Table of Contents
Anti-Infective Drugs Advisory Committee Meeting
Xigris Drotrecogin Alfa (Activated)
Proposed Indication Statement
Burden of Severe Sepsis
Reference Diseases
600 Patients with Severe Sepsis Die Each Day in the United States
Drotrecogin Alfa (Activated) Recombinant Human Activated Protein C
Agenda Lilly Advisory Committee Presentation
External Consultants
Pathophysiology of Severe Sepsis Rationale for Drotrecogin Alfa (Activated) for the Treatment of Severe Sepsis
Sepsis and Severe Sepsis
Pathogenesis of Severe Sepsis: Inflammation/Coagulation as Intervention Target
The Perils of Subgroup Analysis in Sepsis Trials
Activation of Inflammation and Coagulation in Severe Sepsis
Systemic Host Response to Infection–Similar Across Causative Microorganism Class
Activated Protein C – Mechanisms of Activity
Baboon Sepsis Model: Effect of Activated Protein C on Survival
Plasma Human Activated Protein C Versus Heparin: Double-Blind Trial in Disseminated Intravascular Coagulation
Rationale for Use of Activated Protein C in Patients with Severe Sepsis
Efficacy and Safety of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis
Objectives
Proposed Indication Statement
Rationale for Indication Statement
Phase 2 Study F1K-MC-EVAA
Phase 2 Study F1K-MC-EVAA
Study F1K-MC-EVAA Treatment Assignments (N=131)
D-dimer: Median Percent Change from Baseline to End of Infusion
IL-6: Median Percent Change from Baseline to End of Infusion
Dose Selection for Phase 3
Pivotal Phase 3 Study F1K-MC-EVAD
Phase 3 Study F1K-MC-EVAD
Patient Population (EVAD)
Study Design (EVAD)
Timeline of Study (EVAD)
Patient Disposition (EVAD)
Investigator Assessment of Primary Site of Infection (EVAD)
Baseline Microbiology Data (EVAD)
All Patients Had Laboratory Evidence of Coagulopathy
Most Patients Had Evidence of Impaired Fibrinolysis and Systemic Inflammation (EVAD)
Severe Sepsis Population (EVAD)
Drotrecogin Alfa (Activated) Reduced 28-Day All-Cause Mortality
Drotrecogin Alfa (Activated) Improves Survival
28-Day All-Cause Mortality Sensitivity Analyses
Cumulative Mortality for Sites Enrolling Under Both Original and Amended Protocol
Mortality by Patient Demographics (EVAD)
Mortality by Region (EVAD)
Drotrecogin Alfa (Activated) Improves Cardiovascular and Respiratory Function
Safety Assessment
Bleeding Events Reported as Serious Adverse Events (EVAD)
Procedure and Non-Procedure Related Serious Bleeding Events: 28-Day Study Period
No Other Safety Concerns
Overview of Ongoing Severe Sepsis Studies Clinical Update (as of 30 September 2001)
Intracranial Hemorrhage Summary (as of 30 September 2001)
Mortality by Platelet Count (EVAD)
Conclusions from Adult Studies
Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis
Benefit-Risk Objectives
Patient Classification by Survival and Serious Bleeding
Benefit-Risk for Entire Patient Population Net Benefit for Drotrecogin Alfa (Activated)
Explorations of Potential Differential Effects with Drotrecogin Alfa (Activated) Across Subgroups
Caveats Associated with Interpreting Subgroup Analyses
Assessing Consistency Across Subgroups
Subgroups: Bleeding Risk Summary
Mortality Subgroup Analyses
Subgroups – Demographic Characteristics
Subgroups – Disease Severity Measures
Subgroups – Disease Severity Measures
Subgroups – Disease Severity Measures
Benefit: Mortality by Subgroups Consistency Assessment
Favorable Benefit-Risk Associated with Drotrecogin Alfa (Activated)
Advisory Committee Questions based on Subgroup Explorations:
Clinical Trial Definition of DIC
Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use
Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use
Drotrecogin Alfa (Activated) Survival Benefit in Patients with Less Disease Severity
Survival Benefit Evident in Patients with Less Disease Severity
Survival Benefit Evident in Less Severe Patients within 1st APACHE II Quartile
Clinical Perspective of Treatment-by-Disease Severity Analyses
Treatment-by-Severity Analyses
Study F1K-MC-EVAD: Mortality by Number of Organ Failures/Single Organ Failures
Study F1K-MC-EVAD: Mortality by Cardiovascular Disease Severity Measures
Study F1K-MC-EVAD: Mortality by Baseline Cardiovascular SOFA Score
Study F1K-MC-EVAD: Mortality by Baseline Respiratory SOFA Score
1st Apache II Quartile Baseline Characteristics (N=433)
Subgroup Conclusions
Clinical Experience in Pediatric Patients with Severe Sepsis
Rationale for Pediatric Development Program
PPT Slide
Overview of Pediatric Experience (as of 30 September 2001)
Pediatric Phase 1B Study F1K-MC-EVAO
Baseline Characteristics of Pediatric and Adult Patients
Pediatric Baseline Biomarkers of Disease Severity are Similar to Adults
Clearance Versus Age in Adult and Pediatric Patients With Severe Sepsis
Median Pediatric Biomarker Change from Baseline to End of Infusion are Similar to Adult
Serious Bleeding Events – Pediatric and Adult Patients
Safety Summary of All Pediatric Experience (as of 30 September 2001)
Conclusions from Pediatric Studies
Overall Conclusions
Observed Number Needed to Treat (NNT) Compared to Thrombolytic Trials
Proposed Indication Statement
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