1. Division of Oncology Drug Products 1 AREAS OF MAJOR STATISTICAL CONCERNS IN THE M01 STUDY Overall (ITT Population) Finding Liver Metastasis Subgroup Finding

2. Division of Oncology Drug Products 2 Overall Finding PROBLEM 1: Strength of Evidence of Efficacy PROBLEM 2: Multiple Survival Analyses PROBLEM 3: Internal Consistency

3. Division of Oncology Drug Products 3 PROBLEM 1: Strength of Evidence of Efficacy - Results of Survival Analysis in ITT Population

4. Division of Oncology Drug Products 4 PROBLEM 2: Multiple Survival Analyses

5. Division of Oncology Drug Products 5 Adjusted Analyses ICH E-9 Guidelines, Section 5.7: Subgroups, Interactions and Covariates: ‘ When the potential value of an adjustment is in doubt, it is often advisable to nominate the unadjusted analysis as the one for primary attention, the adjusted analysis being supportive.’ ‘ In most cases, however, subgroup and interaction analyses are exploratory and should be clearly identified as such; they should explore the uniformity of any treatment effects found overall.’

6. Division of Oncology Drug Products 6 SUMMARY OF OVERALL (ITT POPULATION) FINDING The one randomized study (M01) conducted by the sponsor in metastatic melanoma patients does not demonstrate convincing evidence of survival benefit with Histamine + IL-2 treatment in the Overall ITT population.

7. Division of Oncology Drug Products 7 LIVER METASTASIS SUBGROUP FINDING PROBLEM 1: Absence of Overall Survival Benefit PROBLEM 2: Imbalances and Multiplicity

8. Division of Oncology Drug Products 8 PROBLEM 1: In the absence of overall survival benefit, any subgroup advantage is questionable ICH E-3 Guidelines: Section 11.4.2.8: Examination of Subgroups: ‘ These analyses are not intended to "salvage" an otherwise non-supportive study but may suggest hypotheses worth examining in other studies or be helpful in refining labelling information, patient selection, dose selection etc.’

9. Division of Oncology Drug Products 9 PROBLEM 2: Imbalances Randomization not Stratified within the Liver Metastasis Subgroup of Patients …. Imbalances favoring Histamine + IL-2 arm

10. Division of Oncology Drug Products 10

11. Division of Oncology Drug Products 11 Adjusted Survival Analysis: Model Selection Sponsor Models: Different models with different data cut off dates FDA Model: Consistent model, No selection - all characteristics with imbalances included.

12. Division of Oncology Drug Products 12 ADJUSTED ANALYSES - Covariates specified in the Statistical Plan submitted 11/18/99

13. Division of Oncology Drug Products 13 Survival Analyses Adjusted for Imbalances in the Liver Subgroup * P-value not adjusted for multiplicity. For example Adjusting only for 2 primary hypotheses testing: P-value = 0.1146 (9/8/00 data)

14. Division of Oncology Drug Products 14 Survival Analyses Adjusted for Covariates in the Liver Metastasis Subgroup Results are sensitive to inclusion and exclusion of a covariate. P-values not Adjusted for Multiplicity - Multiple Subgroups - Multiple Analyses No Robustness To The Subgroup Findings.