# Presentation: 699446

## Anti-Infective Drugs  Advisory Committee MeetingClinical Trial Designs for Community Acquired Pneumonia

**April 1 & 2, 2008**
**Edward Cox, MD MPH**
**Director, Office of Antimicrobial Products**
**OND/CDER/FDA**

## Welcome

**Welcome**
**Topic for discussion**
**Clinical trial designs for Community Acquired Pneumonia (CAP)**
**Primary purpose of the meeting**
**To seek the Advisory Committee’s advice on informative, safe, and ethical trial designs to evaluate the safety and efficacy of antibacterial drugs for the treatment of CAP**
**Work through the key parameters in the design of a CAP trial**
**Very interested to hear the scientific rationale, evidence relied upon and reasoning in arriving at recommendations for clinical trial designs for CAP **

## Background - 1

**Antibacterial drugs discovered many years ago**
**Represented a major advance in medicine**
**Antibacterial therapy incorporated into clinical practice before sophisticated clinical trial designs**
**Standard of care for CAP for years**
**Some of the information that tells us about effect of antibacterial drugs in CAP (compared to “no treatment”) is from literature from many years ago**

## Background - 2

**Science of clinical trials in New Drug Applications (NDAs) has also advanced**
**Microbiologically focused label**
**Respiratory tract infections (RTI)**
**composite data from a variety of RTIs**
**Lower respiratory tract infections (LRTI)**
**composite data ABECB & CAP**
**Community acquired pneumonia (CAP)**
**trials specific for CAP**
**noninferiority design w/ margin of 10 to 15%**
**margin choice based upon convention rather than clear justification based upon evaluation of available data**
**oral agents – mild to moderate severity**

## CAP Indication

**INDICATIONS AND USAGE**
**[Drug Name] is indicated in the treatment of infections caused by  susceptible strains of the designated microorganisms in the conditions listed below:**
**	****Community-acquired pneumonia**** caused by *****Streptococcus pneumoniae*****, *****Haemophilus influenzae*****, *****Staphylococcus aureus,***** *****Moraxella catarrhalis*****, *****Legionella pneumophila,***** *****Chlamydophila pneumoniae*****, or *****Mycoplasma pneumoniae***

## Some Drugs with a CAP or Related Indication

_**Microbiologically “focused”**_
**penicillin G, penicillin V, tetracycline, oxytetracycline, doxycycline, minocycline, demeclocycline, clindamycin, lincomycin, streptomycin**
_**Respiratory tract infections**_** ****(past indication - composite)**
**ampicillin, cephalexin, cefazolin**
**amikacin, gentamicin**
_**Lower respiratory tract infections**_** ****(past indication - AECB & CAP)**
**amoxicillin, amoxicillin/clavulanate, piperacillin, piperacillin/tazobactam, ticarcillin/clavulanate    **
**erythromycin**
**cefotaxime, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefaclor cefuroxime injection, **
**imipenem/cilistatin,        - aztreonam          - tobramycin**
**ciprofloxacin    - metronidazole ****(*****Bacteroides*****)**
_**Community-acquired pneumonia**_
**amoxicillin/clavulanate**
**cefdinir, cefditoren pivoxil, cefpodoxime proxetil, loracarbef, **
**azithromycin, clarithromycin, telithromycin**
**ofloxacin, levofloxacin, moxifloxacin, gemifloxacin, **
**linezolid**

## Importance & Challenges - 1

**Public Health need for new therapeutic options**
**antimicrobial resistance**
**Need informative trials to characterize safety and efficacy**
**weigh risks and benefits**
**Importance of having new drugs in this area also supports the importance of adequately characterizing safety and efficacy**
**Quality information to inform appropriate use**

## Importance & Challenges - 2

**Community acquired pneumonia**
** ****risk of progression or extension of infection**
**Clinical Trials of CAP should**
**not expose patients to significant risk**
**be informative**
**be ethical & acceptable **
**strategies to minimize risk**
**provisions for “rescue therapy”**
**patient selection**
**DSMB**

## Drug Product Approval

**1938: Federal Food, Drug and Cosmetic Act required pre-clearance of drugs for safety & pre-market notification but did not include evaluation of efficacy**
**1962: FDC Act amended to add requirement for demonstration of effectiveness based upon “substantial evidence”**
**“****Substantial evidence” defined in FDC Act 505(d) as:**
**	****“****evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and ****	****experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”**** **

## Adequate and well controlled studies

- 	**21 CFR ****§**** 314.126 Adequate and well-controlled studies. (a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. **
**Active treatment concurrent control...**
**The test drug is compared with known effective therapy; for example, where the condition treated is such that administration of placebo or no treatment would be contrary to the interest of the patient. **
**If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity of test drug and active control can mean either that both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous placebo-controlled studies of the active control drug. **

## Active Controls & Noninferiority - 1

**(e.g. placebo)**

**Active Controls & Noninferiority - 1**

**Test**

**Active Control**

**Response rate**

**Case# 1:  Large treatment effect                      Low spontaneous resolution rate**

## Active Controls & Noninferiority - 2

**Active Control**

**Test**

**Active Controls & Noninferiority - 2**

**Inactive    (e.g. placebo)**

**Case #2: Unclear treatment effect                      High spontaneous resolution rate**

**Response rate**

## Active Controls & Noninferiority - 3

**Inactive**
**(e.g. placebo)**

**Active Control**

**Test**

**Active Controls & Noninferiority - 3**

**Inactive    (e.g. placebo)**

**Test**

**Active Control**

**Response rate**

**Case# 1:  Large treatment effect                      Low spontaneous resolution rate**

**Case #2: Unclear treatment effect                      High spontaneous resolution rate**

**Response rate**

## CAP Trials

**Quantitative estimate of the effect of the active control drug over placebo in a current day study based upon what we know from previously conducted studies**
**treatment effect**
**Treatment effect reflects the types of patients and how studied**
**severity of disease, type of disease**
**endpoint & timing of assessment**
**other factors**
**Accounting for uncertainty – discounting, judgments, rationale **
**Goal of informative trial designs**** **

## CAP Trials in NDAs

**Inpatient studies of CAP**
**Intravenous antibacterial drugs with or without an oral formulation (“step-down” therapy)**
**additional studies with the oral formulation typically done**
**Indication**
**CAP**
**Outpatient studies of CAP**
**Oral antibacterial drugs**
**Indication**
**mild to moderate CAP**

## Key Topics

**Review what we know and don’t know about CAP and issues in clinical trial design**
**treatment effect based upon available data**
**what population**
**what endpoint (when to assess)**
**other key parameters**
**Address key issues in clinical trial design for CAP & describe possible informative CAP trial designs**
**studies of IV drugs - -  studies of oral drugs**
**endpoints**
**what population**
**can noninferiority studies be done? **
**can superiority studies can be done?**

## Overview of the 2-Day Meeting

**Agenda – Day #1**
**IDSA/FDA CAP workshop**
**IDSA perspective**
**ATS/ACCP statement**
**Ethical considerations**
**Noninferiority trials in CAP**

## Overview of the 2-Day Meeting

**Agenda – Day #1 (continued)**
**Historical data on CAP**
**Contemporary CAP trials**
**Approaches to setting an NI margin**
**Exposure-Response analysis for CAP **
**Critical considerations in CAP trial design**
**Day # 2**
**A clinician’s scientific approach to pneumonia**
**Considerations in design of CAP studies**
**Questions and discussion**
**Questions for the AC**

## For questions 1 and 2:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- To rely on noninferiority studies for new drugs to treat CAP, we must be able to estimate the effect size a control drug would have on the primary endpoint used in the current trial. The Agency has presented information on the historical experience that suggest a reduction in mortality with point estimates ranging from 18 to 25% in the observational studies and from approximately 10 to 19% in controlled trials. These data are derived from patients with pneumococcal / lobar pneumonia.

## Question 1a:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- 1. 	Can these data be utilized to select a noninferiority margin for a contemporary CAP study for an IV drug in hospitalized patients?
- a)	To what severity of pneumonia or type of patients would it apply and how should severity be defined?

## Question 1b-1c:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- b)	Should a microbiological diagnosis be necessary for inclusion in the primary analysis population for the trial, and if so, what organisms should be included (e.g., *S. pneumoniae*, other microbes)?
-  c)	Should strategies be utilized to enrich the population for patients with a particular microbial etiology (e.g., *S. pneumoniae*, or other microbes)?

## Question 1d:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- d)  Please discuss whether the evidence which shows a treatment effect based on mortality can be linked to endpoints which are used in current non-inferiority CAP trials (i.e. clinical success/failure).  If so, how?  (Note: the possible components of the clinical failure endpoint might include some of the following mortality, receiving rescue therapy, lack of resolution of clinical signs and symptoms such that additional antibacterial therapy is administered, lack of resolution of signs and symptoms at the time the primary endpoint is assessed.)

## Question 1e:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- e) The historical evidence for a treatment effect is based on studies which evaluated penicillin, sulfonamides, and tetracyclines.  Given the need to preserve the treatment effect (the effect of the comparator agent over placebo or no treatment) in a future study, what are appropriate choices for comparator agents?  Please explain the basis and information that supports the recommendation for comparator agents for a future study.

## Question 1f:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- f) 	What is your best estimate of the treatment effect size (M1) that the historical data support for treatment of hospitalized CAP (based on severity selected in part a of this question, above) in a future CAP trial and what is your recommendation for a noninferiority margin that preserves a portion of the treatment effect (i.e., M2) for a CAP trial in this population with the endpoints discussed above?

## Question 2:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- 2.	Given the information presented, mostly from historical data on the treatment effect of drugs for CAP in patients with pneumococcal / lobar pneumonia, please address the following questions on trials of outpatient CAP (studies using an oral drug).

## Question 2a:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- a)	Can a treatment effect be reliably quantified for a noninferiority study of outpatient CAP (i.e., for an oral drug)?
- To which patient population would this information apply with regards to disease severity and microbiological etiology?
- What endpoint(s) should be utilized?
- iii.	What is the proposed noninferiority margin and what data support the proposed noninferiority margin?

## Question 2b:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- b)	Can placebo-controlled trials be carried out in less severely ill patients with CAP?
- i.	If yes, how can risk to patients be minimized?  What patient population could be enrolled?  What endpoints should be evaluated?

## Question 2c:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- c)	Can you suggest any alternative study designs that could be utilized which would allow for an informative trial of outpatient CAP (i.e., an oral drug) to be conducted?  Please describe.

## Question 3:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- 3.	In a setting of hospitalized CAP as described in question 1 (above), one could study therapy with an intravenous formulation administered initially with subsequent “step down” therapy to an oral formulation as a means to support the use of the oral and IV formulations for severe disease.

## Question 3 continued:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- 	This leaves the question of whether the finding of efficacy for severe CAP would provide evidence of efficacy that could be used to support efficacy of the oral formulation for less severe (i.e., mild and moderate CAP).  Do you believe the finding of efficacy in more severe CAP supports the drug’s effect in less severe CAP, even though the drug has not been directly studied in less severe CAP?

## Question 4:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- 4. If the available evidence for setting a noninferiority margin in current CAP trials is derived primarily from studies of patients with CAP due to *S.pneumoniae*, should noninferiority studies include patients with other etiologies of CAP?

## Question 4 continued:

**Anti-Infective Drugs Advisory Committee meeting**
**April 1 & 2, 2008**

- If not, what additional data/studies are needed to show that antibacterial drugs are effective for specific organisms? When addressing this question please consider the following organisms:
*Chlamydophila pneumoniae *
*Haemophilus influenzae *
*Legionella pneumophila *
*Mycoplasma pneumoniae *
*Staphylococcus aureus*
*Klebsiella pneumoniae *

## Key Issues from the FDA-IDSA Workshop

- John Alexander, MD, MPH
- Medical Team Leader,
- Division of Anti-Infective and Ophthalmology Products, CDER

## FDA-IDSA Workshop

- Held January 17-18, 2008
- Goals
- Examine critical issues in:
- The design and conduct of trials of the safety and efficacy of antibacterial drugs in the treatment of CAP
- The implications of emerging scientific tools that assist in the diagnosis of the etiology of CAP
- Discuss clinical trial design and statistical considerations in demonstrating efficacy in clinical trials of CAP.

## CAP Scenarios

- Day 1 – CAP not requiring hospitalization
- 35 y/o male, 3 days of URI, purulent sputum, coughing
- fever (38.3 C), RR 18, “crackles” at R base
- CXR – bilateral LL infiltrates, R>L
- Day 2 – Hospitalized CAP, not requiring ICU
- 65 y/o female, mild COPD, diabetes, HTN, smoker (35 PY)
- ↑ sputum, ↑ dyspnea, fever (39.2 C), RR 24, O2 sat= 89% RA
- definite L crackles, no rubs, PORT=IV, CURB-65=2
- CXR – LLL consolidation, air bronchogram, large heart

## CAP Presentations – AC Reprise

- Criteria for NI Trials and Clinical Importance
- NI Trials Submitted in the Recent Past
- Historical Data on Treatment Effect
- PK/PD Relationship
- Clinician’s Perspective
- Consultant’s Perspective
- IDSA Perspective
- Open Public Hearing – Industry Presentations
- AC Presentations Informed by CAP Workshop

## CAP Presentations – Diagnostics

- Improved Detection of *S. pneumoniae*
- Molecular Diagnostics for Viral and Bacterial Pathogens
- Etiology of Outpatient CAP
- Etiology of Hospitalized CAP
- Procalcitonin – Biomarker for CAP

## Diagnostics

- * Intensive Care Unit  †Influenza A/B, Adenovirus, RSV, parainfluenza
- # Gram-negative bacilli
- Lancet 2003 (Dec. 13); 362:1991

| Outpatient (Mild) | Non-ICU inpatients | ICU* (Severe) |
| --- | --- | --- |
| S pneumoniae | S pneumoniae | S pneumoniae |
| M pneumoniae | M pneumoniae | Legionella spp. |
| H influenzae | C pneumoniae | H influenzae |
| C pneumoniae | H influenzae | GNB# |
| Resp. Viruses† | Legionella spp. | S aureus |
|  | Aspiration
Resp. Viruses† |  |

## Diagnostics

- Conventional methods (CM) for bacterial diagnosis are limited
- Blood cultures have low yield
- Sputum samples not available for all patients
- Study of 109 patients with CAP (77 hospitalized)*
- Pathogen identified by CM in 54/109
- Transthoracic aspirates identified *S. pneumoniae *as etiologic agent in 33% (18/55) of patients with unknown cause based on conventional methods
- Not practical for clinical trials
- *Ruiz-Gonzalez et al. Am J Med 1999; 106:385-390

## Diagnostics

- Binax Now® *S. pneumoniae* Urinary Ag
- Approved – August 1999
- Prospective study suspected *S pneumo* (sepsis or LRTI)
- Sens 90%, Spec 75% vs. blood culture
- Spanish Study of CAP*
- Concentrated urine samples
- 10/13 (77%) bacteremic pneumococcal CAP
- 9/14 (64%) non-bacteremic pneumococcal CAP
- 69/300 (23%) CAP but no pathogen isolated
- *CID 2003 (Feb 1); 36:286

## Diagnostics

- Atypical Pathogens
- Legionella
- Urinary Ag has replaced other methods for diagnosis (Sens 75-85%; Spec 99% for *L. pneumophila* 1)
- Mycoplasma
- MIF - Serologic testing is current standard
- Chlamydophila (Chlamydia)
- MIF – Poor correlation with culture or PCR*
- PCR – Multiple in-house assays (need standardization)
- CID 2007 (Feb 15); 44:568

## Diagnostics

- xTAGTM Respiratory Virus Panel
- Approved -  Jan. 2008
- PCR system for viral DNA/RNA detection
- Influenza A(H1 & H3)/B, RSV A/B, Adenovirus, Parainfluenzae (1, 2, 3), Human Metapneumovirus, Rhinovirus
- Use for diagnosis of viral infections
-  ?Exclusion of patients from CAP trials?

## Diagnostics

- Procalcitonin (PCT)
- “Hormokine” produced by parenchymal cells
- Increases in response to sepsis
- Attenuated by viral infection-related cytokines
- “Promising” as biomarker for selecting patients more likely to have bacterial vs. viral pathogen
- Limited experience with PCT at a few centers
- Not yet used in trials for drug development

## CAP Presentations

- Pneumonia Severity - PORT Score (a.k.a. PSI)
- Developed as a prediction tool for short-term mortality in CAP patients

## PORT Score

- NEJM 1997; 336(4):243-250

## PORT Score

- _Demographics_	_H & P_			_Laboratory_
- age = yrs (M)		neoplasia (+30)	pH <7.35 (+30)
- age = yrs – 10 (F)	CHF (+10)		BUN >30 (+20)
- nursing home (+10)	renal disease (+10)	Na <130 (+20)
- 				liver disease (+20)	glucose >250 (+10)
- 				CVD (+10)		hct <30% (+10)
- 				pulse >125 (+10)	p02 <60 (+10)
- 				SBP <90 (+20)  	CXR - effusion (+10)
- 				RR >30 (+20)
- 				T >40 C or <35 C (+15)
- 				altered mental status (+20)

- NEJM 1997; 336(4):243-250

## PORT Score

- NEJM 1997; 336(4):243-250

## PORT Score

- Prognostic score for mortality
- Includes elements related to severity, but not a true severity score
- Good tool for reducing unnecessary hospitalization
- Intended to supplement, not override, physician judgment
- Tool was studied in treated patients
- Would it predict mortality in untreated patients?

## Workshop Discussion

- Many concerns about non-inferiority trials
- Selection criteria, diagnostics, endpoints, analysis
- But ... non-inferiority could be supported for some CAP patients
- Need for clear guidance for CAP studies
- For mild pneumonia, more debate about use of NI trials though most still question ethics of placebo control trial or practicality of superiority

## Workshop Discussion

- Disease Severity
- PORT score and CURB-65 both discussed
- Clinical Endpoints
- Emphasis on PRO tool for mild pneumonia
- Objective, but how can PRO measure be related to historic evidence of treatment effect?
- Discussed use of mortality for severe pneumonia
- Advantage – objective, most related to historic data
- Disadvantage – uncommon, treatment alternatives
- Composite Endpoint

## Acknowledgements

- Co-Chairs: Thomas R. Fleming, David Gilbert, Edward Cox
- Rapporteur: Brad Spellberg
- Participants: Paul Ambrose, John G Bartlett, Helen Boucher, John S Bradley, Dale Bratzler, Dennis Dixon, Roger M Echols, Thomas M File Jr, Michael Fine, Karen Higgins, Keith P Klugman, Katherine A Laessig, Lionel A Mandell, Timothy F Murphy, Daniel M Musher, Michael Niederman, Frederick Nolte, Robert O’Neill, Tatiana Oussova, John Powers III, Bruce Psaty, Mary Singer, George H Talbot, Robert Temple, Glenn Tillotson, Richard Wunderink
- http://www.fda.gov/cder/meeting/CAP.htm

## American Thoracic Society/American College of Chest Physicians Perspective

**Richard G. Wunderink MD**
**Northwestern University Feinberg School of Medicine**
**Division of Pulmonary and Critical Care Medicine**

## ATS/ACCP Perspective

**Applaud the Agency’s attempt to improve quality of clinical trials for CAP**
**Agree with concerns about the need for new antibiotics**
**Especially new classes of antibiotics**
**Epidemic of resistant pathogens is incontrovertible, concerning, and unlikely to diminish in future**

## ATS/ACCP Themes/Emphasis

**Clinically relevant**
**Consistent with most recent IDSA/ATS CAP guidelines**

## ATS/ACCP Themes/Emphasis

**Clinically relevant**
**Stratification/definition**

## CAP Categories

**Mild = outpatient **
**Moderate = hospitalized outside the ICU **
**Severe = ICU admission**

## Etiology of Severe CAP

## Severe CAP and Pneumonia Severity Index

**Angus, AJRCCM, 2002**

**27% of ICU Adm**

**Notes:**
Can’t use PSI to denote SCAP. Low PSI patients admitted to ICU, only 1⁄4 with high PSI ever admitted. 27% of admissions to ICU were low risk category PSI I-III.

## Diagnostic Criteria for Severe CAP

**Angus, AJRCCM, 2002**

## Mechanical Ventilation

**- NIV**** or ETT**

**SCAP**
**ICU**

**SCAP**
**ICU**

**Septic Shock**

**C****onfusion****	****	****   Hypothermia**
**U****remia****	****	****     Leukopenia**
**R****R > 30****	****      ****Thrombocytopenia**
**Massive fluid resuscitation for ****B****P**
**PaO****2****/FiO****2**** < 250****             ****Multilobar**

**YES**

**YES**

**NO**

**NO**

**3/9 = SCAP/ICU**

## ATS/ACCP Themes/Emphasis

**Clinically relevant**
**Stratification/definition**
**Inclusion of severe CAP/ICU patients**

## SCAP: IDSA/ATS Guideline-Recommended Therapy

**Beta-lactam (cephalosporin)**
_**PLUS**_
**Macrolide or Fluoroquinolone**

## Combination Therapy in SCAP

**Overall Population**

**Mechanical Ventilation**

**Leroy, Chest, 2005**

## ATS/ACCP Themes/Emphasis

**Clinically relevant**
**Consistent with IDSA/ATS CAP guidelines**
**Exclusion of healthcare-associated pneumonia (HCAP)**

## Risk Factors for MDR Pathogens

**Antimicrobial therapy in preceding 90 days**
**Current hospitalization **_**>**_** 5 days**
**High frequency of antibiotic resistance in community or specific hospital unit**
**Presence of risk factors for HCAP**
_**>**_** 2 days hospitalization in previous 90 days**
**Nursing home or extended care facility residence**
**Home infusion therapy or wound care**
**Chronic dialysis for > 30 days**
**Family member with MDR**
**Immunosuppressive disease or therapy**

## Risk Factors for MDR Pathogens

**Antimicrobial therapy in preceding 90 days**
**	****	****PRSP but ? Pseudomonas, MRSA, Acinetobacter**
**High frequency of antibiotic resistance in community – ****MRSA but Pseudomonas, Acinetobacter**
**Presence of risk factors for HCAP**
_**>**_** 2 days hospitalization in previous 90 days**
**Nursing home or extended care facility residence**
**? Ambulatory vs. Trach/PEG/bedbound**
**Home infusion therapy or wound care**
**Chronic dialysis for > 30 days**
**Family member with MDR**
**Immunosuppressive disease or therapy**

**MRSA but **
**? Pseudomonas,**
**Acinetobacter**

## ATS/ACCP Themes/Emphasis

**Clinically relevant**
**Consistent with IDSA/ATS CAP guidelines**
**Exclusion of healthcare-associated pneumonia (HCAP)**
**Comparator drug**

## ATS/IDSA Guidelines: 		Hospitalized CAP

**Newer fluoroquinolone**
**Cephalosporin plus macrolide**
**For carefully selected patients, azithromycin alone**
**Substitute doxycycline for macrolide**

## Treatment Outcomes Data

**3****rd**** Gen Cephalo**

**Aminoglycoside**

**B****-lactam+Macro**

**Cephalo+Macro**

**Quinolone**

**Treatment Outcomes Data**

**Gleason, Arch **
**Intern Med, 1999**

## Clinically Relevant

**Need to parallel CMS/Joint Commission standards to allow American physicians to participate**
**Easier IRB approval**
**Easier to get participants to get agree to enrollment**
**CAP process of care improvement projects have consistently documented that increased adherence to IDSA/ATS guideline-recommended therapy is associated with lower mortality**
**Newer agents may demonstrate superiority to penicillin for CAP**
** ****would not be clinically relevant **

## Practical Implications

**Would not support placebo-controlled trials**
**Allow enrollment of patients who have already received an initial dose of a once-a-day antibiotic such as ceftriaxone**
**Allow combination therapy for drugs which may not have atypical coverage**
**Shorter duration of therapy**
**Disconnect approval for CAP from linkage to nosocomial pneumonia**

## Mortality as an Endpoint

**Unclear that antibiotics will differentially affect mortality**

## Unchanged CAP Fatality Rates

**www.cdc.gov/nchs/data**

**Clinical use of penicillin starts**

**Effective anti-TB drugs**

## Mortality as an Endpoint

**Unclear that antibiotics will differentially affect mortality**
**Severe CAP – immunomodulation**
**Moderate CAP - ? cardiovascular**
**Mild CAP – ? bad luck**

## The Association between Pneumococcal Pneumonia and Acute Cardiac Events

***p***** < 0.008**
**OR 3.9**

**N=33****  N=137**

**Musher et al, Clin Infect Dis, 2007**

**33/170 ****(19.4%) ****had at least**
**one major cardiac event**

## SCAP: Deaths Age < 5511,684 Admissions in Alberta

**Marrie, CID, 2003**

## Septic Shock and Respiratory Failure in CAP

**Pneumonia**

**Pneumonia = 40% of septic shock**

**Septic shock in approximately 15% of  CAP**

**Resp**
**Failure**

**Septic **
**Shock**

**Lethal **
**Pneumonia**

## Mortality as an Endpoint

**Unclear that antibiotics will differentially affect mortality**
**Exception is inappropriate initial empirical antibiotics in severe CAP**
**But don’t know what antibiotic(s) minimize inappropriate initial empirical since group has not been studied **

## But...

## Treatment Outcomes Data

**3****rd**** Gen Cephalo**

**Aminoglycoside**

**B****-lactam+Macro**

**Cephalo+Macro**

**Quinolone**

**Treatment Outcomes Data**

**Gleason, Arch **
**Intern Med, 1999**

## Atypical Coverage for Bacteremic CAP

**Quinolones most common monotherapy**
**? Quinolone in non-ICU, macrolide combination in critically ill**

*****

*****

*****

**†**

**†**

*** *****p***** < 0.01,  ****† *****p *****< 0.05**

**Metersky, Chest, 2007**

## Combination Therapy of Bacteremic Pneumococcal CAP

## Combination Therapy for SCAP

**Hazard Ratio = 1.69 **
**(95% CI 1.09-2.60)**
***p***** = 0.01**

**Difference remained if inappropriate initial therapy or deaths in**
**initial 48 hours are excluded**** **

**Rodriguez, Crit Care Med, 2007**

## Mortality as an Endpoint

**Important endpoint**
**Requires inclusion of severe, ICU-admitted CAP patients**
**Cannot be primary endpoint in superiority trials**
**For non-inferiority trials, margin should be small**

## Other CAP Endpoints

**For moderate CAP, clinically and financially relevant endpoint is ****hospitalization**
**Favor use of objective criteria, such as time to clinical stability, rather than subjective clinical**
**Hospitalization is often used to correct other medical issues ******** not reliable**
**For intravenous-only study medication, helps solve problem of oral continuation**
**Tools have been already been developed**** **

## Other CAP Endpoints

**For mild CAP, clinically relevant endpoint is ****return to normal activities**
**Favor use of Patient-Reported Outcomes**
**Self limited disease, therefore assessment at a static endpoint time unlikely to demonstrate differences**
**Margins suggested by IDSA committee appear reasonable and supported by prior literature**

## Biomarker Endpoints/ Entry Criteria

**Procalcitonin is not FDA approved for this indication**
**Probably minimal impact on CAP**
**Normal/drop in level may be supportive evidence of “cure” but implications of persistently elevated are less obvious**
**FDA has been barrier to use of point-of-care tests which might improve quality of CAP trials**

## Implicit in these statements are several goals which the ATS/ACCP would strongly support:
Problem of increasing antibiotic resistance is real and an anticipatory approach is needed
Pharmaceutical industry needs clear guidelines and the ability to be more nimble in recruiting patients
Majority of patients in these trials should be studied in healthcare systems that are similar to that of the US  

**Problem of increasing antibiotic resistance is real and an anticipatory approach is needed**
**Pharmaceutical industry needs clear guidelines and the ability to be more nimble in recruiting patients**
**Majority of patients in these trials should be studied in healthcare systems that are similar to that of the US  **

## Thank you

## Ethical Considerations for Trials in Community Acquired Pneumonia

- Robert M. Nelson, M.D., Ph.D.
- Office of Pediatric Therapeutics
- and
- Sara F. Goldkind, M.D., M.A.
- Good Clinical Practice Program
- Food and Drug Administration

- Antiinfective Drugs Advisory Committee, April 1, 2008

## Unmet Needs - Adults

- 6th leading cause of death in USA
- #1 cause of death from an infectious disease in USA
- Approximately 5.6 million cases of CAP occur annually in USA, and 1.1 million require hospitalization
- 80% of patients with CAP treated as outpatients: mortality rate <1-5%
- If hospitalization required: mortality rate 12% overall
- If ICU admission required: mortality rate 12-36%

## Unmet Needs - Children

**Over 2 million deaths per year**

- UNICEF/WHO, Pneumonia: The forgotten killer of children, 2006

## Unmet Needs - Children

- UNICEF/WHO, Pneumonia: The forgotten killer of children, 2006

## Outline of Discussion

- The Ethical Requirement of Scientific Validity
- Choice of Control Group; Assay Sensitivity; Non-Inferiority and Superiority (Placebo) Designs
- Ethical Balance of Risk and Benefit
- Withholding Known Effective Treatment
- Design Modification and other issues in Adult and Pediatric Studies of Antibiotics for CAP
- Conclusion: Ethical and Scientific Standard

## Choice of Control Group

- A Critical Decision affecting...
- Possible Inferences; Ethical Acceptability; Minimizing Bias; Subjects and Recruitment; Endpoints; Credibility of Results; Acceptability to Regulatory Authorities; Other Features of Study, Conduct and Interpretation.
- Key to Scientific Validity (Causal Inference)
- Allows for discrimination of patient outcomes _caused_ by the test treatment from outcomes caused by other factors, such as the natural progression of the disease, observer or patient expectations, or other treatment.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Types of Control Groups

- Concurrent Control (control/test groups chosen from same population, usually by randomization, and treated concurrently)
- Placebo (two or three-arm study)
- Active (Positive)
- Dose-Response (different dose or regimen of study treatment)
- No treatment (not blinded)
- External (including historical) Controls, regardless of comparator treatment

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## External or Non-concurrent Controls

- There are serious concerns about the ability of trials using external (including historical) controls, regardless of comparator treatment, to ensure the comparability of test and control groups, and to minimize important biases.
- Thus, this is an unacceptable study design for antibiotic efficacy studies for CAP.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Dose-Response Design

- Antibiotic trials may compare two regimens (e.g., short vs. long treatment course) using *either* superiority or non-inferiority design (thus, similar issues as _active control trials_).
- Choice of the lower dose (or shorter course) must be a fair comparison since trial conditions should not favor one treatment over the other. If not, cannot assure assay sensitivity, and may raise similar ethical concerns as _placebo controls_.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Focus: Active/Placebo Controls

- Two Approaches to Establish Efficacy
- _Superiority_ of test treatment to control (whether placebo or active control)
- _Similarity_ of test treatment to known effective treatment (active control)
- Equivalence (i.e., equally effective)
- Non-inferiority (i.e., not less effective by NIM)
*Key assumption*: active control is effective under trial conditions (i.e., assay sensitivity)

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Assay Sensitivity

- Definition: the ability of a clinical trial to distinguish effective treatment from less effective or ineffective treatment.
- Lack of assay sensitivity has different implications for superiority and non-inferiority trials.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Assay Sensitivity

- Superiority Trial
- If superiority trial lacks assay sensitivity, it will fail to show that test treatment is superior and will fail to lead to conclusion of efficacy.
- When one treatment is shown to be superior, that finding itself establishes assay sensitivity.
- Non-Inferiority (NI) Trial
- If non-inferiority trial lacks assay sensitivity, trial may find ineffective treatment to be non-inferior; could lead to erroneous conclusion of efficacy.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Assay Sensitivity in NI Trials

- Inferred from two determinations:
- _Historical evidence of sensitivity to drug effects (HESDE)_, i.e., similarly designed past trials regularly distinguish effective from less effective or ineffective treatments; and,
- _Appropriate trial conduct_, i.e., conduct of trial did not undermine ability to distinguish effective from less effective or ineffective treatments (IDSA: “constancy assumption”?).

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## (1) HESDE

- Evaluate _before_ beginning non-inferiority trial
- Appropriately designed and conducted trials using specific treatment (or other treatments with similar effects) to be used as the active control must show treatment effect (optimally, superior to placebo).
- Without well-supported historical evidence of sensitivity to drug effects, demonstration of efficacy using non-inferiority trial design is not possible and should not be attempted.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Choosing a Non-Inferiority Margin (NIM)

- NIM: degree of inferiority of test treatment to control (delta) that trial will attempt to exclude statistically.
- NIM ≤ smallest effect size that active drug would reliably be expected to have compared with placebo in the setting of the planned trial.
- _only_ possible when there is historical evidence of sensitivity to drug effects.
- requires *measure of superiority of active treatment to control*, not uncontrolled measures (e.g., change from baseline).

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## (2) Appropriate Trial Design & Conduct

- Can only be fully evaluated _after_ the non-inferiority trial is completed.
- Planned non-inferiority trial must share critical design characteristics with the historical trials used to determine that evidence of sensitivity to drug effects exists.
- Trial conduct should adhere closely to that of the historical trials and should be of high quality (e.g. good compliance, few losses to follow-up).

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Scrupulous Trial Conduct may be necessary for Assay Sensitivity

- For non-inferiority trials, may be weaker stimulus to engage in efforts to ensure study quality
- Errors that diminish observed treatment differences (e.g., poor compliance, high placebo response, concomitant treatment, misclassification of outcomes) may undermine preservation of assay sensitivity.
- Some trial errors can increase variance, thus decreasing likelihood of showing non-inferiority by widening confidence interval (e.g., poor measurement technique).

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Non-Inferiority Trial Conduct?

- Review non-inferiority trial conduct for factors that
- might obscure differences between treatments
- E.g., observed differences in populations enrolled, use of concomitant therapies, compliance with therapy, and extent of, and reasons for, subjects dropping out?
- might make the trial different from the trials that provided the basis for determining the NIM.
- E.g., atypical outcomes with active control treatment (e.g., unusually high or low antibiotic cure rate) can indicate important differences which undermined assay sensitivity.
- Concurrent trial monitoring may be necessary to minimize risk and assure adequate trial conduct

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Given these problems with NI designs, why not an AC superiority design?

- Scientific and Policy Concerns
- In spite of questions about specifying a reliable treatment effect (i.e., NIM) based on past experience, antibiotics are generally highly effective. Thus, a superiority design may require a larger sample size than a non-inferiority trial (depending on the margin).
- There may be other advantages of new over existing antibiotics that may not be captured by an actively controlled superiority study to establish efficacy (such as different resistance profiles, improved safety, ease of administration, formulation advantages, cost, etc.)

## Ethical preference for AC trial designs?

- Active control trials may pose fewer ethical problems than placebo-controlled trials because all subjects receive active treatment.
- But subjects receiving a new treatment are not receiving standard therapy and thus may be receiving an ineffective or harmful drug.
- If active control therapy improves survival or decreases irreversible morbidity, withholding of such treatment from experimental group raise same concerns that render placebo control unacceptable.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Placebo Control (or Superiority Design) may assure Assay Sensitivity, but can it meet ethical guidelines?

- Placebo-controlled trial for efficacy is as free of assumptions and reliance on external information as possible.
- Most problems in design or conduct of placebo-controlled trial increase likelihood of failure to demonstrate treatment difference (and thereby establish efficacy), so trial contains built-in incentives for excellence.
- When primary purpose of trial is comparison of two active agents, addition of placebo control provides an internal standard that enhances inferences that can be drawn. However, ethical issues with use of placebo control remain a concern with three-arm design.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Ethical Issues with Placebo Controls

- Where an available treatment is known to prevent serious harm, such as death or irreversible morbidity, it is generally inappropriate to use a placebo control. There are exceptions, however, such as when standard therapy has such severe toxicity that many patients refuse to receive it.
- When a new treatment is tested for a condition for which no effective treatment is known, there is usually no ethical problem with a study comparing the new treatment to placebo.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Ethical Issues with Placebo Controls

- When there is no serious harm, it is generally considered ethical to ask patients to participate in a placebo-controlled trial, even if they may experience discomfort, assuming adequate informed and voluntary consent.
- Can a randomized placebo-controlled trial for community acquired pneumonia in adult and pediatric patients meet this standard?

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Slide 113

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Debate over Placebo Controls: Paragraph 29. WMA Declaration of Helsinki (2000)

- “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.”

- http://www.wma.net/e/policy/b3.htm

## Note of Clarification on Paragraph 29

- “The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances...”

- Added by the WMA General Assembly, Washington 2002 (http://www.wma.net/e/policy/b3.htm)

## Note of Clarification on Paragraph 29

- “However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:
- “Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; _or_
- “Where a prophylactic, diagnostic or therapeutic method is being investigated for *a minor condition* and the patients who receive placebo will *not be subject to any additional risk of serious or irreversible harm*.”

- Added by the WMA General Assembly, Washington 2002 (http://www.wma.net/e/policy/b3.htm)

## Choice of control in clinical trials

- “As a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive intervention should receive an established effective intervention. In some circumstances it may be ethically acceptable to use an alternative comparator, such as placebo or "no treatment".

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Choice of control in clinical trials

- “Placebo may be used:
- “When there is no established effective intervention;
- “When withholding an established effective intervention would expose subjects to, at most, temporary discomfort or delay in relief of symptoms;
- “When use of an established effective intervention as comparator would not yield scientifically reliable results _and_ use of placebo would not add any risk of serious or irreversible harm to the subjects.”
- A placebo-controlled trial for CAP may be ethical **IF** the use of placebo would not add _any risk_ of serious or irreversible harm to the subjects.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Design Modifications and Using Other Controls That May Resolve Ethical (and Other) Issues

- Additional Control Groups
- Three-arm Trial; Placebo and Active Control
- Additional Doses
- Factorial Designs
- Other Modifications of Study Design
- Add on Study, Placebo-Controlled; Replacement Study.
- Early Escape; Rescue Treatment
- Limited Placebo Period
- Randomized Withdrawal
- Appear of limited application to antibiotic trials.

- E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001

## Adult Studies of Antibiotics for CAP

## Alter risks based upon choice of study population

- An ethical study requires both:
- Minimization of risks to enrolled subjects
- Maximization of scientific validity (assay sensitivity and study design)
- Choice of study population
- How can these two goals best be achieved?
- Tailoring study population with more rigorous entry criteria, but
- This may affect generalizability of results

## CAP: study in adults

- Heterogeneous population
- Some factors that influence course, response, and mortality
- Elderly (>65 y/o)
- Smokers
- Outpatient vs. inpatient (ward vs. ICU)
- USA vs outside USA
- Co-morbidities
- Functional status
- Virulence of the infectious organism and antibiotic resistance profile

## Clinical diagnosis based upon symptoms and signs -- empiric therapy
Combination of clinical presentation and radiographic findings -- empiric therapy
Empiric therapy is influenced by standard-of-care for that region
Pathogen-directed therapy
Prevalence of resistant organisms (in a given local)
Associated complexities

- Combination of clinical presentation and radiographic findings -- empiric therapy
- Empiric therapy is influenced by standard-of-care for that region
- Pathogen-directed therapy
- Prevalence of resistant organisms (in a given local)
- Associated complexities

- CAP: study in adults

## Minimization of Risk

- Primary imperative is to minimize research-related risks to subjects without compromising reliability of research results upon which to base safety and efficacy claims
- Enroll a less sick study population
- Enroll a study population with ease of access to health care including on-going monitoring (clinical improvement usually occurs by day 3) and follow-up (at 6 wks)

## Minimization of Risk

- If a less sick study population is selected can onset of antibiotic treatment be delayed to mimic PCT?
- Will this choice of study population provide useful information (meaningful endpoint) in light of PCT studies that have already been done on young, low-risk, clinically stable outpatients with mild CAP?
- Some data demonstrate that antibiotic administration within 8 hours of hospital arrival was associated with a significantly lower 30-day mortality and length of hospital stay in both unadjusted and adjusted (for patient risk status) analyses; for those who did not receive pre-hospital antibiotics, 4 hours was associated with decreased mortality & length of hospital stay {Multi-center retrospective cohort study of 14,069 hospitalized elderly patients with pneumonia} Can a delay in treatment be justified?
- Although there are prognostic scoring systems (PSI, CURB, CURB-65) they do not account for all factors contributing to disease severity.

## Scientific validity

- Enrich the study population with responders (e.g., subjects who meet the criteria for a pathogen-directed therapy)
- The only randomized controlled trial of diagnostic strategy in CAP demonstrated no statistically significant differences in mortality rate of length of hospital stay between patients receiving pathogen-directed therapy and patients receiving empirical therapy [IDSA/ATS Guidelines for CAP in Adults, 2007]
- Even when extensive diagnostic testing is used, causative pathogen cannot be identified in up to 50% of cases [ATS Guidelines for Management of Adults with CAP, 2001]
- Given low virulence of atypical and viral pathogens, and effectiveness of approved antibiotics, will studying mild to moderate CAP give reliable results?

## Generalizability of Results

- Ability to generalize study results to the projected use population
- Variations in standard-of-care
- Local vs. universal standards
- Differing prevalence of bacterial pathogens (including resistant organisms)
- Nuanced approaches to CAP (e.g., US outpatient therapy addresses broad antimicrobial coverage; European approach focuses on empiric therapy for S. pneumonia

## Additional Issues from Pediatric Studies of Antibiotics for CAP

## WHO Classification of Pneumonia

- World Health Organization, Pocket Book of Hospital care for children 2005

## Slide 130

- UNICEF/WHO, Pneumonia: The forgotten killer of children, 2006

## Slide 131

- Agarwal et al BMJ 2004

## Slide 132

- Ashgar et al BMJ 2008

## Slide 133

- UNICEF/WHO, Pneumonia: The forgotten killer of children, 2006

## Slide 134

- Hazir et al Lancet 2008

## Wide Agreement on Ethical Principles

- Research involving children _either_ must present a  balance of risks and potential benefits comparable to the available alternatives (21 CFR 50.52), _or_ be restricted to “minimal (or low) risk” absent direct benefit to child (21 CFR 50.51 or 53).
- Under 21 CFR 50, Subpart D, withholding known effective treatment from children enrolled in a control group must present no more than a “minor increase over minimal risk.”

## Ethical Standard for Choice of Control Group in CAP Clinical Trials

- There are concerns that the use of an established effective intervention as the comparator in a NIM design would not yield scientifically reliable results, lending credence to the need for either active superiority or placebo controlled trial designs. The scientific ability to set a credible NIM is key to the resolution of this discussion.
- A placebo-controlled trial for CAP would only be ethical **IF** the use of a placebo would not add _any risk_ of serious or irreversible harm to the subjects. There are doubts that a CAP trial could be designed to meet this standard.
- Cautionary note: “Where a placebo-controlled trial is unethical and an active control trial would not be credible, it may be very difficult to study new drugs at all.” (ICH E-10)

## Challenges

- Active Control Trials
- Assure scientific validity with either
- Selection of an appropriate NIM combined with meticulous trial conduct using non-inferiority design, or
- Use of a superiority design.
- Placebo Control Trials
- Assure ethical treatment of subjects by avoiding any risk of serious or irreversible harm.
- All trials must meet the dual ethical requirements of (1) scientific validity and (2) an appropriate balance of risk and potential benefit.

## “Of these two rocks the one reaches heaven and its peak is lost in a dark cloud.... [There] Scylla sits..., a dreadful monster [that] no one - not even a god - could face...without being terror-struck....No ship ever yet got past her without losing some men, for she shoots out all her heads at once, and carries off a man in each mouth.”

- “Of these two rocks the one reaches heaven and its peak is lost in a dark cloud.... [There] Scylla sits..., a dreadful monster [that] no one - not even a god - could face...without being terror-struck....No ship ever yet got past her without losing some men, for she shoots out all her heads at once, and carries off a man in each mouth.”

- “[With] the other rocks [lies] the sucking whirlpool of Charybdis. Three times [a] day...she vomit[s] forth her waters, and three times she sucks them down again; see that you be not there when she is sucking, for if you are, Neptune himself could not save you; you must hug the Scylla side and drive ship by as fast as you can, for you had better lose six men than your whole crew.”

- ““Is there no way,”' said I, “of escaping Charybdis, and... keeping Scylla off when she is trying to harm my men?”  “You dare-devil,” replied the goddess, ...you will not let yourself be beaten even by the immortals.”

- Odysseus vor Scilla und Charybdis, Johann Heinrich Füssli, 1794-1796

## Issues in 

- Issues in
- Non-Inferiority Trials
- in  CAP
- April 1, 2008
-  Thomas R. Fleming, Ph.D.
*	**	**                       **Professor of Biostatistics*
*	**	**	**           **University of Washington*
-              Fleming TR.  *Statistics in Medicine*, 2008, Vol 27, #3
-      Fleming TR, Powers JH. “*Issues in NI Trials in CAP”, *to appear

**    **

- FDA  Anti Infective Drugs Advisory Committee

## Motivation for Non-Inferiority

-  **~**  Classic setting:  Experimental (EXP) has
-         favorable profile relative to Standard (STD) in
- 	• side effects
- 	• convenience of administration
- 	• cost
-  **~  **Ethical approach

-      Eg :	     _    STD    _          _      EXP     _             _SETTING_
-             Amphotericin B    Voriconazole     Invasive Aspergillosis
- 	     Penicillin       New Quinolone             CAP
- 	   “076” ZDV         Nevirapine           MCT of HIV

## Dual Goals of Non-Inferiority Trials

- 	•  To enable a direct evaluation
-        		 of the clinical efficacy/safety
- 	       		 of **EXP** relative to **STD**
- 	•  To contribute evidence to
-        		 the evaluation of efficacy/safety
- 	       		 of **EXP** relative to **PLA**

## Non-Inferiority Trials... Some Requirements

-     ICH  E9:   STD  should have clinical efficacy
- 	• that is of **substantial magnitude**
- 	• that is **precisely estimated**
- 	• with estimates that are **relevant** to the setting
- 		in which the non-inferiority trial
- 			is being conducted
- 	e.g.,   EXP  vs. Vancomycin  in patients with VRE

## Factors invalidating Constancy Assumption

*(EXP vs. STD NI Trial  vs.  Trials evaluating STD)*

-    patient  characteristics
- e.g.,  Disease caused by pathogens resistant to STD  in NI Trial
-    use of supportive care
- e.g.,  Enhanced concomitant Rx attenuates effect of STD in NI Trial
-    dose, schedule, level of adherence
- e.g., Lower  adherence to STD in  NI trial
-    efficacy and safety endpoints
- 	*         ****~ ****definition **        ****~ ****validation process     ****~ ****missing data*
*          ...**..as in  maintaining conditions of a lab experiment...**** ***

## Illustration   CAP NI Trial:  Choice of Margin

*Illustration*   CAP NI Trial:  Choice of **Margin**

- New Quinolone (EXP)   _*vs.*_  Penicillin (STD)
-                   in Community Acquired Pneumonia
-                          (Pneumococcal pneumonia)
**  ****NON-INFERIORITY TRIAL****	****   **_**Failure**_**        **
**	**New Quinolone 	            38 / 150   ( 25% )
- 	    Penicillin	                        30 / 150   ( 20% )
- 	            (EXP ─ STD)   95% C. I. :  ( ─5%,  **15% **)
** ****PENICILLIN TRIAL                        **_**Failure**_
**               **  Placebo                                87 / 175   ( 50% )
-              Penicillin 		           35 / 175   ( 20% )
-                                                                        (PLA ─ STD)   95% C.I. :  ( 20%, 40% )

## Failure Probability

**	****                       ****0%        ****10%****          ****20%****            ****30%****            40%**

**EXP better **

**        ****EXP compared with STD**

**STD  better**

- %  Failure
- (EXP - STD)

** **        EXP  - STD

## Factors Influencing  the Choice of Margin

- Factors Influencing  the Choice of **Margin**
- and Interpretation of NI Trial Results

**•  *****Effect of the STD regimen***
- •  Clinical Relevance of  Reduction in Efficacy

## Illustration   CAP NI Trial:  Choice of Margin

*Illustration*   CAP NI Trial:  Choice of **Margin**

- New Quinolone (EXP)   _*vs.*_  Penicillin (STD)
-                   in Community Acquired Pneumonia
-                          (Pneumococcal pneumonia)
**  ****NON-INFERIORITY TRIAL****	****   **_**Failure**_**        **
**	**New Quinolone 	            38 / 150   ( 25% )
- 	    Penicillin	                        30 / 150   ( 20% )
- 	            (EXP ─ STD)   95% C. I. :  ( ─5%,  **15% **)
** ****PENICILLIN TRIAL                         **_**Failure**_
**               **  Placebo                                87 / 175   ( 50% )
-              Penicillin 		           35 / 175   ( 20% )
-                                                                        (PLA ─ STD)   95% C.I. :  ( 20%, 40% )

## Failure Probability

**	****                       ****0%        ****10%****          ****20%****            ****30%****            40%**

**Placebo better **

**Placebo compared with STD**

**STD  better**

- %  Failure
- (Placebo - STD)

- Placebo - STD meta-analysis

- Margin of STD benefit

** **        EXP  - STD

## Failure Probability

**	****                       ****0%        ****10%****        ****20%****            ****30%****            40%**

**Placebo better **

**Placebo compared with STD**

**STD  better**

- %  Failure
- (Placebo - STD)

- Placebo - STD meta-analysis

- 50% of   STD benefit

- Margin of STD benefit

** **        EXP  - STD

## Factors Influencing  the Choice of Margin

- Factors Influencing  the Choice of **Margin**
- and Interpretation of NI Trial Results

**•  **Effect of the STD regimen
- •  ***Clinical Relevance of  Reduction in Efficacy***

## Factors Influencing Choice of Margin

- Factors Influencing Choice of **Margin**

**•**** **  Clinical importance of:
-         ─  a reduction in efficacy
-         ─  taking into consideration...
-    safety/tolerance profile
-    resistance or drug/drug interactions
-    convenience of administration

## Failure Probability

**	****                       ****0%        ****10%****          ****20%****            ****30%****            40%**

**Placebo better **

**Placebo compared with STD**

**STD  better**

- %  Failure
- (Placebo - STD)

- Placebo - STD meta-analysis

- 50% of   STD benefit

- Margin of STD benefit

** **        EXP  - STD

## Suppose a NI trial is positive...

- What is the Conclusion about Efficacy?

**•  **The EXP regimen is
-      “***at least as good as***” the STD regimen...
- •  The EXP regimen is
*	**“****not worse than****” *the STD regimen...

## Illustration   CAP NI Trial:  Choice of Margin

*Illustration*   CAP NI Trial:  Choice of **Margin**

- New Quinolone (EXP)   _*vs.*_  Penicillin (STD)
-                   in Community Acquired Pneumonia
-                          (Pneumococcal pneumonia)
**  ****NON-INFERIORITY TRIAL****	****   **_**Failure**_**        **
**	**New Quinolone 	            375 / 1500   ( 25% )
- 	    Penicillin	                        300 / 1500   ( 20% )
- 	            (EXP ─ STD)   95% C. I. :  ( 2%,  8**% **)
** ****PENICILLIN TRIAL                        **_**Failure**_
**               **  Placebo                                87 / 175   ( 50% )
-              Penicillin 		           35 / 175   ( 20% )
-                                                                        (PLA ─ STD)   95% C.I. :  ( 20%, 40% )

## Failure Probability

**	****                       ****0%        ****10%****          ****20%****            ****30%****            40%**

**Placebo better **

**Placebo compared with STD**

**STD  better**

- %  Failure
- (Placebo - STD)

- Placebo - STD meta-analysis

- 50% of   STD benefit

- Margin of STD benefit

** **        EXP  - STD

## Suppose a NI trial is positive...

- What is the Conclusion about Efficacy?

**•  **The EXP regimen is
-      “***at least as good as***” the STD regimen...
- •  The EXP regimen is
*	**“****not worse than****” *the STD regimen...

## Suppose a NI trial is positive...

- What is the Conclusion about Efficacy?

**•  **The EXP regimen is
-      “***at least as good as***” the STD regimen...  **NO!**
- •  The EXP regimen is
*	**“****not worse than****” *the STD regimen...  **NO!**
- •  The EXP regimen is
- 	“***not meaningfully worse than***”
- 			            the STD regimen

## Challenges in 

- Non-Inferiority Trials  in CAP

-    Not simply,
- 	               “Are STD antibiotics effective  at all  in CAP?
-    Rather:    we need to determine...
-   what is the **magnitude** of effect of STD?
-   on what clinically important outcome measures?
-   in what population?
-   in what experimental conditions?

## Issues in Design of 

- Issues in Design of
- Non-Inferiority Trials in CAP

**•  ****Choice of Endpoint**
- •  Addressing Confounding due to
- 	Lack of Randomized Trials evaluating STD
- •  Literature Review to Derive Margins
- 	for Non-Inferiority Trials in CAP
- •  Conclusions

## Lack of Utility of Microbiological Endpoints

- Lack of Utility of Microbiological Endpoints

*“**In a considerable number of bacteremic patients, death occurred in spite of repeatedly negative blood cultures following therapy,  even including the heart’s blood in those who came to autopsy.   Many of them died with purulent focal complications.” *
-   Finland M et al,  Ann Intern Med 1940

## Lack of Utility of Defervescence  as an Endpoint

- Lack of Utility of Defervescence  as an Endpoint

*“**The temperature became normal in three days in about half of treated cases compared with about a quarter of controls...but a secondary pyrexia was fairly common and was considered quite usual...   The average duration of pyrexia in hospital was little affected by the drug, the figures being 4.8 and 5.6 days for treated and control groups.”*
-   Agranat A.L. et al.,  Lancet 1939.

## Lack of Utility of Defervescence  as an Endpoint

- Lack of Utility of Defervescence  as an Endpoint

- Raising or lowering body temperature  may not reflect      	  overall benefits/risks in treatment of pneumonia
- Antipyretics (acetaminophen, non-steroidal anti-inflammatory drugs) can   *lower body temperature    *but do not affect            	  other aspects of pneumonia (*mortality, symptoms*)
- Serum therapy resulted in
*	**	**febrile reactions *in 26% to 44% of subjects  but
*	**	**   **decreased mortality *compared to no specific treatment
- Finland and Brown, Am J Med Sci 1939, p 151, p351, p389

## What are Potential Endpoints?

- All-cause mortality
- Decrease in complications
- 		 – empyema, meningitis, endocarditis
- Resolution of symptoms
- 		 – cough, dyspnea, chest pain, fatigue
- Biomarkers
- 		 – resolution of chest x-ray, physical findings such as 		rales, body temperature, WBC, etc.

## Outcomes Dependent on Measurement Methods

- Outcomes Dependent on Measurement Methods

- Median time to resolution of cough 14 days
- Metlay JP et al Respir Med 1998; 92:1137-42.
- 20% of patients report substantial fatigue at               	3 months from time of initial diagnosis
- Metlay JP et al J Gen Intern Med 1997; 12:423-30.
- Not consistent with rapid resolution of fatigue         	 in single trial  (different form of measurement?)
- Kingston JR et al JAMA 1961; 176:118-123.

## Outcomes

*“**Studies of patients with community-acquired pneumonia have established certain expected rates  of outcomes, including mortality, clinical complications, and time to resolution of symptoms....However, there are no well-controlled studies that provide definitive estimates of the magnitude of the impact of antimicrobial therapy on these outcomes for patients with community-acquired pneumonia.”*
- Metlay JP and Singer DE Clin Micro Infect 2002

## Impact of Age on Outcome

**Dowling H.F. et al Am J Med Sci 1951.**

## Issues in Design of 

- Issues in Design of
- Non-Inferiority Trials in CAP

**•  **Choice of Endpoint
- •  ***Addressing Confounding due to***
***         ******Lack of Randomized Trials evaluating STD***
- •  Literature Review to Derive Margins
- 	for Non-Inferiority Trials in CAP
- •  Conclusions

## Importance of Baseline Comparability

*“**Any presentation concerning mortality from pneumonia is incomplete if it fails to consider the most important factors influencing prognosis in this disease, namely: bacteremia, age, and the presence of systemic complications.”*
- Finland and Brown Am J Med Sci 1939, p 151.

## Impact of Age and Bacteremia on Mortality

**Finland M. Conn State Med J 1943**

## Importance of Baseline Comparability

**Group 1**

**Group 2**

**Mortality (%)**

** ****9/18 (50%)**

**1/18  (6%)**

**Difference  44%**
**P= 0.003**

**sulfanilamide**

**no specific**
**treatment**

_**Group 1 (**__**sulfanilamide**__**)**_
**10/18 (56%) bacteremic**
**11/18 (61% ) multi-lobar**
**13/18 (72%) > age 30**

_**Group 2 (**__**no specific rx.)**_
**0/18 (0%) bacteremic**
**0/18 (0%) over age 30**

**Data from Finland M and Brown JW, Am J Med Sci 1939, 151**

## Issues in Design of 

- Issues in Design of
- Non-Inferiority Trials in CAP

**•  **Choice of Endpoint
- •  Addressing Confounding due to
- 	Lack of Randomized Trials evaluating STD
- •  ***Literature Review to Derive Margins ***
***	******for Non-Inferiority Trials in CAP***
- •  Conclusions

## Literature Review in CAP

-              (rather than reliance on review articles)
-   Lack of use of randomization in pre-1940s
-   Predominantly     *sulfonamide derivatives & penicillin*
-         (closer to current   *beta-lactams & quinolones*)
-               ...inhibition of growth of pathogenic microorganisms
- 	rather than    *serum therapy*
-               ...augmentation of the host immune response
-   Majority subjects with  pneumococcal pneumonia only
*      *and with   microbiological confirmation of disease
-              ...difficult to extrapolate to mycoplasma & chlamydophila

**Literature Review in CAP**

## Literature Review in CAP

- Among articles reviewed:
-  **8** papers provide data by bacteremia and age
-  **5** papers provide data by age alone
-  **3** papers provide data by bacteremia alone
- 	 ...*Search by J. Powers & T. Fleming*

**Literature Review in CAP**

## Slide 174

| 
         By Age
       |  Bacteremic  Subjects
No Specific  
Treatment   Antibiotics |      Non-Bacteremic
No Specific
Treatment    Antibiotics |
| --- | --- | --- |
|               <30   
    # Deaths / # Patients |        81 / 126      4 / 16
       64.3%       25.0% |    90 / 1036      5 / 63
     8.68%        7.94% |
|    Treatment Difference
     Proposed Margin |                39%    (16%, 62%)       
                          10 % |                1%     (-6%, 8%)
                      NONE |
|  |  |  |
|               30-49   
    # Deaths / # Patients |    319 / 428    21 / 66
      74.3%      31.8% |   218 / 1222    12 / 112
     17.8%        10.7% |
|    Treatment Difference
      Proposed Margin |               43%    (31%, 55%)    
                         10 %      |              7%     (1%, 15%)
                      0.5 % |
|  |  |  |
|               ≥ 50   
    # Deaths / # Patients |     368 / 395     32 / 70
     93.2%       45.7% |    353 / 715     20 / 117
    49.4%         17.1% |
|     Treatment Difference
      Proposed Margin |             47%     (35%, 59%)
                        10 % |             32%    (24%, 40%)
                       10 % |

## Important Baseline Risk Factors for Poor Outcomes in Pneumonia

- Important Baseline Risk Factors for Poor Outcomes in Pneumonia

- Older age
- Presence of bacteremia
- Presence of multi-lobar disease
- Bronchopneumonia  (as opposed to lobar pneumonia)
- Type of infecting pneumococcus  (type III highest mortality)
- Presence of co-morbid illness
- Late initiation of treatment
- Tilghman and Finland Arch Intern Med 1937 and others
- Note:   PORT scoring takes into account                                    age  and  presence of co-morbid illness,  not other factors

## PORT Scores Do Not Account for Bacteremia

**30 day mortality 13%**

**30 day mortality 21%**

**Musher D et al. Medicine 2000; 79(4):210-21.**

## Slide 177

| 
         By Age
       |  Bacteremic  Subjects
No Specific  
Treatment   Antibiotics |      Non-Bacteremic
No Specific
Treatment    Antibiotics |
| --- | --- | --- |
|               <30   
    # Deaths / # Patients |        81 / 126      4 / 16
       64.3%       25.0% |    90 / 1036      5 / 63
     8.68%        7.94% |
|    Treatment Difference
     Proposed Margin |                39%    (16%, 62%)       
                          10 % |                1%     (-6%, 8%)
                      NONE |
|  |  |  |
|               30-49   
    # Deaths / # Patients |    319 / 428    21 / 66
      74.3%      31.8% |   218 / 1222    12 / 112
     17.8%        10.7% |
|    Treatment Difference
      Proposed Margin |               43%    (31%, 55%)    
                         10 %      |              7%     (1%, 15%)
                      0.5 % |
|  |  |  |
|               ≥ 50   
    # Deaths / # Patients |     368 / 395     32 / 70
     93.2%       45.7% |    353 / 715     20 / 117
    49.4%         17.1% |
|     Treatment Difference
      Proposed Margin |             47%     (35%, 59%)
                        10 % |             32%    (24%, 40%)
                       10 % |

## Issues in Design of 

- Issues in Design of
- Non-Inferiority Trials in CAP

**•  **Choice of Endpoint
- •  Addressing Confounding due to
- 	Lack of Randomized Trials evaluating STD
- •  Literature Review to Derive Margins
- 	for Non-Inferiority Trials in CAP
- •  ***Conclusions***

## Non-Inferiority Trials

- • Do not establish EXP is “as effective as” STD;
-     NI trial rules out EXP is “unacceptably worse”
- • Margins should be smaller than
-       differences in efficacy  patients & caregivers
-                     consider  to be clinically relevant
- • Margins should not be based on what can be
- 	ruled out  using a pre-specified sample size
-             (1993 FDA Anti-Infective Drugs Guidance Document)
- •  Margins should not be based on
- 	“consensus”  in the absence of data on STD

## Challenges in 

- Non-Inferiority Trials  in CAP

-    Not simply,
- 	               “Are STD antibiotics effective  at all  in CAP?
-    Rather:    we need to determine...
-   what is the **magnitude** of effect of STD?
-   on what clinically important outcome measures?
-   in what population?
-   in what experimental conditions?

## Non-Inferiority Trials  in CAP

- •  NI trial designs should be avoided if possible...
- 	...they share many of the inherent dangers
- 		             of historically controlled trials....
-            Garattine S, Bertele V.   “NI trials are unethical because they
-           disregard patients’ interests.”    *Lancet* 2007; 370: 1875-77
- •  Valid NI Trials can be done in CAP...
-   with an all-cause mortality endpoint
-   in a pop. with ≥15% mortality,  (Bacteremic or Port 4/5)
-    with microbiological confirmation of
- 		pneumococcal pneumonia-like disease
-   with effective STD control regimens
-   with setting-specific margins  ≤  10%

## Treatment Effect of Antibacterial Drugs in Community-Acquired Pneumonia: A Historical Perspective

- Mary Singer, M.D., Ph.D.
-  Medical Officer, Office of Antimicrobial Products, FDA/CDER

**Notes:**
Today I’m going to discuss what we know about the treatment effect of antibacterial drugs in CAP from a historical perspective. A quantitative estimate of the treatment effect, i.e. the difference between active control and  placebo, is necessary to determine a non-inferiority margin. 

## Objectives

- To review evidence for a treatment effect of antibacterial drugs in Community Acquired Pneumonia (CAP)
- To estimate the magnitude of the treatment effect in the context of non-inferiority trials

**Notes:**
My objectives are to review the available evidence for a treatment effect of antibacterial drugs
and to estimate the magnitude ...

## Approach to Estimation of Treatment Effect for Antibacterial Drugs in CAP

**1.**** Historical Data **
- Natural History studies
- Published studies performed **pre- and post** -introduction of antibacterial drugs
- Most were studies of pneumococcal or lobar pneumonia
- Hospitalized patients
- Mortality Endpoint
- Observational studies (treated vs. untreated)
- Controlled trials: antibacterial drugs vs. untreated controls
- Pneumococcal or lobar pneumonia
*Mycoplasma* pneumonia controlled trials
- 2. **Alternative Approaches**

**Notes:**
Generally treatment effect can be determined from placebo controlled trials; but there have been no placebo-controlled studies in CAP since the late 1930’s. 

So we searched the literature for data which might allow an estimation of antibacterial treatment effect in CAP. We looked  for information on the natural history of untreated pneumonia, and focused on studies performed in the pre-antibiotic era and shortly after antibiotics were introduced. 
Most were studies of pneumococcal or lobar pneumonia (these were synonymous at the time)
Most were studies of hospitalized patients.

We identified a number of  observational studies which compared mortality in patients treated with antibacterial drugs compared to those treated only with standard therapy (in other words, patients received no antibiotics or other specific anti-pneumococcal therapy). 

We also found a few controlled clinical trials in which patients were treated with either antibacterial drugs or no specific therapy. The latter group served as the untreated control. These studies evaluated either pneumococcal or lobar pneumonia (which were considered synonymous at the time).
 Notably, none of these controlled studies were performed in way that would be considered adequate for a clinical trial today. None used a true placebo-control, none were blinded, and they all used a rudimentary type of  randomization. 
2. In addition, we also reviewed other more recent data for evidence of antibacterial treatment effect, and Dr. Nambiar will review this information in the next presentation.

## History of Effective Treatment for Pneumococcal Pneumonia

| 1881 | Streptococcus (Diplococcus) pneumoniae identified as ‘the’ cause of pneumonia  |
| --- | --- |
| 1913 - 1940 | Serum Therapy  |
| 1938-1939 | Sulfapyridine |
| 1940 - 1945 | Penicillin and other antibiotics |

**Notes:**
This slide shows a brief history of effective treatment of pneumococcal pneumonia.

Streptococcus pneumoniae (previously called Diplococcus pneumoniae) was first identified  and considered as “the” cause of pneumonia in 1881, simultaneously by  Sternberg  in the US, and Pasteur in France. 

As early as 1913, specific pneumococcal antiserum was used for treatment of pneumococcal pneumonia with some success. (importance of diversity of pneumococcal types wasn’t recognized until 1910 (Neufeld)

In 1938 and 1939, sulfapyridine (a sulfonamide found to have antibacterial properties)  was first introduced into general practice for treatment of pneumonia not long after a few early clinical studies had demonstrated its efficacy. 

The true antibiotics, penicillin, tetracyclines and others first came into use for treatment of pneumonia in the 1940’s

## Natural History of CAP

*“**Recovery followed the ‘crisis’ - an abrupt decrease in temperature over 12 hours, accompanied by passage ‘from a condition of extreme distress and anxiety to one of comparative comfort’ - and occurred in a large proportion of cases. A fatal outcome was noted in 20-35%. Worse prognosis was evident in ‘drunkards’ and the elderly, with fatality increasing to 50-65% in the elderly in those in their 6th and 7th decades.”*
*	**- Sir William Osler, 1894, who succumbed to Haemophilus* 	*influenzae pneumonia in 1919*

**Notes:**
Before I show you the data, I’d like to show a quote from Sir William Osler (who himself died of  H. flu pneumonia and empyema in 1919, at age of 71).. He  described the natural history of CAP in the pre-antibiotic era as follows...

Except for descriptions like this, and a few observational studies of untreated pneumococcal pneumonia, we really know very little about the natural progression of untreated CAP.
For instance, we can’t really answer to the question: What proportion of patients with mild CAP would progress to more severe disease or death if not treated with antibacterial drugs?

## Percentage of Untreated Patients "Terminating by Recovery" by each Day in Seven Different Pneumococcal Types (Bullowa, 1937) 

**Notes:**
This figure was taken from a chapter published by Bullowa (1937) in his textbook on Management of Pneumonia for Med Students and Physicians. He described the proportion of patients with untreated pneumococcal pneumonia who recovered (i.e. had resolution of fever) over time. This figure refers only to resolution of fever. 
 There were 662 untreated cases  of pneumonia caused by 7 different pneumococcal types (each shown by different bar).
Time of fever resolution:  x axis from day 1 to  19 of illness.
% patients- y axis (ranging from 0 to 20%)
Population was not otherwise described.
The pattern of fever resolution followed a bell-shaped curve for this population, but 
Most patients defervesced on days 7 and 8, while only a  very small proportion had resolution of fever in first few days.
According to the author, a fall in the pulse rate could either precede or follow the fall in temperature; while breathing became normal at the same time that the  temperature fell to normal. 

## Pneumococcal Pneumonia (Untreated) in Infants and Children: Effect of Age and Bacteremia on MortalityBullowa (1937)

| Group | Percent Mortality
< 2 years old* | Percent Mortality
> 2 years old** |
| --- | --- | --- |
| Positive BC | 30/38 (79%) | 8/31 (26%)
 |
| Negative BC | 57/400 (14%) | 13/454 (3%) |
| All Cases | 87/438 (20%) | 21/485 (4%) |

- BC = blood culture

- *8.7% bacteremic

- **6.4% bacteremic

**Notes:**
Bullowa also described mortality in untreated pneumococcal pneumonia in infants and children.
This table shows mortality by age  (< 2 or > 2 years old) and by the presence of bacteremia. 

Overall mortality was highest in children under 2 years old compared to older children, and in those with bacteremia. 
Mortality was 79% in bacteremic infants and 14% in those who were non-bacteremic; while in older children, mortality was 26% in those with bacteremia compared to 3% in those who had negative blood cultures.

## OBSERVATIONAL STUDIES

**Notes:**
First, I’ll discuss the data from the observational studies...

## Slide 190

**Notes:**
Tilghman and Finland (1937)  reported percent mortality as a function of age and presence of bacteremia in prospective study 1,586 cases of pneumococcal pneumonia in Boston City Hospital (1929-1935).The majority  (1306/1586, 82%)of patients in this study received no specific treatment; however a small proportion received pneumococcal antiserum (n= 280/1586 (18%) 

This figure shows percent mortality by age (includes both those who received antiserum and those who did not).
Total N= 1586 ; 37% were bacteremic (n=582); 63% non-bacteremic (N=1004) 

Age groups:(63% < 50 years old)
12-19 n=146
20-29 n=235
30-39 n= 297
40-49 n= 319
50-59 n=278
60-69 n= 179
70+ n=132

A couple of important points in this figure from data of Tilghman and Finland 1937 on mortality in pneumococcal bacteremia in relation to age and bacteremia:

Overall mortality increased with age and with bacteremia for all cases (however, timing for determination of mortality was not reported- but was presumably measured during hospitalization): 

In bacteremic patients mortality increased from about 30% in youngest patients to 100% in the oldest patients.

Even in non-bacteremic patients mortality was about 10% in the youngest patients up to about age 40, then increased dramatically. 

2. The proportion of bacteremic cases increased with age (except for oldest patients in this study) (DOTTED LINE)
NOTE: the proportion of patients with bacteremia here is much higher than what we see in clinical trials of CAP today (4-9% for pneumococcal bacteremia in IV studies).

## Mortality in Pneumococcal Pneumonia Tilghman and Finland (1937)

| Treatment | Percent Mortality
Bacteremic
N=582 | Percent Mortality
Non-bacteremic
N=1004 | Percent Mortality
Overall
N=1586 |
| --- | --- | --- | --- |
| Serum | 46/102
(45%) | 21/176 
(12%) | 67/278  
(24%) |
| No serum | 405/480 
(84%) | 261/826 
(32%) | 666/1306 
(51%) |

**Notes:**
Tilghman and Finland  also described overall (all ages) mortality in the subsets of patients treated with serum or with no specific therapy.
Among bacteremic patients overall mortality was 84% (untreated) vs 45% treated (treatment difference of 39%)
 Among non-bacteremic patients, mortality was 32% (untreated) vs. 12% (treated) for treatment difference of 20%.
3. Overall, mortality was 51% (untreated) vs 24% (treated) for treatment difference of 27%

## Pneumococcal Pneumonia: Duration of Acute Illness (Tilghman and Finland, 1937)

**Pneumococcal Pneumonia: Duration of Acute Illness**** ****(Tilghman and Finland, 1937)**

**Notes:**
In the same study, the authors described duration of acute illness by presence of bacteremia  in patients treated with serum or no specific therapy.
This slide is a little difficult to read, so I’ll take some time to explain....
The upper chart refers to patients who received no specific therapy; while the lower chart refers to patients who received serum therapy.
X= duration of acute illness in days 
 y= number of cases (for each time period there are two bars, first represents bacteremic patients, and the second represents non-bacteremic patients. 
Note that the bars also include deaths which are shown at the lower portion of each bar;  while survivors are shown at the upper part of each bar. 

In those who did not receive serum, termination of the acute illness was observed most frequently between the 7th and 9th day; while  

Among patients treated with serum, the termination of the acute illness occurred earlier, most frequently by days 4 to 6. 

## Mortality in Pneumococcal PneumoniaFinland (1943)

**Notes:**
Maxwell Finland (1943) summarized mortality rates in patients with pneumococcal pneumonia at BCH,   comparing mortality in patients who received no specific treatment, to that in those treated with specific antiserum and those treated with sulfonamides. The latter two groups were historical controls.

Show Legend:
Untreated- open white bars (N=2832) (1929-1940)
Serum- treated -cross-hatched bars (N=1029) (1929-1938)
Sulfa-treated (sulfapyridine, sulfathiazole, or sulfadiazine) black bars (N= 1220) (1939-1941)
The upper left part of the figure shows all cases (bacteremic and non-bacteremic): 
Overall mortality (all ages, bacteremic or not) was 41-42% in untreated, and 17-18% in those who received sulfonamides for a treatment difference of  24%. Mortality increased with age. In patients > 50 years old, mortality was about 65% (untreated) and 25% sulfa-treated (treatment difference about 40%).

In the subset of bacteremic patients (lower left) the overall (all ages), mortality was higher (Untreated- 78%; treated- 30%) for a treatment difference  of  48% (78-31). Again in those > 50, mortality was higher (90% untreated, 42% treated)  for a treatment difference of about 48%. Note that number of patients in these subgroups (bacteremia and non-bacteremic) or in each age group was not reported. 

In comparison, for non-bacteremic patients of all ages combined, the treatment difference was relatively small- about 16% (28-12);but for patients 50 and above, the difference increased to about 36% (54-18).

So, if we look only at average treatment effect, regardless of age or bacteremia, we would likely underestimate the effect in older, bacteremic patients, and overestimate that in younger, non-bacteremic patients. 

## Treatment of Pneumococcal Pneumonia with PenicillinMeads, et al. (1945)

| Severity | Penicillin
N=37 | Penicillin after sulfa treatment
N=17 |
| --- | --- | --- |
| Grade 2 (moderate) | 15 | 1 |
| Grade 3 (acutely ill/irrational) | 9 | 5 |
| Grade 4 (shock &/or CHF)	 | 13 | 11 |

**Observational Study in patients with moderate-severe pneumococcal pneumonia**

**Notes:**
This was an small observational study by Max Finland’s group at Boston City Hospital in 1944 in which patients had moderate to severe pneumococcal pneumonia. This study doesn’t directly provide information about treatment effect over placebo, but it does provide some other useful information. 

In contrast to most other studies in this time period, patients were classified by severity at baseline, although no details were provided about how that was done. Grade 2 was defined as moderate severity; while patients with grades 3 and 4 had severe pneumonia (described as acutely ill, irrational; or as having  shock or CHF). 

There were two treatment groups, the first received penicillin alone, and the second received penicillin after failing sulfa or developing intolerance to sulfa. Note that severity is proportionally higher in the latter group (16/17= 94%) compared to 21/37 (56%) in former (pcn alone) group. So the treatment groups were not balanced by severity at baseline.

## Treatment of Pneumococcal Pneumonia with Penicillin: OutcomesMeads, et al. (1945)

| Outcome  | Penicillin 
(N=37) | Penicillin after sulfa failure or intolerance (N=17) |
| --- | --- | --- |
| Death | 7 (19%) | 3 (18%) |
| Relapse | 2 | 1 |
| Complications | 0 | 0 |
| Bacteremia after penicillin treatment | 0/12 | 4/6 |
| Duration of acute symptoms* < 48 hours | 27/30 (90%) | 9/14 (64%) |
| Duration of fever < 48 hours | 24/30 (80%) | 8/14 (57%) |

- *symptoms such as delirium, prostration, and dyspnea

**Notes:**
Outcomes were not reported by severity in this study , but 

We can see that overall mortality was 18-19% in both groups, numbers on the same order of magnitude of what we might expect today in treated patients with severe pneumococcal pneumonia.

 Another important point about this study was that in addition to mortality, other clinical outcomes were reported, including relapse, complications (empyema, etc...), bacteremia, duration of fever, and duration of symptoms such as.. For example, in the penicillin group, there were 2 relapses, 0 pyogenic complications, 0 reports of bacteremia after receipt of penicillin in patients from whom BCs were obtained, and the duration of acute symptoms and fever resolved quickly (in < 48 hours in the large majority of patients who received penicillin as initial therapy).

There were some differences in outcomes  between treatment groups, possibly because of differences in baseline severity, but  the real reason for showing this slide is not to show a treatment difference, but to show what might be expected if we measured other treatment outcomes when we consider alternative endpoints to mortality for CAP studies.

## Case Fatality Rate in Pneumococcal Pneumonia treated with Serum, Sulfonamides or “Antibiotics”  Dowling and Lepper (1951)

**Notes:**
Dowling and Lepper in 1951 compared case fatality rates in patients with pneumococcal pneumonia who received no specific treatment to those who received pneumococcal antiserum, sulfonamides, or penicillin and other antibiotics (1938-1950). The first two groups were historical controls from Boston City Hospital- Finland, and associates  (studied between 1939 and 1940).

This figure includes all patients (bacteremic and non-bacteremic).

Case fatality rate: Y-axis; age: x-axis; 
Legend: 
no specific treatment – solid line; 
pcn- triangles; 
sulfa-open squares; 
serum dotted line with closed circles
N=1087 untreated; 889 serum; 1274 sulfa; 920 pen/tet
Important Points:
1. Approximately 75% patients were < 50 years old; approximately 12% bacteremic
1a. Mortality increased with age in each treatment group
2. Lower mortality with serum therapy, but effect  appeared larger in younger than older patients
3. Treatment with sulfonamides reduced mortality further.
4. The largest treatment effect was seen with penicillin and other antibiotics
Treatment difference (Pcn-untreated)= 52% (> 70 yo), and about 10% for 20-29 yo. (differed with age), even less with the youngest patients shown here.

## Mortality in Pneumococcal Pneumonia with BacteremiaAustrian and Gold (1964)

- Prospective, observational study (1952-1962)
- N= 455 with bacteremic pneumococcal pneumonia without extra-pulmonary complications
- 50% < 50 years old; 55% had pre-existing co-morbidities
- Most treated with penicillin or other antibacterial agents (96%); while  4% received no specific treatment

**Notes:**
In 1964, Austrian and Gold described a prospective observational study of patients with pneumococcal bacteremia from 1952-1962. 
There were 455 patients with bacteremic pneumococcal pneumonia without extrapulmonary complications (e.g. meningitis). 
About half were under 50 years old, and 55% also had comorbidities such as cardiac disease. 
Most were treated with penicillin; while a small proportion (4%) received no specific therapy. This was a concurrent control group.

## Mortality in Pneumococcal Pneumonia with BacteremiaAustrian and Gold (1964)

| Treatment | Case Fatality Rate
n/N (%) |
| --- | --- |
| Penicillin | 57/338 (17%) |
| Tetracyclines | 10/55 (18%) |
| Erythromycin, chloramphenicol, streptomycin | 2/14 (14%) |
| “Mixed” | 6/30 (20%) |
| Any antibacterial treatment | 75/437 (17%) |
| No treatment | 14/17 (82%) |

**Notes:**
This table shows case fatality rate by treatment in this study.
Most patients were treated with penicillin (338), and case fatality rate in that group was 17%.
Similar case fatality rates were observed in all the other antibacterial treatment groups, for an average CFR of 17%.
Among those who received no specific therapy, 14/17 (82%) died.
 So the antibacterial treatment difference in bacteremic pneumococcal pneumonia was large (65%): 82% (untreated) minus 17% (any antibiotic).

## Survival in Bacteremic Pneumococcal Bacteremia Treated with Penicillin or Serum   Austrian and Gold (1964)

**Survival in Bacteremic Pneumococcal Bacteremia Treated with Penicillin or Serum**** ****  Austrian and Gold (1964)**

**Notes:**
Austrian and Gold also looked at survival in patients with bacteremic pneumococcal pneumonia over a 21 day time course in patients treated with penicillin (in their prospective case series) compared to historical controls groups treated with serum or no specific treatment. 

Legend:
Untreated :historical control: (17% survived by day 21) Tilghman and Finland-1929-1935) N= 384
serum: historical control (53% survived) (Tilghman and Finland) N= 93
Penicillin (85% survived) N= 298	

Treatment difference for patients with bacteremic pneumococcal pneumonia (pcn-untreated= 68%) at day 21	

For penicillin treated patients, 50% patients were < 50 years old (Austrian); and from Tilghman and Finland (historical controls) 63% patients were < 50 year years old.

## Observational Studies: Microbiology

| Study | Pathogen |
| --- | --- |
| Finland (1943) | S. pneumoniae |
| Dowling and Lepper (1951) | S. pneumoniae |
| Austrian and Gold (1964) | S. pneumoniae |

**Notes:**
All 3 of these observational studies evaluated only patients with pneumococcal pneumonia. 

## Slide 201

**Notes:**
This figure  summarizes the treatment effect based on mortality in pneumococcal pneumonia from the observational studies. Blue bars show percent mortality among patients who received no specific treatment, compared to that in patients who received sulfonamides or penicillin (lavender or gold). 

For the Finland study, overall mortality  (including all ages, both bacteremic and non-bacteremic patients) was 41% untreated vs. 17% for sulfa treated for a treatment difference of 24%. Remember, however, this is an average, and does not reflect the lower treatment difference in younger, non-bacteremic patients and much higher difference in  bacteremic patients overall (48%) as shown here. 

In the Dowling study, the overall (all ages) treatment difference was 18% for sulfa and 26% for penicillin.

And in the Austrian study, which looked only at bacteremic patients with pneumococcal pneumonia, the overall treatment difference was 65% between penicillin-treated and the concurrent untreated control group. 

## Summary of Antibacterial Drug Treatment Effect in Pneumococcal Pneumonia

| Observational Studies | Treatment vs. Untreated controls | Mortality Difference (95% confidence interval) |
| --- | --- | --- |
| Finland (1943) | Sulfonamides
 | 24% (21, 27)
48% (bacteremic) |
| Dowling and Lepper (1951) | Sulfonamides
Penicillin, tetracyclines | 18.5% (15, 21)
25.4% (22, 28) |
| Austrian and Gold (1964)
 | Penicillin, tetracyclines, other antibacterial drugs
 | 65% (47, 84)
(bacteremic) |

**Notes:**
This table summarizes the point estimates and 95% confidence intervals for the treatment effect (difference in mortality between treated and untreated controls) for patients with pneumococcal pneumonia in the observational studies. 

Overall (all ages) the point estimates for the treatment  difference in the observational studies ranged from approximately 19% (with sulfa treatment)  to 25% ( with penicillin treatment) in Dowling study, 24% overall for Finland study. The treatment difference was higher in bacteremic patients, ranging from 48% (Finland) to 65% (Austrian). 

## Observational Studies: Effect of Age on Mortality 

| Study | Treated < 50 years old | Untreated < 50 years old | Treated ≥ 50 years old | Untreated 
≥ 50 years old
 |
| --- | --- | --- | --- | --- |
| Finland (1943) | NR | NR | NR | NR |
| Dowling and Lepper (1951) | 97/1672 
(6%) | 139/715 (19%)
historical | 107/522 (20%) | 192/362 (53%)
historical |
| Austrian and Gold (1964)
(Bacteremic) | 13/178 
(7%) | 371/693 (73%)
historical | 44/160 
(28%) | 322/345 (93%)
historical |

**Notes:**
Recognizing the potential for bias in this post-hoc subset analysis, we looked at mortality  by age ( in subsets of patients < 50 and ≥ 50 years old) in  the observational studies.

For Finland’s summary, we could not determine the proportion of patients who were younger or older than 50  because  the number of patients was not reported by age.

For the other two studies, mortality was higher in patients who were at least 50 years old (treated or untreated) compared to younger patients. (e.g. in the Dowling and Lepper study, 20% treated patients at least 50 years old died; while 6% of those < 50 yo died; and among those  who received no specific therapy, 53% of those over 50 died in comparison to 19% < 50yo). Similar results were observed in the Austrian study. 

Treatment differences were: 
Dowling: 
19-6 (13%) in < 50
53-20 (33%) > 50
Austrian (bacteremic pn pneumonia):
73-7 (66%) < 50
93-28 (65%)> 50

## Controlled Clinical Trials

**Notes:**
Now I’d like to focus on some of the early controlled trials of antibacterial drugs for treatment of pneumonia. 
Note that None of  these studies would be considered adequate and well-controlled trials by today's standards. 

None use a true placebo-control, randomization methods were rudimentary at best, and neither patients nor investigators were blinded.  

## Controlled Clinical Trial- Serotherapy Park, et al. (1928) 

- Alternate patients with lobar pneumonia
- Treatment:
**Polyvalent antiserum:** pneumococcal types I, II, III
- or:
**Standard treatment:** fluids, pain relief with elastic adhesive plaster, restriction of opiates, no drastic catharsis, oxygen for cyanosis or rapid breathing, digitalization for heart rate > 120

**Notes:**
In this study by Park and colleagues in 1928, alternate patients with lobar pneumonia, who were admitted to Harlem Hospital from 1927-1928, were treated with pneumococcal antiserum (specific for types I, II and III) or with standard treatment, which consisted of...

Alternate- in order of admission
Micro:
Ages: 

## Case Fatality Rate in Patients with Type I Pneumococcal Pneumonia by Severity: (Park, et al., 1928)

| Condition at baseline
 | Serum-treated  | Standard treatment  | Treatment Difference |
| --- | --- | --- | --- |
| Any condition | 20% (N=114) | 34% (N= 109) | 14% |
| Good
(> 70) | 9% | 13% | 4% |
| Fair (50-70) | 29% | 52% | 23% |
| Poor (< 50) | 64% | 100% | 36% |

**Notes:**
This table shows  the case fatality rate for the subset of patients in Park’s study with type I pneumococcal pneumonia. 

These patients were classified by (condition at baseline), but the scoring  method was not described. This was the only study we found that reported outcome by severity. 

Condition at baseline is shown in the first column; and case fatality rate for patients who received either serum treatment or standard therapy are shown in the next two columns. Note that the number of patients classified as good, fair or poor at baseline was not reported. 

For some perspective, the first row shows that the overall  (for all baseline conditions) case fatality rate in those with type I pneumococcal pneumonia (at Harlem hospital only), was 34% with standard treatment and 20% with serum treatment, for a treatment difference of 14%.

Notice that the both case fatality rate and the treatment difference increased with increasing severity of illness regardless of treatment. 

Also note that the case fatality rate for patients in good condition at baseline was relatively low (13% for standard therapy) and only slightly better if treated with antiserum for a treatment difference of only 4%.

 Recognizing the many limitations of these data (not blinded, no true placebo, subset analyses, number in each group unknown, and limited information on severity of illness) if we were to say that the patients in good condition were similar to those  we might classify today as having mild pneumonia , then this number (13% death or 87% survival) without antibacterial treatment could potentially be considered as a minimum estimate of the placebo rate (rate of spontaneous resolution) for patients with mild pneumococcal pneumonia.  
As noted previously, the treatment difference (pneumococcal serum- standard therapy= placebo) for this group is small (only 4%), but might expected a larger treatment difference for antibacterial drug treatment. 

## Controlled Clinical Trial of Treatment of Lobar Pneumonia  Evans and Gaisford (1938)

| All patients | M & B 693
(Sulfapyridine) | Control |
| --- | --- | --- |
| All patients
 | 8/100 (8%) | 27/100 (27%) |
| Age > 50
 | 4/18 (22%) | 7/10 (70%) |

**Treatment:** M&B 693: 2-(p-aminobenzenesulphonamide) pyridine
**Control:** Non-specific treatment (presumed standard of care)
**Population:** Hospitalized patients with lobar pneumonia (8 - 68 years old); 86% < 50 years old; proportion bacteremic not reported; specific pneumococcal serotypes reported in 22%; 78% were not identified.
**Treatment group:** Determined by enrollment on alternate day
**Excluded:** Patients who died within 24 hours

- Case Fatality Rate

**Notes:**
This study by Evans and Gaisford (1938), evaluated case fatality rates in alternate patients with lobar pneumonia treated with sulfapyridine ( called M&B 693) or with no specific treatment. 
Not blinded.
Describe the population: ____
Specific pneumococcal type determined in 44/200 (22%); and in the other 78%, a specific organism was not reported, so there was no information on total proportion patients with pneumococcus. However, at that time, lobar pneumonia was generally thought to be pneumococcal.  Staphylococci were reported in at least a few cases. 

Case-fatality rate was 27% overall in the control group, and 8% in the sulfapyridine group; while in the subset of patients age 50 and above, rates were 70% and 22%, respectively.

Note: low doses sulfapyridine, later considered ineffective by the authors were given early in the study

## Resolution of Fever Evans and Gaisford (1938)

| Treatment Group | N | Cumulative Resolution of Fever within 48 hours
N (%) |
| --- | --- | --- |
| Treated  | 100 | 60 (60%) |
| Control | 100 | 34 (34%) |

**Notes:**
The authors also described the effect of sulfapyridine on fever resolution. 
Among  those treated with sulfapyridine, 60%  had resolution of fever within 48 hours in comparison to 34% of those who received no specific treatment.

## Follow-up Case Series: Gaisford (1939)

- 400 cases lobar pneumonia (hospitalized)
- Includes 100 cases previously described  in Evans and Gaisford (1938)
- Proportion of bacteremic patients not reported
- Excluded deaths within 12 hours of admission

**Notes:**
The following year, Gaisford published a follow-up case series of 400 patients with lobar pneumonia treated with sulfapyridine, including the 100 patients previously described by Evans and Gaisford  (1938).
Microbiology of pneumonia was not described at baseline (except among patients who died (26 deaths- 11 with S. pneumoniae, 2 Staph, 2 strep, 1 TB, 1 Friedlander’s bacillus, 13 not isolated or not reported (probably some mixed infections). 
Proportion bacteremic: not reported
Compared case fatality rates in sulfapyridine-treated patients with historical controls (untreated) at the same hospital in preceding years. 
Excluded deaths within 12 hours of admission.

## Case Fatality Rates by Age in Lobar Pneumonia (Gaisford, 1939)

| Age Range
(years) | Untreated
1936
n/N (%) | Untreated
1937
n/N (%) | Sulfapyridine
1938-1939
n/N (%) |
| --- | --- | --- | --- |
| 5-19 | 5/127 (4) | 7/153 (5) | 0/115 (0) |
| 20-50 | 53/216 (25) | 54/230 (23) | 5/199 (3) |
| ≥ 50  | 35/72 (49) | 39/78 (50) | 21/86 (24) |
| All Ages | 93/415 (22) | 100/461 (22) | 26/400 (7) |

**Notes:**
This table shows the outcomes in 400 patients treated with sulfapyridine between 1938 and 1989, and in  patients who received no specific therapy for lobar pneumonia in the preceding years, 1936 and 1937,  at the same hospital. 
Results are shown by age: 
Age distribution:
50% patients were between 20 and 50 years old
Approximately 30% ages 5-19
19% > 50 years old
Results: 
Case fatality rate increased with age in treated and untreated patients.
Overall (all ages) treatment difference was 15% ( 22% untreated minus 7% treated), and again the treatment difference increased with age: 
 For youngest group treatment difference was approx. 4.5% (4.5-0)
For 20-50 year olds, treatment difference was approx. 21% (24-3)
For > 50 year olds, treatment difference was approx. 26% (49.5-24)

## Controlled Clinical Trial: Treatment of  Pneumococcal Pneumonia with Sulfapyridine Graham, et al. (1939)

| Dagenan (M&B 693)
 | Controls |
| --- | --- |
| 3/50 (6%) | 7/30 (23%)
 |
| 3/17 (18%) bacteremic | 3/6 (50%) bacteremic |

- Hospitalized patients with primarily pneumococcal pneumonia (14% had other unidentified pathogens)
- Alternate patients
- Age < 50 years: 70% overall; bacteremia 29% overall
- Control: no specific therapy (20% bacteremic)
- Dagenan (M&B 693) = Sulfapyridine (34% bacteremic)

- Case Fatality Rate

**Notes:**
In a small study by Graham and colleagues (1939) alternate  patients with pneumococcal pneumonia were treated with sulfapyridine or with no specific therapy **(note 14% patients had other non-pneumococcal pathogens, but these were not identified).
Alternate patients to receive (sulfapyridine) or control
Not blinded
Population- hospitalized; 70% < 50 years old; 29% were bacteremic overall (some imbalance between treatment groups, 34% bacteremic in treated group, 20% in untreated group)
CFR was 23% in untreated and 6% in sulfa-treated patients. Treatment difference was 17% overall. (again small doses were used in the beginning of the study). 
CFR was higher among bacteremic patients (3/17 [18%] –treated; 3/6 [50%]  in control group; for treatment difference of 32%, although the numbers were really quite small. 

## Controlled Clinical Trial: Treatment of  Lobar Pneumonia with SulfapyridineAgranat, et al. (1939)

- Lobar pneumonia (microbiology not described)
- Several study sites in South Africa: results reported separately
- Sulfapyridine vs. control (method of treatment allocation was by admission to separate ward with “no selection”)
- Site 1: Johannesburg Hospital
- Europeans (97% < 50 years old)
- Non-Europeans (81% < 50 years old)
- Mild (+), Moderate (++), Severe (+++)
- 32-33% severe in treated groups
- 17-26% severe in untreated groups
- Proportion bacteremic patients not reported
- Results of other sites not reported here because of differences in patient populations and disease severity

**Notes:**
In another early controlled trial, Agranat and colleagues evaluated sulfapyridine for treatment of lobar pneumonia. As mentioned previously,  in 1938 lobar pneumonia was considered virtually synonymous with pneumococcal pneumonia, and we can probably presume that most cases were pneumococcal. 

There were several study sites, and results were reported separately for each. I’m going to discuss results from only one of the study sites (Johannesburg Hospital)- best described, and patient populations were also quite different at the other sites (younger, less severe disease).  

Patients were allocated to sulfa or no treatment by admission to separate wards reported with no selection.
At this site, there were different medical units for the European and non-European patients, and results for each subset was reported separately (so there were 2 treatment and 2 control groups).   
The large majority of patients in both groups were under 50 years old.
Patients were classified as having mild, moderate, or severe disease graded as 1+ to 3+, but there are no details on exactly how that was done. 
Overall more patients with severe disease were in the treated than untreated groups.
The proportion of patients with bacteremia was not reported. 

## Case Fatality RatesAgranat, et al. (1939)

| Subset | Control | Sulfapyridine |
| --- | --- | --- |
| Europeans
 | 6/27 (22%) | 2/22 (7%) |
| Non-Europeans | 16/86 (19%) | 6/71 (9%) |

- Case Fatality Rate

**Notes:**
In each of the subsets, case fatality rates were higher in the control groups than the sulfapyridine treatment groups, with treatment differences of 15% (European) and 10% (non-European).

## Resolution of FeverAgranat, et al. (1939)

| Days hospitalized with fever | Non-European
Control
N=86 | Non-European
Treated
N=71 | European
Control
N=23 | European 
Treated
N=22 |
| --- | --- | --- | --- | --- |
|  | % patients | % patients | % patients | % patients |
| 1 | 1.4 | 12.3 | 0 | 26.1 |
| 2 | 8.6 | 21.5 | 0 | 34.8 |
| 3 | 17.1 | 18.5 | 10 | 8.7 |
| Cumulative % at 3 days | 27 | 52 | 10 | 70% |

**Notes:**
These investigators also reported the number of days of hospitalization with fever after receipt of sulfa or control. (return to normal temperature). 
In the subset of non-European patients, 52% treated patients had resolution of fever within 3 days compared to 27% of those who received no treatment; while in the European subset, 70% patients had resolution of fever within 3 days compared to 10% of those who received no treatment. 

## Controlled Trials :Microbiology 

| Observational Studies: | Pathogens Reported |
| --- | --- |
| Evans and Gaisford (1938) | Pneumococcal types I, II, III, and IV in 44/200 (22%) cases; 78% not reported  |
| Graham, et al. (1939) | S. pneumoniae in 69/80 (86%); 11/86 (14%) not pneumococcal |
| Agranat et al. (1939) | Not reported except in 2 deaths: 
S. pneumoniae, Staphylococcus |

**Notes:**
This table summarizes what we know about the microbiology of pneumonia in each of the 3 controlled studies which describe an antibacterial treatment effect. 
In Evans and Gaisford, specific pneumococcal types, I, II, III and IV were reported in 44 cases (22%) cases; but the pathogen was not reported in the other 78%- these could have been pneumococcus of other serologic types or other pathogens.

In the Graham study, S. pneumoniae was identified in 86% cases; while other non-pneumococcal pathogens (specific organisms were not reported) were present in 14%.

In the Agranat study, microbiological findings were not reported at baseline, but were reported for two of the deaths -S. pneumoniae was isolated in one patient who died, and Staph aureus in another.

## Slide 216

**Notes:**
This slide summarizes the Antibacterial Treatment effect from the controlled clinical trials of CAP which I just described.  
Treatment difference varied from 10%-15%  in the two subsets of patients in the Agranat study, 
In comparison, treatment differences were 17% (Graham) and  19% (Evans) 
----------------------------
Why are the treatment  differences smaller than those seen in the observational studies described earlier?
we think a number of factors could account for this difference: 

These studies were done before the availability of penicillin and other more active antibiotics, so the treatment differences are smaller than what I’ve described in the observational studies.  Additionally, we know very little about the baseline severity in these patients. In some cases (Agranat), patients who died within 24 hours were excluded from the analysis (also severity was greater in treated than untreated groups). Also in some cases (In Evans study), low doses, later considered ineffective were given early in the study.

Previously showed that in the Evans study if you look only at patients age 50 and above, the treatment difference was 48% (70-22%).
Details:
Agranat: Number of issues with this study. There were several sub-studies in different locations, details of all were not reported. In these 2 sub-studies, Higher severity at baseline  in treated patients, and There was a higher proportion of patients under 50 among untreated patients. They also excluded 2 patients who died in the control from the analysis.

Graham: Treatment difference was 17% overall (sulfa vs non-specific) (again small doses were used in the beginning of the study). Proportion of bacteremias was higher in treated group-34% and 20% in untreated group, and Mortality among bacteremic patients was higher- 3/17 (17%) –treated; 50% in control group. 

Evans: lobar pneumonia-treatment difference was 19% (sulfa pyridine- smaller doses given in the beginning of the study). Patients who died within 24 hours of admission were excluded in both groups. (There were 26% 3+ severe cases and 7/26 (27%) died- not clear how many in each group).

.

## Summary of Antibacterial Drug Treatment Effect in Pneumococcal Pneumonia

| Controlled Studies | Treatment vs. untreated controls | Difference in Case Fatality Rate 
(95% confidence interval) |
| --- | --- | --- |
| Evans and Gaisford (1938) | Sulfapyridine
 | 19% (8.8, 29.2) |
| Graham, et al., (1939) | Sulfapyridine
 | 17% (0.1, 36.4)
32% (bacteremic) |
| Agranat, et al. (1939) | Sulfapyridine
 | 10% (-0.3, 20.6)
15% (-6.2, 35.5) |

**Notes:**
This table summarizes both the point estimates and 95% confidence intervals for  the treatment difference (difference in case-fatality rates) reported in the early controlled trials:
As already mentioned, the point estimates for the Treatment differences varied from 10%-15% (Agranat study), 17% (Graham- sulfa) ( 32% in bacteremic patients, to 19% (Evans- sulfa). Dr. Valappil will be discussing the statistical implications of these data later today, but note the wide confidence intervals here which may be due in part to relatively small numbers of patients in the studies. 
-----------------------------------------------------------------------

Previously showed that in the Evans study if you look only at patients age 50 and above, the treatment difference was 48% (70-22%).
Details:
Agranat: Number of issues with this study. There were several sub-studies in different locations, details of all were not reported. In these 2 sub-studies, Higher severity at baseline  in treated patients, and There was a higher proportion of patients under 50 among untreated patients. They also excluded 2 patients who died in the control from the analysis.

Graham: Treatment difference was 17% overall (sulfa vs non-specific) (again small doses were used in the beginning of the study). Proportion of bacteremias was higher in treated group-34% and 20% in untreated group, and Mortality among bacteremic patients was higher- 3/17 (17%) –treated; 50% in control group. 

Evans: lobar pneumonia-treatment difference was 19% (sulfa pyridine- smaller doses given in the beginning of the study). Patients who died within 24 hours of admission were excluded in both groups. (There were 26% 3+ severe cases and 7/26 (27%) died- not clear how many in each group).

.

## Mycoplasma Pneumonia: Randomized Controlled TrialsKingston, et al. (1961)

- Randomized, double-blind, placebo-controlled trial
- Military recruits (age 17-22);
- Total N= 300; (subgroup of “Eaton-agent” positive N=133)
- “Eaton agent” (*Mycoplasma*) diagnosed serologically; and nose and throat cultures were negative for pneumococcus and streptococci.
- Treatment: Tetracycline (demeclocycline) vs. placebo

**Notes:**
The next few slides discuss evidence for a treatment effect in CAP due to Mycoplasma. 
The organism, Mycoplasma pneumoniae causes atypical pneumonia (pneumonia caused by an atypical pathogen- initially thought not to be bacteria because they are difficult to culture). Mycoplasma pneumonia was  previously referred to as  “walking pneumonia” named as such because it is generally fairly benign in its course and only rarely results in death. Mycoplasma is common in patients with CAP treated in the outpatient setting. 

There are two published randomized, double-blind, placebo- controlled trials of pneumonia due to Mycoplasma. 

In the first study, Kingston and colleagues in 1961 studied young, healthy military recruits ages 17-22. A total of 300 patients enrolled (290 completed study), and 133 patients were positive for the “Eaton agent” (the old name for Mycoplasma) as determined by 4-fold rise in antibody titer.(109 had Mycoplasma alone, while 24 had Mycoplasma plus respiratory virus; and 35 had respiratory virus alone, and 122 had no pathogen identified).
Patients were included in the study only if they had an illness of < 5 days duration, a temperature of more than 100 F, a  CXR consistent with atypical pneumonia, and negative cultures of the nose and throat for pneumococci or streptococci.
Patients were randomized to  demeclocycline  (a tetracycline) or placebo capsules. (Randomization was performed by using a table of random numbers).
All patients were treated in an open ward, with the same symptomatic treatment, and all received 4 days of bedrest. Each patient was examined daily and questioned for cough , sputum, fatigue, malaise, headache and anorexia. Temperatures were recorded 4 times daily. 

## Duration of Fever in Mycoplasma Pneumonia: Effect of Treatment(Kingston, et al. 1961)

**Notes:**
This figure from Kingston’s study, shows duration of fever over time (x-axis= days) by the cumulative percentage of patients (y-axis).  By day 3, fever had resolved in 70% treated patients compared to approximately 5% of  untreated patients, for a treatment difference at day 3of 65%. Although I’m not going to show the figure, the treatment difference at day 3 was approximately  40% in the subset of patients who had no identified pathogen, but were negative for respiratory viruses. Presumably those patients also had Mycoplasma or another atypical pathogen.  

These data on fever resolution should be interpreted with caution (not a true Kaplan-Meier analysis), but rather shows cumulative percentage over time, so the treatment effect  may be magnified. 

Additionally, this was a subset analysis and Mycoplasma was identified serologically, which even today is not a very sensitive or specific test. 

## Mycoplasma Pneumonia: OutcomesKingston, et al., (1961)

| Parameter | Treated
Mean Duration (days) | Placebo
Mean Duration (days) | Treatment Difference (days) |
| --- | --- | --- | --- |
| Temperature 100oF | 2.1 | 8.1 | 6.0 |
| Abnormal CXR | 9.5 | 20.0 | 10.5 |
| Rales | 6.9 | 15.5 | 8.6 |
| Cough | 9.7 | 22.0 | 12.3 |
| Bed rest | 5.8 | 9.2 | 3.4 |
| Fatigue, malaise | 2.7 | 8.5 | 5.8 |
| Anorexia | 2.0 | 7.0 | 5.0 |

**Notes:**
Kingston also looked at mean duration of fever and other parameters, including  cough, fatigue, anorexia, etc...in  the subset of patient with Mycoplasma alone (n=109). 
A treatment difference based on mean duration (in days) was determined. So, for example,  the treatment differences were 6 days for fever < 100 F, 12.3 days for duration of cough, and 10.5 days for duration of CXR abnormalities, and so on. 

## Mycoplasma Pneumonia: Randomized, Controlled Trials (Smilack, et al., 1974) 

- Randomized, placebo-controlled, double-blind trial
- Population: hospitalized military personnel, mostly male, 17 to 23 years old (n=130; *Mycoplasma* confirmed in 32)
- Diagnosis: serological; bacterial pathogen-negative by culture
- Treatment: clindamycin (n=9), tetracycline (n=15), or placebo (n=8)
- Antipyretic use in 8 patients (clindamycin:1; tetracycline: 4; placebo: 3)

**Notes:**
The second randomized, double-blind, placebo-controlled trial which evaluated treatment of Mycoplasma pneumonia was published by Smilack, and colleagues in 1974. 
Again the population studied was hospitalized military personnel, who were young (17-23) and healthy. 
Total number enrolled was 130, but only 32 were found to have Mycoplasma serologically (4-fold rise in CF titer). 
Of the 32 patients with Mycoplasma, 9 received clindamycin, 15 received tetracycline, and 8 received placebo. It’s not clear why the numbers of patients were so different for each group, if patients were truly randomized. 
Endpoints were fever duration and length of time required for clearing of pulmonary infiltrates on CXR . 

Antipyretic (aspirin or acetominophen) use was reported in ....

## Mycoplasma Pneumonia: OutcomesSmilack, et al. (1974)

- Duration of Fever > 99o F

**Notes:**
This figure shows outcome (duration of fever > 99 F) in hours on the Y-axis ; and X-axis  shows treatment groups (clinda, tet, and placebo).
Circles represent individual patients, and the heavy horizontal line represents average duration of fever in hours. 
The mean duration of fever was 39 hours in the tetracycline group, 72 hours in the clindamycin group, and 76 hours in the placebo group. The authors found that the difference in fever duration between the clindamycin and placebo group was not significant (Kruskal-Wallis one way ANOVA for non-parametric analysis); whereas treatment with tetracycline was associated with a significant reduction in duration of fever  relative to placebo (p= .01 by the same type of analysis).

Among 18 patients who had follow-up CXRs, time required for clearing of infiltrates was shorter in those who received tetracycline compared to placebo, but was not significant at a level of p > .05. (16.3 days (placebo), 17.6 days (clinda), and 10.7 days (tet).

## Summary: Mycoplasma Pneumonia Studies

- Treatment effect of antibacterial drugs shown in young, healthy patients on:
- Decreased duration of fever (and other signs and symptoms), hospitalization, CXR abnormalities
- Caveats: Reporting of antipyretic use  inconsistent among studies; and some uncertainty in data
- Can these data be extrapolated to all outpatients with CAP?
- Can these data be used to determine a non-inferiority margin for outpatient CAP?

**Notes:**
So to summarize the studies of Mycoplasma pneumonia, there  appears to be an antibacterial  treatment effect in young, healthy patients based on duration of fever and other signs and symptoms. However, among other caveats, reporting of antipyretic use was inconsistent, and outcomes may have been confounded by use of these concomitant medications,  and there also remains some uncertainty in these data,. (small studies, subset analysis...) This leaves us with the questions...

## Limitations of using the Historical Data to Estimate Treatment Effect

**Differences in Patient Populations: **
- e.g. co-morbidities, immune status, pneumococcal vaccination
**Differences in Organisms/Disease:**
- Mostly hospitalized patients with pneumococcal pneumonia
- Severity was not well-characterized
- Most CAP now treated in outpatient setting
*S. pneumoniae* isolated less frequently
- Atypical organisms common in mild CAP
**Differences in Standard of Care**
**Differences in Study Design:**
- Observational data
- Controlled trials were not randomized or blinded
- Endpoints: mortality vs. clinical response
- Study drugs: penicillin, sulfonamides, tetracyclines

**Notes:**
There are many limitations to using the data from the early studies I described today, to estimate the  treatment difference between antibacterial drugs and placebo, including...
Differences in patient populations between early studies and today (due to...)
Differences in the organisms and the disease (the older studies evaluated..)
Differences in Standards of Care
And Difference in study design. Some of the data presented were from observational studies; while except for the more recent Mycoplasma studies, the controlled trials were not truly randomized, were not blinded, and did not use a true placebo. 
Different Endpoints: Mortality or case fatality rates were generally assessed as endpoints in the older studies; while in current CAP studies, clinical response has generally been used as the primary endpoint. 
 As Dr. Nambiar will discuss further, it may be very difficult to use mortality as a primary endpoint for CAP studies today. In the recent CAP studies, mortality rates are relatively low probably for a variety of reasons, including availability of effective therapy,  higher standards of care than when the early studies were performed, and pneumococcal vaccination. Additionally, patients are diagnosed and treated earlier today, and patients who are failing study therapy would receive some type of rescue therapy to prevent disease progression and death.

## Conclusions

- Evidence for treatment effect of antibacterial drugs in hospitalized patients with CAP (pneumococcal or lobar pneumonia) based primarily on a mortality benefit
- Limited data on the treatment effect for other endpoints such as time to resolution of signs and symptoms of CAP
- Evidence, albeit limited, for antibacterial effect on resolution of signs and symptoms in atypical (*Mycoplasma*) pneumonia

**Notes:**
In conclusion, I have shown evidence for....
There is also limited data on...
Additionally, there is some limited evidence for an antibacterial treatment effect on resolution of signs and symptoms in pneumonia caused by Mycoplasma. 
Thank you for your attention.

## Contemporary CAP trials and determination of treatment effect

- Sumati Nambiar MD MPH
- Medical Team Leader
- Division of Anti-Infective
- and Ophthalmology Products

## Overview

- Summary of recent CAP trials (oral and IV studies)
- Linking historical studies to contemporary CAP trials
- Alternate approaches to determining treatment effect

**Notes:**
Remember to acknowledge Karen, say it was presented at workshop etc.

## Study design

- Inclusion criteria included presence of new infiltrate(s) on chest x-ray AND at least 2 of the following signs or symptoms:
- cough, sputum production, auscultatory findings, dyspnea, tachypnea, fever, elevated WBC, hypoxemia
- Microbiologic evaluation was to be performed on each patient
- isolation of a pathogen not required for overall evaluability
- Primary endpoint was clinical cure at the test of cure visit, 7 – 21 days after completion of therapy
- Primary analyses populations: ITT and per protocol

**Notes:**
All 7 studies were randomized, double-blind trials designed to show similar effectiveness to an approved product... so they were all NI studies.  

In general the diagnosis of CAP was based on the presence of a new infiltrate on chest x-ray and at least 2 of the following signs and symptoms:  cough, sputum production, auscultatory findings, dyspnea or tachypnea (TA-kip-nea), fever, elevated WBC, hypoxemia .  Note the inclusion/exclusion varied slightly from study to study.  

Some of the studies limited enrollment to patients in Fine Class <= II or <= III.

Microbiologic evaluation was performed on each patient, though isolation of a pathogen was not required for overall evaluability.
---------------------------------------------

## Outcomes

- Clinical cure:
- Complete resolution or improvement of all signs and symptoms
- Improvement or lack of progression of all abnormalities on chest radiograph
- No additional antibacterial therapy required
- Microbiologic response:
- Eradication: Absence of original pathogen from TOC culture
- Persistence: Presence of original pathogen in TOC culture
- Presumed eradication: Clinical cure without specimen for culture
- Presumed persistence: Clinical failure without culture of specimen

**Notes:**
Patients were assessed for outcome at the test of cure visit which in most all the studies occurred 7 – 21 days after completion of therapy.  The clinical outcome was primary and defined as:
complete resolution or improvement of all signs and symptoms of pneumonia and improvement or lack of progression of all abnormalities on chest radiograph such that no additional antibacterial therapy is required.

A microbiological response was also defined with outcomes being 
	Eradication: absence of original pathogen from TOC culture,
	Presumed eradication: Clinical cure without specimen for culture
	Persistence:  Presence of original pathogen in TOC culture
	Presumed persistence: Clinical failure without culture of specimen
----------------------------------------------------------------------------------------------

## Analysis Populations

- Intent to treat (ITT)
- All randomized patients
- Per Protocol or Clinically Evaluable
- ITT patients without any major protocol violations
- Modified/Microbiologic ITT (MITT):
- ITT patients with baseline pathogen, including serologic diagnosis
- Microbiologically Evaluable:
- MITT patients without any major protocol violations

**Notes:**
The following four analysis populations were often defined in the protocol or discussed in the FDA reviews.  They were the Intent to treat population defined as all randomized subjects.  
The per protocol population, sometimes called the clinically evaluable, which includes all ITT subjects who do not have any major protocol violations.  
The Modified (or microbiological) ITT, which contain all ITT subjects with a pre-treatment pathogen isolated.  
And the Microevaluable, which includes all MITT subjects who do not have any major protocol violation.  
Since not all subjects were required or expected in these studies to have a pre-treatment pathogen isolated, analyses using these last two populations are usually considered as sensitivity analyses only.

Regarding which population should be considered primary:  Many believe that the per protocol population is the most relevant for NI studies, because it removes subjects who may otherwise cloud the ability to see a treatment effect if one actually existed.  For example, if some subjects in each arm did not receive a minimally effective dose of therapy, including these subjects into the analysis may have the effect of making the two treatment arms look more similar than they actually are. Thereby making the ITT population a “less conservative” population compared to the per protocol.   

However, many others are uncomfortable with the per protocol population alone as primary because this population excludes subjects after randomization for reasons that may be drug-related and therefore you may end up with a biased population.  A population where the two treatment arms may not be similar at baseline, potentially losing much of the benefit of randomization.  

For NI studies, there ARE drawbacks with both populations which is why the PP and ITT are often considered equally important. 
----------------------------------------------------------------------------

## Oral CAP studies

- Seven comparative studies conducted from
-     2000-present
- Most were multinational
- Randomized, double-blind, non-inferiority trials
- Pre-specified non-inferiority margin was 10 or 15%
- 300-500 randomized patients per study
- Active controls included clarithromycin, amoxicillin/clavulanate and levofloxacin

**Notes:**
So those are NI issues to keep in mind as I give you an overview of recent CAP trials seen at FDA.

As I stated earlier, I will review recent oral-only studies for CAP. I looked at only comparative studies, that were conducted within the last 8 years. 

There were 7 studies. Their sizes ranged from approximately 300 subjects to 500 subjects.  
The control varied but included clalrithromycin, amoxicillin/clavulanate, and levofloxacin.  All of these studies closely followed the 1998 Draft guidance for the developing antimicrobial drugs for treatment of CAP.  
----------------------------------------------------

## Clinical Features

- Cough: 97 - 100%
- Sputum Production: 75% - 100%
- Fever: 19% -33% (98% outlier)
- Chills: 1-6% (69% outlier)
- Shortness of Breath: 18% - 100%
- Chest Pain: 41% - 76%
- Multilobe involvement: 16-25%

**Notes:**
This slide is to give a sense of the signs and symptoms seen at baseline.  As mentioned earlier, some amount of signs and symptoms were necessary for inclusion into the study.

 I’ve highlighted in turquoise the outliers when one existed.  

Almost all patients in all studies had cough and sputum production. Note that many of the studies REQUIRED cough and sputum production for entry.  A smaller percentage of subjects had fever, the 98% is an outlier (and a requirement for that particular study).  The percentage of subjects with shortness of breath varied greatly among studies – anywhere from 18% to 100%.  This is also true for Chest Pain (varied from 41% to 100%).  Multilobe involvement based on x-ray was close to 20% in all studies.  Note that all studies required some amount of x-ray finding. Bacteremia was rare, between 0 and 8%, with 0 to 2% Strep. Pneumo bacteremia.  
-----------------------------------------------------------------------------------------------------------------

## Baseline pathogens

## Clinical outcomes

**Clinical outcomes**

**  **

** **

**Intent to Treat**

**Per Protocol**

**Notes:**
The shows the comparative results (the primary analysis) for clinical response. The bars represent the 95% CI for the treatment difference, those with the green squares the ITT and those with the pink squares PP populations. Most studies 80% or more ITT, 90% for PP

Each study is here twice. The green squares are the point estimates of the difference for the ITT population and the pink squares are for the PP population, the white lines are the 95% confidence interval of the difference. In all of these studies the PP and the ITT track very closely.  

Notice that there is no clear pattern with which – the PP or ITT – will lead to a larger point estimate, or a higher lower bound.

CLICK
All of these studies would have been able to claim NI with a 15% margin.  

CLICK
All but two with a 10% margin.
---------------------------------------------------------------------------------------------------------------------

## Summary of oral CAP studies

- Age
- Mean 46 years (range 18 to 98 years)
- Middle 50% of the population ranged from 35 – 55 years
- PORT scores
- Majority of patients had PORT scores  II
- 5 to 10% of patients had PORT score of III
- Microbiology:
- Baseline pathogens identified in 45%-75%
- 6-20% had *S. pneumoniae*
- 0-2% had* S. pneumoniae *bacteremia
- Outcomes:
- Clinical cure, > 80% ITT and ≥90% PP
- Mortality <2%

**Notes:**
All of these studes were multi-national studies.  Five of the 7 studies included subjects from the US.  However, US subjects made up over 50% of the population in only 2 studies.
Many subjects were also enrolled from Europe, South America and Canada.
The number of countries per study ranged from 3 to 14 countries. 
The number of sites included in a study ranged from 40 to 80 sites.

The age of subjects ranged from 18 to 98 years.  
The Mean age was 46,  The median age was 45
The middle 50% of the population ranged from 35 to 55 years old.

## IV CAP studies

- Similar design as the oral only studies
- Some were open label
- Endpoints and analysis populations similar to oral CAP studies
- Study size ranged from about 300 – 700 patients

**Notes:**
These next two slides give a brief summary of the IV to oral CAP studies recently seen at the FDA.

These studies were similarly designed as the oral studies.  Some however were not blinded.  

A requirement for IV studies was that patients be newly hospitalized, within 24 hours prior to enrollment into the study.

The endpoints, definition of analysis populations, and primary analysis were the same as the oral studies.  

The sizes of the studies ranged from about 300 to about 700 subjects.
----------------------------------------------------------------------------

## Summary of IV CAP studies

- Age:
- Mean 56 years (range 13-97 years)
- Middle 50% 40-70 years
- PORT scores:
- 55% PORT I and II
- 20% PORT III or PORT IV
- < 5% PORT V
- Microbiology:
- Baseline pathogens identified in 30-55%
- 20% had *S. pneumoniae*
- 4-9 % had *S. pneumoniae* bacteremia
- Outcomes:
- Clinical cure, 80% ITT and 90% PP
- Mortality, 2-4%

## Bridging the gap

## CAP Studies in early 1900’s

- Hospitalized patients
- Severity of disease unclear
- Reasonable to assume that most had moderate-severe disease
- No standardized classification system
- Most studies were primarily in patients with pneumococcal pneumonia
- Some studies included patients without confirmed pneumococcal etiology

## Current CAP Trials

- Majority have been oral CAP studies
- NI trials with a pre-specified margin of 10-15%
- Patient characteristics:
- Otherwise healthy patients with mild-moderate CAP
- Few patients had PORT scores ≥III
- Proportion of patients with *S. pneumoniae *small
- Number of patients with bacteremia small
- Primary endpoint was clinical outcome
- High success rates and small differences in efficacy
- Mortality low in most studies

## Linking Historical Data with Current CAP trials

- Patient populations
- Difficult to define a patient population identical to those in historical studies
- Can patients in current CAP trials be compared to those in historical studies if matched for age?
- More than 75 % of patients in the controlled historical studies and ~50-75% of patients in the observational studies were < 50 years of age
- Is it acceptable to assign PORT scores for patients in the historical studies based on age alone?
- Only limited data are available on co-morbidities

## Linking Historical Data with Current CAP trials

- Microbiology
- Historical data, is primarily from patients with pneumococcal pneumonia; in a few patients     *S. aureus, *or hemolytic streptococci were identified, and some had no baseline pathogen
- In current studies, *S. pneumoniae* is isolated in only a small fraction of cases and only a small proportion of patients have bacteremia
- Can the treatment effect be extrapolated to organisms other than *S. pneumoniae*?

**Notes:**
As summarized by Dr. Singer.... 

## Linking Historical Data with Current CAP trials

- Endpoints
- Treatment effect for mortality can be estimated
- Treatment effect is larger in patients older than 50 years and in bacteremic patients
- In current studies, mortality is low; rescue therapy is used in patients failing treatment
- Clinical outcome is primary endpoint rather than mortality
- Based on limited data for other endpoints from historical studies, is it reasonable to extrapolate from the treatment effect seen with mortality in historical data to clinical outcome in present trials?
- As death is included in clinical failure, can we assume that the treatment effect for  clinical outcome is likely to be greater than that seen for mortality?

## Alternative approaches

## Alternate approaches

- Outcomes from studies of ‘discordant’ treatment
- Non-adherence to treatment guidelines
- In vitro susceptibility
- Timing of antibiotic administration
- ‘Failed’ active comparator studies
- Superiority studies
- Dose-ranging studies

**Notes:**

In an attempt to further substantiate the treatment effect of antibiotics in CAP, the following supportive data were reviewed.

## Discordant Therapy

- Discordance based on guidelines
- Retrospective studies that used varying definitions of discordant therapy
- Endpoints varied;48-hour mortality, 30-day mortality, in-hospital mortality
- Number of patients who received discordant therapy was small
- Some studies did not adjust for severity of illness or other covariates
- Discordance based on *in vitro* susceptibility of *S. pneumoniae* to beta-lactams
- No difference in mortality/clinical success seen (Falagas 2006)
- With the recent change in penicillin breakpoints, definitions used in some studies may not be applicable
- 	(http://www.fda.gov/cder/foi/label/2008/050638s012lbl.pdf)

**Notes:**
Definition usually based on guideline recommendations at that point of time, generally based on the ATS or IDSA guidelines. Concordance of therapy based on antibioitcs administerd in first 48 hours usually assessed. Meningeal, <=0.06 (S), >= 0.12 ( R) ; pneumonia <=2, 4 (I) , >=8; older breakpoints were <=0.06, 0.12-1, >=2

Small case series have described clinical failure with pneumococcal infections with increasing MICs to macrolides and quinolones

## Other Supportive Data

- Active comparator studies
- Most studies have been NI studies, few have shown superiority (Finch et al. AAC 2002, File et al. AAC 1997)
- All classes effective; summary reviews have not demonstrated superiority of one class over another (Mills et al. 2005, Shefet et al. 2005)
- Estimate of treatment difference would be an underestimate
- Very few studies demonstrated superiority, likely by chance alone
- Timing of antibiotic administration
- Data from observational studies
- Time to first antibiotic dose (TFAD) of 4 hours associated with better outcomes
- Dose-response studies
- No studies identified that showed superiority of one dosing regimen over another

**Notes:**
both open label 
Finch Moxifloxacin vs. amox-clav (+- clarithromycin), (ITT difference 8.25, 3.13-13.6, PP 93.4, 85.4, 8.05 (2.91-13.19)
File-Levo vs. cefriaxone/cefuroxime (doxy/erythromycin per inv. discretion;  PP 96% vs. 90, (-10.7, -1.3)

## ‘Failed’ active comparator studies

- Phase 3 randomized, double-blind non-inferiority trials in hospitalized CAP patients (Pertel et al. CID 2008)
- Second study stopped early based on results of first study
- Studies were conducted from October 2000- February 2002
- 413 daptomycin and 421ceftriaxone-treated patients (pooled)
- PORT scores: ~42% class II, 30% class III, remainder class IV
- Microbiology:
- MITT population: 132/467 (28.3%) daptomycin-treated and 116/469 (24.7%) ceftriaxone-treated
- Bacteremia: 30 (7.3%) daptomycin-treated and 29 (6.9%) in ceftriaxone-treated patients

## Results

- Clinical Outcome (Daptomycin vs. Ceftriaxone, pooled data):
- ITT population: 70.9% vs.77.4%; -6.5%, (-12.4, -0.6)
- CE population: 79.4% vs. 87.9%; -8.5% , (-13.8, -3.2)
- MITT population: 74.2 % vs. 79.3%; -5.1%, (-15.6%, 5.4%)
- Mortality: 21 (4.6%) daptomycin-treated patients and 12 (2.6%) ceftriaxone-treated patients died during the study
- Post hoc analysis in the pooled CE population showed that daptomycin-treated patients who received prior effective therapy for < 24 hrs had higher success rates than those who did not receive such therapy
- Though daptomycin has been shown to interact with pulmonary surfactant, daptomycin effect likely larger than placebo

## Other endpoints

- Some studies have demonstrated superiority of one regimen over another in time to resolution of symptoms as a secondary endpoint or as a subgroup analysis (Anzueto et al. CID 2006, Finch et al. AAC 2002, Welte et al. CID 2005)
- Some studies have used clinician reported outcomes, while some have used patient reported outcomes that were not validated
- CAP-Sym, is a patient based outcome measure that has been evaluated in outpatients with CAP (Lamping et al. Chest 2002)
- Has not been used as a primary endpoint in registrational trials

## Summary of Supportive Data	

- Overall, studies support effectiveness of antibacterials in CAP
- Choice of antibacterial and timing of administration appear to be important
- Supportive information not contributory to determining magnitude of treatment effect
- Alternate endpoints such as time to resolution of signs and symptoms may be an option

- http://www.unicef.org/publications/files/Pneumonia_The_Forgotten_Killer_of_Children.pdf

**Notes:**
I would be remiss in my role as a pediatrician if I did not briefly touch upon pneumonia in children. It is certainly not our intention to forget this important entity in children. Several of the issues being discussed over the course of these two days are just as relevant to the discussion of pneumonia in children

## Pediatric CAP studies

- As in adults, historical studies in children showed reduction in mortality after introduction of sulfonamides (Raycraft 1941, Ormiston 1942)
- Most recent trials have been ‘equivalency trials’ (APPIS study, NO-SHOTS study)
- Studied children with severe or very severe pneumonia based on WHO classification system
- Regimens varied: oral amoxicillin vs. iv ampicillin/ penicillin chloramphenicol vs. ampicillin/gentamicin
- In most studies results similar in both treatment groups
- One recent study (SPEAR study) showed that ampicillin + gentamicin was superior to chloramphenicol in children aged 2-59 months with very severe pneumonia (Asghar et al. BMJ 2008)

**Notes:**
Raycraft- 200 infants treated 10% mortality, untreated historical controls 31-32%, shorter febrile period. 731 older than 1 yr. 45% bronchopneumonia, remaining lobar, 78% pneumo, 17% staph/strep, mortality 3%, 1/3rd afebrile in 24 hours, > 90% in 48 hrs.
Ormiston: 66 cases, 41 infants 52 treated with sulfa, 14 not treated as they did not appear ill. In the responders, 28 hrs elapsed between start of therapy and permanent lowering of temp, in untreated 4.5 days, 5.5 days in those with poor response. Mortality in treated was 4%

## Summary

- Overview of recent CAP trials (oral and IV)
- study design, endpoints, analysis populations, microbiology and outcomes
- Although treatment effect was demonstrated in historical studies, there are difficulties in linking historical data to current CAP trials
- Overview of additional data that are supportive of antibacterial effect in CAP, though not directly contributory to estimating a treatment effect

## Conclusions

- Patient populations described in the historical studies differ from those seen in current CAP trials
- In current trials patients may be less ill
- A small proportion have *S. pneumoniae* as the baseline pathogen
- Very few are bacteremic
- Endpoints evaluated in historical studies are different from those used in current CAP trials
- For non-inferiority trials in CAP we need to
- Define patient populations and endpoints that are best supported by the treatment effect seen in historical studies

## NI Margin for CAP StudiesIssues and Approaches

- Thamban Valappil, Ph.D.
- Statistical Team Leader,
- Office of Translational Science
- Center for Drug Evaluation and Research
- U.S. Food and Drug Administration

- Anti-Infectives Drugs Advisory Committee April 1-2, 2008

## Outline

- Critical Steps in Designing a NI trial
- Statistical Uncertainties in NI Studies
- Discounting and Preservation of Control Treatment Effect
- Historical Evidence in CAP studies
- Magnitude of Treatment Benefit
- Future Trial Design Considerations

## Critical steps in designing a NI trial

- Determine whether historical evidence of sensitivity to drug effect (HESDE) exists.
- Determine the design features of the historical placebo-controlled trials from which HESDE has been established.
- Determine a scientifically justifiable non-inferiority margin.
- Assure the quality of the trial and its conduct.
- Any kind of “subjectivity or imprecision” can be rewarded in a non-inferiority trial and can artificially make the treatments look similar, when in fact, that they are _not similar._

## Statistical Uncertainties in NI Studies

**What are the sources of uncertainties?**
- Magnitude and precision of the estimate of active control treatment effect based on historical placebo-controlled studies.
- Lack of constancy assumption i.e. the potential lack of comparability of historical evidence to estimate the size of the treatment effect in the current NI study.
- The observed treatment effect from a single study or collection of studies may not be reproducible introducing bias.
- Control for the overall type I error rate in the estimate of the treatment difference between the test drug and active control in the current NI study.

**Notes:**
Lack of placebo-controlled historical studies, lack of reproducibility of the control effect or lack of internal consistency in the historical evidence of treatment effect.
If there is a lack of comparability between previously conducted studies and the current NISD, the estimates of effect size from the previously conducted studies may represent a biased estimate of the true effect size for the population in the current NISD.  Lack of comparability may be derived from any of a number of sources, including advances in adjunctive medical care, differences in the patient populations or endpoints under study.
More importantly, a change in the true treatment effect size, such that the estimate of effect size from previously conducted studies is no longer directly applicable or relevant to the current NI study.

## Unclear treatment effect

**“****Untreated”**

**Active Control**

**Test Drug**

**Treatment Effect**

**Unclear treatment effect**

## Substantial treatment benefit

**Untreated **

**Active Control**

**Test Drug**** **

**Treatment Effect**

**	**

**Substantial treatment benefit**

## How to account for statistical uncertainties in estimating an NI Margin?

- Discounting (reduction) of the historical control effect size
-                      AND
- 2.	Preservation of the control effect

## Discounting of the control effect size

- 	Discounting of the historical control effect size is required to account for various sources of uncertainties, for example:
-  Lack of constancy assumption
-  Lack of intra-trial variability
-  Differences in the patient population, differences in dosing or duration of control drug

## Preservation of the control effect

- Preservation of the discounted treatment effect size (M1) is based on the 95% CI around the difference in treatment effects.
- The proportion of the control effect preserved (M2) is based on good clinical judgment.
- Smaller NI margin should be chosen when treatment failures result in irreversible outcome such as mortality.

## Why Smaller NI Margin?

-    Let us consider an example, using the  endpoint “clinical success/failure”.
- _Clinical Success(%)_	_Clinical Failures(%)*_
-             95%                        5%
- 	        85%                        15%

** ****3 times!**

- * Clinical failures include mortality

## Non-Inferiority - Inference

- 	Let us assume that we have established a NI margin based  on “adequate and well-controlled” historical studies.
-    What would be the statistical inference?

## Non-Inferiority - Inference

**0**

**Test Drug Better**

**Non-inferiority shown**

**Non-inferiority shown, but more variability **

-  **Non-inferiority not shown**

**Non-inferiority shown/**
**Superiority is shown**

**NI Margin**

**Treatment Difference (Test Drug – Control)**
**95% Confidence Intervals**

**(1)**

**(2)**

**(3)**

**(4)**

## Historical Evidence in CAP Studies

**Reliability of the control effect;**
- The historical data for CAP would not be considered adequate based on the current standard for  “adequate and well controlled” studies.
- There are several design issues which may have  introduced bias.
- All-cause mortality rates were evaluated in these historical studies.
- There was limited information on the resolution of clinical signs and symptoms as measured in the current CAP studies.

**Notes:**
Dr. Singer has gone through a great length in summarizing these studies and I am not going thru it again here other than making an overall conclusion

## Historical Evidence in CAP Studies (cont...)

- No “true” placebo-controlled studies were conducted. However, studies which used no specific treatment (symptomatic therapy) were considered as “untreated/placebo”.
- There are major limitations in the historical studies including (but not limited to) the following:
- These studies were not blinded
- Some were observational studies, while some were controlled although not randomized per current standards.
- Majority of patients were hospitalized with pneumococcal/lobar pneumonia

**Notes:**
Dr. Singer explained these data

## Historical Evidence in CAP Studies (cont...)

- Subjects  were assigned to antibacterial drugs including *penicillin* and *sulfonamides *in these studies.
- There was significant variability in mortality rates across studies.
- The difference in overall mortality based on _**point estimates**_ in pneumococcal/lobar pneumonia from the controlled studies was in the range of 10-19%. However, there is significant variability in these estimates and therefore it lacks reliability.

**Notes:**
Dr. Singer explained these data

## Evans and 

**Gaisford (1938)**

**Graham et. al (1938)**

**Agranat et. al (1939), Non Europeans**

**Agranat et. al (1939) Europeans**

## Historical Evidence in CAP Studies (cont...)

**Is the control effect reproducible?**** **
- There appears to be a mortality benefit in hospitalized CAP patients assumed to have “moderate to severe” pneumococcal /lobar pneumonia.
- However, there is significant variability and associated uncertainties in the estimated historical mortality rates.
- The magnitude of effect may not be reliable or reproducible in all CAP patients who appear to have less severe disease.

## Historical Evidence in CAP Studies (cont...)

**Constancy of the Control effect**
- Does the control effect remain constant over time?
- How do historical trials compare to current trials?
- Patient population, disease definition, outcome criteria, dose, duration of control and, timing of the outcome assessment.
- What is the internal variability of the effect size in the historical trials?

## Historical Evidence CAP Studies (cont...)

- The antibacterials used in these studies included *sulfonamides*, *penicillin and tetracycline*
- The mortality rates in current studies are not very high (~4%).
- The lack of comparability between historical CAP studies and the current studies raise concerns in determining a precise estimate of treatment effect.
- This can be due to any of a number of sources, including differences in patient population, advances in standard of care, differences in the endpoints (mortality or clinical outcomes) or emerging drug resistance issues.

**Notes:**
There are additional may affect factors which the assumption. (3rd bullet)

## Study Quality and Conduct 

- The historical CAP studies were not randomized per current standards, blinded or controlled for potential biases.
- In general, when using historical studies, the following issues can undermine its ability to reliably estimate the treatment benefit.
-  Subjective endpoint
-  Lack of specificity in the diagnosis of patients
-  Spontaneous resolution of signs and symptoms
-  Treatment non-compliance
-  Contribution of adjunctive therapies
-  Misclassification of outcomes

## Summary of Historical  Evidence

- Historical data may be primarily limited to those with moderate-severe disease due to *Streptococcus pneumoniae. *
- Historical studies do not provide _quantitative _estimates of clinical benefit other than all-cause mortality.
- The microbiological etiology in historical studies differs from recent CAP studies.

**Notes:**
As Dr. Singer presented, treatment effect for M. pneumonia was available for other non-mortality endpoints (2nd bullet)

As discussed in Dr. Nambiars presentation...

## Few Comments-1

- This presentation focused only on “controlled studies” while the IDSA position paper has also considered other studies.
- IDSA position paper reported absolute mortality rate in the controlled studies by pooling studies and did not take into consideration the lack of internal consistency in the mortality rates across studies.
- Pooling studies makes several strong assumptions including similarity in the patient population, disease characteristics, treatment duration and it may be difficult to meaningfully interpret the results.

## Few Comments-2

- Kingston et al. JAMA 1961
- Tetracycline (demeclocycline) vs. placebo was studied in 290 healthy marine recruits between age 17-22 years with mild CAP.
*M. pneumoniae* was the etiology in 133 (46%) – which is only a subgroup of patients.
- Several endpoints: mean time to defervescence (temperature < 99F), normalization of chest X-ray,  resolution of cough and few other endpoints.
- There are potential multiple testing issues and the inflation of overall type I error rate.
- Duration of fever is based on cumulative percent and it is not clear how missing values were accounted and it has the potential  for overestimating the treatment effect.
- Findings are based on a single study and subgroup analysis. It cannot be generalized.

## Magnitude of Treatment Benefit

- There appears to be a treatment benefit based on all-cause mortality rate in historical studies (although the estimates lacks precision) in hospitalized CAP patients with pneumococcal /lobar pneumonia.
- However, mortality is lower in current studies due to availability of alternative therapies which could rescue patients and prevent death.
- 	**The question is, can we translate the mortality benefit observed in historical studies to a clinical benefit as measured in current studies or will it be **_**misleading**_**? **

## Magnitude of Treatment Benefit (cont...)

- The margin chosen for a non-inferiority trial cannot be greater than the *smallest effect size that the active drug would be reliably expected to have* compared with placebo in the _setting of the planned trial_ (ICH E10).
- A non-inferiority trial design is possible if we use mortality as the endpoint or scientifically justify the extrapolation of the mortality benefit seen in historical trials to another clinically meaningful endpoint.

## Clinical Failures (~15%) and Mortality Rates Differential Effects (Hypothetical Example)

**Figure 1**

**Figure 2**

**Figure 3**

**Mortality Rate**

**T**

**C**

**T**

**C**

**C**

**T**

**Rescue Rate*******

-    * Patient who received alternative therapy for rescue;  **  Failures other than mortality

**T = Test **
**C = Comparator**

**Clinical Failures in Test and Control Drug**

**Failure********

**15%**

## Future Trial Design Considerations

**Primary Endpoint(s):**
- All-cause mortality
- Clinical failure including mortality
- PRO Instrument (lacks historical data to link and therefore at this time can only be used in superiority trials to establish effect)
- E.g. Time to resolution of clinical signs and symptoms

## Future Trial Design Considerations (cont...)

**Primary Hypothesis:**
- Superiority or Non-inferiority?
- Choice of NI margin (if non-inferiority)
- What is the magnitude of antibacterial treatment  effect based on historical studies?
- Did we control for variability in the historical data and discount for the uncertainties?
- If so, in what patient population and for which endpoint?
- Did we preserve some fraction of the control effect?

## Future Trial Design Considerations (cont...)

**Patient Population:**
- Identify patient populations that are comparable to those in historical studies to precisely estimate the treatment benefit.
- Who should be enrolled?
- Should it based on PORT scores or some other criteria?
- Should only patients with confirmed bacterial etiology be enrolled?

## 
Thank you!

**Thank you!**

## Exposure-Response Analysis forCommunity-Acquired Pneumonia

- April 1st, 2008

- Christoffer Wenzel Tornoe, Ph.D.
- Pharmacometrics, Office of Clinical Pharmacology
- Center of Drug Evaluation and Research
- Food and Drug Administration

## Question

- Can exposure-response analysis contribute to the discussion of anon-inferiority margin for studies of CAP?

## Y-intercept as “Untreated/Placebo” Response Estimate

- Forrest A  et al. Pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother. 1997;40 Suppl A:45-57.

- Grepafloxacin against AECB

- Treatment Effect

- “Untreated/Placebo” Response

**AUC/MIC**

**Notes:**
Clinical outcome can be associated with drug exposure and the response at the lowest ranges of drug exposure can be used as a conservative estimate of response in an “untreated/placebo” control.

## Bottom Line Up Front

- What is the exposure-response derived treatment effect against *Streptococcus pneumoniae* in patients with mild-moderate CAP?
- 37% (95%CI -6;80%)
- Can exposure-response analysis support the choice of non-inferiority margin in CAP trials?
- Very likely, but more data (with low free AUC/MIC ratios) are needed to precisely quantify the treatment effect

## Background

- Data available
- Fluoroquinolone antibiotics have been widely studied in the treatment of CAP
- Reported to exhibit concentration-dependent killing of pathogens responsible for CAP
- Free AUC/MIC ratio is the PK/PD parameter that correlates with therapeutic effectiveness

## Pre-clinical Information

- Craig WA, Andes DR. Correlation of the Magnitude of the AUC24/MIC for 6 Fluoroquinolones against *Streptococcus pneumoniae* with survival and bactericidal activity in an animal model. In Abstracts of the 40th ICAAC, Toronto, Canada, Sept. 17-20, 2000. Abs-289.

- Ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and sitafloxacin

**Free AUC/MIC**

**Free AUC/MIC**

## Methodology

- Drug Class
- Fluoroquinolone antibiotics
- Enrollment Criteria
- Clinical signs and symptoms of CAP (e.g., fever, cough, chest pain, sputum production)
- Presence of a new or progressive infiltrate on chest x-ray

## Methodology (cont’)

- Patient Population
- Mild-moderate (few severe) CAP
- In- or outpatient based on clinical status
- Most patients between 40 and 65 years
- Treatment and Administration
- 7-14 days of treatment
- Oral therapy (mild-moderate disease)
- IV/PO (moderate-severe disease)

## Exposure-Response Data

| Drug

Dose | Location/
Date/
Protocol | Population
(ITT / PK) | Admin. Route/
Hospitalized/
Duration | Primary Endpoint (TOC) | Clinical response (ITT/PP) |
| --- | --- | --- | --- | --- | --- |
| Garenoxacin

400 mg daily | Multinational
1999-2000

AI464-004 | Mild-severe

N=199/106 | Oral
Out patients
10 days  | 7-14 days post Rx | 

0.84/0.91 |
| 
Gatifloxacin

Gati 400 mg daily
Levo 500 mg daily | 
US
1997-1998

AI420-038 AI420-038 | 
Mild-severe

N=203/12
N=197/16 | 
IVOral, Oral
In/Out patients

7-14 days
7-14 days | 
7-14 
(5-28)
days post Rx | 

0.89/0.90
0.95/0.93 |
| 
Gemifloxacin

320 mg daily | 
Multinational
1998-1999

049/
061 | 
Mild-moderate

N=290/46
N=216/71 | 
Oral
In/Out patients

7-14 days
7 days | 
14-21 days post Rx | 

0.88/0.94
0.83/0.92 |

## Top 5 Pathogens in CAP Studies

|  |  |  |  |  |
| --- | --- | --- | --- | --- |
|  | N | Free AUC | MIC | Free AUC/MIC |
| Levofloxacin |  |  |  |  |
| Streptococcus pneumoniae | 16 | 40 (18-61) | 0.72 (0.06-1) | 97 (26-689) |
| Gemifloxacin |  |  |  |  |
| Streptococcus pneumoniae | 30 | 3.8 (1.7-15) | 0.01 (0.002-0.06) | 353 (38-1938) |
| Haemophilus influenzae | 16 | 4.4 (2.2-7.5) | 0.003 (0.001-0.01) | 2158 (212-6101) |
| Staphylococcus aureus | 14 | 3.4 (2.0-5.8) | 0.01 (0.004-0.01) | 3996 (134-923) |
| Haemophilus parainfluenzae | 9 | 3.4 (1.9-4.6) | 0.01 (0.004-0.03) | 401 (119-932) |
| Moraxella catarrhalis | 5 | 3.0 (2.1-4.6) | 0.02 (0.01-0.06) | 316 (46-568) |
| Garenoxacin |  |  |  |  |
| Haemophilus parainfluenzae | 26 | 23 (13-51) | 0.1 (0.01-2) | 716 (26-2202) |
| Staphylococcus aureus | 19 | 26 (14-54) | 0.08 (0.01-1) | 1302 (27-3823) |
| Streptococcus pneumoniae | 16 | 23 (13-41) | 0.05 (0.01-0.06) | 595 (222-1337) |
| Haemophilus influenzae | 16 | 23 (15-43) | 0.03 (0.004-0.12) | 1903 (206-5562) |
| Moraxella catarrhalis | 7 | 20 (16-26) | 0.03 (0.01-0.03) | 877 (540-1710) |
| Gatifloxacin |  |  |  |  |
| Streptococcus pneumoniae | 12 | 38 (27-53) | 0.2 (0.03-0.25) | 365 (107-1759) |

## Methodology

- Drug Exposure
- AUC
- Protein binding
- MIC
- Clinical Response
- Resolution of signs and symptoms of pneumonia at test-of-cure visit
- Exposure-Response Analysis
- Classification and Regression Tree (CART) Analysis
- Logistic Regression

- Free AUC/MIC

## MethodologyDrug Exposure

- Dose

- Demographic Covariates

- Observed PK

**Patients with observed PK were used for the E-R analysis**

## Protein Binding was Taken into Account when Pooling Data Across Drugs

- Craig WA, Andes DR. In Abstracts of the 40th ICAAC, Toronto, Canada, Sept. 17-20, 2000. Abs-289;

## MethodologyMIC

- All Pathogens

- Pathogens with MIC

*Pathogen with highest MIC*

**Patients with Strep. pneumoniae being the most****resistant pathogen were used for the E-R analysis**

*Strep. pneumoniae with MIC*

## Greater Variation in MIC than Free AUC 

- +

## Only Few Patients with Low Free AUC/MIC

## CART AnalysisOnly 5 Patients with Free AUC/MIC<37

- Estimated Free AUC:MIC break-point = 37

**CART Analysis: Select Optimal Free AUC/MIC Breakpoint that               Maximally Distinguishes the Response**

## Estimated Treatment Effect of 37% (95%CI -6;80%) for Fluoroquinolones in CAP against S. Pneumoniae

- 60%

- 97%

**Estimated Treatment Effect of 37% (95%CI -6;80%) for Fluoroquinolones in CAP against *****S. Pneumoniae***

## Summary

- Relationship between free AUC/MIC and clinical response was established
- Exposure-response analysis limitations
- Limited number of patients (5 out of 74) with sub-therapeutic AUC/MIC ratios since most quinolones are dosed in a manner that result in significantly higher exposures than those associated with failure in animal infection models
- Only Levofloxacin treated patients with sub-therapeutic exposures
- Few clinical failures (4 out of 74)
- More exposure-response data with low AUC/MIC ratios needed to quantify the treatment effect

## Conclusions

- What is the exposure-response derived treatment effect against *Streptococcus pneumoniae* in patients with mild-moderate CAP?
- 37% (95%CI -6;80%)
- Can exposure-response analysis support the choice of non-inferiority margin in CAP trials?
- Very likely, but more data (with low free AUC/MIC ratios) are needed to precisely quantify the treatment effect

## Slide 306

## Clinical Failures

**Mean                                71       169       51      91               21.2     0.20          353**

| Drug | Study | Pathogen | Weight | Height | Age | CrCL | Sex | Free
AUC | MIC | Free
AUC/MIC | Micro |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Levo | 038 | Str. Pneu | 93 | 168 | 54 | 152 | F | 26.1 | 1.0 | 26.1 | Failure |
| Levo | 038 | Str. Pneu | 79 | 180 | 32 | 100 | M | 33.7 | 1.0 | 33.7 | Failure |
| Gareno | 004 | Str. Pneu | 57 | 170 | 53 | 17 | F | 40.1 | 0.03 | 1337 | Presumed
Persisted |
| Gareno | 004 | Str. Pneu | 57 | 163 | 38 | 110 | F | 17.9 | 0.03 | 597 | Presumed persisted |

## Sub-therapeutic patients

**Mean                                71       169      51      91                21.2     0.20          353**

| Drug | Study | Pathogen | Weight | Height | Age | CrCL | Sex | Free
AUC | MIC | Free
AUC/MIC | Clinical |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Levo | 038 | Str. Pneu | 93 | 168 | 54 | 152 | F | 26.1 | 1.0 | 26.1 | Failure |
| Levo | 038 | Str. Pneu | 79 | 180 | 32 | 100 | M | 33.7 | 1.0 | 33.7 | Failure |
| Levo | 038 | Str. Pneu | 67 | 185 | 37 | 229 | M | 18.2 | 0.5 | 36.3 | Success |
| Levo | 038 | Str. Pneu | 87 | 160 | 54 | 132 | F | 27.0 | 1.0 | 27.0 | Success |
| Levo | 038 | Str. Pneu | 83 | 163 | 32 | 111 | F | 31.2 | 1.0 | 31.2 | Success |

## AUC vs. Covariates

- Body weight

- Age

- Creatinine Clearance

## AUC percentiles

## Free AUC percentiles

## MIC percentiles

## Levofloxacin MIC percentiles

## Free AUC/MIC percentiles

## No cut-point identified for Free AUC vs. Clinical Response Rate for Strep. Pneumoniae

## 67% (95% CI: 30-93%) Clinical Response Rate for Strep. Pneumoniae with MIC>0.75

- Estimated MIC break-point = 0.75

## Exposure-Response Relationship for Haemophilus influenzae

## Exposure-Response Relationship for Haemophilus parainfluenzae

**Exposure-Response Relationship for ****Haemophilus parainfluenzae**

- Estimated fAUC:MIC break-point = 201

## Exposure-Response Relationship for Staphylococcus aureus

## Exposure-Response Relationship for Moraxella catarrhalis

## Levofloxacin (Pulmonary 001)

## Mean (range) Free AUC, MIC, and Free AUC/MIC by Pathogen in CAP Studies

|  |  |  |  |  |
| --- | --- | --- | --- | --- |
|  | N | Free AUC | MIC | Free AUC/MIC |
| Streptococcus pneumoniae | 74 | 21 (1.7-61) | 0.2 (0.002-1) | 352 (26-1938) |
| Haemophilus parainfluenzae | 35 | 18 (1.9-51) | 0.1 (0.004-2) | 635 (26-2202) |
| Haemophilus influenzae  | 32 | 13 (2-43) | 0.01 (0.001-0.12) | 2031 (206-6101) |
| Staphylococcus aureus | 33 | 17 (2-54) | 0.05 (0.004-1) | 918 (27-3823) |
| Moraxella catarrhalis | 12 | 13 (2-26) | 0.02 (0.01-0.06) | 643 (46-1708) |

## Levofloxacin for Community-Acquired Infection

- Preston SL *et al*.   Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA. 1998;279:125-9.

**Results were reproduced using data from LFOVIB-MULT-001 study in NDA 20634 ****but mainly driven by non-*****S. pneumoniae***** pathogens and not valid for determining M1**

## Clinical Response vs. Free AUC/MIC with “Placebo” response of 70%

**Levo/Gati/Gemi**_*** (N=36/12/31)**_
**Ambrose Analysis**

- *Ambrose PG, Bhavnani SM, Owens RC.  PK-PD of antimicrobial therapy: It’s not just for mice anymore. Clin Infect Dis. 2007;44:79-86.

- Estimated “breakpoint” = 33.8 hr

## Critical Considerations in CAP Trial DesignA Consultant’s PerspectiveFDA Advisory Committee Meeting1 April 2008

**George H. Talbot, MD, FIDSA**

## FDA’s Charge

- Provide for the AC:
- A “*reality check regarding what is feasible vis-à-vis trials conducted by industry, based on your discussions with industry colleagues, investigators, and other regulatory agencies.  *
*Your vision of what might be a reasonable path forward for future trials for CAP products ...*”

## Discussion Points	

- Why do we need new antibiotics for CAP?
- Undertaking a CAP clinical trial program
- Major trial design issues
- Conclusions
- Next steps

## Disclosures

- June 2006-Oct 2007: CMO of Cerexa, Inc.
- Consultancies to Actelion, Calixa, Cerexa, PTC, Shire, Theravance, ViroPharma, Wyeth; advise Cerexa on CAP program
- Equity option grants: Calixa, Mpex
- Diversified healthcare equity portfolio
- Member of IDSA’s AATF
- Self-supported to attend this meeting

**Perspectives Presented are Mine**

## Why Do We Need New Antibiotics for CAP?

## Why Do We Need New Antibiotics for CAP?

- Emerging resistance in CAP pathogens
*Streptococcus pneumoniae*
- Macrolide
- Cephalosporin (ceftriaxone)
- MRSA?
- Treatment options for other RTIs
- Some patients with sinusitis, acute exacerbation of chronic bronchitis, or acute otitis media DO require antibiotic therapy
- If new antibiotics can’t easily be studied in those indications, CAP becomes the last bastion for RTI drug development

## Why Do We Need New Antibiotics for CAP?

- Antibiotic pipeline in general is at risk
- Decreasing investment by large pharma
- “Deconstructed” basic R&D platforms
- Increased clinical trials costs & uncertainty
- Better opportunities elsewhere
- New molecules often from Japanese innovators
- The “new” descriptor can be falsely reassuring
- Many “new” compounds are recycled from older innovators

## Why Do We Need New Antibiotics for CAP?

- The CAP pipeline has had problems
- Telithromycin (oral)
- Faropenem (oral)
- Gemifloxacin (oral)
- Gatifloxacin (oral)
- Oral, as well as IV, options are needed
- Hospital admission/discharge pressures
- Lots of outpatient CAP
- Many hurdles for oral compounds
- New classes/ MOAs desirable

## Why Do We Need New Antibiotics for CAP?

- One day, some of us, or one of our family members, will need one....
- Decisions made in 2008 will determine what antibiotics are available in 2015.

**“****The lesson of history is that **
**we need a pipeline.”  **
**John Bartlett, MD **

## Undertaking a CAP Clinical Trial Program

## Thinking about “Industry”

- “Industry” is not a monolith
- Large pharma vs. “Biotech”
- Differing goals, assumptions, & constraints
- However, there are....
- Common denominators for pharma R&D
- Finding funding,
- Fiduciary responsibility to shareholders, AND
- Doing the right thing for patients and society

**Decisions are Complex**
**R&D Scientists Believe in What They Do**

## Context of a Starting a CAP Program

- The multiplicity of audiences, worldwide
- Patients
- Investigators
- IRBs/ ECs
- Regulatory agencies
- Prescribing physicians (medical need)
- Formularies and insurance companies

**Varying Needs Add Risk & Uncertainty**

## Will the Trial Program Prove to Be:

- Credible?
- Predictable?
- Feasible?

## Credibility 

- Scientific Considerations:
- Are validated methods/ tools available to design, conduct and analyze clinical trials?
- Will the data/ conclusions withstand rigorous scientific examination?
- Will regulators worldwide find the results acceptable?
- Will the results address an unmet need or provide data relevant to current practice?

## Credibility 

- Ethical Considerations:
- Is trial design acceptable to all audiences?
- VERY difficult for pharmaceutical companies to be innovators if doing so requires contravening established clinical practice guidelines/ investigational precedent.
*Example*: placebo-controlled trials when audiences expect active controls

**Examine Controversial Hypotheses in **
**Non-pharma Sponsored Trials **

## Predictability 

- What predictability *ISN’T*: Stacking the deck to ensure the results you want!
- What it *IS*: Identifying the clinical, statistical, regulatory, & commercial variables that impact the trial results – and accounting for them carefully in design, conduct, & analysis

**Predictability is an Essential Consideration -- Trial Timeframes are Measured in Years, and Costs in Millions of $ **

## Why is Predictability So Important?

|  | Direct Study Costs | Fully Loaded Costs | Patients Enrolled | Cost per Patient |
| --- | --- | --- | --- | --- |
| Trial #1 

 | $18.1 million | $19.6 million | ~550 | $36,600 |
| Trial #2
 | $18.5 million | ~$19.0 million | ~600 | $31,700 |

## Why is Predictability So Important?

|  | Direct Study Costs | Fully Loaded Costs | Patients Enrolled | Cost per Patient |
| --- | --- | --- | --- | --- |
| Trial #3
 | $17.2 million | $21.0 million | ~430 | $48,800 |
| Trial #4
 | $9.2 
million | $12.6 million | 425 | $29,600 |

## Why is Predictability So Important?

|  | Direct Study Costs | Fully Loaded Costs | Patients Enrolled | Cost per Patient |
| --- | --- | --- | --- | --- |
| Trial #5
 | $28.0 million | $41.5 million
 | ~600 | $69,100 |
| Trial #6

 | $19.0 million | $31.6 million

 | ~625 | $50,500 |

## What’s at Stake: A Lot ...

- For early stage development, venture capital interest is high now, but opinions can shift rapidly
- For Phase 3, smaller companies generally need a large pharma partner
- So, $$ currently targeted for CAP could go elsewhere –
- Other indications,
- Other therapeutic areas,
- Even other industries

## Compounds at Risk on the Predictability Axis

- Recently completed or ongoing P3 trials
- Cethromycin
- Tigecycline
- Ceftobiprole
- Ceftaroline
- Potential for late-stage development
- Nemonoxacin
- Faropenem
- EDP-420
- Rx-1741
- etc.....

- Clinicaltrials.gov accessed 3/27/08

## Compounds at Risk on the Predictability Axis

- Overhanging issues:
- NI design and acceptable NI margin
- Outcome measures
- Populations studied
- Example: Recent CAP studies
- NI margin: 10%
- Populations: PSI I-V, ~80% II-IV
- Outcome measure: Clinical response, incl. death, in Clinically Evaluable patients (i.e., regardless of whether pathogen isolated)

**Poster L-1450, ICAAC 2007**

## Compounds at Risk on the Predictability Axis

- CAP pathogens (% of enrolled)

**Poster L-1450, ICAAC 2007**

| Pathogen | n | % |
| --- | --- | --- |
| Atypicals | 147 | 17.4 |
| H. influenzae | 33 | 3.9 |
| M. catarrhalis | 8 | 1.0 |
| S. pneumoniae | 190 | 22.5 |
|    Culture | 109 | 12.9 |
|    Urine Ag | 81 | 9.6 |

**Culture + Patients are in the Minority**

## Feasibility

- Are the scientific & regulatory requirements understood?
- Can the trials be completed within an acceptable time frame, especially:
- Design
- Enrollment
- Regulatory review
- Will the costs of the trials make sense compared to other options?

## Deciding to Start a CAP Trial: Summary

**Deciding to Start a CAP Trial: Summary**

## Major Design Issues in CAP Clinical Trials

## Specific Design Considerations

- Spectrum of Study Drug
- Dose Selection
- Choice of Comparator*
- IV-Oral Switch
- Inclusion/Exclusion Criteria*
- Statistical Assumptions*
- * Focus points

## Spectrum of Study Drug

- Macrolides & FQs efficacious vs. the spectrum of CAP pathogens
- Conundrum for cephalosporins:
- Some data showing improved outcome with addition of macrolide in pneumococcal CAP
- The spectrum of cephs does not include atypical pathogens....

**How to Provide Optimal Therapy, without an Overlap in Spectrum that Confounds Efficacy Assessment?**

## Issues in Dose Selection Rationale for CAP 

- Potency (MIC) against target organisms
- Activity in animal pneumonia models
- Human Phase 1 PK
- Known PK-PD relationships (plasma)
- PK-PD modeling
- Lung penetration
- Consideration of active site in lung
- Prior experience with class
- Phase 2 data if available

## Dose Selection

- State of the art science allows prediction of efficacious dosing regimens
- However, we must beware the unexpected:
- Different pathogens than anticipated
- Higher than expected MICs of target pathogens
- Drug inactivation at target site
- PK variability
- Drug-drug interactions

## Choice of Comparator

- There is a substantial, consistent antibiotic treatment effect in CAP (HESDE)
- Mortality
- Morbidity
- Historical, discordant Rx, daptomycin data
- Effect size varies by severity of illness
- Most pronounced in moderate to severe CAP, but clinically meaningful in mild CAP
- Asking industry to conduct placebo-controlled studies in CAP would place them in an untenable position with many of their audiences

**IDSA CAP position paper**

## Choice of Comparator

- Exercise due care in comparator selection:
- Spectrum of activity
- Dosing regimen (which may have changed since initial regulatory approval)
- Tolerability
*What isn’t acceptable *
- Use of a comparator that is suboptimal re: these parameters - in hopes of demonstrating superiority in an active-control study

## IV-Oral Switch

- Standard of care in many countries
- Pressure from insurers, hospitals
- Clinical trial design utilizing oral switch
- Relevant to clinical practice
- Improves trial feasibility
- Conundrum: potential confounding of efficacy and safety assessments

## Inclusion/Exclusion: Patient Populations

- CAP severity can be defined
- Well studied, validated _prediction _tools
- Can be adapted as severity assessment
- Meet constancy assumption
- Feasible for patient trial enrollment
- Relevant to clinical practice & product label
- Suggested approach
- Pneumonia Severity Index as base
- Adjust PSI for selected other variables that reflect severity but are not in PSI

**IDSA CAP position paper**

## Inclusion/ Exclusion: Prior Antibiotic Therapy

- Artifactually improves response in CAP
- The “obvious” solution – avoid prior Rx – has major logistical consequences
- We need better approaches to this issue
- At present, the most attractive is to allow a single dose of a short-acting agent
- In the future, rapid diagnostics may facilitate inclusion of non-treated patients only

***Clin Infect Dis*****, 2008; 46: 1142 **

## Inclusion/ Exclusion: Which Pathogens?

- Documentation of treatment effect
- Data abundant for *S. pneumoniae *and, to a lesser extent, “Atypicals”
- Fewer data for *H. influenzae*, other “Typicals”
- However,
- Diagnostic accuracy to allow _timely_ triage for trial entry is not yet feasible for typical or “atypical” pathogens
- In clinical practice, pathogen often not known

**IDSA CAP position paper**

## Inclusion/ Exclusion: Which Pathogens?

- Restricting primary trial analysis to
*Typical pathogens *only - will at least double clinical trial sample size
*S. pneumoniae *only - will multiply 4-5-fold the required sample size
- Such increased “N” will add time & cost – each a powerful deterrent
- Trial data based on clinically defined populations are useful and generalizable
- Logistically, retaining clinical criteria for primary evaluation is desirable

## Statistical assumptions: NI or Not NI?

- NI design justified- based on HESDA & constancy
- Moderate to severe CAP with dichotomous outcome: 10% delta
- Mild CAP: 5% delta with dichotomous outcome
- Mild CAP: ?10% delta for time-to-events
- Superiority design neither feasible nor justifiable for registration trials – patients would be enrolled:
- Little chance of the trial meeting its endpoint
- Potentially exposed to suboptimal comparator

## Statistical Assumptions: Outcome Measures

- Relevant outcome measures (endpoints) have been identified
- Moderate-severe CAP
- Mortality & morbidity
- Consider composites: Death, time to discharge, etc.
- Mild CAP
- Morbidity
- Time-to analyses??
- Issue: instruments validated?
- Needed now: studies of mild-mod CAP

## In Conclusion (1)

- Society will benefit from the availability of new antibiotics for treatment of CAP
- NOT just for CAP
- Resistance is increasing
- Decisions now determine our options in 2015
- CAP trials must be
- Credible, predictable, and feasible
- Needed: updated, clear, & specific guidance

## In Conclusion (2)

- A substantial treatment effect of antibiotics in CAP has been established
- Superiority design?
- Placebo-controlled: very problematic
- Active control: difficult & unnecessary
- Each could place patients at risk
- NI design?
- Scientifically appropriate
- Logistically feasible

## In Conclusion (3)

- Utilizing an NI design
- Patient populations can be defined that satisfy clinical & regulatory demands: “PSI-plus” for defining severity
- Outcome measures incorporating both morbidity and mortality are appropriate
- Pathogens
- Technology does not yet allow identification at entry to enrich study population
- Restricting trial analysis to micro subsets will add lots of time and cost to trials

## How the Advisory Committee Can Help

- Consider the proposals presented on both their scientific merits AND the ability of companies to implement them
- Make the best possible, balanced decisions today (maybe they won’t be perfect...)
- Help our FDA to give prompt, clear guidance for antibiotics in the wings

**Facilitate the Development of Safe and Effective New CAP Therapies**

## Acknowledgements

- FDA-IDSA CAP Workshop discussions
- IDSA’s AATF
- Advanced Life Sciences, Cerexa, Replidyne, and Wyeth for CAP trial cost data

## Thank you for your attention!