# Presentation: 823574

## Clinical Trial Design for Mild/Moderate CAP: A Drug Development Perspective

- Anti-infective Drugs Advisory Committee
- April 2, 2008
- Roger M. Echols, M.D.
- Chief Medical Officer
- Replidyne, Inc.
- Previous positions: V.P. Clinical R&D – Infectious Diseases, Bristol Myers Squibb 1997 – 2004
- 			Medical Director – Anti-Infectives, Miles/Bayer 1989 - 1996

## Points to Consider

- CAP is a continuum of disease from mild to severe
- Fine Class does not define infection severity, it’s a predictor of 30 day mortality
*S. pneumoniae* is a leading cause of CAP for all Fine Classes
- Untreated CAP does not get better quickly
- Non-inferiority margins can be determined using clinical response, not just mortality
- Historical data
- Contemporary trials showing superiority
- If treatment benefit (M1) is large, what matters most is M2 which is based on clinical judgment

## Superiority Trials in CAP not Feasible

- 1992 FDA’s “Points to Consider”
**Placebo control**: “ethically unacceptable not to treat infected patients when therapy is available”
**Active control**: “high cure rates make it nearly impossible or impractical for a new antimicrobial drug product to demonstrate statistical or clinically relevant superiority to an approved comparator agent”
- Recent experience with placebo controlled studies in AECB and ABS - reasons for rejections:
- placebo (even with rescue therapy) conflicts with treatment guidelines
- Without comparator, study of no value (unethical)

## Clinical Trial Experience in CAP 2000-2002

- Dataset of 7 CAP trials conducted globally: N=2128 subjects
- 6 NI studies: 2 oral Rx only; 2 IV/PO; 2 optional IV/PO or oral
- 1 uncontrolled CAP oral Rx only
- All subjects characterized by Fine Class
- 2 oral Rx only studies restricted to Fine Class 1-2; no restrictions for other studies
- Microbiology included 1257 typical pathogens; 810 atypical pathogens
- Fine Class distribution:
- Class 1 = 46%
- Class 2 = 32%
- Class 3 = 13%
- Class 4 = 8%
- Class 5 = 1.5%

**78%**

## Distribution of Respiratory Pathogens by Fine Class – Clinical Trial Experience

| No. of Pathogens/Total Pathogens (%)a |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  |  | Fine Class |  |  |  |
| 
Pathogen | I
N=976b |  | II
N=674b | III
N=272b | IV
N=175b | V
N=31b |
| Total Pathogens | 944 |  | 656 | 250 | 131 | 29 |
| S. pneumoniae | 154 (16) |  | 111 (17) | 57 (23) | 24 (18) | 7 (24) |
| H. influenzae | 90 (10) |  | 72 (11) | 25 (10) | 16 (12) | 5 (17) |
| S. aureus | 98 (10) |  | 51 (8) | 17 (7) | 12 (9) | 3 (10) |
| M. catarrhalis | 17 (2) |  | 22 (3) | 11 (4) | 5 (4) | 2 (7) |
| Other Gram-positive | 60 (6) |  | 60 (9) | 16 (6) | 7 (5) | 4 (14) |
| Other Gram-negative | 109 (12) |  | 110 (17) | 38 (15) | 18 (14) | 2 (7) |
| M. pneumoniae
C. pneumoniae
L. pneumophila | 270 (29)
96 (10)
50 (5) |  | 108 (16)
68 (10)
54 (8) | 32 (13)
12 (5)
12 (5) | 20 (15)
11 (8)
11 (8) | 3 (10)
3 (10)
0 (0)
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**a**-percentages are based on the total number of pathogens in each Fine Class Category
**B**** – N=number of subjects in each Fine Class**

## Large Mortality Benefit of Chemotherapy in Pneumonia (CAP) - Historical Data

- Evans, G.M. and Gaisford W.F. - 1938 _Lancet_
- 200 cases of “lobar pneumonia” admitted March - June 1938
- Not randomized, treatment allocation based on admission ward
- Variable dosing with 2-(*p-*aminobenzenesulphonamide) pyridine (sulfapyridine)
- Case mortality rate - treated (n=100) - 8%
-  		          untreated (n=100) - 27%

- Evans, G.M. and Gaisford W.F. - 1938 _Lancet_, pages 14-19

## Rapid Clinical Response to Chemotherapy in CAP - Historical Data, Flippin, et al. 

- 100 cases – sulfapyridine only (25 grams total)
- All serotyped *S.pneumoniae* (8 with bacteremia)
- Case mortality – 4% (3/4 Type III)
- Temperature response:
- 24 hours – 46%
- 48 hours – 37%
- 120 hours – all patients
- Summary: “a conspicuous effect of the drug seemed to be its ability to bring about, within twenty-four to forty-eight hours, a critical drop in temperature followed by prompt clinical improvement”

**83% **_**<**_** 48 hours**

- Flippin, H.F. et al. JAMA, 1939; 112:529-34

## Untreated Pneumococcal Pneumonia – Response by Crisis

**Untreated Pneumococcal Pneumonia – Response by Crisis**
**Cecil, R, Textbook of Medicine, 1942**

**Temp**
**Pulse**

## Pneumococcal Pneumonia – Response to Sulfapyridine 

**Pneumococcal Pneumonia – Response to Sulfapyridine **
**Cecil, R, Textbook of Medicine, 1942**

## Historical Data – Clinical Response

- Bullowa dataset from *Management of the Pneumonias*, 1937
- Cohort of 662 untreated patients with *S. pneumoniae* pneumonia who spontaneously recovered (survived)
- Day of initial response or “crisis” recorded: mode day 8-9, only 3% by day 3; 14%>2 weeks
- Agranat study from *The Lancet*, 1938
- Four hospitals in S. Africa; 550 patients
- Treatment allocated by admission ward
- Day of “pyrexia termination” recorded: at day 3, 70% vs. 15% responded

## Initial clinical response in untreated patients (N=662) with confirmed pneumococcal pneumonia*

- ***Adapted from Bullowa, 1937**

- % of patients

- days

## Large Treatment Benefit in Clinical Response Observed with Sulfapyridine in 1938

- days

- % of patients

**Adapted from Agranat et al., 1938**** **

** *********Difference @ day 3**
** ****55.6% with**
**95% CI (48.5%, 62.7%)**

*****

**Time to pyrexia termination among sulfapyridine treated or untreated patients (N=550) with community acquired pneumonia, South Africa 1938**

## Measuring Clinical Response in CAP

- Post treatment physician assessment
- global response, takes into account early relapse
- established dataset for comparison
- Patient Reported Outcome (PRO)
- Lamping et al is not a PRO, it’s a patient questionnaire
- Not sensitive to differentiate between active treatments
- No historical data upon which to base a NI margin

## CAP Symptom Questionnaire Score Does Not Discriminate: CAP 2000 Study

**CAP Symptom Questionnaire Score Does Not Discriminate: CAP 2000 Study**

**Standard treatment**

**Moxifloxacin**

**Score**

- 	Source: Table 5 in Effectiveness of oral moxifloxacin in standard first-line therapy in community-acquired pneumonia, Eur Respir J 2003; 21:135-143 (Torres et al.)

## A New Primary Endpoint in CAP

- Composite clinical response that captures:
- Early response @ 72 hours
- Objective measures, i.e. temperature, WBC, respiratory rate, cough
- Confirmed by TOC clinical response
- Mortality = failure
- Represents physician assessment with objective criteria
- Minimizes individual investigator bias
- Includes early clinical response
- Captures historical evidence of treatment benefit

## Superiority Trial in Mild/Moderate CAP: Levofloxacin vs. Ceftriaxone/cefuroxime

- Multicenter, prospective, randomized, open label
- Levofloxacin 500 mg q.d. (IV or PO) x 7-14 days
- Ceftriaxone (1 or 2 gram) q.d. or cefuroxime 500 mg bid x 7-14 days
- Patients ambulatory or hospitalized
- Diagnosis:  sputum and blood culture, DFA and urinary antigen for *L.* *pneumophila*, serology for atypicals
- 590 patients (295/arm): 53% outpatient; 84% mild–moderate infection
- Levo: 61% oral only	cef/cef: 50.4% oral only
_**Population**__**	**__**Levofloxacin**__**	**__**Cef/Cef **__**	**__**Diff**__**	**__**95% CI**_
- Clinical Eval1	95%		83%   		12%	(6.2, 18.6)
- Micro Eval1	96%		80%  		16%	(7.4, 23.5)
- 1. FDA. Medical Officer’s review, NDA 20-634 Levaquin Tablets. 1996

## Defining the NI Margin – M2 and Clinical Judgment

- Evidence exists for large treatment benefit for clinical response
- M1> 50% for early clinical improvement
- If large treatment benefit, M2 should be based on clinical judgment: “how much less effective than standard of care is clinically acceptable?”
- A new drug that is “not much worse than” standard of care may have advantages
- Treatment of resistant pathogens
- Better safety or tolerability
- Improved compliance
- Decrease pressure for resistance to current drugs
- All about benefit-risk, i.e. clinical judgment

## What Population for Analysis?Impact on Sample Size

- FDA prefers “co-primary” analysis for NI trials
- Previously: Clinically evaluable (CE) and ITT
- Currently: CE and mITT (ITT with positive micro)
- Clinically evaluable population ~ 85% of enrolled subjects
- mITT ~ 30-35% for typical pathogens
- Study powered for CE population @10%∆: N=484
- Study powered for mITT population @15%∆: N=556						(if 10%∆: N=1172)
- Two studies required for approval of CAP

## Mild/Moderate CAP – An Industry Perspective

- CAP is a continuum of disease
- Superiority trials in mild/moderate CAP
- placebo not possible
- active control high risk, unethical if use substandard Rx
- Non-inferiority margin can be determined using clinical judgment and statistical reasoning
- Impact on drug development
- population for analysis impacts sample size
- CAP only one indication, but “anchor” for RTI indications
- Study design clarity and acceptable feasibility is critical.  Without clarity investment in new antimicrobials will diminish further