# Presentation: 549289

## Anti-Infective Drugs Advisory Committee Meeting

**XigrisTM**
**Drotrecogin Alfa (Activated)**
**October 16, 2001**
**Eli Lilly and Company**

**6058.01**

## XigrisDrotrecogin Alfa (Activated)

**Holger K. Schilske, MD, PhD**
**Executive Director and **
**Xigris**TM** Product Team Leader**
**Eli Lilly and Company**

**6743.01**

## Proposed Indication Statement

**Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis) **
**Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis**

**6105.01**

## Burden of Severe Sepsis 

**Annual incidence:  ~750,000 cases in US**1
**Case fatality rate:  28% to 50%**2
**Direct costs – National costs:  ~$16.7 billion**1
**Incidence on the rise:**
**Aging population**
**Incidence projected to rise to 1.0 million cases annually in US during the next decade**1

- 1 Angus DC et al. 2001. Crit Care Med 29:1303-1310.
- 2 Natanson. 1998. Crit Care Med 26:1927-1931.

**6747.02**

## Reference Diseases

**Incidence in US (cases per 100,000)**
**AIDS**1** ****	****17**
**Colon and rectal cancer**2**	****48**
**Breast cancer**2** ****	****112**
**Congestive heart failure**3**	**** ~196**
**Severe sepsis**4** ****	****~300**
**Number of deaths in US each year**
**Acute myocardial infarction**5** ****	****218,000**
**Severe sepsis**4**	**** 215,000**

**6748.01**

- 1Centers for Disease Control and Prevention. 2000. Incidence rate for 1999.
- 2American Cancer Society. 2001. Incidence rate for 1993-1997.
- 3American Heart Association. 2000.
- 4Angus DC et al. 2001. Crit Care Med 29:1303-1310.
- 5National Center for Health Statistics. 2001.
** **

##  600 Patients with Severe Sepsis Die Each Day in the United States

**Xigris Reduces the Relative Risk of**
** ****28-Day All-Cause Mortality by 19.4%**

**9141.01**

## Drotrecogin Alfa (Activated) Recombinant Human Activated Protein C

**Drotrecogin Alfa (Activated) ****Recombinant Human Activated Protein C**

## Agenda Lilly Advisory Committee Presentation 

**Introduction**
**Holger K. Schilske, MD, PhD – Eli Lilly and Company**
**Pathophysiology of Severe Sepsis, Rationale for Drotrecogin Alfa (Activated) for the Treatment of Severe Sepsis**
**Steven M. Opal, MD –  Professor of Medicine, Brown University School of Medicine**
**Efficacy and Safety of Drotrecogin Alfa (Activated)****in the Treatment of Severe Sepsis**
**William Macias, MD, PhD – Eli Lilly and Company**
**Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis**
**Jeffrey Helterbrand, PhD – Eli Lilly and Company**
**Clinical Experience in Pediatric Patients with Severe Sepsis****and Overall Conclusions**
**William Macias, MD, PhD – Eli Lilly and Company**

**6516.01**

## External Consultants

**Gordon Bernard, MD****          ****Professor of Medicine ****Pulmonary Medicine Division Vanderbilt University       ****Medical Center**** **
**Brett Giroir, MD****              ****Chief**** ****Medical Officer****Children's Medical Center, Dallas            ****Associate Dean for Clinical Affairs****UT Southwestern Medical Center**
**Mitchell Levy, M.D.**
**Associate Professor of Medicine **
**Brown University School of Medicine**
**Medical Director**
**Medical Intensive Care Unit**
**Rhode Island Hospital**

**6744.02**

**Steven M. Opal, MD***** ***
**Professor of Medicine  **
**Brown University School of Medicine **
**Chief Infectious Disease Division**
**Memorial Hospital of Rhode Island**
**Michael Seneff, M.D.**
**Medical Director**
**Intensive Care Unit**
**George Washington University**
**Medical Center**

## Pathophysiology of Severe SepsisRationale for Drotrecogin Alfa(Activated) for the Treatment of Severe Sepsis

**Steven M. Opal, MD**
**Professor of Medicine,**
**Brown University School of Medicine**
**Chief, Infectious Disease Division****Memorial Hospital of Rhode Island**

**6254.01**

## Sepsis and Severe Sepsis

***Sepsis***** is a syndrome characterized by host systemic inflammatory and procoagulant responses (SIRS) to pathogens**
**An intense host response may lead to organ dysfunction; this is designated **_***severe sepsis***_
**The mortality rate in severe sepsis remains high despite appropriate antibiotic and supportive therapy**

**9142.02**

## Pathogenesis of Severe Sepsis: Inflammation/Coagulation as Intervention Target

**Microbial Products**
**(exotoxin/endotoxin)**

**Cellular Responses**

**Oxidases**

**Platelet**
**Activation**

**Kinins**
**Complement**

**Coagulopathy/DIC**
**Vascular/Organ System Injury**

**Multi-Organ Failure**

**Death**

**Endothelial**** ****damage**

**Endothelial damage**

**Coagulation****Activation**

**Cytokines**
**TNF, IL-1, IL-6**

**9143.01**

**Pathogenesis of Severe Sepsis: ****Inflammation/Coagulation as Intervention Target**

## The Perils of Subgroup Analysis in Sepsis Trials

| Compound | Post-hoc Subgroup 
with Potential Efficacy | Outcome of 
Follow-up Study |
| --- | --- | --- |
| HA-1A | Gm– Bacteremia
49% vs. 30% (p=0.014) | Gm– Bacteremia
32% vs. 33% (p=0.86) |
| E5 | Gm– Sepsis w/o Shock
49% vs. 30% (p=0.01) | Gm– Sepsis w/o Shock
30% vs. 26% (p=0.21) |
| p55 TNF | Severe Sepsis w/ Early Septic Shock
36% vs. 37% vs. 23%
(p=0.07) | Severe Sepsis w/ Early Septic Shock
28% vs. 27% (p=0.14) |
| IL-1ra | Predicted Risk of Mortality Greater than 24%
45% vs. 38% vs. 35% 
(p=0.005) | Severe Sepsis 
36% vs. 33% (p=0.36) |

**9282.01**

## Activation of Inflammation and Coagulation in Severe Sepsis

**Activation of coagulation occurs early in severe sepsis and is associated with:**
**Increased thrombin generation and fibrin formation**
**Impaired fibrinolysis**
**Depletion of key regulatory proteins (eg, Protein C and antithrombin)**
**Decreased capacity to activate Protein C**
**Systemic inflammation resulting from activation of monocytes, neutrophils, and endothelium**

**9147.02**

## Systemic Host Response to Infection–Similar Across Causative Microorganism Class

- Causative microorganism classification–CEC adjudicated
- Baseline biomarker data from Study F1K-MC-EVAD

**9145.01**

**Percent of Patients with Abnormal Values**

**0**

**20**

**40**

**60**

**80**

**100**

**Suspected - No**

**Organism Identified**

**Pure Fungal**

**Pure Gram Positive**

**Pure Gram Negative**

**IL-6**

**Prothrombin**

**Time**

**Protein C**

**D-Dimer**

## Activated Protein C – Mechanisms of Activity

**EPCR**

**?**

** **

**X**

**X**

**X**

**X**

**X**

**Activated Protein C – Mechanisms of Activity**

**9146.02**

**Monocyte**
**Activation**

**Increased Fibrinolysis**

**Prothrombin**

**Coagulation**
**Cascade**

**Neutrophil**
**Adhesion**

**Thrombin**

**Va**

**VIIIa**

**Cell Activation**
**Via PARs**

**Fibrin/Platelets**

**aPC**
**Receptor**

**PAI-1**

**PC**

**Thrombomodulin**

**Thrombin**

**aPC**

**Tr**

**P**
**S**

**CD1/**
**MHC**

## Baboon Sepsis Model:Effect of Activated Protein C on Survival

_**Lethal **__***E coli***__** Model**_
**	****Infusing exogenous Activated Protein C reduces mortality**
_**Sub-lethal **__***E coli***__** Model**_
**	****Administration of anti-APC antibodies converts a sub-lethal dose to lethal dose **
**   ****Administration of exogenous Activated Protein C with anti-APC antibodies prevents increase in lethality**
**   **

- Taylor FB et al.* *1987. J Clin Invest 79:918-925.

**9148.01**

## Plasma Human Activated Protein C Versus Heparin: Double-Blind Trial in Disseminated Intravascular Coagulation

- Okajima et al.  2000. Blood 96:50a Abstract 208.

**9174.01**

## Rationale for Use of Activated Protein C in Patients with Severe Sepsis

**Pathophysiology of sepsis–infection, inflammation, and coagulation activation are tightly linked**
**Multiple mechanisms of action of Activated Protein C may disrupt the linkage between inflammation and coagulation resulting in improved survival**
**Baboon *****E coli *****sepsis model suggests critical role of Activated Protein C for survival**
**Activated Protein C is preferred because the patient's ability to convert Protein C in vivo may be impaired**

**9149.01**

## Efficacy and Safety of Drotrecogin Alfa (Activated)in the Treatment of Severe Sepsis

**William Macias, MD, PhD**** Medical Director**
**Xigris Product Team**
**Eli Lilly and Company**

**6285.01**

## Objectives

**Provide rationale for proposed indication statement**
**Review data supporting recommended dose and dose duration for drotrecogin alfa (activated)**
**24 ********g/kg/hr dose for 96 hours **
**Review primary efficacy and safety data from pivotal Phase 3 study F1K-MC-EVAD**
**Favorable benefit-risk profile in severe sepsis**
**Provide clinical update on ongoing studies**
**Review clinical experience in pediatric patients with severe sepsis**** **

**9009.01**

## Proposed Indication Statement

**Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis) **
**Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis**

**6105.01**

**Drotrecogin alfa (activated) is recommended**
**for use as adjunctive therapy ****to best  **
**standard care**

## Rationale for Indication Statement

**Definitions of sepsis and severe sepsis**
**Based on 1991 SCCM/ACCP consensus conference **
**Efficacy in adults with severe sepsis**
**Based on data from one pivotal Phase 3 study with supporting data from one Phase 2 study **
**Use in pediatric patients with severe sepsis**
**Supported by open-label, safety, and pharmacokinetic ****studies in patients aged 38 weeks gestation to 18 years**
**Efficacy requires extrapolation from adult studies**
**Inclusion of mortality reduction**
**Primary benefit is improved survival**
**For use in patients at risk of death from severe sepsis**

**9258.01**

## Phase 2 StudyF1K-MC-EVAA

**6291.01**

## Phase 2 Study F1K-MC-EVAA

**Randomized, double-blind, placebo-controlled study of drotrecogin alfa (activated) in patients with severe sepsis**
**Primary objectives**
**Assess safety of drotrecogin alfa (activated) as a function of infusion rate and infusion duration**
**Assess impact of drotrecogin alfa (activated) on coagulation abnormalities as a function of infusion rate and infusion duration**
**Assess pharmacokinetics of drotrecogin alfa (activated)**
**Determine dose for Phase 3 testing (based on change in D-dimer)**

**6110.01**

## Study F1K-MC-EVAA Treatment Assignments (N=131)

**6111.02**

## D-dimer: Median Percent Change from Baseline to End of Infusion 

**6116.02**

**Analysis based on ranked response data.**

## IL-6: Median Percent Change from Baseline to End of Infusion

**6293.02**

## Dose Selection for Phase 3

**No safety concerns noted**
**Linear pharmacokinetics**
**Decline in D-dimer and IL-6 most evident at >18 ********g/kg/hr**
**Largest decrease in D-dimer most evident at the end of 96-hour infusion**
**24 ********g/kg/hr for 96 hours recommended for future Phase 3 studies**** **

**6294.01**

## Pivotal Phase 3 StudyF1K-MC-EVAD

**6295.01**

## Phase 3 Study F1K-MC-EVAD

**Randomized, double-blind, placebo-controlled study in adult patients with severe sepsis**
**164 sites in 11 countries**
**Single-dose study**
**24 ********g/kg/hr** **drotrecogin alfa (activated) or placebo for 96 hours **
**Primary objective**
**Effect on 28-day all-cause mortality**
**Secondary objectives**
**Safety**
**Effect on organ function**
**Pharmacokinetics and pharmacodynamics**

**6510.01**

## Patient Population (EVAD)

**Severe Sepsis**
**Known or suspected infection**
**Evidence of a systemic response to infection**
**Three or four of the criteria defining SIRS **
**One or more sepsis-induced organ dysfunctions**
**Cardiovascular**
**Respiratory**
**Renal**
**Hematologic**
**Metabolic acidosis**

**6760.01**

## Study Design (EVAD)

**6125.01**

**Start of study drug infusion**

**24 hr **
**to meet entry criteria **
**  **

**End of 96-hour infusion **
**of study drug**

**28-day all-cause mortality assessed**

**Routine Patient Care**

**24 hr from meeting entry criteria to start of drug**

## Timeline of Study (EVAD)

**Timeline of Study (EVAD)**

**9150.02**

## Patient Disposition (EVAD)

**N=1728**
**Patients Enrolled**

**N=857**
**Randomized**

**N=871**
**Randomized**

**N=17**
**Not Treated **

**N=840 Treated**

**N=850 Completed **
**Protocol**

**N=840 Completed **
**Protocol**

**N=21**
**Not Treated **

**Drotrecogin Alfa (activated)**

**Placebo**

**N=850 Treated**

**6129.01**

## Investigator Assessment of Primary Site of Infection (EVAD)

**6075.02**

**Percent of Patients**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**Placebo N=840**

**Drotrecogin Alfa**

**(activated) N=850**

**Other**

**Skin**

**Blood**

**Urinary**

**Tract**

**Intra-**

**Abdominal**

**Lung**

**Site of Infection**

## Baseline Microbiology Data (EVAD)

**6076.01**

***No bacterial, fungal, or viral pathogen identified.**

## All Patients Had Laboratory Evidence of Coagulopathy

**6077.01**

**100**

**80**

**60**

**40**

**20**

**0**

**20**

**40**

**60**

**80**

**100**

**D-dimer**

**TATc**

**F1.2**

**Protein C**

**Protein S**

**Anti-**

**thrombin**

**Percent of**

**patients with**

**abnormally**

**high values**

**Percent of**

**patients with**

**abnormally**

**low values**

**Drotrecogin Alfa**

**(activated)**

**Placebo**

## Most Patients Had Evidence of Impaired Fibrinolysis and Systemic Inflammation (EVAD)

**6078.01**

**40**

**20**

**0**

**20**

**40**

**60**

**80**

**100**

**PAI-1**

**IL-6**

**PT**

**APTT**

**Platelet**
**Count**

**Percent of**

**patients with**

**abnormally**

**high values**

**Percent of**

**patients with**

**abnormally**

**low values**

**Drotrecogin Alfa**

**(activated)**

**Placebo**

## Majority of patients with documented infection
Evidence of a systemic response characterized by:
Systemic inflammation 
Thrombin generation
Fibrin deposition      
Impaired fibrinolysis
Systemic response similar despite different types of infecting organisms
Majority of patients had respiratory and/or cardiovascular dysfunction

**Evidence of a systemic response characterized by:**
**Systemic inflammation **
**Thrombin generation**
**Fibrin deposition      **
**Impaired fibrinolysis**
**Systemic response similar despite different types of infecting organisms**
**Majority of patients had respiratory and/or cardiovascular dysfunction**

**Severe Sepsis Population (EVAD)**

**9151.01**

** ****99.9% with laboratory**
** ****evidence of DIC**

## Drotrecogin Alfa (Activated) Reduced 28-Day All-Cause Mortality

**6138.01**

## Drotrecogin Alfa (Activated) Improves  Survival

**6139.01**

## 28-Day All-Cause Mortality         Sensitivity Analyses

**6140.01**

## Cumulative Mortality for Sites Enrolling Under Both Original and Amended Protocol 

**6404.02**

## Mortality by Patient Demographics (EVAD)

**6778.01**

## Mortality by Region (EVAD)

**6312.02**

***Other = Brazil, South Africa, Australia, New Zealand.**

## Drotrecogin Alfa (Activated) Improves Cardiovascular and Respiratory Function

**Improvement in cardiovascular function**
**Reduction in time-averaged CV SOFA scores**
**Increase in vasopressor-free days**
**Fewer deaths from septic shock**
**Improvement in respiratory function**
**Reduction in time-averaged respiratory SOFA scores**
**Increase in ventilator-free days**
**Fewer deaths from respiratory failure**
**Comparison of 28-day survivors**
**Similar patient location and functional status**

**9283.01**

## Safety Assessment

**9152.01**

## Bleeding Events Reported as Serious Adverse Events (EVAD)

**6178.01**

**Placebo**
**N=840**

**Drotrecogin Alfa ****(activated)**
**N=850**

**0.0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**3.0**

**3.5**

**28-Day**

**Study Period**

**Study Drug**

**Infusion Period**

**p=0.024**

**p=0.060**

**Percent of Patients**

**2.4%**
**(n=20)**

**1.0%**
**(n=8)**

**3.5%**
**(n=30)**

**2.0%**
**(n=17)**

**n=number of patients**

## Procedure and Non-Procedure Related Serious Bleeding Events: 28-Day Study Period

**Procedure and Non-Procedure Related Serious Bleeding Events: 28-Day Study Period**

**9154.01**

## No Other Safety Concerns

**Similar incidence of serious thrombotic events**
** ****Drotrecogin alfa (activated) 2.0%**
** ****Placebo 3.0% **
**Similar incidence of postbaseline infections**
** ****Drotrecogin alfa (activated) 25.5%**
** ****Placebo 25.1% **
**<0.5% Incidence of anti-APC antibody formation**
** ****Low level and non-neutralizing**
**No other safety concerns identified based on:**
** ****Other adverse events and serious adverse events**
** ****Organ function**
** ****Hematology and chemistry data**

**6174.01**

## Overview of Ongoing Severe Sepsis Studies Clinical Update (as of 30 September 2001)

**9284.02**

**Overview of Ongoing Severe Sepsis Studies ****Clinical Update (as of 30 September 2001)**

## Intracranial Hemorrhage Summary(as of 30 September 2001)

**Intracranial Hemorrhage Summary****(as of 30 September 2001)**

**9285.02**

**H. Infarct = Hemorrhagic infarction**
**SAH = Subarachanoid hemorrhage**
**Cerebral H. = Cerebral Hemorrhage**
***Event occurred on Study Day 14 while receiving heparin for dialysis**

## Mortality by Platelet Count (EVAD)

**9015.01**

## Conclusions from Adult Studies

**Drotrecogin alfa (activated) in adult patients with severe sepsis:**** **
**Substantially**** reduces 28-day all-cause mortality**
**6.1% absolute, 19.4% relative risk reduction**** ****(****2-sided p-value = 0.005)**
**Improves cardiovascular and respiratory function**
**Increased risk of serious bleeding events**
**Infrequent serious bleeding events **
**Increased risk with vessel trauma or severe coagulopathy**
**Very favorable benefit-risk profile**

**6777.01**

## Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated)in the Treatment of Severe Sepsis

**Jeffrey Helterbrand, PhD****Senior Statistical Scientist**
**Xigris **** ****Product Team ****Eli Lilly and Company**

**6774.01**

## Benefit-Risk Objectives

**Assess benefit-risk for overall population**
**Explore potential differential effects across subgroups (70 subgroups)**
** ****Bleeding risk**
** ****Survival Benefit**
**Benefit-Risk Conclusion:****  ****Drotrecogin alfa (activated) is associated with a positive benefit-risk profile across the diverse population of patients enrolled in the study**
**Address Advisory Committee Subgroup Questions**
**Patients without laboratory evidence of DIC**
**Low-dose heparin exposure**
**Less severe disease patients**

**9155.01**

## Patient Classification by Survival and Serious Bleeding

**9286.01**

******* Value subjectively chosen by the decision maker**

## Benefit-Risk for Entire Patient PopulationNet Benefit for Drotrecogin Alfa (Activated)

**6781.01**

## Explorations of Potential Differential Effects with Drotrecogin Alfa (Activated) Across Subgroups

**6782.01**

## Caveats Associated with Interpreting Subgroup Analyses

**Trial sized to detect treatment benefit for entire population only**
**No trial can ensure definitive statistical evidence of a benefit in all subgroups **
**No adjustments for multiplicity**

**6512.01**

## Assessing Consistency Across Subgroups 

- † †     FDA Clinical Studies Section of Labeling for Prescription       Drugs and Biologics - Content and Format Draft Guidance
- † † †  The Revised CONSORT Statement

- A. Agresti, Categorical Data Analysis, 1990, page 149
- D. Altman et al., Ann Intern Med. 2001; 134: 663-694

**Lilly Analyses**
**Measures:**
**	****Relative Risks **
**	****Odds Ratios****†**
**Methods: **
**	****Confidence Intervals ****††**
**	****Interaction Tests ****† † †**

**9287.02**

**Assessing Consistency Across Subgroups**

## Subgroups: Bleeding Risk Summary

**Serious bleeding events:**** **
**Few events to assess differential risk**
**No clinically relevant differential effects observed**
**Treatment emergent bleeding events:**
**More events to assess differential risk**
**No clinically relevant differential effects observed**

**Conclusion: Based on trial results,**
**relative risk of bleeding consistent across subgroups**

**9156.01**

## Mortality Subgroup Analyses

**9288.01**

## Subgroups – Demographic Characteristics

**6763.01**

## Subgroups – Disease Severity Measures

**6764.01**

## Subgroups – Disease Severity Measures

**6765.01**

## Subgroups – Disease Severity Measures

**6766.01**

## Benefit: Mortality by Subgroups Consistency Assessment

**Lower mortality observed for 68 of 70 subgroups **
**Exceptions: 1st APACHE II Quartile and Urinary Tract Infection**
**Consistent treatment effect for 69 of 70 subgroups**
**Overall RR Point Estimate = 0.806**
**Lower RR estimate for 1st IL-6 Quartile patients**
**Point estimate = 0.47, 95% RR CI: 0.29 to 0.77**

**6784.01**

## Favorable Benefit-Risk Associated with Drotrecogin Alfa (Activated)

**Drotrecogin alfa (activated) is associated with a positive benefit risk profile across the diverse population of patients enrolled in the pivotal Phase 3 study**

**6768.01**

## Advisory Committee Questions based on Subgroup Explorations:

**Treatment effect in patients without laboratory evidence of Disseminated Intravascular Coagulation (DIC)**
**Treatment effect and concomitant low-dose heparin exposure**
**Treatment effect in less severe disease patients**

**9289.01**

## Clinical Trial Definition of  DIC

**Patient classified with (non-overt) DIC if at least 2 of the following 4 criteria met:**
**Platelet < 100k or 50% decrease in past 3 days**
**PT or APTT > 1.2x ULN**
**D-dimer > ULN**
**Protein C, Protein S or Antithromibin < LLN**
**No biochemical data for 113 of 115 patients   **
**99.9% of patients with laboratory data met clinical trial definition of (non-overt) DIC **
**Other severe sepsis studies confirm this observation**

**9290.03**

**The inclusion criteria employed in study essentially defines a population with sepsis-associated coagulopathy**

## Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use

**Similar bleeding rates in drotrecogin alfa (activated) patients receiving and not receiving heparin - no treatment by heparin interaction **
**Lower mortality with drotrecogin alfa (activated) in all subgroups defined by either baseline or concomitant heparin exposure (all RR <0.90)**
**Concomitant heparin analyses are biased**
**Reason: Many patients move from "no heparin" group  to "heparin" group with post-baseline exposure**

**9291.01**

## Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use

**Valid analyses of low-dose heparin exposure: **
**Baseline (BL)**
**Treatment-by-heparin interaction p=0.30**
**Placebo group p= 0.71**
**Drotrecogin alfa (activated) group p=0.28 **
**Incorporating post-BL exposure (time-dependent covariate)***
**Treatment-by-heparin interaction  p=0.16 (p=0.29**)**
**Placebo group p=0.69 (p=0.57**)**
**Drotrecogin alfa (activated) group p=0.11 (p=0.26**)**

*** ****Therneau and Grambsch, Modeling Survival Data: Extending the Cox Model (2000)**
****Analysis adjusted by baseline APACHE II score**

**9292.01**

## Drotrecogin Alfa (Activated) Survival Benefit in Patients with Less Disease Severity

**Observed variation in relative risk estimates across subgroups consistent with random chance if treatment uniformly beneficial**
**Higher mortality for effective treatment **
**Expected for 5 of 70 subgroups**
**Observed for  2 subgroups**
**Survival benefit evident in less severe patients almost uniformly across the totality of measures of disease severity**
**Survival benefit evident in patients with less disease severity within the 1st APACHE II Quartile**

**9157.01**

## Survival Benefit Evident in Patients with Less Disease Severity

**0.5**

**0.6**

**0.7**

**0.8**

**1**

**1.25**

**1.67**

**2**

**0.9**

**Relative Risk of Death (95% Confidence Interval)**

**Overall**

**APACHE II 1st Quartile**

**No Shock within 6 hr**

**1 Organ Failure**

**Platelet Count **_**>**_**LLN**

**No Metabolic OF**

**No Cardiovascular OF**

**Hematologic SOFA 0 or 1**

**Any Shock–No**

**No Hematologic OF**

**No Renal OF**

**Renal SOFA 0 or 1**

**No Respiratory OF**

**No Mechanical Ventilation**

**Antithrombin Not Deficient**

**Hepatic SOFA 0 or 1**

**Cardiovascular SOFA 0 or 1**

**APTT **_**<**_** 37 sec**

**PT **_**<**_** 14.5 sec**

**Protein C Not Deficient**

**Respiratory SOFA 0 or 1**

**IL-6 1st Quartile**

**6787.01**

**Survival Benefit Evident in Patients with Less Disease Severity**

**6788.01**

**Conclusion: Survival benefit evident in less**
**severe disease patients enrolled in pivotal study**

**Similar benefit evident in patients with low IL-6, **
**normal PT, normal APTT levels within the 1st Quartile**** **

**Survival Benefit Evident in Less Severe Patients within 1st APACHE II Quartile**

## Clinical Perspective of Treatment-by-Disease Severity Analyses

**9293.01**

## Treatment-by-Severity Analyses

**APACHE II observation does not reconcile with other treatment-by-disease severity analyses**
**APACHE II data not collected and score not calculated according to published method**
**Not used in EVAD to predict mortality**
**APACHE II score rarely used to make individual patient treatment decisions**

**9294.02**

## Study F1K-MC-EVAD: Mortality by Number of Organ Failures/Single Organ Failures

**9045.01**

**Breslow-Day interaction p=0.93**

## Study F1K-MC-EVAD: Mortality by Cardiovascular Disease Severity Measures

**      ****Drotrecogin**

**             ****Alfa**

**   **_** **__**N   (activated)  Placebo**_

**Overall**

**Shock within 48 hrs**

**1214     25.1        32.0**

**  ****1362     26.0        32.5**

**476     23.8        27.6**

**Yes**

**No**

**Cardiovascular SOFA**

**Shock within 6 hrs**

**Yes**

**No**

**Any Shock**

**Yes**

**No**

**1200     26.3        34.2**

**490     21.0        22.3**

**328     19.7        23.3**

**0.5**

**0.6**

**0.7**

**0.8**

**1**

**1.25**

**1.67**

**2**

**0.9**

**Relative Risk of Death (Point Estimate and 95% CI)**

**1690     24.7        30.8**

**6314.03**

## Study F1K-MC-EVAD: Mortality by Baseline Cardiovascular SOFA Score

**Breslow-Day interaction p=0.65**
**Logistic interaction p=0.95**

**6634.01**

## Study F1K-MC-EVAD: Mortality by Baseline Respiratory SOFA Score

**6635.01**

**Breslow-Day interaction p=0.27**
**Logistic interaction p=0.55**

## 1st Apache II Quartile Baseline Characteristics (N=433)

**2 or more organ failures****	****61.2%**
**Respiratory failure****	****69.1%**
**Mechanical ventilation****	****59.4%**
**Shock****	****55.7%**
**High-dose vasopressors****	****           46.7%**
**Severe Protein C deficiency****	****65.1%**

**6792.01**

**69.5% of patients had 2 or more organ failures**
**and/or required high dose vasopressor support**

## Subgroup Conclusions

**F1K-MC-EVAD tested one primary hypothesis - results show that drotrecogin alfa (activated) significantly reduces mortality in population of patients defined by inclusion/exclusion criteria**
**Caution should be exercised in interpreting individual exploratory subgroup results (multiplicity, natural variability, supportive evidence)**
**No clear evidence to support a differential effect of drotrecogin alfa (activated) by disease severity**

**9296.02**

## Clinical Experience in Pediatric Patients with Severe Sepsis

**6775.01**

## Rationale for Pediatric Development Program

**Provide guidance to pediatric intensivists**
**If approved, drotrecogin alfa (activated) will be used in pediatric patients with severe sepsis**
**Development program based on:**
**ICH guidelines**
**Code of Federal Regulations **
**Collaboration with FDA**

**6340.03**

** ****Majority of drugs used by pediatric intensivists**** are not approved for use in pediatric patients**

##   Where the course of the disease and the effects of the drug are sufficiently similar in adult and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients such as pharmacokinetic studies.
						21 CFR 314.55(a) 				                     CPMP/ICH/2711/99

**	****	****	****	****	****	****21 CFR 314.55(a) ****	****	****	****	****                     CPMP/ICH/2711/99**

**9306.01**

**Extrapolation of Efficacy**

## Overview of Pediatric Experience(as of 30 September 2001)

**6338.01**

**Overview of Pediatric Experience****(as of 30 September 2001)**

## Pediatric Phase 1B StudyF1K-MC-EVAO

**9297.01**

## Baseline Characteristics of Pediatric and Adult Patients

**6524.01**

## Pediatric Baseline Biomarkers of Disease Severity are Similar to Adults

**100**

**80**

**60**

**40**

**20**

**0**

**20**

**40**

**60**

**80**

**100**

**Adult Patients**
**N =1550-1574**

**Pediatric Patients **
**N=78-79**

**Protein C**

**D-dimer**

**Antithrombin**

**Percent of**

**patients with**

**abnormally**

**high values**

**Percent of**

**patients with**

**abnormally**

**low values**

**Pediatric Baseline Biomarkers of Disease Severity are Similar to Adults**

**6770.01**

## Clearance Versus Age in Adult and Pediatric Patients With Severe Sepsis

**6159.02**

## Median Pediatric Biomarker Change from Baseline to End of Infusion are Similar to Adult

**Protein C Activity**

**    ****% Increase**

**    ****No. of patients**

**D-dimer Level**

**    ****% Decrease**

**    ****No. of patients**

**Antithrombin Activity**

**    ****% Increase**

**    ****No. of patients**

**27%**

**770**

**17%**

**772**

**18%**

**746**

**-7%**

**729**

**15%**

**734**

**Pediatric Patients ****F1K-MC-EVAO ****Part 2**** 0  to <18 yr**

**  **

**Adult Patients ****F1K-MC-EVAD**

**Drotrecogin ****Alfa ****(activated) **

**Placebo**

** **

**6771.02**

## Serious Bleeding Events – Pediatric and Adult Patients

**6773.01**

## Safety Summary of All Pediatric Experience(as of 30 September 2001)

**Safety Summary of All Pediatric Experience****(as of 30 September 2001)**

## Conclusions from Pediatric Studies

** ****Pediatric patients are similar to adults based upon**
**Similar inclusion criteria**
**Presence of coagulopathy**
**Effect of drotrecogin alfa (activated) is similar in adult and pediatric patients**
**PK of drotrecogin alfa (activated)**
**PD effect of drotrecogin alfa (activated) on D-dimer**
**Safety profile**
**Results of the pediatric study support drotrecogin alfa (activated) use in pediatric patients with severe sepsis**
** ****Extrapolation of efficacy results from Phase 3 study F1K-MC-EVAD in adult patients with severe sepsis**

**6538.01**

## Overall Conclusions

**Drotrecogin alfa (activated) reduces mortality in patients with severe sepsis and is associated with a favorable benefit-risk profile in patients with severe sepsis.**** **

**9257.01**

## Observed Number Needed to Treat (NNT) Compared to Thrombolytic Trials

- 1 ISIS-2. 1988. Lancet 2:349-360.
- 2 Activase® USPI.

**6762.01**

## Proposed Indication Statement

**Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis) **
**Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis**

**6105.01**