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sNDA 20-221

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  1. sNDA 20-221 ETHYOL FOR RADIATION INDUCED XEROSTOMIA

  2. REVIEW TEAM

  3. WR-0038 A Phase III Trial of Radiation Therapy  Amifostine in Patients with Head and Neck Cancer

  4. PRETREATMENT CHARACTERISTICS • Balanced Site of Disease Clinical Stage Nodal Status Volume of Parotid Glands for RT Type of Radiation

  5. INTENDED RADIATION DOSE“Type of Radiation” Inoperable 66-70 Gy Post-Operative, High-Risk 60-66 Gy Post-Operative, Low-Risk 50-60 Gy

  6. ACTUAL RADIATION RECEIVED Overall : p=0.056

  7. PRIMARY ENDPOINTS

  8. Applicant: Significant Reduction of Grade 2 Xerostomia A+RT (51%) vs. RT (78%) (p<0.0001) FDA: Agree No difference in overall incidence (Gr 1 + 2) A+RT (90%) vs. RT (94%) (p=0.07) PRIMARY ENDPOINT:Acute Xerostomia

  9. Applicant: 365  31 days Significant Reduction in Grade 2 or greater A+RT (34%) vs. RT (57%) (p<0.0019) FDA Comments: Disagree with applicant’s definition Reanalysis necessary PRIMARY ENDPOINT: Late Xerostomia

  10. FDA Review (revised):Late Xerostomia

  11. LATE XEROSTOMIA vs. TOTAL RADIATION DOSE

  12. No difference (Grade 3 or greater) A+RT (35%) vs. RT (39%) (p=0.48) Grade 1 to 4 A+RT (95%) vs RT (99%) PRIMARY ENDPOINT: Acute Mucositis

  13. SUMMARY OF PRIMARY EFFICACY ENDPOINT FINDINGS • Significantly lower incidence of moderate acute xerostomia • Significantly lower incidence of moderate to severe late xerostomia • No difference in the incidence of acute mucositis

  14. SECONDARY ENDPOINTS Related to Efficacy: • Saliva Measurements • Patient Benefit Questionnaire Related to Non-Tumor Protection: • One Year Locoregional Control (Primary Endpoint) • DFS • Overall Survival Safety

  15. Applicant: Significant difference in unstimulated saliva at one year (> 0.1 gm) A+RT (72%) vs. RT (49%) (p=0.003) Not confirmed by stimulated saliva collections A+RT (33%) vs. RT (41%) (p=0.3) FDA Comments: Longitudinal analysis of unstimulated saliva production non-confirmatory Retrospective definition of time point comparisons Retrospective definition of clinically significant cut-off values SECONDARY ENDPOINTSaliva Measurements

  16. FDA ANALYSIS:Change from Baseline

  17. SUMMARY OF SECONDARY EFFICACY ENDPOINT FINDINGS:Saliva Measurements

  18. Reasons for Different Analyses FDA Analysis Results Summary SECONDARY ENDPOINT:Patient Benefit Questionnaire

  19. Analysis of PBQ Data • Different measures of clinical benefit • Sponsor: mean score of 8 questions • FDA: 3 individual subscales • Functional well-being (speaking, eating) • General condition (dryness) • Use of external aids (frequency of fluid intake for eating & comfort not associated with eating) • Number of data points • Sponsor: excluded data beyond the 1 year follow-up visit • FDA: all data points

  20. FDA Analysis of PBQ Data • Cutoff value in defining dropouts and completers: 1 year • Number of Patients • Method: Longitudinal analysis with GEE quadratic models

  21. Functional Well-beingCompleters & Dropouts GEE quadratic model

  22. General ConditionCompleters & Dropouts GEE quadratic model

  23. Use of External AidsCompleters & Dropouts GEE quadratic model

  24. Functional Well-beingAll Patients

  25. General ConditionAll Patients

  26. Use of External AidsAll Patients

  27. SUMMARY • Results: Descriptive and exploratory • Subjective nature of the questionnaire • Open-label trial design • Adjustment of multiple comparisons • Trends in favor of the Ethyol: • General Condition • Use of External Aids • Trend in favor of the Ethyol arm for Functional Well-being ?

  28. SECONDARY ENDPOINTTumor Control Applicant: • Primary: no difference in locoregional control at one year (72% vs. 71%, p=1.0) • no difference in DFS, overall survival • WR-9001 in Rectal Cancer: no significant difference in overall survival FDA Comments: • WR-0038: immature data, high censor rate • Selection of 0.7 as the lower limit of a 1-sided C.I. is liberal

  29. SAFETY • Significantly greater frequency of known adverse events • Large number of dropouts in A+RT • 29/150 (19%) • More radiotherapy doses missed in A+RT • More hospitalizations in A+RT • A+RT:101 vs. RT:63

  30. Well-designed, well-controlled trials Substantial evidence of efficacy and safety CONSIDERATIONS FOR APPROVAL

  31. Safety • Significant but expected toxicities • More drop-outs, hospitalizations, missed doses • Ability to deliver optimal doses of therapy and potential effect on the efficacy ? • Should be weighed against strength of other evidence

  32. Efficacy • Significant difference in moderate to severe acute and late xerostomia • PBQ and Salivary Measurement data supportive ?

  33. Adequate and well controlled clinical trials • Single phase 3 trial