) (-13.6, 5.2) mITT 3001 86(199)79(205) (-0.5, 15.3) 3006 79(204)81(212) (-9.9, 6.5) 3009 82(100)86(104) (-14.7, 7.5) 1 Amoxicillin, 2 Clarithromycin, 3 Trovafloxacin

9. Acute Exacerbation Of Chronic Bronchitis

10. 10 AECB Definitions Inclusion: Documented history of chronic bronchitis, FEV 1 /FVC < 70% (tests made in the previous 12 months) Presentation:  cough,  sputum volume,  sputum purulence, and/or dyspnea Cure: resolution of all symptoms and no subsequent antimicrobial therapy at TOC

11. 11 AECB: Clinical Response -TOC Telithromycin 5 days Comparators 10 days 95% C.I. %(N)% (%) PPc 3003 1 86(115)82(112) (-6.4, 14.3) 3007 2 86(140)83(142) (-5.7, 12.4) mITT 300381(160)78(160) (-6.3, 12.6) 300778(182)72(191) (-3.5, 15.1) 1 Augmentin, 2 Cefuroxime axetil

12. ACUTE MAXILLARY SINUSITIS

13. 13 Sinusitis: Clinical Response -TOC Telithromycin 5 day Comparators 10 day 95% C.I. %(N)% (%) PPc 3005 1 75(146)75(137)(-9.9, 11.7) 3011 2 85(189)82(89)(-7.1, 13.4) mITT 3005 70(201)68(202)(-8.2, 10.9) 3011 80(240)72(116)(-2.2, 18.2) 1 Augmentin, 2 Cefuroxime

14. GROUP A  -HEMOLYTIC STREPTOCOCCAL TONSILLITIS/PHARYNGITIS

15. 15 T/P: Regulatory Considerations Penicillin is the gold standard comparator Primary efficacy is based on microbiologic eradication Any product with an absolute eradication rate of < 85% in the PP population should not be considered first line therapy

16. 16 T/P: Conclusion T/P is a mild disease Targeted population is typically children Many alternative therapies Insufficient evidence of activity against erythromycin resistant S. pyogenes Risk/Benefit must be considered

17. 17 Overall Conclusion FDA’s efficacy analyses are consistent with those of the applicant. Adequate, well-controlled trials must demonstrate safety and efficacy.