# Presentation: 774129

## Hospital Acquired Pneumonia(HAP)Joint FDA/IDSA/PhRMA Workshop

- Sary Beidas, MD
- Medical Officer
- CDER/DSPIDP

- November 20, 2002

- Early

- Late

- 0

- 2-5

**Day**

- Prior Antibiotic Use

- 10

- EOT

_**Outcomes**_

_**Test-drug**_

- 7

- 21

- TOC

- Clinical
- Laboratory
- Microbiologic

- _Clinical_
- Cure
- Failure

- Microbiological*
- Isolating an organism?
- Preferred method (QET,FOB, BAL, other)?
- Quantification?

_**Inclusion:**_ Clinical, radiographic, & microbiologic criteria

- _Clinical:_ Temp, WBC, Sputum, <7 days after discharge
- _Radiographic_: new infiltrate, progressive infiltrate
- _Microbiologic*_: isolate an organism
- Risk Factors: ex- ET tube, underlying condition, age

## Definitions & Diagnosis

** **

## Are patients with VAP sufficiently different from other patients with HAP to warrant studying them separately?

**Definitions & Diagnosis**

## What is the best way to identify the etiologic pathogen?

- _Methods used to diagnose HAP_
*Craven & Steger. Infect Control Hosp Epidemiol 1997;18:783-795*
- Clinical
**CPIS**
- FOB: PSB or BAL
- Nonbronchoscopic BAL
- Quantitative Endotracheal Aspirate
- Transthoracic
- Autopsy

## Study Considerations:

- _Inclusion / Exclusion Criteria_
- Should patients already on ATBs be excluded?

- 0

- 2-4

**Day**

- 10

- EOT

- Admission

- Onset
**(Patient Enrollment)**

- Early

- Late

**Antibiotic Rx**

## Comparator

- Examples
- Linezolid + azt
- Levofloxacin + ceftaz

- Vancomycin + azt
- Imipenem/Cipro + amg

- When you study drugs in combination that have overlaping antimicrobial coverage, how do you know which one is exerting the effect you are looking for?

## Test Drug

- Should a drug without *Pseudo / Staph*. coverage be tested in HAP?
- Related issues:
*Kollef & Ward. Chest 1999;115:462-474*
- Survival is linked to early empiric Rx
- Empiric Rx is better guided if you know local resistance/susceptibility patterns.

## Outcomes / Endpoints

- <date/time>

**Outcomes / Endpoints**

- What _[endpoints](slide2.xml)_ should we be looking at ?
- Bacterial eradication
- Clinical cure
- Radiologic resolution
- Combination
- How do we define a failure / cure?

## Delta & Non-Inferiority

- Delta-1:
- Do we believe that the effect of drug over placebo is >20%?
- Delta-2:
- What is an acceptable loss of efficacy relative to a control for a serious illness like  HAP?

## Questions for Discussion-1:

- What is the best way to establish the diagnosis of HAP? Discuss the strengths & limitations of clinical criteria & quantitative microbiologic data obtained through various methods.
- Should VAP be studied separately from the other forms of HAP? Can a successful study of VAP support an indication for HAP?
- Are there inclusion/exclusion criteria (e.g.CPIS) that would help select for patients most likely to have HAP and therefore most likely to demonstrate a treatment effect? Have these methods been sufficiently validated?

## Questions for Discussion:

- What are the optimal characteristics of a test drug and a control drug for studies of HAP? For studies of VAP?
- Is the benefit of antimicrobial Rx over placebo (delta-1) sufficiently large (>20%) that the choice of a non-inferiority margin in active controlled trials of HAP should be based on the acceptable loss of efficacy relative to control (delta-2)? If so, what would be an acceptable loss of efficacy relative to control given the serious nature of the disease and the practicalities of performing clinical trials of HAP?