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Issues in Conduct of Catheter Related Infection (CRI) Studies

Issues in Conduct of Catheter Related Infection (CRI) Studies. Charles Knirsch, MD, MPH FDA Anti-infective Advisory Committee Meeting October 14, 2004. Epidemiology. >5 million CVCs inserted annually in US >200,000 nosocomial bloodstream infections each year

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Issues in Conduct of Catheter Related Infection (CRI) Studies

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

  2. 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

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

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

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

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

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

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

  9. 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

  10. 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.

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

  12. 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

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