Workshop on Antimicrobial Drug Development

Workshop on Antimicrobial Drug Development FDA/IDSA/PhRMA Bacterial Meningitis November 20, 2002 John S. Bradley, MD IDSA Bacterial Meningitis Problems in Performing Studies • Decreasing numbers of children with invasive pneumococcal disease, including meningitis, in the US due to the increasing use of conjugate pneumococcal vaccine (CDC Active Bacterial Core surveillance, IDSA 2002) – Large scale clinical trials in children in the US are increasingly difficult • Increasing resistance in pneumococcus – Need fluoroquinolones if vancomycin resistance develops in pneumococcus (FDA AIDAC 1998) Bacterial Meningitis • Bacterial meningitis is a serious infection – Ineffective antibiotic therapy is not acceptable Bacterial Meningitis Clinical vs. Microbiological Endpoints • Clinical assessment in bacterial meningitis is largely a function of CNS inflammation and resultant vascular insufficiency and/or CNS damage • It is generally agreed that inflammation correlates with the presence of organisms in the subarachnoid space Bacterial Meningitis Clinical vs. Microbiological Endpoints • Microbiologic eradication of organisms should lead to resolution of inflammation – In defined patient populations, delayed sterilization may lead to increased neurological sequelae (eg, hearing loss in cefuroxime-treated children: Lebel et al 1989 J. Pediatr; Schaad et al 1990 NEJM) – Adjunctive therapy which targets inflammation (dexamethasone) may lead to improved outcomes (eg, hearing loss in H. influenzae, type b meningitis) Bacterial Meningitis Clinical vs. Microbiological Endpoints • Clinical outcomes in children may vary by country, using the same protocol to treat the same organisms at all study sites (meropenem meningitis trial in the Americas; Odio et al 1999 Pediatr Infect Dis J) – Access to medical care, time to presentation, and critical care resources available to children may all vary by study site, complicating the interpretation of clinical endpoints which may have little to do with microbiological efficacy Bacterial Meningitis Clinical vs. Microbiological Endpoints • Clinical (neurological/audiological/developmental) response endpoints are global (death, severe sequelae, mild sequelae, cure) • Clinical endpoints are vague (“the criteria for judging the severity of neurological sequelae should be provided in the protocol”) • Vague clinical outcome endpoints may lead to differences in interpretation, particularly by country • Differences in qualifications of evaluators may vary at each worldwide study site (neuro, audio, developmental) • No standardized, cross-cultural, multi-lingual developmental scoring system currently exists. Bacterial Meningitis Clinical vs. Microbiological Endpoints • A solution: microbiological endpoint at 36-48 hours – Microbiological efficacy rates higher than clinical efficacy rates – Can be standardized across all multinational study sites – Quantitative cultures? Bacterial Meningitis Clinical vs. Microbiological Endpoints • We have greater sophistication at prediction of microbiological endpoints, based on PK/PD data from infection models – Data collected in children can be correlated with CSF PK/PD data from animals (AUC:MBC as the PD “driver,” McCracken 2000 Clin Infect Dis; McCracken 2001 Antimicrob Agents Chemother) Bacterial Meningitis Clinical vs. Microbiological Endpoints • Disadvantages of a microbiological endpoint – Not all children entered into the study will have positive CSF cultures (some will have positive blood cultures with a CSF pleocytosis): fewer evaluable patients – up to 50% less – Might an early microbiological time point favor antibiotics which have concentration-dependent killing? – Is rapid killing (with release of cytokines) the most desirable antibiotic effect? Bacterial Meningitis Clinical vs. Microbiological Endpoints • Secondary clinical endpoints still important – Rates of neurological sequelae and developmental delay can be correlated with previous publications to give insight into the pathogenesis of meningitis by organism, by study site, by level of care provided and by adjunctive therapy – Blinding of treatment arms particularly important for “soft” neurological outcomes (developmental delay, mild motor dysfunction) – Safety assessments for drug toxicity Bacterial Meningitis Clinical vs. Microbiological Endpoints • Secondary clinical endpoints still important – Inclusion criteria to keep children in study beyond initial 48-72 hr may be strengthened to obtain a more consistent population (eg, based on a neurological assessment score, GCS) – Clinical endpoints should be better defined (anatomic assessment, developmental assessment, functional assessment) Bacterial Meningitis The “Delta” • For serious infections, a delta of 10% may be appropriate, particularly applied to a microbiological endpoint, where efficacy is typically 90-95% • For clinical endpoints, treatment “success” (cure plus minor sequelae) rates of 70-75%, a 10% delta is unrealistic in terms of patient enrollment • Only 50% of children treated with meropenem/cefotaxime (Odio 1999) or trovafloxacin/ceftriaxone (Saez-Llorens 2002) were “cured;” 20-25% had mild sequelae • “Biocreep” less likely in future comparative trials if a microbiological endpoint is used • Consideration of different deltas for microbiological and clinical endpoints (Powers, FDA) Bacterial Meningitis Clinical Endpoints To Be Defined • Neurological: are deficits present? – Which systems? • Motor • Cognitive • Hearing – How profound? How to score? • Developmental delay: are deficits present? – Which standardized tests for which age groups? – Qualifications of those administering tests? • Functional assessment: do the deficits interfere with activities? – At home? At school? To what degree?