Microbiologic Surrogate Endpoints in Clinical Trials

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 Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm Infections For Which Microbiologic Surrogate Endpoints Are Useful for Clinical Trials • Group A streptococcus pharyngitis • Uncomplicated lower urinary tract infection • Shigella gastroenteritis 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 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 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 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 lineassociated bacteremia • Pertussis 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 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 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 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 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 Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children Variable Ceftriaxone Cefuroxime P value + CSF culture at f/up (all Hib) Hearing loss 1/52 6/52 0.112 2 (4%) 9 (17%) 0.052 Schaad et al N Engl J Med 1990;332:141-7 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 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 Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children Hearing Repeat CSF sterile 90 9 Repeat CSF positive 5 2 Total Normal Impaired 95 11 Total 99 7 106 Sensitivity-90/99=91% Specificity-2/7=29% 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 Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children Variable Ceftriaxone Cefuroxime P value + CSF culture at f/up Hearing loss “Uniformly sterile” 16/148 (11%) 14/157 (8.9%) 25/139 (18%) < 0.001 NS Lebel et al J Pediatr 1989;114:1049-54 Meropenem vs Cefotaxime for Bacterial Meningitis in Children End of Treatment Evaluable Cure Mild sequelae Meropenem N=79 36 (46%) 21 Cefotaxime N=75 42 (58%) 20 Severe sequelae 2nd CSF sterile 2nd CSF delayed sterilization 20 75 (95%) 10 72 (96%) 2 1 Hib Hib Odio et al Pediatr Infect Dis J 1999;18:581-90 Trovafloxacin vs Ceftriaxone for Bacterial Meningitis in Children End of Treatment Evaluable Cure Mild sequelae Trovafloxacin N=108 53 (49%) 28 Ceftriaxone N=95 57 (60%) 21 Severe sequelae Failure 2nd CSF delayed sterilization 20 5 5 13 1 3 Sáez-Llorens et al Pediatr Infect Dis J 2002;21:14-22 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