1 Study F1K-MC-EVAD: Relative Risk under Original and Amended Protocols Interaction P-Value Amended Protocol Original ProtocolPatient Population Sites Enrolling under Both Protocols Entire Population Relative Risk

2 Study F1K-MC-EVAD: Relative Risk by Site Enrollment (970)0.94 (720)164 (1690)All Sites (887)0.89 (664)105 (1551)  (718)0.86 (537)62 (1255)  (956) 20 (655) 11 (457) No. of Sites (no. of patients) Interaction P-Value Amended Protocol (no. of patients) Original Protocol (no. of patients) Site Enrollment (539)0.79 (417)  (364)0.84 (291)  (255)0.91 (202)  25 Relative Risk

3 Study F1K-MC-EVAD: Mortality by Type of Clinical Trial Material

4 Study F1K-MC-EVAD: Cox Regression Analysis by Baseline and Any Heparin Exposure Placebo Patients

5 Study F1K-MC-EVAD: Patient Populations within First APACHE II Quartile – IL-6 Level

6 Study F1K-MC-EVAD: Location and Functional Status – Original vs Amended Protocol

7 Study F1K-MC-EVAD: Safeguards to Maintain Study Blind during Conduct of Interim Analyses Patient entered at investigative site External CRO provides randomized treatment code to unblinded pharmacist at site Unblinded pharmacist provides drotrecogin alfa (activated) or placebo to investigator Patient receives study drug and up to 28 days of follow-up Data management functions performed by Lilly blinded to patient treatment codes Blinded interim analysis data sets prepared by Lilly and sent to external statistical services organization (SSO) SSO merged patient treatment codes provided by CRO and prepared interim analysis reports SSO provided interim analysis reports to DSMB DSMB provides recommendation to Lilly

8 Study F1K-MC-EVAD: Mortality by Adequate Use of Antibiotics (CEC)

9 Study F1K-MC-EVAD: Mortality by Culture or Blood Culture (CEC)

10 Study F1K-MC-EVAD: Stepwise Multiple Logistic Regression Common approach to model selection Model provides probability of death estimates based on important covariates and treatment Intuitively, covariates are included based on their explanatory "value" Assess evidence of potential differential treatment effects with drotrecogin alfa (activated) accounting for the condition of the patient from multiple perspectives

11 Study F1K-MC-EVAD: Stepwise Multiple Logistic Regression 21 variables considered for inclusion Demographics: age, gender, origin, geographic region Patient location prior to hospitalization, co- morbidity status, functional dependency status Infection site and type, surgical status Clinical markers: APACHE II, number of organ failures, renal SOFA score, respiratory SOFA score, cardiovascular SOFA score, ventilation status, shock status Biochemical markers: Protein C activity, prothrombin time, APTT, log IL

12 Treatment required in model All two-factor interactions (e.g., age by treatment, age by gender) included in stepwise procedure Schwartz criterion chosen as method to select terms Forward and backward steps Goodness-of-fit assessed using the Hosmer- Lemeshow chi-square statistic Study F1K-MC-EVAD: Stepwise Multiple Logistic Regression

13 Following covariates retained in model Age APACHE II score PT, log IL-6 Dependency status, urosepsis or not Goodness-of-fit statistic supports model's adequacy (p=0.50) Estimated constant 40.2% increase in the odds of survival with drotrecogin alfa (activated) across the population No interaction terms –no treatment-by-covariate interactions Study F1K-MC-EVAD: Stepwise Multiple Logistic Regression Results

14 Study F1K-MC-EVAD: Data Safety Monitoring Board Members Steven Opal, M.D. (Chairman) Professor of Medicine, Brown University Edward Abraham, M.D. Professor of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Science Center Steve Lowry, M.D. Chairman and Professor, University of Medicine and Dentistry of New Jersey. Janet Wittes, Ph.D. Statistician, Statistics Collaborative Incorporation, Washington, DC Statistician resource- Pat O'Meara, PhD Pat O'Meara Associates, Inc, a Statistical Services Organization (SSO)

15 Study F1K-MC-EVAD: Cumulative Mortality Over Time (by Covance Randomization Date) 1 Aug Nov Feb May Aug Nov Feb May Jul 2000 Number of Sites = 164 Number of Patients = 1690 Placebo Drotrecogin Alfa (activated) Last patient enrolled - original protocolFirst patient enrolled - amended protocol 28-Day Mortality Rate

16 Study F1K-MC-EVAD: Cumulative Mortality Sites Enrolling under Original and Amended Protocols Aug Nov Feb May Aug Feb May Jul 2000 Over Time (by Covance Randomization Date) Number of Sites = 99 Number of Patients = Nov 1999 Placebo Drotrecogin Alfa (activated) Last patient enrolled - original protocol First patient enrolled - amended protocol 28-Day Mortality Rate

17 Why not a randomized controlled trial in kids? Assuming a 12.5% placebo mortality rate and 10% drotrecogin alfa (activated) mortality rate Using a 2-sided chi-square test for equality of proportions with an alpha level of 5% With 80% power need 5172 patients Largest pediatric trial ever was 396 patients

18 Controlled Trial Sample Size Estimates Using a 2-sided chi-square test for equality of proportions with an alpha level of 5% and 80% power to detect a treatment effect

19 Studies F1K-MC-EVAO/EVAD: Number of Organ Failures at Baseline – Pediatric versus Adult Patients *Wilkinson JD et al, 1987 J. Pediatr. 111(3):

20 Studies F1K-MC-EVAO/EVAD: Type of Organ Failure at Baseline – Pediatric versus Adult Patients *Wilkinson JD et al, 1987 J. Pediatr. 111(3):

21 Studies F1K-MC-EVAO/EVAD: Percent of Patients with Positive Cultures at Baseline Percent of Patients Adult Patients (N=1690) Pediatric Patients (N=83) ViralFungalGram Mixed Gram Negative Gram Positive

22 Reporting of Adverse Events – Study F1K- MC-EVAO versus Study F1K-MC-EVAD Study F1K-MC-EVAO: All clinical manifestations of severe sepsis were collected as adverse events Study F1K-MC-EVAD: Clinical manifestations of severe sepsis were not collected as adverse events unless considered drug related

23 Study F1K-MC-EVAO: Adverse Events Occurring in  5% of Patients – Part

24 Study F1K-MC-EVAO: Baseline Organ Failures for Selected Safety Categories

25 Study F1K-MC-EVAO: Intracerebral Hemorrhage – Patient Scenario 1 14 year-old enrolled with N. meningitidis in blood and cerebral spinal fluid, severe multi-organ dysfunction, shock requiring multiple inotropes, and coagulopathy. Anisocoria diagnosed and drotrecogin alfa (activated) stopped after 10.5 hours (platelet count 26x10 3 /μL). Continuous veno-venous hemofiltration with heparin began about 10 hours post study drug and continued until the patient died. Clinical brain death diagnosed on Study Day 13. Postmortem CT scan revealed a right frontal parachymal hematoma, severe cerebral edema, and subarachnoid hemorrhage. The severe intracranial hemorrhage was considered possibly related to study drug infusion by the investigator

26 Study F1K-MC-EVAD: Location Prior to Hospitalization – First APACHE II Quartile