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Atrasentan For Men with Metastatic Hormone Refractory Prostate Cancer ODAC September 13 th , 2005

Atrasentan For Men with Metastatic Hormone Refractory Prostate Cancer ODAC September 13 th , 2005. Clinical-Statistical Presentation Amna Ibrahim MD Shenghui Tang PhD DDOP, FDA. Outline of Presentation. 1- Past approvals 2- Phase III study Study design

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Atrasentan For Men with Metastatic Hormone Refractory Prostate Cancer ODAC September 13 th , 2005

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  1. Atrasentan For Men with Metastatic Hormone Refractory Prostate CancerODAC September 13th, 2005 Clinical-Statistical Presentation Amna Ibrahim MD Shenghui Tang PhD DDOP, FDA

  2. Outline of Presentation 1- Past approvals 2- Phase III study • Study design • Results of protocol-specified endpoints • Subgroup analyses • Reliability of results • Clinical relevance of results 3- Phase II study Protocol, conduct and results 4- Major safety concerns- Phase III and II

  3. Past HRPC Approvals • Mitoxantrone + Prednisone (approved 1996) - Primary endpoint: confirmed improvement in pain - Interpretable pain severity scale - Pre-specified analysis plan for pain evaluation - Improved time to progression • Taxotere + Prednisone (approved 2004) - Primary endpoint: Overall survival For Both Approvals: Primary endpoint: Pre-specified Results: Persuasive- statistically & clinically

  4. Design of the Atrasentan StudyPhase III Study • Double blinded randomized study • Central independent review blinded to PSA • QoL was tertiary endpoint without detailed analysis plan • No mention of a specific measurement of pain submitted

  5. Disease Progression Definition Phase III Study Protocol-specified Primary Endpoint: Time to Disease Progression- ITT Events constituting Disease Progression (DP) • Radiographic Progression • Pain requiring intervention • Prostate Cancer complications requiring interventions • Skeletal Related Events (SREs)

  6. Events defining DPPhase III Study- applicant analyses For both treatments arms combined (all progression events) A- Radiographic Progression 74% B- Pain 20% C- Interventions 3% D- SREs 2%

  7. Results of Protocol-Specified Endpoints Phase III Study • Failed primary endpoint TDP • Failed 4 of 5 secondary endpoints(-) OS, Time to PSA progression, change in bone scan index, & PFS (+) Mean change in ALP but difference of only 20 ng/ml, and missing data • Failed several tertiary endpoints(-) QoL adjusted TDP (QATDP), KPS and mean change in PSA.

  8. Phase II Study • Randomized 3-arm, phase II study • Pretreated population • different from Ph III study • Any therapy (except hormones) 75% on placebo & 66% atrasentan 10 mg • prior chemo: 25% on placebo & 18% on Atrasentan 10 mg • Pts with prostate ca pain not excluded • Primary endpoint: TDP (defined differently from Ph III)

  9. Disease ProgressionPhase II Study Disease Progression Definition • intervention for cancer-related event • new symptoms related to tumor growth • New pain requiring opioids (evidence of disease and duration not required) • Other investigator defined measures not well-defined (incl. PSA rise, weakness, steroids use and deterioration)

  10. Conduct of Studies (Applicant analyses for Phase III & II Studies) Phase III study protocol violations: Atrasentan 10 mg: 12% Placebo: 18% Phase II study protocol violations: Atrasentan 10 mg: 58% Placebo: 38% Phase II missing data for imaging studies: < 50% paired bone scans and CT scans available

  11. FDA Statistical Review Shenghui Tang, PhD Mathematical StatisticianFDA/CDER/Division of Biometrics I

  12. Outline:Major Statistical Problems • Early closure of the phase III study • Failed primary efficacy (Phase II & III) • Submitted analyses are post hoc: • subgroup & pooled analyses • QoL and pain analyses • No adjustment for multiple comparisons

  13. Early Closure of Phase III Study • Independent Data Monitoring Committee recommended closure of the phase III study due to lack of efficacy • The study closed on March 19, 2003 809 patients, 343 TDP events

  14. Failed primary efficacyPhase III & II ITT Analyses

  15. Failed primary efficacy Phase II & III • No alpha left for further testing • Any further analysis inflates false positive rate

  16. Secondary Efficacy Analyses • Time to onset of PSA progression unadjusted nominal p-value=0.344 • Mean rate of change from baseline to final value in total bone scan index unadjusted nominal p-value=0.051 • Overall survival unadjusted nominal p-value=0.791, HR=0.982 • Mean change from baseline to final value in bone alkaline phosphatase (ALP) unadjusted nominal p-value=0.001

  17. Secondary and Tertiary Efficacy Analyses are Exploratory Per applicant’s specified protocol: “…….If the primary efficacy analysis is not statistically significant at the α=0.05 level, then statistical significance will not be declared for any of these secondary analyses, regardless of the observed p-values.”

  18. Subgroup Analyses Two main subgroup analyses in phase III study were submitted: • Per-protocol patient population (12/04) 83% overall patient population • Patients with bone metastases at baseline (BM) (12/04) - Clinical Disease Progression analysis in BM subgroup (First reported in the briefing package)

  19. Subgroup TDP Analyses Phase III Per-Protocol & Bone Mets at Baseline

  20. Subgroup TDP Analyses Phase III Per-Protocol & Bone Mets at Baseline • Protocol stated that significance will not be declared for the per-protocol analysis • Bone metastatic subgroup analysis is a post-hoc analysis

  21. Clinical Disease Progression Analysis • Not pre-specified • Not adjusted for multiple comparisons • Informative censoring of radiological progressions • >75% censored for progression

  22. Guidelines for Statistical Principles for Clinical Trials (ICH E9) • ‘…, adjustment should always be considered and the details of any adjustment procedure… should be set out in the analysis plan.’ • ‘ 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.’

  23. Guidelines for Structure and Contents of Clinical Study Reports (ICH E3) 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.’

  24. Problems with Subgroup Analyses • High false positive or false negative rates. • False positive finding increases with number of significance tests • Not pre-specified = Post-hoc analysis • Primary failed → P-value not interpretable Subgroup Analyses are Exploratory

  25. Pooled Analysis of Phase II & Phase III Studies Pooled analysis not acceptable: • Neither trial individually shows a statistically significant difference 2. Different Definitions of TDP 3. Different Patient populations 4. Atrasentan formulations not bioequivalent Continued

  26. Pooled Analysis Phase II & Phase III Studies (cont’d) 5. Post-hoc analysis 6. No independent review of progression evaluation conducted in Phase II study 7. Pooling data causes imbalance in randomization 8. Type I error not controlled

  27. Quality of Life Analysis • QoL tertiary endpoint • Measured using FACT-P and EORTC-C30 • No hypothesis for QoL analysis • Compare differences in mean scores •No adjustment for multiple comparisons

  28. Quality of Life Analysis Mean Change from Baseline to Final Assessment for FACT-P and Subscores: ITT Subject Population

  29. Prostate Cancer Subscore (PCS) • I am losing weight • I have a good appetite • I have aches and pain that bother me • I have certain areas of my body where I experience significant pain • My pain keeps me from doing things I want to do • I am satisfied with my present comfort level • I am able to feel like a man • I have trouble moving my bowels • I have difficulty urinating • I urinate more frequently than usual • My problems with urinating limit my activities • I am able to have and maintain an erection

  30. Problems with QoL Analysis • Clinical significance of the PCS mean change of 1.02 on a scale of 0-48 • Recall Bias • PCS score does not capture all the patient perceived impact of atrasentan treatment • Missing data

  31. Pain Analyses • Change in pain-related scores (12/04) • Time to 50% deterioration (First reported in briefing package, 8/05)

  32. Pain-related Questions in PCS • I have aches and pain that bother me • I have certain areas of my body where I experience significant pain • My pain keeps me from doing things I want to do • I am satisfied with my present comfort level Not Specific to Bone or Prostate Cancer Pain

  33. Mean Change in Pain-related Scores in PCS • Not designed or validated for such use. • Clinical significance of the PCS pain score mean change of 0.7 on a scale of 0 to 16 • Each pain item measures a different attribute of pain • 7-day recall period. • Questions not specific to bone pain. Do not adequately measure pain

  34. Time to 50% Deterioration in FACT-P Pain-Related QoL Scores Analysis in BM

  35. Clinical Review ContinuedOutline • Clinical relevance of results (TDP) • Reliability of results (TDP) • Post hoc analyses (clinical aspects) • Safety • Conclusion

  36. Hazards of the Hazard Ratio Regarding Ratios (e.g. HR, proportions and odds ratios) Meaningful only if also clinically relevant • Units of time not represented (improvement of 3 days to 6 days same as 3 years to 6 years) • For primary endpoint in the 3 populations, HR <1, but not clinically meaningful.

  37. Clinical Relevance of TDP ResultsPhase III Study – Applicant Analyses

  38. Reliability of difference in rTDPhypothetical situation Actual Progression Arm A Actual Progression Arm B Imaging Study Months 3 Time Zero TDP is 3 months on both arms

  39. Reliability of TDP ResultsPhase III Study • Time to radiographic progression is time to imaging • Radiographic progressions drove study results (74% of DP events) • Imaging scheduled q 12 weeks per protocol (84 d) • Median TDP is ~ 89 days • No reliable effect of atrasentan was observed

  40. Mean time to bone scanPhase III study

  41. Subgroup AnalysesPhase III Study - Applicant Table from CSR

  42. Subgroup AnalysesPhase III Study - Applicant Table from CSR

  43. Pain • Pain not primary endpoint for atrasentan studies unlike mitoxantrone study. Mitoxantrone & Prednisone study - 2 point improvement in 6 point scale of at least 6 weeks of duration (29% vs 12%) - Improved median time to progression (4.4 mo vs. 2.3 mo.) Atrasentan study - ~1 in 0-48 point scale (FACT-PCS) - 0.2 in a 2-8 point scale (EORTC QLQ-C30, 2 items only) & 0.7 in a 0-16 point scale (4 of 12 items from PCS) • Magnitude of effect on pain small and duration not considered in atrasentan study

  44. Retrospective Pain Analysis Time to 1st AE of bone pain - No requirement for routine assessment of bone pain in AE reporting - for e.g. prostate cancer AE reporting was 12% on atrasentan and 16% on placebo arm AE reporting not meant to be used as an endpoint

  45. Changing Efficacy Analyses

  46. Efficacy Summary Phase II study is not acceptable. Phase III Study: • Primary endpoint failed • Secondary endpoints failed or not clinically meaningful (includes bone markers, & QoL) • Bone markers & QoL endpoints pre-specified in the secondary and tertiary analyses failed • Marginal improvement of questionable clinical relevance and reliability in all 3 populations presented • Multiple post hoc analyses warrant further study

  47. SafetyPhase III & II studies

  48. SafetyPhase III Study

  49. Coronary Artery DiseasePhase III Study

  50. Coronary Artery DiseasePhase II Study

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