1 / 34

sNDA 20-221

sNDA 20-221. ETHYOL FOR RADIATION INDUCED XEROSTOMIA. REVIEW TEAM. WR-0038 . A Phase III Trial of Radiation Therapy  Amifostine in Patients with Head and Neck Cancer. PRETREATMENT CHARACTERISTICS. Balanced Site of Disease Clinical Stage Nodal Status

tymon
Download Presentation

sNDA 20-221

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related