Microbiologic Surrogate Endpoints in Clinical Trials-IDSA FDA/IDSA/ISAP Workshop April 15, 2004

1. Microbiologic Surrogate Endpoints in Clinical Trials-IDSAFDA/IDSA/ISAP WorkshopApril 15, 2004 Sheldon L. Kaplan, MD Baylor College of Medicine Texas Children’s Hospital Houston, TX

2. Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

3. Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

4. Infections For Which Microbiologic Surrogate EndpointsAre Useful for Clinical Trials • Group A streptococcus pharyngitis • Uncomplicated lower urinary tract infection • Shigella gastroenteritis

5. Infections For Which Microbiologic Surrogate EndpointsAre Useful for Clinical Trials • Group A Streptococcus Pharyngitis -symptoms will resolve regardless of therapy; time to resolution can be compared -suppurative and non-suppurative complications occur too infrequently to use as endpoints

6. Infections For Which Microbiologic Surrogate EndpointsAre Not Useful or Unproven for Clinical Trials • Skin and skin structure infections • Pneumonia • Acute hematogenous osteomyelitis or septic arthritis • Intra-abdominal infections • Viral meningitis or encephalitis

7. Infections For Which Microbiologic Surrogate EndpointsAre Not Useful or Unproven for Clinical Trials • Sites of infection are difficult to resample in order to document microbiologic eradication • Lack of eradication of the organism may not equal clinical failure-VAP and tracheal aspirates • Eradication of organism may not equal substantial clinical benefit-URI and pleconaril

8. Infections For Which Microbiologic Surrogate EndpointsMay be Useful for Clinical Trials • Bacterial meningitis • Acute otitis media and sinusitis • VP shunt infections • Coagulase-negative staphylococcus line-associated bacteremia • Pertussis

9. Antimicrobial Drug Development for Acute Bacterial MeningitisJoint FDA/IDSA/PhRMA Workshop Imo Ibia, MD, MPH Medical Officer FDA/CDER/DSPIDP November 20, 2002 Office of New Drugs IV Center for Drug Evaluation and Research www.fda.gov

10. Outcomes • Are there data to show bacteriologic outcome is a good surrogate for clinical outcome? • Would bacterial endpoint alone miss the potential differential effect of drugs on inflammatory response? • How should clinical success/failure be defined and what should constitute the primary efficacy population? • ITT or evaluable? • How best can preclinical and early phase clinical trial data be used in meningitis trials to help address some of these issues? Imo Ibia 2002 FDA/IDSA/PhRMA Workshop 2002

11. Evaluations • Timing of repeat lumbar puncture • Is there data to establish the best time? • What factors could impact that time and how should they be factored in? • organism, baseline quantity, drug, host factors • How many organisms in repeat LP constitute delayed sterilization and what is its utility in trials? • Few and patient improving, optional (IDSA 1992) • Quantification of baseline CSF pathogens • How feasible and consistent across multinational sites? Imo Ibia 2002 FDA/IDSA/PhRMA Workshop 2002

12. Outcome of Bacterial meningitis • IDSA Guidelines 1992: Endpoints of -cure -survival with mild neurologic sequelae -survival with severe neurologic sequelae (somewhat dependent on the observer and some sequelae improve with time) -death • Mortality is low in US • Audiology testing is an objective and quantifiable measure • As with other sequelae, hearing loss may improve over time

13. Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children • Prospective, randomized multicenter study • Ceftriaxone (n=53) or cefuroxime (n=53) • Repeat CSF culture at 18-36 hours • No significant differences in clinical characteristics between the groups at enrollment Schaad et al N Engl J Med 1990;332:141-7

14. Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children Schaad et al N Engl J Med 1990;332:141-7

15. Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children • Hearing loss for H. influenzae type b Ceftriaxone-2/27 (7%); Cefuroxime-6/35 (17%) • 2 of 6 children who had hearing loss after cefuroxime therapy for Hib had delayed sterilization of the CSF i.e. 4 did not have delayed sterilization of CSF Schaad et al N Engl J Med 1990;332:141-7

16. Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children • Hearing loss for S. pneumoniae Ceftriaxone-0/7; Cefuroxime-2/6 None with hearing loss due to S. pneumoniae had delayed CSF sterilization Schaad et al N Engl J Med 1990;332:141-7

17. Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children Sensitivity-90/99=91% Specificity-2/7=29%

18. Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children • Four prospective studies conducted in Dallas-last 3 were dexamethasone trials. None of the studies were direct comparisons • Ceftriaxone-174; Cefuroxime-159 • No significant differences between the groups at initiation of therapy Lebel et al J Pediatr 1989;114:1049-54

19. Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children Lebel et al J Pediatr 1989;114:1049-54

20. Meropenem vs Cefotaxime for Bacterial Meningitis in Children

21. Trovafloxacin vs Ceftriaxone for Bacterial Meningitis in Children

22. Conclusions • Not clear how well repeat CSF culture at 24-36 hours after initiation of treatment predicts hearing impairment or overall outcome (vast majority of patients with severe sequelae have sterile 2nd CSF) ● Not clear if findings for Hib meningitis are applicable to pneumococcal or meningococcal meningitis