1. Zometa for Patients with Bone Metastases Overview and Review of Study 010 Grant Williams, M.D. Medical Team Leader Division of Oncology Drug Products

2. FDA Clinical Review Team Project ManagerDebra Vause MedicalAmna Ibrahim, M.D. Nancy Scher, M.D. Grant Williams, M.D. Richard Pazdur, M.D. StatisticsRajeshwari Sridhara, Ph.D. Ning Li, Ph.D. Gang Chen, Ph.D. Clinical Brian Booth, Ph.D. PharmacologyJoga Gobburu, Ph.D. Atiqur Rahman, Ph.D. DSI (Clinical Audit) Khin U, M.D.

3. Outline of Presentation Overview and Regulatory Framework Study 010 (Myeloma and Breast Ca) –Non-inferiority trial design –Results –Examination of assumptions

4. Proposed Zometa Indication "treatment of osteolytic, osteoblastic, and mixed bone metastases of solid tumors and osteolytic lesions of multiple myeloma, in conjunction with standard antineoplastic therapy”

5. Efficacy requirement 1962 amendment to the Federal Food Drug and Cosmetic Act Substantial evidence from adequate and well-controlled investigations

6. FDA-Applicant Design Assumptions Efficacy evidence from one indication may support another –Study 010 combined data from myeloma and breast cancer –Only a single trial for each indication was planned – Multiple different tumor types were included in Study 011

7. SRE Analyses Proportion of patients with SRE during study Time to first SRE Both use only the patient’s first event

8. SRE Analyses Both endpoints are affected by dropout –Leads to underestimation in the Proportions analysis –Potential for “informative censoring” in Time to SRE analysis. Problem of competing risks Bias in estimation of effect size is likely No evidence of bias between the study arms

9. Critical Questions Myeloma and Breast Cancer Efficacy is based on a single trial of non-inferiority design. Do other NDA data provide supportive evidence for breast cancer and myeloma indications?

10. Critical Questions Prostate Cancer (Study 039) Considering both the Zol 4 mg and Zol 8/4 mg arms, how convincing is Study 039? Can data from treatment of lytic disease provide support?

11. Critical Questions Other Solid Tumors (Study 011) Efficacy of Zometa seems convincing in the population entered with other solid tumors Are data adequate to support approval for treatment of all individuals with all solid tumors?

12. Study 010 Design Randomized, double -blind, active control Stratified Zometa efficacy determined from a non-inferiority analysis

13. Study 010 Design Assumes data on bisphosphonate efficacy from myeloma and breast cancer can be combined Steps in analysis: –Estimate the historical Aredia effect size versus placebo –Compare Zometa and Aredia results in current study –Determine Zometa efficacy by showing that a reasonable fraction of the Aredia effect size is proven for Zometa using statistical methodology. –Evaluate the constancy assumption

14. Historical Aredia Effect *  =Placebo-Aredia

15. Zometa versus Aredia *  =Zometa-Aredia

16. Determing Zometa Effect Point estimate compared to Aredia: –Zometa had 2% fewer events (44% vs 46%) Worst case scenario: Zometa retains 49% of the Aredia vs Placebo effect: –Historical estimate of Aredia effect using lower 95% ci: 7.3% –Worst-case estimate of Zometa - Aredia using upper 95% ci: 3.7% –(7.3%-3.7%)/7.3% = 49%

17. Constancy Assumption The control drug (Aredia) would have shown the same measurable efficacy versus placebo that it did in the historical trials Potential problems –Different study populations –Changes in supportive care over time –Sloppy trial conduct may obscure differences

18. Differences Between Historical Population and NDA Population

19. Evaluating Assumption (1) Approach: Evaluate the Aredia vs placebo effect in historical subgroups. Results: The Aredia effect was fully evident in the following historical subgroups: Recently diagnosed patients (dx < 6 mos) Patients with previous SREs

20. Evaluating Assumption (2) Approach: Evaluate the Zometa vs. Aredia effect in Study 010 in subgroup with lytic breast cancer disease Results: No suggestion of Zometa inferiority in subgroup with lytic disease Breast Chemo: SRE in 49% (Z) vs 57% (A) Breast Hormones: SRE in 47% (Z) vs 59% (A)

21. Evaluating Assumption (3) Approach: Evaluate the type of skeletal related events comprising results in the historical versus the current study Results Event types were similar, mostly fractures and RT to bone

22. Myeloma And Breast Cancer FDA Conclusion Study 010 is a single study of non-inferiority design demonstrating efficacy of Zometa for patients with bone lesions of Myeloma and Breast Cancer. With regard to evidence of Zometa treatment of Myeloma and Breast Cancer, does ODAC agree that this trial along with other NDA data meet the regulatory requirement for substantial evidence of efficacy from well controlled clinical trials?

24. Questions to ODAC

25. Critical Questions: Myeloma and Breast Cancer Efficacy is based on a single trial of non-inferiority design. Can other NDA data provide supportive evidence for breast cancer and myeloma indications?

26. Critical Questions Prostate Cancer (Study 039) Considering both the Zol 4 mg and Zol 8/4 mg arms, how convincing is Study 039? Do data from treatment of lytic disease provide support?

27. Efficacy of Zometa seems convincing in the population entered with other solid tumors Are data adequate to support approval for treatment of all individuals with all solid tumors? Critical Questions Other Solid Tumors (Study 011)

28. Efficacy requirement Substantial evidence from adequate and well-controlled investigations