# Presentation: 787791

## 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**** **

## Summary

**What are the strengths and limitations of bacteriologic and microbiologic endpoints?**
**What is an acceptable loss of clinical efficacy relative to control for meningitis trials?**
**What other issues of study design deserve consideration when designing a trial in meningitis? **

## What Are Current Issues in Drug Development for the Treatment of Meningitis?

## Outline

**Entry criteria (culture, Ag test, Gram stain)**
**Treatment (choice of comparator)**
**Timing of assessments (LP, follow up)**
**Endpoints (clinical, bacteriologic, other)**
**Population (children, adults, foreign data)**
**Statistics (study design, size, number, deltas)**

## Adjunctive Dexamethasone and Empiric Vancomycin 

- Kellner et al PIDJ 2002;21:903-9

## Protocol and Entry Criteria

**Study population**
**Separate protocol for neonates and young infants (1998 Draft Guidance Document)**
**Should older children and adults be enrolled in a single or separate protocol?**
**Impact of prior antibiotic therapy**
**What role, if any, should Ag testing Gram stain, and/or other non-culture based tests play in enrollment?**
**Should degree of diagnostic certainty be ranked?**

## Choice of Comparator

**Blinding challenges**
**Example: Trial with a two-drug arm Vs. a single agent  with IV-to-oral step down **
**What is the magnitude of the potential impact of sham infusions on patients who may have cerebral edema?**
**In this scenario are too many questions being sought in one trial?**

## 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?**

## Evaluations

**When should follow up evaluations be done and should all patients come for all visits?**
**5-7 wk, 6-12 mo for all (IDSA 1992)**
**2 wk (TOC), 6 mo for subset abnormal at 2 wk (AC meeting 1998)**
**Is there data on long term outcome of patients that are “normal” at the early visit?**
**Do late neurologic sequelae tell us anything about differences in drug efficacy in meningitis?**

## Outcomes

- X

- Y

- 95.0%

- 94.6%

- 72%

- 80.0%

- Bacteriologic

- Clinical

- Difference in Clinical Outcome (X-Y) = -8
- 95% CI of the Difference = -16.3, 2.5

## Outcomes

**Strengths of Clinical Endpoint**
**Relevant to patients and clinicians**
**Drug treats disease**
**Enables comparison of differences in host effects on cure rates**
**Allows a measure of safety**
**Limitations of Bacteriologic Endpoint**
**Potential for misleading appraisal of drug benefit in a serious disease **
**Often eradication is presumed from clinical response**
**Lacks ability to estimate impact of drug on inflammatory response**
**Uninformative about safety of test drug**
**No individual level data on correlation with clinical response**

## 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?**

## Study Design, Size, and Statistics

**How much evidence is needed to show efficacy in meningitis trials?**** **
**Should pivotal trials be randomized, active controlled, and blinded? **
**What role, if any, should non-comparative studies play?**
**Is a single trial sufficient by itself or is a confirmatory trial needed?**
**What are the appropriate non-inferiority margins and sample size?**

## Non-Inferiority Margins 

## Summary

**What are the strengths and limitations of bacteriologic and microbiologic endpoints?**
**What is an acceptable loss of clinical efficacy relative to control for meningitis trials?**
**What other issues of study design deserve consideration when designing a trial in meningitis? **