1. 1 Issues in Conduct of Catheter Related Infection (CRI) Studies Charles Knirsch, MD, MPH FDA Anti-infective Advisory Committee Meeting October 14, 2004

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3. 3 Epidemiology  >5 million CVCs inserted annually in US  >200,000 nosocomial bloodstream infections each year  Associated with significant morbidity and mortality  A medical need exists for an approved agent for CRI Mermel LA et al; CID 2001;32:1249-72

4. 4 Linezolid CRI Program Culture Sources *catheter site = catheter blood/tip/wound exudate  Multi-center, randomized, controlled Phase III study c/w CR-BSI Guidance (1999)  Estimated pooled microbiology in approximately 600 patients enrolled: u S. aureus 96 (16%) from catheter site* AND peripheral blood 84 (14%) from catheter site only u CNS (including S. epidermidis) 38 (6%) from catheter site AND peripheral blood 195 (33%) from catheter site only

5. 5 LINEZOLID - Phase III Studies ProtocolIndication (Comparator)# of Patients 31MRSA (vancomycin)460 33Inpatient CAP (cephalosporins)747 39AUS-Simple SST (clarithromycin)753 39EU-Simple SST (clarithromycin)332 48AInpatient HAP (vancomycin)396 51Outpatient CAP (cefpodoxime)540 54AVRE (600 vs 200 mg linezolid)145 55 Complicated SST (oxacillin/dicloxacillin)819 4192

6. 6 Size of Clinical Program for Concordant Micro Endpoint  Concordant = paired specimen from catheter and blood (CRBSI)  Statistical assumptions (  = 0.05,  =15, 80% Power, micro success rate 70%)  Equivalence Trial with 147 micro patients/arm u ~980 patients need to be entered per study with estimated 30% of patients evaluable u Current FDA CRBSI Guidance calls for 2 studies: 1960 patients

7. 7 Pfizer Experience - All US Sites CRI Program  24 US Sites  Enrollment : 7.6 % patients screened  Top 5 reasons for exclusion: u Previous antibiotic treatment > 24 hours u Infection, not catheter-related u Bacteremia-not Gram-positive pathogen u Premature removal of catheter u No local or clinical signs of catheter infection

8. 8 Screening Requirements to meet Concordant Micro Endpoint At 7.6 % entry rate: 25,654 patients need to be screened to achieve 1960 patients enrolled

9. 9 Suggestions to Improve Feasibility of CRI Studies  Allow >24 hours of anti-staphylococcal therapy  Apply different criteria for S. aureus than for CNS u 1 positive culture for S. aureus u > 2 for CNS with PFGE  Require one adequately powered study u Supportive data in relevant indication(s)

10. 10 Summary of IDSA CRI Definition  Catheter-related infection: an infection that involves the catheter at any point, including the intravascular, subcutaneous, and exit-site portions  CRI may or may not be accompanied by bacteremia Mermel LA et al; CID 2001;32:1249-72

11. 11 Catheter Related Infections  Septic Phlebitis  Exit-site infection  Tunnel infection  Pocket infection  Catheter Tip Infection Bloodstream infection Pearson ML, Infect Control Hosp Epidemiol 1996; 17:438 73.

12. 12 Bacteremia UTI Complicated IABD Meningitis Osteomyelitis CAP Endocarditis CRI CRI as an Indication cSSTI Modified from AIDAC Oct 1998

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14. 14 Issues in CRI Studies Summary  A well powered CRI study complimentary to an existing relevant indication addresses the medical need for a drug approval for CRI  Drug Development : Guidelines Implementation  Re-modeling the process  Continuous dialogue will help preserve innovation and allow a continuous supply of anti-infectives for the future