1. Microbiologic Surrogate Endpoints in Clinical Trials-IDSA FDA/IDSA/ISAP Workshop April 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

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

5. Infections For Which Microbiologic Surrogate Endpoints Are 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 Endpoints Are 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 Endpoints Are 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 Endpoints May 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 Meningitis Joint 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 VariableCeftriaxoneCefuroximeP value + CSF culture at f/up (all Hib) 1/526/520.112 Hearing loss2 (4%)9 (17%)0.052 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 HearingRepeat CSF sterile Repeat CSF positive Total Normal90595 Impaired9211 Total997106 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 VariableCeftriaxoneCefuroximeP value + CSF culture at f/up “Uniformly sterile” 14/157 (8.9%) < 0.001 Hearing loss16/148 (11%) 25/139 (18%) NS Lebel et al J Pediatr 1989;114:1049-54

20. Meropenem vs Cefotaxime for Bacterial Meningitis in Children End of Treatment Evaluable Meropenem N=79 Cefotaxime N=75 Cure36 (46%)42 (58%) Mild sequelae2120 Severe sequelae2010 2 nd CSF sterile75 (95%)72 (96%) 2 nd CSF delayed sterilization 2 Hib 1 Hib Odio et al Pediatr Infect Dis J 1999;18:581-90

21. Trovafloxacin vs Ceftriaxone for Bacterial Meningitis in Children End of Treatment Evaluable Trovafloxacin N=108 Ceftriaxone N=95 Cure53 (49%)57 (60%) Mild sequelae2821 Severe sequelae2013 Failure51 2 nd CSF delayed sterilization 53 Sáez-Llorens et al Pediatr Infect Dis J 2002;21:14-22

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 2 nd CSF) ● Not clear if findings for Hib meningitis are applicable to pneumococcal or meningococcal meningitis