# Presentation: 055995

## Issues in Antibacterial Clinical Trials for Nosocomial Pneumonia

- -PhRMA Antibiotics Working Group-
- Richard Gesser MD, Merck Research  Laboratories
- November 20, 2002

## Overview

- Background -
- HAP the disease
- HAP: recent antibacterial clinical trials
- Issues in HAP trial design
- diagnosis
- treatment
- outcome assessment
- logistics
- Questions for discussion

## Background - HAP the Disease

- Acute illness in pts with serious _active_ co-existing morbidity
_**all**_ pts with additional conditions requiring hospitalization or long-term care
- obscures diagnosis; limits enrollment; confounds efficacy & safety determinations
- Heterogenous population
- VAP vs non-VAP HAP, Nursing Home Acquired Pneumonia
- early-onset vs late-onset
- risk factors and severity
- Delta 1 difficult to quantify - clearly substantial benefit of antibacterial therapy for documented pneumonia
- Mortality high but variable, even with antibacterial treatment
- overall only ~50% crude HAP mortality attributable to bacterial pneumonia
- reflecting the underlying conditions - highest in VAP and with nonfermenting GNB

## HAP - relevant pathogens and spectrum of existing or potential antibacterial agents

**G- =Gram negative****	****	****`R` = “resistant”**
**G+ =Gram positive****	****	**** NF =non-fermenting**

_**anaerobes**_

_**aerobes **_

**`R`G+**

**G+**

**NF G-**

**`R` Enteric G-**

**Enteric G-**

**`R` NF G-**

## HAP - Recent double blind comparative pivotal trials - Enrollment-

- Study A: Drug A (broad spectrum agent) vs comparator (ciprofloxacin)
- 87 centers (US, Canada, Europe, Costa Rica)
- 264 patients treated; 34 with VAP
- 16 month enrollment (2/95-6/96)
- aztreonam, vancomycin, clindamycin or metronidazole as indicated
- approved 12/1998
- Study B: Drug B (Gram positive agent) vs comparator (vancomycin)
- 90 centers (N. Am, Europe, Lat Am, Israel, Austral., S. Africa)
- 396 patients treated; 110 with VAP
- 9 month enrollment (10/98-7/99)
- plus aztreonam  (optional if only G+), aminoglycoside as indicated
- approved 4/2000

## Recent double blind pivotal HAP trials-  FDA study populations -

## Issues which impact clinical trial design - Diagnosis -

- _Definitive_ diagnostic criteria for VAP in critically ill patients yet to be established
- clinical criteria
- fever, respiratory signs/symptoms, leukocytosis, purulent tracheal secretions
- radiologic criteria
- new or worsening alveolar density, air bronchogram
- micro criteria
- cultures results imprecise
- even when available, controversy exists as “best” method
- “invasive” vs “noninvasive”
- quantitative vs qualitative or semi-qualitative
- culture results influenced by prior antibacterials
- both quantitatively and qualitatively

## Issues which impact clinical trial design - Treatment -

- broad initial empiric antibacterial coverage standard of care
- cultures results generally not available to guide initial treatment
- inadequate initial coverage associated with increased morbidity & mortality
- difficult/impossible to cover all potential pathogens including resistant organisms
- empiric coverage should take into account major risk factors:
- duration of hospitalization and ventilation
- duration & spectrum of prior antibacterial Rx
- local microbiology/susceptibility

## Issues in clinical trial design - Outcome Determination -

- Primary assessment (VAP and nonVAP)
- subjective (blinded) assessment of post-treatment _clinical_ response - antibacterials no longer required
- sufficient time posttherapy
- complete resolution or return to baseline with resolution of acute sxs (fever, leukocytosis, sputum purulence)
- Micro assessments (VAP vs nonVAP)
- qualitative & quantitative results do not completely correlate with clinical response
- follow-up cultures often not obtained or justified in “cures”

## Issues in clinical trial design - Logistics -

- Large, multicenter, multinational clinical trials
- Study plan must be acceptable across many institutions and countries
- Study design must be acceptable to investigators, patients, and local IRB/ERC
- Take into account regional differences in susceptibilities, diagnosis and management of the disease
- procedures need to be standardized
- done by qualified personnel
- invasive procedures need to be justified as standard of care and/or improving outcome

## HAP - Questions

- _Diagnosis:_
- Can diagnostic specificity be increased and still maintaining broad applicability?
- without significantly impacting participation of study sites and enrollment of appropriate patients?
- Do culture results improve diagnostic specificity/sensitivity? What is the preferred approach to microbiologic diagnosis?
- Is one method truly “better” than another?
- If so, can it be applied universally and are methods reproducible from center to center, country to country?
- consequences of choosing one culture method over another

## HAP - Questions

- _Trial Design:_
- Most patients with rare emerging resistant pathogens have received exclusionary prior therapy (>24 hrs)
- How can studies be designed to include  these patients?

## HAP - Questions

- _Therapy_:
- How should  published guidelines for empiric treatment be incorporated into antibacterial clinical trials?
- Does initial empiric anti-pseudomonal coverage need to be “double”?
- In what circumstance is empiric MRSA coverage required?
- Can new anti-pseudomonal agents be studied as mono-therapy in HAP?
- Avoiding  “bio-creep”
- What are key properties of  licensed agents/regimens considered appropriate comparators?

## HAP - Questions

- _Outcome (VAP and nonVAP)_:
- What is the most appropriate primary outcome variable?
- Clinical? Microbiological? Other?
- Should follow-up cultures be obtained in patients other than those clinically failures?
- Are there reliable culture methods such that follow-up “eradication” could be used as the primary measure of effectiveness?
- invasive follow-up cultures cannot be justified in “cures”
- How should missing results be dealt with?
- How should patients be evaluated in cases of concomitant therapy overlapping the spectrum of the investigational agent?
- What criterion should be met to demonstrate “non-inferiority” of an investigational antibacterial?