Zometa for Patients with Bone Metastases Overview and Review of Study 010 Grant Williams, M.D....
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Transcript of Zometa for Patients with Bone Metastases Overview and Review of Study 010 Grant Williams, M.D....
Zometa for Patients with Bone Metastases
Overview and Review of Study 010
Grant Williams, M.D.Medical Team Leader
Division of Oncology Drug Products
FDA Clinical Review TeamProject Manager Debra Vause
Medical Amna Ibrahim, M.D.
Nancy Scher, M.D.
Grant Williams, M.D.
Richard Pazdur, M.D.
Statistics Rajeshwari Sridhara, Ph.D.
Ning Li, Ph.D.
Gang Chen, Ph.D.
Clinical Brian Booth, Ph.D.
Pharmacology Joga Gobburu, Ph.D.
Atiqur Rahman, Ph.D.
DSI (Clinical Audit) Khin U, M.D.
Outline of Presentation
• Overview and Regulatory Framework
• Study 010 (Myeloma and Breast Ca)– Non-inferiority trial design– Results– Examination of assumptions
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”
Efficacy requirement
• 1962 amendment to the Federal Food Drug and Cosmetic Act
• Substantial evidence from adequate and well-controlled investigations
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
SRE Analyses
• Proportion of patients with SRE during study
• Time to first SRE
• Both use only the patient’s first event
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
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?
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?
Critical QuestionsOther 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?
Study 010 Design
• Randomized, double -blind, active control
• Stratified
• Zometa efficacy determined from a non-inferiority analysis
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
Placebo Aredia Difference
(95% CI)*
p-value*
Myeloma44% 28% 16%
0.001
Breast
(Chemo) 56% 43% 13.7% 0.007
Breast
(Hormonal) 55% 47% 8% 0.108
Total 52.0%
(293/563)
38.9%
(220/565)
13.1%
(7.3%, 18.9%) <0.0001
Historical Aredia Effect
*=Placebo-Aredia
Zometa versus Aredia
*=Zometa-Aredia
Zometa(4mg)
Aredia Difference (95% CI)* p-value
Myeloma47% 49% -2% 0.694
Breast(Chemo) 44% 43% 1% 0.806
Breast(Hormonal) 42% 47% -5% 0.277
Total 44%(248/561)
46%(257/555)
-2%(-7.9%, 3.7%)
0.461
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%
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
Differences Between Historical Population and NDA Population
Time since bonemetastases
Patients (%) withhistory of SRE
Patients (%) withbaseline lytic bonelesions
Historical NDA Historical NDA Historical NDA
Myeloma 17 mo 3 mo 31% 81% 100% 100%
BreastCancer
14-17mo 4 mo 30% 62% 95% 50%
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
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)
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
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?
Questions to ODAC
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?
Critical QuestionsProstate 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?
• 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 QuestionsOther Solid Tumors (Study 011)
Efficacy requirement
Substantial evidence from adequate and well-controlled investigations