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Hospital-Acquired Bacterial Pneumonia & Ventilator-Associated Bacterial Pneumonia

October 12, 2012

Joseph G. Toerner, MD, MPH Associate Director for Medical Affairs

Office of Antimicrobial Products CDER, FDA

∗ Collaborative efforts and public-private partnerships in antibacterial drug development ∗ CTTI’s “Accelerating Antibacterial Drug Development” ∗ Brookings Council on Antibacterial Drug Development ∗ Biomarkers Consortium of the FNIH for CABP & ABSSSI Bring together the thought-leaders in the field to move drug

development forward

∗ Potential for synergy with current ongoing efforts ∗ FNIH is currently in process for development of an endpoint

for pneumonia (CABP)

Issues in Clinical Trial Design for Drug Development to Treat Patients with HABP/VABP

∗ Background information ∗ Workshop/Draft Guidance/AIDAC Nov 2011

∗ Overview of outcome assessments ∗ Biomarkers, clinician-reported outcomes, clinical endpoints

∗ Management of patients with HABP/VABP ∗ Clinical care of patients

∗ Design strategies and operational efficiency for HABP/VABP ∗ Feasibility issues

∗ Successful approaches to endpoint development ∗ FNIH Biomarkers Consortium for CABP

Summary for Today’s Presentations HABP/VABP

Highlights of the Workshop Discussions ∗ Evaluating drugs for HABP/VABP challenging

∗ Efforts to minimize hospital-acquired infections: CMS, Joint Commission

∗ Multicenter trials: bacterial etiologies and ICU management strategies differs among centers

∗ All-cause mortality endpoint discussed ∗ Treatment effect from historical studies ∗ Concerns with evaluating mortality

∗ Non-respiratory events contributing to mortality ∗ Timing: 14 days – 28 days

FDA Co-Sponsored Workshop for HAPB/VABP

Spring 2009: Proceedings: CID Aug 2010 (51) Suppl 1

Highlights of the Workshop Discussions ∗ Non-mortality endpoints discussed

∗ “days in ICU”; “days on ventilator”, “PaO2/FiO2 ratio” ∗ Lack of consistent evaluation of clinical endpoints in trials:

treatment effects unknown ∗ Definition of HABP and VABP for enrollment

∗ Enrich for bacterial disease (CPIS scores for VABP) ∗ Analysis population: micro-ITT (easier for VABP) ∗ Role of quantitative cultures in mechanical ventilation

∗ Consortia or cooperative groups could enhance protocol development and implementation

FDA Co-Sponsored Workshop for HAPB/VABP

∗ Draft Guidance issued November 29, 2010 ∗ Enrollment criteria

∗ Sufficiently ill trial population, mortality ~ 20% ∗ Adequate period of hospitalization/ventilation (e.g. > 48 hours) ∗ New radiographic findings ∗ Clinical criteria (e.g. fever, cough, dyspnea, hypoxemia) ∗ Microbiologic criteria

Draft Guidance for HAPB/VABP

∗ Efficacy Considerations ∗ All-cause mortality primary endpoint

∗ 28-days after randomization ∗ Active-control NI trial design: M1 20% ∗ Appendix justification NI margin: NI margin 10% ∗ Sample size: 481 per arm (AIDAC background)

∗ Recommend only VABP or only HABP trials ∗ Efficacy/safety demonstrated in VABP support indication for

both HABP and VABP ∗ Efficacy/safety demonstrated in HABP support indication for

HABP


∗ Efficacy Considerations, cont. ∗ Micro-ITT analysis population (70% micro-evaluable VABP) ∗ Historical trials offered no data on clinical signs/symptoms

∗ Other Considerations ∗ Exclude patients with receipt of prior antibacterial drugs ∗ Acknowledged empirical use of concomitant antibacterial

drugs ∗ Avoid concomitant antibacterial drugs with overlapping activity

∗ Trials in patients with unmet need


∗ 14 responses submitted to the docket ∗ Most from industry, several from individuals

∗ 9 areas of criticism ∗ In general, guidance is not practical ∗ Efficacy endpoint: concern with all-cause mortality ∗ Statistical considerations: too conservative ∗ Comparator antibacterial drugs ∗ Issue of prior antibacterial drugs ∗ Trial population considerations ∗ Clinical microbiology considerations ∗ Entry criteria concerns ∗ Trials in patients with unmet need

Comment to the Draft Guidance for HAPB/VABP

∗ 14 responses submitted to the docket ∗ Most from industry, several from individuals

∗ Nov 4, 2011 AIDAC addressed 5 areas of criticism ∗ In general, guidance is not practical ∗ Efficacy endpoint: concern with all-cause mortality ∗ Statistical considerations: too conservative ∗ Comparator antibacterial drugs ∗ Issue of prior antibacterial drugs ∗ Trial population considerations ∗ Clinical microbiology considerations ∗ Entry criteria concerns ∗ Trials in patients with unmet need


∗ In general, guidance is not practical ∗ Efficacy endpoint: all-cause mortality

∗ Advances in ICU care, mortality < 20% ∗ Requirement for micro-ITT analysis population: trials too large ∗ Uncertainty about the timing of day 28 all-cause mortality


∗ Statistical considerations

∗ Extensive discounting to arrive at NI margin ∗ 12.5% NI margin supportable

∗ (sample size = approx. 320 per arm) ∗ Questions about choice of OR metric of 1.67 ∗ Sample size estimates: trials too large


∗ Issue of prior antibacterial drugs ∗ Excluding prior use unjustified and impractical ∗ Perioperative antibacterial drugs commonly used in

trauma/surgical patients


∗ Discussion about these topics: ∗ Limitations and merits of a single trial plus supportive

evidence ∗ Discuss NI margin of 10% and use of the odds ratio ∗ Preferred timing of the all-cause mortality endpoint ∗ Prior antibacterial drug administration

November 4, 2011 AIDAC on HAPB/VABP

∗ Limitations and merits of a single trial plus supportive evidence

In general, the committee agreed that a single trial can be used to support efficacy and safety in the evaluation of a new antibacterial drug for the treatment of HABP/VABP

Types of supportive data: ∗ Another trial in another indication (cIAI, CABP. ABSSSI) ∗ Nonclinical data (animal models, PK/PD)


∗ Discuss NI margin of 10% and use of the odds ratio

∗ An approach without having absolute certainty with a >20% mortality in the control group ∗ Addresses the “moving target” of mortality

∗ Some concern about higher sample sizes


∗ Prior antibacterial drug administration The use of antibacterial drugs for the current episode of

HABP/VABP in the 24 hours prior to enrollment appears to be acceptable along with efforts to minimize patients that receive prior effective antibacterial drugs.


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∗ Preferred timing of the all-cause mortality endpoint The timing of the all-cause mortality endpoint should be

between 14 and 28 days

Other comments during discussion about mortality endpoint ∗ Patients can be maintained in ICU setting “artificially” ∗ Should look at other clinical endpoints ∗ Primary endpoint should be clinically-based ∗ PK/PD can help define clinical endpoint ∗ Look at endpoints earlier in therapy (e.g., CABP)


∗ All-cause mortality endpoint ∗ Always evaluate mortality in trials ∗ Difficulty in planning for trials based on an anticipated rate of

mortality in the control group ∗ Deaths may be due to other co-morbid conditions

∗ Clinical endpoint ∗ Work done in other areas have established new efficacy

endpoint: CABP and ABSSSI ∗ Efforts to identify a new clinical endpoint or biomarker in

HABP/VABP may be valuable

HAPB/VABP Current Thinking

∗ Prior antibacterial drug therapy ∗ A rationale to permit use of prior therapy for the current

episode of HABP/VABP for up to 24 hours prior to enrollment ∗ AIDAC discussion in the context of a 28-day all-cause mortality

endpoint ∗ Are anticipatory informed consent procedures upon hospital or

ICU admission possible? ∗ Alleviate the concerns about an effect of prior effective therapy

HAPB/VABP Current Thinking

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The document outlines a format to approach the FDA with new endpoint or biomarker development

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∗ Endpoints ∗ All-cause mortality: feasibility ∗ Clinical endpoints

∗ Ways to identify a clinical endpoint ∗ FNIH approach successful for CABP and work continues

∗ May be possible to use a similar approach for HABP/VABP

∗ Clinical Trial Design ∗ Operational efficiencies ∗ HABP & VABP patients together in one trial or separate

evaluation ∗ Potential role of clinical trial networks

HAPB/VABP Summary for Today’s Discussion

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