Anti-Infective Drugs Advisory Committee April 1 & 2, 2008 1 Anti-Infective Drugs Advisory Committee Meeting Clinical Trial Designs for Community Acquired

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

Anti-Infective Drugs Anti-Infective Drugs Advisory Committee MeetingAdvisory Committee Meeting

Clinical Trial Designs for Clinical Trial Designs for Community Acquired PneumoniaCommunity Acquired Pneumonia

Anti-Infective Drugs Anti-Infective Drugs Advisory Committee MeetingAdvisory Committee Meeting

Clinical Trial Designs for Clinical Trial Designs for Community Acquired PneumoniaCommunity Acquired Pneumonia

April 1 & 2, 2008

Edward Cox, MD MPHDirector, Office of Antimicrobial Products

OND/CDER/FDA

April 1 & 2, 2008

Edward Cox, MD MPHDirector, Office of Antimicrobial Products

OND/CDER/FDA


WelcomeWelcomeWelcomeWelcome• 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

• 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 - 1Background - 1Background - 1Background - 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

• 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 - 2Background - 2Background - 2Background - 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

• 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 IndicationCAP IndicationCAP IndicationCAP 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

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 IndicationSome Drugs with a CAP or Related IndicationSome Drugs with a CAP or Related IndicationSome 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

• 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 - 1Importance & Challenges - 1Importance & Challenges - 1Importance & 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

• 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 - 2Importance & Challenges - 2Importance & Challenges - 2Importance & 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

• 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 ApprovalDrug Product ApprovalDrug Product ApprovalDrug 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.”

• 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 Adequate and well controlled studiesstudies

Adequate and well controlled Adequate and well controlled studiesstudies

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.

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.


Inactive(e.g. placebo)

Active Controls & Noninferiority - 1Active Controls & Noninferiority - 1Active Controls & Noninferiority - 1Active Controls & Noninferiority - 1

Test

Active Control

Response rate

Case# 1: Large treatment effect Low spontaneous

resolution rate


Active Control

Test


Inactive (e.g. placebo)

Case #2: Unclear treatment effect High spontaneous

resolution rate

Response rate


Inactive(e.g. placebo)

Active Control

Test


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 TrialsCAP TrialsCAP TrialsCAP 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

• 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 NDAsCAP Trials in NDAsCAP Trials in NDAsCAP 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

• 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 TopicsKey TopicsKey TopicsKey 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?

- 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 MeetingOverview of the 2-Day MeetingOverview of the 2-Day MeetingOverview of the 2-Day Meeting

• Agenda – Day #1

– IDSA/FDA CAP workshop

– IDSA perspective

– ATS/ACCP statement

– Ethical considerations

– Noninferiority trials in CAP

• Agenda – Day #1

– IDSA/FDA CAP workshop

– IDSA perspective

– ATS/ACCP statement

– Ethical considerations

– Noninferiority trials in CAP


Overview of the 2-Day MeetingOverview of the 2-Day MeetingOverview of the 2-Day MeetingOverview 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

• 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

19

For questions 1 and 2:

Anti-Infective Drugs Advisory Committee meetingAnti-Infective Drugs Advisory Committee meetingApril 1 & 2, 2008April 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.

20

Question 1a:


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?

21

Question 1b-1c:


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)?

22

Question 1d:


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.)

23

Question 1e:


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.

24

Question 1f:


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?

25

Question 2:


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).

26

Question 2a:


a) Can a treatment effect be reliably quantified for a noninferiority study of outpatient CAP (i.e., for an oral drug)?

i. To which patient population would this information apply with regards to disease severity and microbiological etiology?

ii. What endpoint(s) should be utilized?

iii. What is the proposed noninferiority margin and what data support the proposed noninferiority margin?

27

Question 2b:


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?

28

Question 2c:


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.

29

Question 3:


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.

30

Question 3 continued:


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?

31

Question 4:


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?

32

Question 4 continued:


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

33

Key Issues from Key Issues from the FDA-IDSA the FDA-IDSA

WorkshopWorkshopJohn Alexander, MD, MPHJohn Alexander, MD, MPH

Medical Team Leader,Medical Team Leader,Division of Anti-Infective and Division of Anti-Infective and

Ophthalmology Products, Ophthalmology Products, CDERCDER

34

FDA-IDSA WorkshopFDA-IDSA Workshop

Held January 17-18, 2008Held January 17-18, 2008 GoalsGoals

Examine critical issues in:Examine critical issues in: The design and conduct of trials of the safety The design and conduct of trials of the safety

and efficacy of antibacterial drugs in the and efficacy of antibacterial drugs in the treatment of CAPtreatment of CAP

The implications of emerging scientific tools The implications of emerging scientific tools that assist in the diagnosis of the etiology of that assist in the diagnosis of the etiology of CAPCAP

Discuss clinical trial design and statistical Discuss clinical trial design and statistical considerations in demonstrating efficacy considerations in demonstrating efficacy in clinical trials of CAP.in clinical trials of CAP.

35

CAP ScenariosCAP Scenarios Day 1 – CAP not requiring hospitalizationDay 1 – CAP not requiring hospitalization35 y/o male, 3 days of URI, purulent sputum, coughing35 y/o male, 3 days of URI, purulent sputum, coughing fever (38.3 C),fever (38.3 C), RR 18, “crackles” at R base RR 18, “crackles” at R baseCXR – bilateral LL infiltrates, R>LCXR – bilateral LL infiltrates, R>L Day 2 – Hospitalized CAP, not requiring ICUDay 2 – Hospitalized CAP, not requiring ICU65 y/o female, mild COPD, diabetes, HTN, smoker (35 65 y/o female, mild COPD, diabetes, HTN, smoker (35

PY)PY)

↑ ↑ sputum, ↑ dyspnea, fever (39.2 C), RR 24, Osputum, ↑ dyspnea, fever (39.2 C), RR 24, O22 sat= sat= 89% RA89% RA

definite L crackles, no rubs, PORT=IV, CURB-65=2definite L crackles, no rubs, PORT=IV, CURB-65=2CXR – LLL consolidation, air bronchogram, large heartCXR – LLL consolidation, air bronchogram, large heart

36

CAP Presentations – AC CAP Presentations – AC RepriseReprise

Criteria for NI Trials and Clinical ImportanceCriteria for NI Trials and Clinical Importance NI Trials Submitted in the Recent PastNI Trials Submitted in the Recent Past Historical Data on Treatment EffectHistorical Data on Treatment Effect PK/PD RelationshipPK/PD Relationship Clinician’s PerspectiveClinician’s Perspective Consultant’s PerspectiveConsultant’s Perspective IDSA PerspectiveIDSA Perspective Open Public Hearing – Industry PresentationsOpen Public Hearing – Industry Presentations

AC Presentations Informed by CAP Workshop AC Presentations Informed by CAP Workshop

37

CAP Presentations – CAP Presentations – DiagnosticsDiagnostics

Improved Detection of Improved Detection of S. S. pneumoniaepneumoniae

Molecular Diagnostics for Viral and Molecular Diagnostics for Viral and Bacterial PathogensBacterial Pathogens

Etiology of Outpatient CAPEtiology of Outpatient CAP Etiology of Hospitalized CAPEtiology of Hospitalized CAP Procalcitonin – Biomarker for CAPProcalcitonin – Biomarker for CAP

38

DiagnosticsDiagnostics

* Intensive Care Unit * Intensive Care Unit ††Influenza A/B, Adenovirus, RSV, parainfluenza Influenza A/B, Adenovirus, RSV, parainfluenza ## Gram-negative bacilli Gram-negative bacilli

Lancet 2003 (Dec. 13); 362:1991Lancet 2003 (Dec. 13); 362:1991

Outpatient Outpatient (Mild)(Mild)

Non-ICU Non-ICU inpatientsinpatients

ICU* (Severe)ICU* (Severe)

S pneumoniaeS pneumoniae S pneumoniaeS pneumoniae S pneumoniaeS pneumoniae

M pneumoniaeM pneumoniae M pneumoniaeM pneumoniae LegionellaLegionella spp. spp.

H influenzaeH influenzae C pneumoniaeC pneumoniae H influenzaeH influenzae

C pneumoniaeC pneumoniae H influenzaeH influenzae GNBGNB##

Resp. VirusesResp. Viruses†† LegionellaLegionella spp. spp. S aureusS aureus

AspirationAspiration

Resp. VirusesResp. Viruses††

39

DiagnosticsDiagnostics Conventional methods (CM) for bacterial Conventional methods (CM) for bacterial

diagnosis are limiteddiagnosis are limited Blood cultures have low yieldBlood cultures have low yield Sputum samples not available for all patientsSputum samples not available for all patients

Study of 109 patients with CAP (77 Study of 109 patients with CAP (77 hospitalized)*hospitalized)*

Pathogen identified by CM in 54/109Pathogen identified by CM in 54/109 Transthoracic aspirates identified Transthoracic aspirates identified S. S.

pneumoniae pneumoniae as etiologic agent in 33% as etiologic agent in 33% (18/55) of patients with unknown cause (18/55) of patients with unknown cause based on conventional methodsbased on conventional methods Not practical for clinical trialsNot practical for clinical trials

*Ruiz-Gonzalez et al. Am J Med 1999; 106:385-390*Ruiz-Gonzalez et al. Am J Med 1999; 106:385-390

40


Binax NowBinax Now®® S. pneumoniaeS. pneumoniae Urinary Ag Urinary Ag Approved – August 1999Approved – August 1999

Prospective study suspected Prospective study suspected S pneumoS pneumo (sepsis (sepsis or LRTI)or LRTI)

Sens 90%, Spec 75% vs. blood culture Sens 90%, Spec 75% vs. blood culture Spanish Study of CAP* Spanish Study of CAP*

Concentrated urine samplesConcentrated urine samples 10/13 (77%) bacteremic pneumococcal CAP10/13 (77%) bacteremic pneumococcal CAP 9/14 (64%) non-bacteremic pneumococcal CAP9/14 (64%) non-bacteremic pneumococcal CAP 69/300 (23%) CAP but no pathogen isolated69/300 (23%) CAP but no pathogen isolated

*CID 2003 (Feb 1); 36:286*CID 2003 (Feb 1); 36:286

41


Atypical PathogensAtypical Pathogens LegionellaLegionella

Urinary Ag has replaced other methods for Urinary Ag has replaced other methods for diagnosis (Sens 75-85%; Spec 99% for diagnosis (Sens 75-85%; Spec 99% for L. L. pneumophilapneumophila 1) 1)

MycoplasmaMycoplasma MIF - Serologic testing is current standardMIF - Serologic testing is current standard

Chlamydophila (Chlamydia)Chlamydophila (Chlamydia) MIF – Poor correlation with culture or PCR*MIF – Poor correlation with culture or PCR* PCR – Multiple in-house assays (need PCR – Multiple in-house assays (need

standardization) standardization) CID 2007 (Feb 15); 44:568CID 2007 (Feb 15); 44:568

42


xTAG™ Respiratory Virus PanelxTAG™ Respiratory Virus Panel Approved - Jan. 2008Approved - Jan. 2008 PCR system for viral DNA/RNA PCR system for viral DNA/RNA

detectiondetection Influenza A(H1 & H3)/B, RSV A/B, Influenza A(H1 & H3)/B, RSV A/B,

Adenovirus, Parainfluenzae (1, 2, 3), Adenovirus, Parainfluenzae (1, 2, 3), Human Metapneumovirus, RhinovirusHuman Metapneumovirus, Rhinovirus

Use for diagnosis of viral infectionsUse for diagnosis of viral infections ?Exclusion of patients from CAP trials??Exclusion of patients from CAP trials?

43


Procalcitonin (PCT)Procalcitonin (PCT) ““Hormokine” produced by parenchymal cellsHormokine” produced by parenchymal cells Increases in response to sepsisIncreases in response to sepsis Attenuated by viral infection-related cytokinesAttenuated by viral infection-related cytokines ““Promising” as biomarker for selecting patients Promising” as biomarker for selecting patients

more likely to have bacterial vs. viral pathogen more likely to have bacterial vs. viral pathogen Limited experience with PCT at a few centersLimited experience with PCT at a few centers Not yet used in trials for drug developmentNot yet used in trials for drug development

44

CAP PresentationsCAP Presentations

Pneumonia Severity - PORT Score Pneumonia Severity - PORT Score (a.k.a. PSI)(a.k.a. PSI) Developed as a prediction tool for short-Developed as a prediction tool for short-

term mortality in CAP patientsterm mortality in CAP patients

45

PORT ScorePORT Score

NEJM 1997; 336(4):243-250

46


DemographicsDemographics H & PH & P LaboratoryLaboratoryage = yrs (M)age = yrs (M) neoplasia (+30)neoplasia (+30) pH <7.35 (+30)pH <7.35 (+30)age = yrs – 10 (F)age = yrs – 10 (F) CHF (+10)CHF (+10) BUN >30 (+20)BUN >30 (+20)nursing home (+10)nursing home (+10) renal disease (+10)renal disease (+10) Na <130 Na <130

(+20)(+20)liver disease (+20)liver disease (+20) glucose >250 (+10)glucose >250 (+10)CVD (+10)CVD (+10) hct <30% (+10)hct <30% (+10)

pulse >125 (+10)pulse >125 (+10) p0p022 <60 (+10) <60 (+10)SBP <90 (+20) SBP <90 (+20) CXR - effusion (+10)CXR - effusion (+10)RR >30 (+20)RR >30 (+20)T >40 C or <35 C (+15)T >40 C or <35 C (+15)altered mental status (+20)altered mental status (+20)

NEJM 1997; 336(4):243-250

47


NEJM 1997; 336(4):243-250

48


Prognostic score for mortalityPrognostic score for mortality Includes elements related to severity, but Includes elements related to severity, but

not a true severity scorenot a true severity score Good tool for reducing unnecessary Good tool for reducing unnecessary

hospitalization hospitalization Intended to supplement, not override, Intended to supplement, not override,

physician judgmentphysician judgment Tool was studied in treated patientsTool was studied in treated patients Would it predict mortality in untreated Would it predict mortality in untreated

patients?patients?

49

Workshop DiscussionWorkshop Discussion

Many concerns about non-inferiority trialsMany concerns about non-inferiority trials Selection criteria, diagnostics, endpoints, Selection criteria, diagnostics, endpoints,

analysisanalysis But … non-inferiority could be supported But … non-inferiority could be supported

for some CAP patientsfor some CAP patients Need for clear guidance for CAP studiesNeed for clear guidance for CAP studies For mild pneumonia, more debate about For mild pneumonia, more debate about

use of NI trials though most still question use of NI trials though most still question ethics of placebo control trial or ethics of placebo control trial or practicality of superioritypracticality of superiority

50

Workshop DiscussionWorkshop Discussion Disease SeverityDisease Severity

PORT score and CURB-65 both discussedPORT score and CURB-65 both discussed Clinical EndpointsClinical Endpoints

Emphasis on PRO tool for mild pneumoniaEmphasis on PRO tool for mild pneumonia Objective, but how can PRO measure be related to Objective, but how can PRO measure be related to

historic evidence of treatment effect?historic evidence of treatment effect? Discussed use of mortality for severe Discussed use of mortality for severe

pneumoniapneumonia Advantage – objective, most related to historic Advantage – objective, most related to historic

datadata Disadvantage – uncommon, treatment alternatives Disadvantage – uncommon, treatment alternatives

Composite EndpointComposite Endpoint

51

AcknowledgementsAcknowledgements

Co-Chairs: Thomas R. Fleming, David Gilbert, Edward Co-Chairs: Thomas R. Fleming, David Gilbert, Edward CoxCox

Rapporteur: Brad SpellbergRapporteur: Brad SpellbergParticipants: Paul Ambrose, John G Bartlett, Helen Participants: Paul Ambrose, John G Bartlett, Helen

Boucher, John S Bradley, Dale Bratzler, Dennis Dixon, Boucher, John S Bradley, Dale Bratzler, Dennis Dixon, Roger M Echols, Thomas M File Jr, Michael Fine, Roger M Echols, Thomas M File Jr, Michael Fine, Karen Higgins, Keith P Klugman, Katherine A Karen Higgins, Keith P Klugman, Katherine A Laessig, Lionel A Mandell, Timothy F Murphy, Daniel Laessig, Lionel A Mandell, Timothy F Murphy, Daniel M Musher, Michael Niederman, Frederick Nolte, M Musher, Michael Niederman, Frederick Nolte, Robert O’Neill, Tatiana Oussova, John Powers III, Robert O’Neill, Tatiana Oussova, John Powers III, Bruce Psaty, Mary Singer, George H Talbot, Robert Bruce Psaty, Mary Singer, George H Talbot, Robert Temple, Glenn Tillotson, Richard WunderinkTemple, Glenn Tillotson, Richard Wunderink

http://www.fda.gov/cder/meeting/CAP.htmhttp://www.fda.gov/cder/meeting/CAP.htm

52

American Thoracic Society/American College of Chest Physicians Perspective

Richard G. Wunderink MDNorthwestern University Feinberg School of Medicine

Division of Pulmonary and Critical Care Medicine

53

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

54

ATS/ACCP Themes/Emphasis

Clinically relevantConsistent with most recent

IDSA/ATS CAP guidelines

55


Clinically relevantStratification/definition

56

CAP CategoriesMild = outpatient Moderate = hospitalized

outside the ICU Severe = ICU admission

57

Etiology of Severe CAP

4323 13 18

19

86

11

13

38

1619

10 23

27

32

15 8

3820

0%

20%

40%

60%

80%

100%

OtherS.pneumoEnterobacNonfermS.aureus

58

Severe CAP and Pneumonia Severity Index

6 5.68.7

15.9

23.8

0

5

10

15

20

25

ICU

Adm

issi

on (

%)

I II III IV V

Pneumonia Severity Index Class

Angus, AJRCCM, 2002

27% of ICU Adm

59

Diagnostic Criteria for Severe CAP

60

17

33.3

26 2420

49

18.5 16.7

23.7

0

10

20

30

40

50

60

%

ATS Revised ATS BTS PSI IV-V PSI V

Met Criteria for SCAP

If met, admitted to ICU

Angus, AJRCCM, 2002

60

Mechanical Ventilation- NIV or ETT

SCAPICU

SCAPICU

Septic Shock

•Confusion Hypothermia•Uremia Leukopenia•RR > 30 Thrombocytopenia•Massive fluid resuscitation for BP•PaO2/FiO2 < 250 Multilobar

YES

YES

NO

NO

3/9 = SCAP/ICU

61


Clinically relevantStratification/definitionInclusion of severe CAP/ICU

patients

62

SCAP: IDSA/ATS Guideline-Recommended Therapy

Beta-lactam (cephalosporin)

PLUSMacrolide or Fluoroquinolone

63

Combination Therapy in SCAP

71.8

6370.7

60.5

0

10

20

30

40

50

60

70

80

Cli

nica

l Cur

e (%

)

Protocol mITT Protocol mITT

Cefotax/OfloxLevoflox

Overall Population Mechanical Ventilation

Leroy, Chest, 2005

64


Clinically relevantConsistent with IDSA/ATS

CAP guidelinesExclusion of healthcare-

associated pneumonia (HCAP)

65

Risk Factors for MDR Pathogens

Antimicrobial therapy in preceding 90 daysCurrent hospitalization > 5 daysHigh frequency of antibiotic resistance in

community or specific hospital unitPresence 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

66

Risk Factors for MDR Pathogens

Antimicrobial therapy in preceding 90 daysPRSP 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

67


Clinically relevantConsistent with IDSA/ATS

CAP guidelinesExclusion of healthcare-

associated pneumonia (HCAP)Comparator drug

68

ATS/IDSA Guidelines: Hospitalized CAP

Newer fluoroquinoloneCephalosporin plus macrolide

For carefully selected patients, azithromycin alone

• Substitute doxycycline for macrolide

69

3rd Gen Cephalo

Aminoglycoside

B-lactam+Macro

Cephalo+MacroQuinolone

Treatment Outcomes Data

Gleason, Arch Intern Med, 1999

70

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

71

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

72

Mortality as an Endpoint

Unclear that antibiotics will differentially affect mortality

73

Unchanged CAP Fatality Rates

1

10

100

1000

Dea

ths

/100

,000

Pneumonia Tuberculosis Sepsis AIDS

www.cdc.gov/nchs/data

Clinical use of penicillin starts

Effective anti-TB drugs

74


Unclear that antibiotics will differentially affect mortalitySevere CAP – immunomodulationModerate CAP - ? cardiovascularMild CAP – ? bad luck

75

The Association between Pneumococcal Pneumonia and Acute Cardiac Events

0

5

10

15

20

MyoardialInfarct

CHF

Pat

ient

s

With CHFWith ArrhythmiaAlone

27.3

8.8

0

5

10

15

20

25

30

%

Mortality

Acute Cardiac None

p < 0.008OR 3.9

N=33 N=137

Musher et al, Clin Infect Dis, 2007

33/170 (19.4%) had at leastone major cardiac event

76

SCAP: Deaths Age < 5511,684 Admissions in Alberta

3

26.9 26.1

1.8

12.4

17.6

1.6

22.517.8

8.2

4743.1

0

5

10

15

20

25

30

35

40

45

50

%

ARF/RespArr MechVent Shock ICUAdm

Overall Death < 11 days All Deaths

Marrie, CID, 2003

77

Septic Shock and Respiratory Failure in CAP

PneumoniaPneumonia = 40% of septic

shock

Septic shock in approximately 15%

of CAP

RespFailure

Septic Shock

Lethal Pneumonia

78


Unclear that antibiotics will differentially affect mortality

Exception is inappropriate initial empirical antibiotics in severe CAPBut don’t know what antibiotic(s)

minimize inappropriate initial empirical since group has not been studied

79

But…

80

3rd Gen Cephalo

Aminoglycoside

B-lactam+Macro

Cephalo+MacroQuinolone

Treatment Outcomes Data

Gleason, Arch Intern Med, 1999

81

Atypical Coverage for Bacteremic CAP

• Quinolones most common monotherapy

• ? Quinolone in non-ICU, macrolide combination in critically ill 0

0.2

0.4

0.6

0.8

1

1.2

1.4

Mor

tali

ty O

dds

Rat

io

Mono Atyp Macro Quin Doxy

Hospital 30 day

* **† †

* p < 0.01, † p < 0.05Metersky, Chest, 2007

82

Combination Therapy of Bacteremic Pneumococcal CAP

0.220.3

0.4 0.42

0.29

1

0

0.2

0.4

0.6

0.8

1

Mor

talit

y O

dds

Rat

io

Waterer Mufson Martinez Baddour Weiss Harbarth

83

Combination Therapy for SCAP

No shock Shock

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

p = 0.01

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

Rodriguez, Crit Care Med, 2007

84


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

85

Other CAP EndpointsFor moderate CAP, clinically and financially

relevant endpoint is hospitalizationFavor use of objective criteria, such as time to

clinical stability, rather than subjective clinicalHospitalization is often used to correct other

medical issues not reliableFor intravenous-only study medication, helps

solve problem of oral continuationTools have been already been developed

86

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

87

Biomarker Endpoints/ Entry Criteria

Procalcitonin is not FDA approved for this indicationProbably minimal impact on CAPNormal/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

88

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

89

Thank you

Antiinfective Drugs Advisory Committee, April 1, 2008Antiinfective Drugs Advisory Committee, April 1, 2008 9090

Ethical Considerations for Trials Ethical Considerations for Trials in Community Acquired in Community Acquired

PneumoniaPneumonia

Robert M. Nelson, M.D., Ph.D.Robert M. Nelson, M.D., Ph.D.Office of Pediatric TherapeuticsOffice of Pediatric Therapeutics

andandSara F. Goldkind, M.D., M.A.Sara F. Goldkind, M.D., M.A.

Good Clinical Practice ProgramGood Clinical Practice Program

Food and Drug AdministrationFood and Drug Administration

9191

Unmet Needs - AdultsUnmet Needs - Adults

66thth leading cause of death in USA leading cause of death in USA– #1 cause of death from an infectious disease in USA #1 cause of death from an infectious disease in USA

Approximately 5.6 million cases of CAP Approximately 5.6 million cases of CAP occur annually in USA, and 1.1 million occur annually in USA, and 1.1 million require hospitalizationrequire hospitalization– 80% of patients with CAP treated as outpatients: 80% of patients with CAP treated as outpatients:

mortality rate <1-5%mortality rate <1-5%– If hospitalization required: mortality rate 12% overallIf hospitalization required: mortality rate 12% overall– If ICU admission required: mortality rate 12-36%If ICU admission required: mortality rate 12-36%

UNICEF/WHO, Pneumonia: The forgotten killer of children, 2006UNICEF/WHO, Pneumonia: The forgotten killer of children, 2006 9292

Unmet Needs - ChildrenUnmet Needs - Children

Over 2 million deaths per year


Unmet Needs - ChildrenUnmet Needs - Children

9494

Outline of DiscussionOutline of Discussion

The Ethical Requirement of Scientific ValidityThe Ethical Requirement of Scientific Validity– Choice of Control Group; Assay Sensitivity; Non-Choice of Control Group; Assay Sensitivity; Non-

Inferiority and Superiority (Placebo) DesignsInferiority and Superiority (Placebo) Designs

Ethical Balance of Risk and BenefitEthical Balance of Risk and Benefit– Withholding Known Effective TreatmentWithholding Known Effective Treatment

Design Modification and other issues in Adult Design Modification and other issues in Adult and Pediatric Studies of Antibiotics for CAPand Pediatric Studies of Antibiotics for CAPConclusion: Ethical and Scientific StandardConclusion: Ethical and Scientific Standard

E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001E-10 Choice of Control Group and Related Issues in Clinical Trials, May 2001 9595

Choice of Control GroupChoice of Control GroupA Critical Decision affecting…A Critical Decision affecting…– Possible Inferences; Ethical Acceptability; Possible Inferences; Ethical Acceptability;

Minimizing Bias; Subjects and Recruitment; Minimizing Bias; Subjects and Recruitment; Endpoints; Credibility of Results; Acceptability Endpoints; Credibility of Results; Acceptability to Regulatory Authorities; Other Features of to Regulatory Authorities; Other Features of Study, Conduct and Interpretation.Study, Conduct and Interpretation.

Key to Scientific Validity (Causal Inference)Key to Scientific Validity (Causal Inference)– Allows for discrimination of patient outcomes Allows for discrimination of patient outcomes

causedcaused by the test treatment from outcomes by the test treatment from outcomes caused by other factors, such as the natural caused by other factors, such as the natural progression of the disease, observer or patient progression of the disease, observer or patient expectations, or other treatment.expectations, or other treatment.


Types of Control GroupsTypes of Control Groups

Concurrent Control (control/test groups Concurrent Control (control/test groups chosen from same population, usually by chosen from same population, usually by randomization, and treated concurrently)randomization, and treated concurrently)– Placebo (two or three-arm study)Placebo (two or three-arm study)– Active (Positive)Active (Positive)– Dose-Response (different dose or regimen of study Dose-Response (different dose or regimen of study

treatment)treatment)– No treatment (not blinded)No treatment (not blinded)

External (including historical) Controls, External (including historical) Controls, regardless of comparator treatmentregardless of comparator treatment


External or Non-concurrent External or Non-concurrent ControlsControls

There are serious concerns about the There are serious concerns about the ability of trials using external (including ability of trials using external (including historical) controls, regardless of historical) controls, regardless of comparator treatment, to ensure the comparator treatment, to ensure the comparability of test and control groups, comparability of test and control groups, and to minimize important biases.and to minimize important biases.

Thus, this is an unacceptable study design Thus, this is an unacceptable study design for antibiotic efficacy studies for CAP.for antibiotic efficacy studies for CAP.


Dose-Response DesignDose-Response DesignAntibiotic trials may compare two regimens Antibiotic trials may compare two regimens (e.g., short vs. long treatment course) using (e.g., short vs. long treatment course) using eithereither superiority or non-inferiority design superiority or non-inferiority design (thus, similar issues as (thus, similar issues as active control trialsactive control trials).).Choice of the lower dose (or shorter course) Choice of the lower dose (or shorter course) must be a fair comparison since trial must be a fair comparison since trial conditions should not favor one treatment conditions should not favor one treatment over the other. If not, cannot assure assay over the other. If not, cannot assure assay sensitivity, and may raise similar ethical sensitivity, and may raise similar ethical concerns as concerns as placebo controlsplacebo controls..


Focus: Active/Placebo ControlsFocus: Active/Placebo Controls

Two Approaches to Establish EfficacyTwo Approaches to Establish EfficacySuperioritySuperiority of test treatment to control of test treatment to control (whether placebo or active control)(whether placebo or active control)

SimilaritySimilarity of test treatment to known of test treatment to known effective treatment (active control)effective treatment (active control)– Equivalence (i.e., equally effective)Equivalence (i.e., equally effective)– Non-inferiority (i.e., not less effective by NIM)Non-inferiority (i.e., not less effective by NIM)– Key assumptionKey assumption: active control is effective : active control is effective

under trial conditions (i.e., assay sensitivity)under trial conditions (i.e., assay sensitivity)


Assay SensitivityAssay Sensitivity

Definition: the ability of a clinical trial Definition: the ability of a clinical trial to distinguish effective treatment from to distinguish effective treatment from less effective or ineffective treatment.less effective or ineffective treatment.

Lack of assay sensitivity has different Lack of assay sensitivity has different implications for superiority and non-implications for superiority and non-inferiority trials.inferiority trials.


Assay SensitivityAssay SensitivitySuperiority TrialSuperiority Trial– If superiority trial lacks assay sensitivity, it will fail If superiority trial lacks assay sensitivity, it will fail

to show that test treatment is superior and will to show that test treatment is superior and will fail to lead to conclusion of efficacy.fail to lead to conclusion of efficacy.

– When one treatment is shown to be superior, that When one treatment is shown to be superior, that finding itself establishes assay sensitivity.finding itself establishes assay sensitivity.

Non-Inferiority (NI) TrialNon-Inferiority (NI) Trial– If non-inferiority trial lacks assay sensitivity, trial If non-inferiority trial lacks assay sensitivity, trial

may find ineffective treatment to be non-inferior; may find ineffective treatment to be non-inferior; could lead to erroneous conclusion of efficacy.could lead to erroneous conclusion of efficacy.


Assay Sensitivity in NI TrialsAssay Sensitivity in NI Trials

Inferred from two determinations:Inferred from two determinations:1)1) Historical evidence of sensitivity to drug Historical evidence of sensitivity to drug

effects (HESDE)effects (HESDE), i.e., similarly designed past , i.e., similarly designed past trials regularly distinguish effective from less trials regularly distinguish effective from less effective or ineffective treatments; and,effective or ineffective treatments; and,

2)2) Appropriate trial conductAppropriate trial conduct, i.e., conduct of trial , i.e., conduct of trial did not undermine ability to distinguish did not undermine ability to distinguish effective from less effective or ineffective effective from less effective or ineffective treatments (IDSA: “constancy assumption”?).treatments (IDSA: “constancy assumption”?).


(1) HESDE(1) HESDE

Evaluate Evaluate beforebefore beginning non-inferiority trial beginning non-inferiority trial

Appropriately designed and conducted trials using Appropriately designed and conducted trials using specific treatment (or other treatments with similar specific treatment (or other treatments with similar effects) to be used as the active control must show effects) to be used as the active control must show treatment effect (optimally, superior to placebo).treatment effect (optimally, superior to placebo).

Without well-supported historical evidence of Without well-supported historical evidence of sensitivity to drug effects, demonstration of efficacy sensitivity to drug effects, demonstration of efficacy using non-inferiority trial design is not possible and using non-inferiority trial design is not possible and should not be attempted.should not be attempted.


Choosing a Non-Inferiority Margin (NIM)Choosing a Non-Inferiority Margin (NIM)

NIM: degree of inferiority of test treatment to NIM: degree of inferiority of test treatment to control (delta) that trial will attempt to exclude control (delta) that trial will attempt to exclude statistically.statistically.

NIM NIM ≤≤ smallest effect size that active drug smallest effect size that active drug would reliably be expected to have compared would reliably be expected to have compared with placebo in the setting of the planned trial.with placebo in the setting of the planned trial.– onlyonly possible when there is historical evidence of sensitivity possible when there is historical evidence of sensitivity

to drug effects.to drug effects.– requires requires measure of superiority of active treatment to controlmeasure of superiority of active treatment to control, ,

not uncontrolled measures (e.g., change from baseline).not uncontrolled measures (e.g., change from baseline).


(2) Appropriate Trial Design & Conduct(2) Appropriate Trial Design & Conduct

Can only be fully evaluated Can only be fully evaluated afterafter the non- the non-inferiority trial is completed. inferiority trial is completed.

Planned non-inferiority trial must share critical Planned non-inferiority trial must share critical design characteristics with the historical trials design characteristics with the historical trials used to determine that evidence of sensitivity to used to determine that evidence of sensitivity to drug effects exists.drug effects exists.

Trial conduct should adhere closely to that of Trial conduct should adhere closely to that of the historical trials and should be of high quality the historical trials and should be of high quality (e.g. good compliance, few losses to follow-up).(e.g. good compliance, few losses to follow-up).


Scrupulous Trial Conduct may be Scrupulous Trial Conduct may be necessary for Assay Sensitivitynecessary for Assay Sensitivity

For non-inferiority trials, may be weaker For non-inferiority trials, may be weaker stimulus to engage in efforts to ensure study stimulus to engage in efforts to ensure study qualityquality– Errors that diminish observed treatment differences (e.g., Errors that diminish observed treatment differences (e.g.,

poor compliance, high placebo response, concomitant poor compliance, high placebo response, concomitant treatment, misclassification of outcomes) may undermine treatment, misclassification of outcomes) may undermine preservation of assay sensitivity. preservation of assay sensitivity.

– Some trial errors can increase variance, thus decreasing Some trial errors can increase variance, thus decreasing likelihood of showing non-inferiority by widening likelihood of showing non-inferiority by widening confidence interval (e.g., poor measurement technique).confidence interval (e.g., poor measurement technique).


Non-Inferiority Trial Conduct?Non-Inferiority Trial Conduct?Review non-inferiority trial conduct for factors Review non-inferiority trial conduct for factors that that – might obscure differences between treatmentsmight obscure differences between treatments

E.g., observed differences in populations enrolled, use of E.g., observed differences in populations enrolled, use of concomitant therapies, compliance with therapy, and extent of, and concomitant therapies, compliance with therapy, and extent of, and reasons for, subjects dropping out?reasons for, subjects dropping out?

– might make the trial different from the trials that provided the might make the trial different from the trials that provided the basis for determining the NIM.basis for determining the NIM.

E.g., atypical outcomes with active control treatment (e.g., unusually E.g., atypical outcomes with active control treatment (e.g., unusually high or low antibiotic cure rate) can indicate important differences high or low antibiotic cure rate) can indicate important differences which undermined assay sensitivity.which undermined assay sensitivity.

Concurrent trial monitoring may be necessary to Concurrent trial monitoring may be necessary to minimize risk and assure adequate trial conductminimize risk and assure adequate trial conduct

108108

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

Scientific and Policy ConcernsScientific and Policy Concerns– In spite of questions about specifying a reliable In spite of questions about specifying a reliable

treatment effect (i.e., NIM) based on past experience, treatment effect (i.e., NIM) based on past experience, antibiotics are generally highly effective. Thus, a antibiotics are generally highly effective. Thus, a superiority design may require a larger sample size superiority design may require a larger sample size than a non-inferiority trial (depending on the margin).than a non-inferiority trial (depending on the margin).

– There may be other advantages of new over existing There may be other advantages of new over existing antibiotics that may not be captured by an actively antibiotics that may not be captured by an actively controlled superiority study to establish efficacy (such controlled superiority study to establish efficacy (such as different resistance profiles, improved safety, ease of as different resistance profiles, improved safety, ease of administration, formulation advantages, cost, etc.)administration, formulation advantages, cost, etc.)


Ethical preference for AC trial designs?Ethical preference for AC trial designs?

Active control trials may pose fewer ethical Active control trials may pose fewer ethical problems than placebo-controlled trials because all problems than placebo-controlled trials because all subjects receive active treatment. subjects receive active treatment. – But subjects receiving a new treatment are not receiving standard But subjects receiving a new treatment are not receiving standard

therapy and thus may be receiving an ineffective or harmful drug. therapy and thus may be receiving an ineffective or harmful drug.

If active control therapy improves survival or If active control therapy improves survival or decreases irreversible morbidity, withholding of decreases irreversible morbidity, withholding of such treatment from experimental group raise such treatment from experimental group raise same concerns that render placebo control same concerns that render placebo control unacceptable.unacceptable.


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

Placebo-controlled trial for efficacy is as free of assumptions Placebo-controlled trial for efficacy is as free of assumptions and reliance on external information as possible.and reliance on external information as possible.

Most problems in design or conduct of placebo-controlled Most problems in design or conduct of placebo-controlled trial increase likelihood of failure to demonstrate treatment trial increase likelihood of failure to demonstrate treatment difference (and thereby establish efficacy), so trial contains difference (and thereby establish efficacy), so trial contains built-in incentives for excellence.built-in incentives for excellence.

When primary purpose of trial is comparison of two active When primary purpose of trial is comparison of two active agents, addition of placebo control provides an internal agents, addition of placebo control provides an internal standard that enhances inferences that can be drawn. standard that enhances inferences that can be drawn. However, ethical issues with use of placebo control remain a However, ethical issues with use of placebo control remain a concern with three-arm design.concern with three-arm design.


Ethical Issues with Placebo Ethical Issues with Placebo ControlsControls

Where an available treatment is known to prevent Where an available treatment is known to prevent serious harm, such as death or irreversible serious harm, such as death or irreversible morbidity, it is generally inappropriate to use a morbidity, it is generally inappropriate to use a placebo control. There are exceptions, however, placebo control. There are exceptions, however, such as when standard therapy has such severe such as when standard therapy has such severe toxicity that many patients refuse to receive it.toxicity that many patients refuse to receive it.

When a new treatment is tested for a condition for When a new treatment is tested for a condition for which no effective treatment is known, there is which no effective treatment is known, there is usually no ethical problem with a study comparing usually no ethical problem with a study comparing the new treatment to placebo. the new treatment to placebo.


Ethical Issues with Placebo Ethical Issues with Placebo ControlsControls

When there is no serious harm, it is generally When there is no serious harm, it is generally considered ethical to ask patients to considered ethical to ask patients to participate in a placebo-controlled trial, even participate in a placebo-controlled trial, even if they may experience discomfort, assuming if they may experience discomfort, assuming adequate informed and voluntary consent.adequate informed and voluntary consent.

Can a randomized placebo-controlled trial for Can a randomized placebo-controlled trial for community acquired pneumonia in adult and community acquired pneumonia in adult and pediatric patients meet this standard?pediatric patients meet this standard?


http://www.wma.net/e/policy/b3.htmhttp://www.wma.net/e/policy/b3.htm 114114

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

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

Added by the WMA General Assembly, Washington 2002 (http://www.wma.net/e/policy/b3.htm)Added by the WMA General Assembly, Washington 2002 (http://www.wma.net/e/policy/b3.htm) 115115

Note of Clarification on Paragraph 29Note of Clarification on Paragraph 29

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

Added by the WMA General Assembly, Washington 2002 (http://www.wma.net/e/policy/b3.htm)Added by the WMA General Assembly, Washington 2002 (http://www.wma.net/e/policy/b3.htm) 116116

Note of Clarification on Paragraph 29Note of Clarification on Paragraph 29

““However, a placebo-controlled trial may be However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is ethically acceptable, even if proven therapy is available, under the following circumstances:available, under the following circumstances:– ““Where for compelling and scientifically sound Where for compelling and scientifically sound

methodological reasons its use is necessary to determine methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or the efficacy or safety of a prophylactic, diagnostic or therapeutic method; therapeutic method; oror

– ““Where a prophylactic, diagnostic or therapeutic method is Where a prophylactic, diagnostic or therapeutic method is being investigated for being investigated for a minor conditiona minor condition and the patients and the patients who receive placebo will who receive placebo will not be subject to any additional not be subject to any additional risk of serious or irreversible harmrisk of serious or irreversible harm.”.”


Choice of control in clinical trialsChoice of control in clinical trials

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


Choice of control in clinical trialsChoice of control in clinical trials““Placebo may be used:Placebo may be used:– ““When there is no established effective intervention;When there is no established effective intervention;– ““When withholding an established effective intervention would When withholding an established effective intervention would

expose subjects to, at most, temporary discomfort or delay in expose subjects to, at most, temporary discomfort or delay in relief of symptoms;relief of symptoms;

– ““When use of an established effective intervention as When use of an established effective intervention as comparator would not yield scientifically reliable results comparator would not yield scientifically reliable results andand use of placebo would not add any risk of serious or use of placebo would not add any risk of serious or irreversible harm to the subjects.”irreversible harm to the subjects.”

A placebo-controlled trial for CAP may be ethical A placebo-controlled trial for CAP may be ethical IFIF the use of placebo would not add the use of placebo would not add any riskany risk of of serious or irreversible harm to the subjects.serious or irreversible harm to the subjects.


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

Additional Control GroupsAdditional Control Groups– Three-arm Trial; Placebo and Active ControlThree-arm Trial; Placebo and Active Control– Additional DosesAdditional Doses– Factorial DesignsFactorial Designs

Other Modifications of Study DesignOther Modifications of Study Design– Add on Study, Placebo-Controlled; Replacement Study.Add on Study, Placebo-Controlled; Replacement Study.– Early Escape; Rescue TreatmentEarly Escape; Rescue Treatment– Limited Placebo PeriodLimited Placebo Period– Randomized WithdrawalRandomized Withdrawal

Appear of limited application to antibiotic Appear of limited application to antibiotic trials.trials.

120120

Adult Studies of Adult Studies of Antibiotics for CAPAntibiotics for CAP

121121

Alter risks based upon choice of Alter risks based upon choice of study populationstudy population

An ethical study requires both:An ethical study requires both:– Minimization of risks to enrolled subjectsMinimization of risks to enrolled subjects– Maximization of scientific validity (assay Maximization of scientific validity (assay

sensitivity and study design)sensitivity and study design)Choice of study populationChoice of study population

How can these two goals best be achieved?How can these two goals best be achieved?– Tailoring study population with more rigorous Tailoring study population with more rigorous

entry criteria, butentry criteria, but– This may affect generalizability of resultsThis may affect generalizability of results

122122

CAP: study in adultsCAP: study in adultsHeterogeneous populationHeterogeneous populationSome factors that influence course, Some factors that influence course, response, and mortalityresponse, and mortality– Elderly (>65 y/o)Elderly (>65 y/o)– SmokersSmokers– Outpatient vs. inpatient (ward vs. ICU)Outpatient vs. inpatient (ward vs. ICU)– USA vs outside USAUSA vs outside USA– Co-morbiditiesCo-morbidities– Functional statusFunctional status– Virulence of the infectious organism and Virulence of the infectious organism and

antibiotic resistance profileantibiotic resistance profile

123123

Clinical diagnosis based upon symptoms Clinical diagnosis based upon symptoms and signs -- empiric therapyand signs -- empiric therapyCombination of clinical presentation and Combination of clinical presentation and radiographic findings -- empiric therapyradiographic findings -- empiric therapyEmpiric therapy is influenced by standard-Empiric therapy is influenced by standard-of-care for that regionof-care for that regionPathogen-directed therapyPathogen-directed therapy– Prevalence of resistant organisms (in a given Prevalence of resistant organisms (in a given

local)local)– Associated complexitiesAssociated complexities

CAP: study in adultsCAP: study in adults

124124

Minimization of RiskMinimization of Risk

Primary imperative is to minimize Primary imperative is to minimize research-related risks to subjects without research-related risks to subjects without compromising reliability of research results compromising reliability of research results upon which to base safety and efficacy upon which to base safety and efficacy claimsclaims– Enroll a less sick study populationEnroll a less sick study population– Enroll a study population with ease of access Enroll a study population with ease of access

to health care including on-going monitoring to health care including on-going monitoring (clinical improvement usually occurs by day 3) (clinical improvement usually occurs by day 3) and follow-up (at 6 wks)and follow-up (at 6 wks)

125125

Minimization of RiskMinimization of RiskIf a less sick study population is selected can onset of If a less sick study population is selected can onset of antibiotic treatment be delayed to mimic PCT?antibiotic treatment be delayed to mimic PCT?– Will this choice of study population provide useful information Will this choice of study population provide useful information

(meaningful endpoint) in light of PCT studies that have already (meaningful endpoint) in light of PCT studies that have already been done on young, low-risk, clinically stable outpatients with been done on young, low-risk, clinically stable outpatients with mild CAP? mild CAP?

– Some data demonstrate that antibiotic administration within 8 Some data demonstrate that antibiotic administration within 8 hours of hospital arrival was associated with a significantly lower hours of hospital arrival was associated with a significantly lower 30-day mortality and length of hospital stay in both unadjusted 30-day mortality and length of hospital stay in both unadjusted and adjusted (for patient risk status) analyses; for those who did and adjusted (for patient risk status) analyses; for those who did not receive pre-hospital antibiotics, 4 hours was associated with not receive pre-hospital antibiotics, 4 hours was associated with decreased mortality & length of hospital stay {Multi-center decreased mortality & length of hospital stay {Multi-center retrospective cohort study of 14,069 hospitalized elderly patients retrospective cohort study of 14,069 hospitalized elderly patients with pneumonia} Can a delay in treatment be justified?with pneumonia} Can a delay in treatment be justified?

– Although there are prognostic scoring systems (PSI, CURB, Although there are prognostic scoring systems (PSI, CURB, CURB-65) they do not account for all factors contributing to CURB-65) they do not account for all factors contributing to disease severity.disease severity.

126126

Scientific validityScientific validity

Enrich the study population with responders (e.g., Enrich the study population with responders (e.g., subjects who meet the criteria for a pathogen-directed subjects who meet the criteria for a pathogen-directed therapy)therapy)– The only randomized controlled trial of diagnostic strategy in CAP The only randomized controlled trial of diagnostic strategy in CAP

demonstrated no statistically significant differences in mortality demonstrated no statistically significant differences in mortality rate of length of hospital stay between patients receiving rate of length of hospital stay between patients receiving pathogen-directed therapy and patients receiving empirical pathogen-directed therapy and patients receiving empirical therapy [IDSA/ATS Guidelines for CAP in Adults, 2007]therapy [IDSA/ATS Guidelines for CAP in Adults, 2007]

– Even when extensive diagnostic testing is used, causative Even when extensive diagnostic testing is used, causative pathogen cannot be identified in up to 50% of cases [ATS pathogen cannot be identified in up to 50% of cases [ATS Guidelines for Management of Adults with CAP, 2001]Guidelines for Management of Adults with CAP, 2001]

Given low virulence of atypical and viral pathogens, and Given low virulence of atypical and viral pathogens, and effectiveness of approved antibiotics, will studying mild to effectiveness of approved antibiotics, will studying mild to moderate CAP give reliable results?moderate CAP give reliable results?

127127

Generalizability of ResultsGeneralizability of Results

Ability to generalize study results to the Ability to generalize study results to the projected use population projected use population – Variations in standard-of-care Variations in standard-of-care

Local vs. universal standardsLocal vs. universal standards

– Differing prevalence of bacterial pathogens Differing prevalence of bacterial pathogens (including resistant organisms)(including resistant organisms)

– Nuanced approaches to CAP (e.g., US Nuanced approaches to CAP (e.g., US outpatient therapy addresses broad outpatient therapy addresses broad antimicrobial coverage; European approach antimicrobial coverage; European approach focuses on empiric therapy for S. pneumoniafocuses on empiric therapy for S. pneumonia

128128

Additional Issues from Additional Issues from Pediatric Studies of Pediatric Studies of Antibiotics for CAPAntibiotics for CAP

World Health Organization, Pocket Book of Hospital care for children 2005World Health Organization, Pocket Book of Hospital care for children 2005 129129

WHO Classification of PneumoniaWHO Classification of Pneumonia


Agarwal et al BMJ 2004Agarwal et al BMJ 2004 131131

Ashgar et al BMJ 2008Ashgar et al BMJ 2008 132132


Hazir et al Lancet 2008Hazir et al Lancet 2008 134134

135135

Wide Agreement on Ethical Wide Agreement on Ethical PrinciplesPrinciples

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

136136

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

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

137137

ChallengesChallengesActive Control TrialsActive Control Trials– Assure scientific validity with eitherAssure scientific validity with either

Selection of an appropriate NIM combined with meticulous trial Selection of an appropriate NIM combined with meticulous trial conduct using non-inferiority design, orconduct using non-inferiority design, or

Use of a superiority design.Use of a superiority design.

Placebo Control TrialsPlacebo Control Trials– Assure ethical treatment of subjects by avoiding any risk of Assure ethical treatment of subjects by avoiding any risk of

serious or irreversible harm.serious or irreversible harm.

All trials must meet the dual ethical All trials must meet the dual ethical requirements of (1) scientific validity and (2) an requirements of (1) scientific validity and (2) an appropriate balance of risk and potential appropriate balance of risk and potential benefit.benefit.

Odysseus vor Scilla und Charybdis, Johann Heinrich Füssli, 1794-1796Odysseus vor Scilla und Charybdis, Johann Heinrich Füssli, 1794-1796 138138

“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.”

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 characteristicse.g., Disease caused by pathogens resistant to STD in NI Trial

use of supportive caree.g., Enhanced concomitant Rx attenuates effect of STD in NI Trial

dose, schedule, level of adherencee.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

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 Marginand Interpretation of NI Trial Results

• Effect of the STD regimen

• Clinical Relevance of Reduction in Efficacy





(EXP ─ STD) 95% C. I. : ( ─5%, 15% )



(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


STD better

% Failure

(Placebo - STD)


50% of STD benefit


EXP - STD

Factors Influencing the Choice of Marginand Interpretation of NI Trial Results

• Effect of the STD regimen

• Clinical Relevance of Reduction in Efficacy

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


STD better

% Failure

(Placebo - STD)


50% 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…





(EXP ─ STD) 95% C. I. : ( 2%, 8% )



(PLA ─ STD) 95% C.I. : ( 20%, 40% )

Failure Probability

0% 10% 20% 30% 40%

Placebo better


STD better

% Failure

(Placebo - STD)


50% of STD benefit


EXP - STD


• The EXP regimen is “at least as good as” the STD regimen…

• The EXP regimen is“not worse than” the STD regimen…


• 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 Non-Inferiority Trials in CAP

• Choice of Endpoint

• Addressing Confounding due toLack of Randomized Trials evaluating STD

• Literature Review to Derive Margins for Non-Inferiority Trials in CAP

• Conclusions

160

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

161

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.

162

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.

164

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.

165

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

166

Impact of Age on Outcome

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



• Addressing Confounding due to Lack of Randomized Trials evaluating STD


• Conclusions

168

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.

169

Impact of Age and Bacteremia on Mortality

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

170

Importance of Baseline Comparability

Group 1Group 1

Group 2Group 2

Mortality (%)Mortality (%)

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

1/18 (6%)1/18 (6%)

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

sulfanilamidesulfanilamide

no specificno specifictreatmenttreatment

Group 1 (Group 1 (sulfanilamidesulfanilamide))10/18 (56%) bacteremic10/18 (56%) bacteremic11/18 (61% ) multi-lobar11/18 (61% ) multi-lobar13/18 (72%) > age 3013/18 (72%) > age 30

Group 2 (Group 2 (no specific rx.)no specific rx.)0/18 (0%) bacteremic0/18 (0%) bacteremic0/18 (0%) over age 300/18 (0%) over age 30

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





• Conclusions

• Extensive review of original source articles (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

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

By Age

Bacteremic Subjects

No Specific

Treatment Antibiotics

Non-Bacteremic

No Specific


<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


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


Proposed Margin

47% (35%, 59%) 10 %

32% (24%, 40%)

10 %

175

Important Baseline Risk Factors for Poor Outcomes in Pneumonia

1. Older age

2. Presence of bacteremia

3. Presence of multi-lobar disease

4. Bronchopneumonia (as opposed to lobar pneumonia)

5. Type of infecting pneumococcus (type III highest mortality)

6. Presence of co-morbid illness

7. 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.

By Age

Bacteremic Subjects

No Specific


Non-Bacteremic

No Specific


<30 # Deaths / # Patients

81 / 126 4 / 16

64.3% 25.0%

90 / 1036 5 / 63


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


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


Proposed Margin

47% (35%, 59%) 10 %

32% (24%, 40%)

10 %





• 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%

182

Treatment Effect of Antibacterial Treatment Effect of Antibacterial Drugs in Community-Acquired Drugs in Community-Acquired

Pneumonia: Pneumonia: A Historical PerspectiveA Historical Perspective

Mary Singer, M.D., Ph.D.Mary Singer, M.D., Ph.D.

Medical Officer, Office of Antimicrobial Medical Officer, Office of Antimicrobial Products, FDA/CDERProducts, FDA/CDER

183

ObjectivesObjectives

To review evidence for a treatment effect of To review evidence for a treatment effect of antibacterial drugs in Community Acquired antibacterial drugs in Community Acquired Pneumonia (CAP)Pneumonia (CAP)

To estimate the magnitude of the treatment To estimate the magnitude of the treatment effect in the context of non-inferiority trialseffect in the context of non-inferiority trials

184

Approach to Estimation of Approach to Estimation of Treatment Effect for Antibacterial Treatment Effect for Antibacterial

Drugs in CAPDrugs in CAP

1.1. Historical Data Historical Data • Natural History studiesNatural History studies• Published studies performed Published studies performed pre- and postpre- and post - -

introduction of antibacterial drugsintroduction of antibacterial drugs Most were studies of pneumococcal or lobar pneumoniaMost were studies of pneumococcal or lobar pneumonia Hospitalized patientsHospitalized patients Mortality EndpointMortality Endpoint

Observational studies (treated vs. untreated)Observational studies (treated vs. untreated) Controlled trials: antibacterial drugs vs. untreated Controlled trials: antibacterial drugs vs. untreated

controlscontrols Pneumococcal or lobar pneumonia Pneumococcal or lobar pneumonia MycoplasmaMycoplasma pneumonia controlled trials pneumonia controlled trials

2.2. Alternative ApproachesAlternative Approaches

185

History of Effective Treatment History of Effective Treatment for Pneumococcal Pneumoniafor Pneumococcal Pneumonia

18811881 Streptococcus (Diplococcus) Streptococcus (Diplococcus) pneumoniaepneumoniae identified as ‘the’ cause of identified as ‘the’ cause of pneumonia pneumonia

1913 - 19401913 - 1940 Serum Therapy Serum Therapy

1938-19391938-1939 SulfapyridineSulfapyridine

1940 - 19451940 - 1945 Penicillin and other antibioticsPenicillin and other antibiotics

186

Natural History of CAPNatural History of CAP

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

- Sir William Osler, 1894, who succumbed to - Sir William Osler, 1894, who succumbed to HaemophilusHaemophilus influenzae pneumonia in 1919influenzae pneumonia in 1919

187

Percentage of Untreated Patients "Terminating by Percentage of Untreated Patients "Terminating by Recovery" by each Day in Seven Different Pneumococcal Recovery" by each Day in Seven Different Pneumococcal

TypesTypes

(Bullowa, 1937)(Bullowa, 1937)

188

Pneumococcal Pneumonia (Untreated) in Pneumococcal Pneumonia (Untreated) in Infants and Children: Effect of Age and Infants and Children: Effect of Age and

Bacteremia on MortalityBacteremia on MortalityBullowa (1937)Bullowa (1937)

GroupGroup Percent MortalityPercent Mortality

< 2 years old*< 2 years old*

Percent MortalityPercent Mortality

> 2 years old**> 2 years old**

Positive BCPositive BC 30/38 (79%)30/38 (79%) 8/31 (26%)8/31 (26%)

Negative BCNegative BC 57/400 (14%)57/400 (14%) 13/454 (3%)13/454 (3%)

All CasesAll Cases 87/438 (20%)87/438 (20%) 21/485 (4%)21/485 (4%)

BC = blood culture *8.7% *8.7% bacteremicbacteremic

**6.4% bacteremic**6.4% bacteremic

189

OBSERVATIONAL STUDIESOBSERVATIONAL STUDIES

190

191

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

TreatmentTreatment Percent MortalityPercent Mortality

BacteremicBacteremic

N=582N=582


Non-bacteremicNon-bacteremic

N=1004N=1004


OverallOverall

N=1586N=1586

SerumSerum 46/10246/102

(45%)(45%)

21/176 21/176

(12%)(12%)

67/278 67/278

(24%)(24%)

No serumNo serum 405/480 405/480

(84%)(84%)

261/826 261/826

(32%)(32%)

666/1306 666/1306

(51%)(51%)

192

Pneumococcal Pneumonia: Duration of Acute Pneumococcal Pneumonia: Duration of Acute IllnessIllness

(Tilghman and Finland, 1937)(Tilghman and Finland, 1937)

193

Mortality in Pneumococcal PneumoniaMortality in Pneumococcal PneumoniaFinland (1943)Finland (1943)

194

Treatment of Pneumococcal Treatment of Pneumococcal Pneumonia with PenicillinPneumonia with Penicillin

Meads, et al. (1945)Meads, et al. (1945)

SeveritySeverity PenicillinPenicillin

N=37N=37

Penicillin after Penicillin after sulfa treatmentsulfa treatment

N=17N=17

Grade 2 Grade 2 (moderate)(moderate)

1515 11

Grade 3 (acutely Grade 3 (acutely ill/irrational)ill/irrational)

99 55

Grade 4 (shock Grade 4 (shock &/or CHF)&/or CHF)

1313 1111

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

195

Treatment of Pneumococcal Treatment of Pneumococcal Pneumonia with Penicillin: Pneumonia with Penicillin:

OutcomesOutcomesMeads, et al. (1945)Meads, et al. (1945)

Outcome Outcome Penicillin Penicillin

(N=37)(N=37)

Penicillin after sulfa failure Penicillin after sulfa failure or intolerance (N=17)or intolerance (N=17)

DeathDeath 7 (19%)7 (19%) 3 (18%)3 (18%)

RelapseRelapse 22 11

ComplicationsComplications 00 00

Bacteremia after Bacteremia after penicillin treatmentpenicillin treatment

0/120/12 4/64/6

Duration of acute Duration of acute symptoms* < 48 symptoms* < 48 hourshours

27/30 (90%)27/30 (90%) 9/14 (64%)9/14 (64%)

Duration of fever < Duration of fever < 48 hours48 hours

24/30 (80%)24/30 (80%) 8/14 (57%)8/14 (57%)

*symptoms such as delirium, prostration, and dyspnea

196

Case Fatality Rate in Pneumococcal Pneumonia Case Fatality Rate in Pneumococcal Pneumonia treated with Serum, Sulfonamides or “Antibiotics”treated with Serum, Sulfonamides or “Antibiotics”

Dowling and Lepper (1951) Dowling and Lepper (1951)

197

Mortality in Pneumococcal Pneumonia Mortality in Pneumococcal Pneumonia with Bacteremiawith Bacteremia

Austrian and Gold (1964)Austrian and Gold (1964)

Prospective, observational study (1952-1962)Prospective, observational study (1952-1962) N= 455 with bacteremic pneumococcal N= 455 with bacteremic pneumococcal

pneumonia without extra-pulmonary pneumonia without extra-pulmonary complicationscomplications

50% < 50 years old; 55% had pre-existing co-50% < 50 years old; 55% had pre-existing co-morbiditiesmorbidities

Most treated with penicillin or other Most treated with penicillin or other antibacterial agents (96%); while 4% received antibacterial agents (96%); while 4% received no specific treatmentno specific treatment

198

Mortality in Pneumococcal Pneumonia Mortality in Pneumococcal Pneumonia with Bacteremiawith Bacteremia

Austrian and Gold (1964)Austrian and Gold (1964)

TreatmentTreatment Case Fatality RateCase Fatality Rate

n/N (%)n/N (%)

PenicillinPenicillin 57/338 (17%)57/338 (17%)

TetracyclinesTetracyclines 10/55 (18%)10/55 (18%)

Erythromycin, chloramphenicol, Erythromycin, chloramphenicol, streptomycinstreptomycin

2/14 (14%)2/14 (14%)

““Mixed”Mixed” 6/30 (20%)6/30 (20%)

Any antibacterial treatmentAny antibacterial treatment 75/437 (17%)75/437 (17%)

No treatmentNo treatment 14/17 (82%)14/17 (82%)

199

Survival in Bacteremic Pneumococcal Bacteremia Survival in Bacteremic Pneumococcal Bacteremia Treated with Penicillin or SerumTreated with Penicillin or Serum

Austrian and Gold (1964) Austrian and Gold (1964)

200

Observational Studies: MicrobiologyObservational Studies: Microbiology

StudyStudy PathogenPathogen

Finland (1943)Finland (1943) S. pneumoniaeS. pneumoniae

Dowling and Lepper (1951)Dowling and Lepper (1951) S. pneumoniaeS. pneumoniae

Austrian and Gold (1964)Austrian and Gold (1964) S. pneumoniaeS. pneumoniae

201

Treatment Effect:Observational Studies

41

78

31

82

17

30

135

17

0102030405060708090

Finland Finland(BC+)

Dowling Austrian(BC+)

Mo

rta

lity

%

Untreated Sulfa Penicillin

202

Summary of Antibacterial Drug Summary of Antibacterial Drug Treatment Effect in Pneumococcal Treatment Effect in Pneumococcal

PneumoniaPneumoniaObservational StudiesObservational Studies Treatment vs. Treatment vs.

Untreated controlsUntreated controlsMortality Difference Mortality Difference (95% confidence (95% confidence interval)interval)

Finland (1943)Finland (1943) SulfonamidesSulfonamides 24% (21, 27)24% (21, 27)

48% (bacteremic)48% (bacteremic)

Dowling and Lepper Dowling and Lepper (1951)(1951)

SulfonamidesSulfonamides

Penicillin, tetracyclinesPenicillin, tetracyclines

18.5% (15, 21)18.5% (15, 21)

25.4% (22, 28)25.4% (22, 28)

Austrian and Gold Austrian and Gold (1964)(1964)

Penicillin, Penicillin, tetracyclines, other tetracyclines, other antibacterial drugsantibacterial drugs

65% (47, 84)65% (47, 84)

(bacteremic)(bacteremic)

203

Observational Studies: Observational Studies:

Effect of Age on MortalityEffect of Age on Mortality

StudyStudy Treated < Treated < 50 years old50 years old

Untreated < Untreated < 50 years old50 years old

Treated ≥ 50 Treated ≥ 50 years oldyears old

Untreated Untreated

≥ ≥ 50 years 50 years oldold

Finland Finland (1943)(1943)

NRNR NRNR NRNR NRNR

Dowling and Dowling and Lepper Lepper (1951)(1951)

97/1672 97/1672

(6%)(6%)

139/715 139/715 (19%)(19%)

historicalhistorical

107/522 107/522 (20%)(20%)

192/362 192/362 (53%)(53%)


Austrian and Austrian and Gold (1964)Gold (1964)

(Bacteremic)(Bacteremic)

13/178 13/178

(7%)(7%)

371/693 371/693 (73%)(73%)


44/160 44/160

(28%)(28%)

322/345 322/345 (93%)(93%)


204

Controlled Clinical TrialsControlled Clinical Trials

205

Controlled Clinical Trial- SerotherapyControlled Clinical Trial- Serotherapy

Park, et al. (1928)Park, et al. (1928) Alternate patients with lobar pneumoniaAlternate patients with lobar pneumonia Treatment:Treatment:

Polyvalent antiserum:Polyvalent antiserum: pneumococcal types I, II, III pneumococcal types I, II, III

or:or: Standard treatment:Standard treatment: fluids, pain relief with elastic fluids, pain relief with elastic

adhesive plaster, restriction of opiates, no drastic adhesive plaster, restriction of opiates, no drastic catharsis, oxygen for cyanosis or rapid breathing, catharsis, oxygen for cyanosis or rapid breathing, digitalization for heart rate > 120digitalization for heart rate > 120

206

Case Fatality Rate in Patients with Type Case Fatality Rate in Patients with Type I Pneumococcal Pneumonia by Severity: I Pneumococcal Pneumonia by Severity:

(Park, et al., 1928)(Park, et al., 1928)Condition at Condition at baselinebaseline

Serum-treated Serum-treated Standard Standard treatment treatment

Treatment Treatment DifferenceDifference

Any conditionAny condition 20% (N=114)20% (N=114) 34% (N= 109)34% (N= 109) 14%14%

GoodGood

(> 70)(> 70)

9%9% 13%13% 4%4%

Fair (50-70)Fair (50-70) 29%29% 52%52% 23%23%

Poor (< 50)Poor (< 50) 64%64% 100%100% 36%36%

207

Controlled Clinical Trial of Treatment of Controlled Clinical Trial of Treatment of Lobar Pneumonia Lobar Pneumonia

Evans and Gaisford (1938)Evans and Gaisford (1938)

All patientsAll patients M & B 693M & B 693

(Sulfapyridine)(Sulfapyridine)

ControlControl

All patientsAll patients 8/100 (8%)8/100 (8%) 27/100 (27%)27/100 (27%)

Age > 50Age > 50 4/18 (22%)4/18 (22%) 7/10 (70%)7/10 (70%)

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

Case Fatality Rate

208

Resolution of FeverResolution of Fever Evans and Gaisford (1938)Evans and Gaisford (1938)

Treatment Treatment GroupGroup

NN Cumulative Resolution of Cumulative Resolution of Fever within 48 hoursFever within 48 hours

N (%)N (%)

Treated Treated 100100 60 (60%)60 (60%)

ControlControl 100100 34 (34%)34 (34%)

209

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

400 cases lobar pneumonia (hospitalized)400 cases lobar pneumonia (hospitalized) Includes 100 cases previously described in Includes 100 cases previously described in

Evans and Gaisford (1938)Evans and Gaisford (1938) Proportion of bacteremic patients not reportedProportion of bacteremic patients not reported Excluded deaths within 12 hours of admissionExcluded deaths within 12 hours of admission

210

Case Fatality Rates by Age in Lobar Case Fatality Rates by Age in Lobar PneumoniaPneumonia

(Gaisford, 1939) (Gaisford, 1939)

Age RangeAge Range

(years)(years)

UntreatedUntreated

19361936

n/N (%)n/N (%)

UntreatedUntreated

19371937

n/N (%)n/N (%)

SulfapyridineSulfapyridine

1938-19391938-1939

n/N (%)n/N (%)

5-195-19 5/127 (4)5/127 (4) 7/153 (5)7/153 (5) 0/115 (0)0/115 (0)

20-5020-50 53/216 (25)53/216 (25) 54/230 (23)54/230 (23) 5/199 (3)5/199 (3)

≥ ≥ 50 50 35/72 (49)35/72 (49) 39/78 (50)39/78 (50) 21/86 (24)21/86 (24)

All AgesAll Ages 93/415 (22)93/415 (22) 100/461 (22)100/461 (22) 26/400 (7)26/400 (7)

211

Controlled Clinical Trial: Treatment of Controlled Clinical Trial: Treatment of Pneumococcal Pneumonia with Pneumococcal Pneumonia with

SulfapyridineSulfapyridine Graham, et al. (1939)Graham, et al. (1939)

Dagenan (M&B 693)Dagenan (M&B 693) ControlsControls

3/50 (6%)3/50 (6%) 7/30 (23%)7/30 (23%)

3/17 (18%) bacteremic3/17 (18%) bacteremic 3/6 (50%) bacteremic3/6 (50%) bacteremic

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

Case Fatality Rate

212

Controlled Clinical Trial: Treatment of Controlled Clinical Trial: Treatment of Lobar Pneumonia with SulfapyridineLobar Pneumonia with Sulfapyridine

Agranat, et al. (1939)Agranat, et al. (1939) Lobar pneumonia (microbiology not described)Lobar pneumonia (microbiology not described) Several study sites in South Africa: results reported Several study sites in South Africa: results reported

separatelyseparately Sulfapyridine vs. control (method of treatment allocation Sulfapyridine vs. control (method of treatment allocation

was by admission to separate ward with “no selection”)was by admission to separate ward with “no selection”) Site 1: Johannesburg Hospital Site 1: Johannesburg Hospital

Europeans (97% < 50 years old)Europeans (97% < 50 years old) Non-Europeans (81% < 50 years old)Non-Europeans (81% < 50 years old) Mild (+), Moderate (++), Severe (+++)Mild (+), Moderate (++), Severe (+++)

32-33% severe in treated groups32-33% severe in treated groups 17-26% severe in untreated groups17-26% severe in untreated groups

Proportion bacteremic patients not reportedProportion bacteremic patients not reported Results of other sites not reported here because of Results of other sites not reported here because of

differences in patient populations and disease severitydifferences in patient populations and disease severity

213

Case Fatality RatesCase Fatality RatesAgranat, et al. (1939)Agranat, et al. (1939)

SubsetSubset ControlControl SulfapyridineSulfapyridine

EuropeansEuropeans 6/27 (22%)6/27 (22%) 2/22 (7%)2/22 (7%)

Non-EuropeansNon-Europeans 16/86 (19%)16/86 (19%) 6/71 (9%)6/71 (9%)

Case Fatality Rate

214

Resolution of FeverResolution of FeverAgranat, et al. (1939)Agranat, et al. (1939)

Days Days hospitalized hospitalized with feverwith fever

Non-Non-EuropeanEuropean

ControlControl

N=86N=86

Non-Non-EuropeanEuropean

TreatedTreated

N=71N=71

EuropeanEuropean

ControlControl

N=23N=23

European European

TreatedTreated

N=22N=22

% patients% patients % patients% patients % patients% patients % patients% patients

11 1.41.4 12.312.3 00 26.126.1

22 8.68.6 21.521.5 00 34.834.8

33 17.117.1 18.518.5 1010 8.78.7

Cumulative % Cumulative % at 3 daysat 3 days

2727 5252 1010 70%70%

215

Controlled Trials :MicrobiologyControlled Trials :Microbiology

Observational Studies:Observational Studies: Pathogens ReportedPathogens Reported

Evans and Gaisford (1938)Evans and Gaisford (1938) Pneumococcal types I, II, III, and Pneumococcal types I, II, III, and IV in 44/200 (22%) cases; 78% not IV in 44/200 (22%) cases; 78% not reported reported

Graham, et al. (1939)Graham, et al. (1939) S. pneumoniaeS. pneumoniae in 69/80 (86%); in 69/80 (86%); 11/86 (14%) not pneumococcal11/86 (14%) not pneumococcal

Agranat et al. (1939)Agranat et al. (1939) Not reported except in 2 deaths: Not reported except in 2 deaths:

S. pneumoniaeS. pneumoniae, , StaphylococcusStaphylococcus

216

Treatment Effect:Controlled Trials

2723

1922

86

97

0

5

10

15

20

25

30

Evans Graham Agranat(1)

Agranat(2)

Ca

se

Fa

talit

y R

ate

Untreated Sulfa

217

Summary of Antibacterial Drug Summary of Antibacterial Drug Treatment Effect in Pneumococcal Treatment Effect in Pneumococcal

PneumoniaPneumonia

Controlled StudiesControlled Studies Treatment vs. Treatment vs. untreated controlsuntreated controls

Difference in Case Difference in Case Fatality Rate Fatality Rate

(95% confidence (95% confidence interval)interval)

Evans and Gaisford Evans and Gaisford (1938)(1938)

SulfapyridineSulfapyridine 19% (8.8, 29.2)19% (8.8, 29.2)

Graham, et al., (1939)Graham, et al., (1939) SulfapyridineSulfapyridine 17% (0.1, 36.4)17% (0.1, 36.4)

32% (bacteremic)32% (bacteremic)

Agranat, et al. (1939)Agranat, et al. (1939) SulfapyridineSulfapyridine 10% (-0.3, 20.6)10% (-0.3, 20.6)

15% (-6.2, 35.5)15% (-6.2, 35.5)

218

MycoplasmaMycoplasma Pneumonia: Randomized Pneumonia: Randomized Controlled TrialsControlled Trials

Kingston, et al. (1961)Kingston, et al. (1961)

Randomized, double-blind, placebo-controlled Randomized, double-blind, placebo-controlled trialtrial

Military recruits (age 17-22); Military recruits (age 17-22); Total N= 300; (subgroup of “Eaton-agent” Total N= 300; (subgroup of “Eaton-agent”

positive N=133)positive N=133) ““Eaton agent” (Eaton agent” (MycoplasmaMycoplasma) diagnosed ) diagnosed

serologically; and nose and throat cultures serologically; and nose and throat cultures were negative for pneumococcus and were negative for pneumococcus and streptococci.streptococci.

Treatment: Tetracycline (demeclocycline) vs. Treatment: Tetracycline (demeclocycline) vs. placeboplacebo

219

Duration of Fever in Duration of Fever in MycoplasmaMycoplasma Pneumonia: Pneumonia: Effect of TreatmentEffect of Treatment

(Kingston, et al. 1961)(Kingston, et al. 1961)

220

MycoplasmaMycoplasma Pneumonia: Outcomes Pneumonia: OutcomesKingston, et al., (1961)Kingston, et al., (1961)

ParameterParameter TreatedTreated

Mean Duration Mean Duration (days)(days)

PlaceboPlacebo

Mean Duration Mean Duration (days)(days)

Treatment Treatment Difference (days)Difference (days)

Temperature 100ºFTemperature 100ºF 2.12.1 8.18.1 6.06.0

Abnormal CXRAbnormal CXR 9.59.5 20.020.0 10.510.5

RalesRales 6.96.9 15.515.5 8.68.6

CoughCough 9.79.7 22.022.0 12.312.3

Bed restBed rest 5.85.8 9.29.2 3.43.4

Fatigue, malaiseFatigue, malaise 2.72.7 8.58.5 5.85.8

AnorexiaAnorexia 2.02.0 7.07.0 5.05.0

221

MycoplasmaMycoplasma Pneumonia: Randomized, Pneumonia: Randomized, Controlled TrialsControlled Trials (Smilack, et al., 1974)(Smilack, et al., 1974)

Randomized, placebo-controlled, double-blind Randomized, placebo-controlled, double-blind trialtrial

Population: hospitalized military personnel, Population: hospitalized military personnel, mostly male, 17 to 23 years old (n=130; mostly male, 17 to 23 years old (n=130; MycoplasmaMycoplasma confirmed in 32) confirmed in 32)

Diagnosis: serological; bacterial pathogen-Diagnosis: serological; bacterial pathogen-negative by culturenegative by culture

Treatment: clindamycin (n=9), tetracycline Treatment: clindamycin (n=9), tetracycline (n=15), or placebo (n=8)(n=15), or placebo (n=8)

Antipyretic use in 8 patients (clindamycin:1; Antipyretic use in 8 patients (clindamycin:1; tetracycline: 4; placebo: 3)tetracycline: 4; placebo: 3)

222

MycoplasmaMycoplasma Pneumonia: Outcomes Pneumonia: OutcomesSmilack, et al. (1974)Smilack, et al. (1974)

Duration of Fever > 99º F

223

Summary: Summary: MycoplasmaMycoplasma Pneumonia Pneumonia StudiesStudies

Treatment effect of antibacterial drugs shown in Treatment effect of antibacterial drugs shown in young, healthy patients on:young, healthy patients on: Decreased duration of fever (and other signs Decreased duration of fever (and other signs

and symptoms), hospitalization, CXR and symptoms), hospitalization, CXR abnormalitiesabnormalities

Caveats: Reporting of antipyretic use Caveats: Reporting of antipyretic use inconsistent among studies; and some inconsistent among studies; and some uncertainty in datauncertainty in data

Can these data be extrapolated to all Can these data be extrapolated to all outpatients with CAP?outpatients with CAP?

Can these data be used to determine a non-Can these data be used to determine a non-inferiority margin for outpatient CAP? inferiority margin for outpatient CAP?

224

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

Differences in Patient Populations: Differences in Patient Populations: e.g. co-morbidities, immune status, pneumococcal e.g. co-morbidities, immune status, pneumococcal

vaccinationvaccination Differences in Organisms/Disease:Differences in Organisms/Disease:

Mostly hospitalized patients with pneumococcal Mostly hospitalized patients with pneumococcal pneumonia pneumonia

Severity was not well-characterizedSeverity was not well-characterized Most CAP now treated in outpatient settingMost CAP now treated in outpatient setting S. pneumoniaeS. pneumoniae isolated less frequently isolated less frequently Atypical organisms common in mild CAPAtypical organisms common in mild CAP

Differences in Standard of CareDifferences in Standard of Care Differences in Study Design:Differences in Study Design:

Observational dataObservational data Controlled trials were not randomized or blindedControlled trials were not randomized or blinded Endpoints: mortality vs. clinical responseEndpoints: mortality vs. clinical response Study drugs: penicillin, sulfonamides, tetracyclinesStudy drugs: penicillin, sulfonamides, tetracyclines

225

ConclusionsConclusions

Evidence for treatment effect of Evidence for treatment effect of antibacterial drugs in hospitalized patients antibacterial drugs in hospitalized patients with CAP (pneumococcal or lobar with CAP (pneumococcal or lobar pneumonia) based primarily on a mortality pneumonia) based primarily on a mortality benefit benefit Limited data on the treatment effect for other Limited data on the treatment effect for other

endpoints such as time to resolution of signs and endpoints such as time to resolution of signs and symptoms of CAPsymptoms of CAP

Evidence, albeit limited, for antibacterial Evidence, albeit limited, for antibacterial effect on resolution of signs and symptoms effect on resolution of signs and symptoms in atypical (in atypical (MycoplasmaMycoplasma) pneumonia) pneumonia

226

Contemporary CAP trials and determination of treatment effect

Sumati Nambiar MD MPHMedical Team Leader

Division of Anti-Infective

and Ophthalmology Products

227

Overview

Summary of recent CAP trials (oral and IV studies) Linking historical studies to contemporary CAP

trials Alternate approaches to determining

treatment effect

228

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

229

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

230

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

231

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

232

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%

233

Baseline pathogens

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7

S. pneumoniae

234

Clinical outcomes

-20

0

20

1 2 3 4 5 6 7

Study

Test

- C

ontr

ol

-15

-10

Intent to TreatPer Protocol

235

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%

236

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

237

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%

238

Bridging the gap

239

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

240

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

241

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

242


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?

243


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?

244

Alternative approaches

245

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

246

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)

247

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

248

‘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

249

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

250

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

251

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

252

“Pneumonia kills more children than any other illness – more than AIDS, malaria and measles combined. Over 2 million children die from pneumonia each year, accounting for almost 1 in 5 underfive deaths worldwide”

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

253

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)

254

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

255

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

256

NI Margin for CAP StudiesIssues and Approaches

Thamban Valappil, Ph.D.Statistical Team Leader,

Office of Translational ScienceCenter for Drug Evaluation and Research

U.S. Food and Drug Administration

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

257

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

258

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.

259

Statistical Uncertainties in NI StudiesWhat 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.

260

“Untreated”

Active Control

Test Drug

Treatment Effect

Unclear treatment effect

261

Untreated Active Control

Test Drug

Treatment Effect

Substantial treatment benefit

262

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

1. Discounting (reduction) of the historical control effect size

AND

2. Preservation of the control effect

263

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

264

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.

265

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

266

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?

267

Non-Inferiority - Inference

0Test 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)Treatment Difference (Test Drug – Control)95% Confidence Intervals95% Confidence Intervals

(1)

(2)

(3)

(4)

268

Historical Evidence in CAP StudiesReliability 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.

269

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

270


• 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.

271

Evans and Evans and

Gaisford Gaisford (1938)(1938)

Graham et. al (1938)

Agranat et. al (1939), Non Europeans

Agranat et. al (1939) Europeans

Controlled Clinical TrialsVariability in Mortality Rates

8.80%

0.10% -0.30%

-6.20%

19%17%

15%

29.20%

36.40%

20.60%

35.50%

10%

-10%

0%

10%

20%

30%

40%

272


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.

273


Constancy of the Control effectConstancy of the Control effect

• Does the control effect remain constant over Does the control effect remain constant over time?time?

• How do historical trials compare to current How do historical trials compare to current trials?trials?• Patient population, disease definition, outcome Patient population, disease definition, outcome

criteria, dose, duration of control and, timing of criteria, dose, duration of control and, timing of the outcome assessment.the outcome assessment.

• What is the internal variability of the effect size What is the internal variability of the effect size in the historical trials?in the historical trials?

274

Historical Evidence CAP Studies (cont…)• The antibacterials used in these studies 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.

275

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

276

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.

277

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.

278

Few Comments-2Kingston 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 <

99F), 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.

279

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?

280

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.

281

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

Figure 1 Figure 2 Figure 3

Mortality Rate

T C T C CT

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%

282

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

283

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?

284

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?

285

Thank you!

286

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 ResearchFood and Drug Administration

287

Question

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

288

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

289

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

290

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

291

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/MICFree AUC/MIC

292

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

293

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)

294

Exposure-Response DataDrug

Dose

Location/Date/Protocol

Population(ITT / PK)

Admin. Route/Hospitalized/Duration

Primary Endpoint (TOC)

Clinical response (ITT/PP)

Garenoxacin

400 mg daily

Multinational1999-2000

AI464-004

Mild-severe

N=199/106

OralOut patients10 days

7-14 days post Rx

0.84/0.91

Gatifloxacin

Gati 400 mg dailyLevo 500 mg daily

US1997-1998

AI420-038 AI420-038

Mild-severe

N=203/12N=197/16

IVOral, OralIn/Out patients

7-14 days7-14 days

7-14 (5-28)days post Rx 0.89/0.90

0.95/0.93

Gemifloxacin

320 mg daily

Multinational1998-1999

049/061

Mild-moderate

N=290/46N=216/71

OralIn/Out patients

7-14 days7 days

14-21 days post Rx

0.88/0.940.83/0.92

295

Top 5 Pathogens in CAP Studies

N Free AUC MIC Free AUC/MICLevofloxacin

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)

GarenoxacinHaemophilus 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)

GatifloxacinStreptococcus pneumoniae 12 38 (27-53) 0.2 (0.03-0.25) 365 (107-1759)

296

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

297

MethodologyDrug Exposure

Dose

Demographic Covariates

Observed PK

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

298

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;

299

MethodologyMIC

All Pathogens

Pathogens with MIC

Pathogen with highest MIC

Patients with Strep. pneumoniae being the mostresistant pathogen were used for the E-R analysis

Strep. pneumoniae with MIC

300

Greater Variation in MIC than Free AUC

0.01

0.1

1

0 20 40 60 80 100

Percentile

MIC

(m

cg/m

L)

GarenoxacinGatifloxacinGemifloxacinLevofloxacin

10

0 20 40 60 80 100

Percentile

Fre

e A

UC

(m

cg h

r/m

L)


+

301

Only Few Patients with Low Free AUC/MIC

100

1000

0 20 40 60 80 100

Percentile

Fre

e A

UC

/MIC


302

CART AnalysisOnly 5 Patients with Free AUC/MIC<37

0.0

0.2

0.4

0.6

0.8

1.0

50 100 200 500 1000

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse


Estimated Free AUC:MIC break-point = 37

0.0

0.2

0.4

0.6

0.8

1.0

50 100 200 500 1000

| | |N=5 N=69

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse


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

303

0.0

0.2

0.4

0.6

0.8

1.0

50 100 200 500 1000

| | |N=5 N=69

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse


0.0

0.2

0.4

0.6

0.8

1.0

50 100 200 500 1000

| | |N=5 N=69

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse


60%

97%

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

304

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

305

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

306

307

Clinical Failures

Mean 71 169 51 91 21.2 0.20 353

Drug Study Pathogen Weight Height Age CrCL SexFreeAUC

MICFree

AUC/MICMicro

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 1337PresumedPersisted

Gareno

004 Str. Pneu 57 163 38 110 F 17.9 0.03 597Presumed persisted

308

Sub-therapeutic patients

Mean 71 169 51 91 21.2 0.20 353

Drug Study Pathogen Weight Height Age CrCL SexFreeAUC

MICFree

AUC/MICClinical

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

309

AUC vs. Covariates

10

100

40 60 80 100 120

Body weight (kg)

AU

C (

mcg

hr/

mL)


10

100

20 40 60 80

Age (years)

AU

C (

mcg

hr/

mL)


10

100

50 100 150 200

Creatinine clearance (mL/min)

AU

C (

mcg

hr/

mL)

GarenoxacinGatifloxacinLevofloxacin

Body weight Age

Creatinine Clearance

310

AUC percentiles

10

100

0 20 40 60 80 100

Percentile

AU

C (

mcg

hr/

mL)


311

Free AUC percentiles

10

0 20 40 60 80 100

Percentile

Fre

e A

UC

(m

cg h

r/m

L)


312

MIC percentiles

0.01

0.1

1

0 20 40 60 80 100

Percentile

MIC

(m

cg/m

L)


313

Levofloxacin MIC percentiles

0.1

1

0 20 40 60 80 100

Percentile

Levo

floxa

cin

MIC

(m

cg/m

L)

GarenoxacinGemifloxacinLevofloxacin

314

Free AUC/MIC percentiles

100

1000

0 20 40 60 80 100

Percentile

Fre

e A

UC

/MIC


315

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

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60

||||||||||||||||||||||||||| || | ||| ||||

|

| | | |

|

|||| ||| | | ||

|

| | |||

|

||| ||| | | || | | |

N=74

Free AUC

Pro

babi

lity

of C

linic

al R

espo

nse

Streptococcus pneumoniae

316

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

Estimated MIC break-point = 0.75

0.0

0.2

0.4

0.6

0.8

1.0

0.01 0.1 1 2 4 8

| ||||||||| ||||||||||||||||||||||

||

|||||||| ||||||||||||||||

|

||||||||||||||||

|

||||| |||||||

||

||||||

|| | |

N=88 N=9

MIC

Pro

babi

lity

of C

linic

al R

espo

nse

Streptococcus pneumoniae

317

Exposure-Response Relationship for Haemophilus influenzae

0.0

0.2

0.4

0.6

0.8

1.0

500 1000 2000 4000

| || |

|

| || || | || || || | |||| || || || ||| |

N=32

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse

Haemophilus influenzae

318

0.0

0.2

0.4

0.6

0.8

1.0

50 100 200 500 1000 2000

|

|

| ||

|

|| | || |

|

|| || || || || ||| ||

| |

||| ||

| | |N=8 N=27

Free AUC/MIC

Pro

ba

bili

ty o

f C

linic

al R

esp

on

seHaemophilus parainfluenzae

Exposure-Response Relationship for

Haemophilus parainfluenzae

Estimated fAUC:MIC break-point = 201

319


Staphylococcus aureus

0.0

0.2

0.4

0.6

0.8

1.0

25 50 100 200 500 1000 2000

||| || | || | ||

|

| | || || || ||| | | || | |

| | |

|

N=33

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse

Staphyloccocus aureus

320


Moraxella catarrhalis

0.0

0.2

0.4

0.6

0.8

1.0

50 100 200 500 1000

|| || | || || ||

|

N=12

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse

Moraxella catarrhalis

321

Levofloxacin (Pulmonary 001)

0.0

0.2

0.4

0.6

0.8

1.0

20 40 60 80 100 150

| | | | |

N=5N=5

N=5N=5

Free AUC/MIC

Pro

babi

lity

of C

linic

al R

espo

nse

Levofloxacin

322

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)

323

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

324

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 Meeting1 April 2008

George H. Talbot, MD, FIDSA

3/31/08 Talbot

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 ...”

3/31/08 Talbot

Discussion Points

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

3/31/08 Talbot

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?

3/31/08 Talbot


• 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

3/31/08 Talbot


• 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

3/31/08 Talbot


• 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

3/31/08 Talbot


• 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

3/31/08 Talbot

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

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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

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Will the Trial Program Prove to Be:

• Credible?

• Predictable?

• Feasible?

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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 Will regulators worldwide find the results

acceptable?acceptable?• Will the results address an unmet need or

provide data relevant to current practice?

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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

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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 $

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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

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Direct Study Costs

Fully Loaded Costs

Patients Enrolled

Cost per Patient


Trial #4 $9.2 million

$12.6 million 425 $29,600

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Direct Study Costs

Fully Loaded Costs

Patients Enrolled

Cost per Patient



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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

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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

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• 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

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• 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

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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?

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Clear Regulatory Guidance is Essential – Ideally, Without Jeopardizing Decisions

Already Made in Good Faith

Deciding to Start a CAP Trial: Summary

Major Design Issues in CAP Clinical Trials

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Specific Design Considerations

• Spectrum of Study Drug

• Dose Selection

• Choice of Comparator*Choice of Comparator*

• IV-Oral Switch

• Inclusion/Exclusion Criteria*Inclusion/Exclusion Criteria*

• Statistical Assumptions*Statistical Assumptions*

* Focus points* Focus points

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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?

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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

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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

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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

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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

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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

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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


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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

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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


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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

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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

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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

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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

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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

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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

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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

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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!

Documents

Anti-Infective Drugs Advisory Committee April 1 & 2, 2008 1 Anti-Infective Drugs Advisory Committee Meeting Clinical Trial Designs for Community Acquired