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FDA Presentation NDA 21-661 RSR13 ( efaproxiral sodium )

FDA Presentation NDA 21-661 RSR13 ( efaproxiral sodium ). Oncology Drug Advisory Committee Meeting May 3, 2004. Chemistry Josephine Jee, Ph.D. Hasmukh Patel, Ph.D. Pharmacology Anwar Goheer, Ph.D. John Leighton, Ph.D. Biopharmaceutics Atul Bhattaram, Ph.D. Joga Gobburu, Ph.D.

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FDA Presentation NDA 21-661 RSR13 ( efaproxiral sodium )

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  1. FDA PresentationNDA 21-661RSR13(efaproxiral sodium) Oncology Drug Advisory Committee Meeting May 3, 2004

  2. Chemistry Josephine Jee, Ph.D. Hasmukh Patel, Ph.D. Pharmacology Anwar Goheer, Ph.D. John Leighton, Ph.D. Biopharmaceutics Atul Bhattaram, Ph.D. Joga Gobburu, Ph.D. Atiq Rahman, Ph.D. Microbiology Vinnie Pawar, Ph.D Peter Cooney, Ph.D. Statistics Rajeshwari Sridhara, Ph.D. Kooros Mahjoob, Ph.D. Clinical Kevin Ridenhour, M.D. Ramzi Dagher, M.D. Project Manager Christy Cottrell Review Team

  3. Outline • Background • Description of Clinical Trials • Results of RT-009 • Demographics • Efficacy • Safety • Conclusions

  4. Proposed Indication Adjunctive therapy to whole brain radiation for the treatment of brain metastases originating from breast cancer.

  5. RT-009: Regulatory History • June 13, 1995: IND 48,171 submitted to FDA. • June 19, 2003: Discussed concerns with the applicant regarding findings in the non-prespecified subgroup of patients with breast cancer. • July 25, 2003: Pharmacology data was submitted as the first component of a rolling NDA. • December 4, 2003: Clinical and Statistical components submitted to finalize NDA submission.

  6. Description of Clinical Trials • RT-009: A randomized, open-label study of standard WBRT/oxygen, with or without RSR13, in patients with brain metastases. Control arm N = 267; RSR13 arm N= 271 • RT-008: A single-arm study of RSR13 administered to patients receiving standard WBRT with oxygen for brain metastases. N = 69

  7. RT-009: Treatment Plan • RSR13 arm • 100 or 75 mg/kg central IV infusion over 30 minutes daily within 30 minutes of WBRT • WBRT given as 30 Gy in 10 fractions. • Control arm • WBRT given as 30 Gy in 10 fractions. • 4L/min supplemental oxygen (both arms) • 35 minutes prior to, during, and for at least 15 minutes after completion of WBRT.

  8. RT-009: Endpoints • Primary: Survival • Overall Population (protocol version #1) • NSCLC/Breast Subgroup (amendment #2) • Secondary Endpoints • Time to Radiographic Tumor Progression in the Brain • Time to Clinical Tumor Progression in the Brain • Response Rate in the Brain • Cause of Death • Quality of Life

  9. RT-009: Eligibility Criteria • KPS > or = to 70 • Radiographic studies consistent with brain metastases • Resting / exercise SpO2 > 90% (room air) • Concurrent corticosteroid therapy allowed • Cytologically confirmed primary malignancy (small cell carcinoma, germ cell and lymphomas were excluded)

  10. RT-009: Tumor Histology

  11. Post-Randomization Systemic Treatment(RT-009 Overall Population)

  12. Post-Randomization Systemic Therapy(RT-009 Breast Subgroup)

  13. RT-009: Number of Brain Lesions at Baseline (Overall Population)

  14. RT-009: Number of Brain Lesions by Primary Site

  15. RT-009: Analysis of Survival • No survival advantage demonstrated in the overall population (p = 0.1688, logrank) • No survival advantage in the NSCLC/Breast co-populations (p= 0.1217, logrank) • A survival advantage was seen in a non-prespecified breast population considered exploratory at this time (p = 0.0061, logrank)

  16. RT-009: Response Rates in the Brain According to Applicant (Overall Population)

  17. Cause of Death(RT-009 Overall Population)

  18. RT-009: Steroids Received(Overall Population)

  19. RT-009: Response Rate in the Brain According to Applicant • Given that there is no apparent advantage in response rate in the brain with RSR13, WBRT and oxygen vs. WBRT/oxygen, there does not appear to be a contribution of RSR13 to tumor response. • More than 90% of patients in both arms received steroids. • Response duration cannot be assessed since confirmatory imaging studies were not required. • The designation of CR/PR was given irrespective of the appearance of a new brain parenchymal lesion.

  20. RT-009: Other Secondary Endpoints • No statistically significant difference between the control arm and RSR13 arm in: • Time to radiographic tumor progression in the brain. • Time to clinical tumor progression in the brain. • Quality of life.

  21. RT-008 • N = 69: Lung, breast, melanoma, “other” • Median survival 6.4 months • Response rate in the brain of 29%

  22. RT-009: RSR13 and Radiation Exposure • RSR13 exposure was similar in the Overall Population and NSCLC/Breast populations • Radiation exposure was similar in the Overall Population and NSCLC/Breast populations • The FDA was able to reproduce the applicant’s analyses for RSR13 and radiation exposure

  23. Oxygen Exposure for the Overall Population (RT-009)

  24. RT-009: All Grade Treatment-Emergent Adverse Events

  25. RT-009: Grade 3 / 4 Adverse Events

  26. Conclusions • No survival advantage demonstrated for the RSR13 arm vs. control arm in RT-009. • No advantage demonstrated for RSR13 vs. control in secondary endpoints. • Most common all grade treatment adverse events included hypoxia, hypotension, nausea, vomiting, and headache. • The exploratory analysis demonstrating a survival advantage in the breast cancer subgroup is being further evaluated in a randomized study.

  27. Statistical Review of Efficacy

  28. Areas of Major Statistical Issues • Overall Finding (ITT Population) • Subgroup Findings • NSCLC/Breast Primary Subgroup • Breast Primary Subgroup • Multiplicity

  29. Overall Finding 1. Evidence of Efficacy 2. Multiple Survival Analyses 3. Internal Consistency

  30. Evidence of Efficacy in ITT Population

  31. Evidence of Efficacy in ITT (Contd.) *NDA Analysis as of January 31, 2003 **Updated Analysis as of January, 2004 ***P-values from comparison of survival distributions using log-rank test. Not adjusted for Multiple Looks. P-values should not be compared to 0.05

  32. 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.’

  33. Applicant’s Description • The primary analysis was clearly stated to be based on unadjusted log-rank test • in all protocol amendments (in ITT population) • and in the final statistical analysis plan • In SAP under the section on covariates: “While designated prospectively, supporting analyses should be considered exploratory in nature, and inferences made based on p-values should be done so with caution. Primary reasons for exploratory analyses are for estimation rather than hypothesis testing”.

  34. Protocol / SAP Exploratory Analyses

  35. Exploratory Covariate Adjusted Analysis Covariates Included (protocol listed): RPA Class (Class 1 = 0 vs. Class 2 = 1) Breast primary (No breast = 0 vs. Breast = 1) NSCLC primary (No NSCLC = 0 vs. NSCLC = 1) Primary control (No = 0 vs. Yes =1) Age group (< 65 = 0 vs. 65 or older = 1) Presence of extracranial mets. (No = 0 vs. Yes = 1) KPS group (90 or greater = 0 vs. < 90 = 1) Brain lesions (Single = 0 vs. Multiple = 1)

  36. Exploratory Covariate Adjusted FDA Analysis – Treatment Effect (Control = 0 vs. RSR13 = 1) * By Cox model, Not adjusted for multiple analyses

  37. Summary of Overall Finding The Single, Randomized RT-009 Study conducted in patients with brain metastases does not demonstrate substantial evidence of benefit with respect to Survival in the Overall ITT population

  38. Subgroup Findings • NSCLC/Breast Primary Subgroup (Specified as co-primary hypothesis during the study) • Breast Primary Subgroup

  39. NSCLC/Breast Primary Subgroup Finding

  40. Summary of NSCLC/Breast Primary Subgroup Finding The Single, Randomized RT-009 Study conducted in patients with brain metastases does not demonstrate substantial evidence of benefit with respect to Survival in the Subgroup of Patients with NSCLC/Breast Primary Cancer. P-values should not be compared to 0.05

  41. Breast Primary Subgroup Finding 1. Absence of Overall Survival Benefit 2. Very Small Subgroup 3. Imbalances

  42. Issue 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.’

  43. Issue 2: Small Breast Primary Subgroup

  44. Issue 3: Imbalances within Breast Primary Subgroup– Important Factors None of these were individually statistically significant; P-value for Brain lesions (single vs. multiple) = 0.07)

  45. Exploratory Breast Primary Subgroup Finding *P-value not adjusted for multiplicity

  46. Breast Primary Subgroup Finding • Imbalances were observed and true finding can not be isolated • No robustness to the subgroup finding • P-values not adjusted for multiplicity • At best Exploratory and Hypothesis Generating

  47. Multiplicity • Multiple Hypotheses (per protocol Amendment 2, two co-primary hypotheses, alpha adjusted using modified Boneferroni, after accounting for one interim analysis) • Multiple Analyses of the same hypothesis (at different times, unadjusted and numerous adjusted analyses) • Multiple Subgroups (site of primary, diagnosis timing, etc.)

  48. Results from Single Study Persuasive? • Inherent variability may produce a positive trial by chance alone (p =0.05 implies 1/40 studies of ineffective drugs will be positive) • FDA Guidance: ‘it is critical that the possibility of an incorrect outcome be considered and that all the available data be examined for their potential to either support or undercut reliance on a single multicenter trial’ • Statistically Persuasive? – can only be verified by replication

  49. Review of Results • Randomized, Controlled, Open-label, Multicenter, Single Trial • Analysis of Primary Endpoint Overall Survival Not Statistically Significant • No significant difference in the overall ITT population • No significant difference in the subgroup of patients with NSCLC/Breast primary • No significant benefit observed in any of the secondary efficacy endpoints

  50. Review of Results • Apparent survival benefit in a subset of patients with breast cancer primary is questionable because of: • Post-hoc, exploratory analysis • Very small sample size from a single study • Imbalances possibly influencing treatment effect

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