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-Risk60-66 Gy Post-Operative, Low-Risk50-60 Gy

6. ACTUAL RADIATION RECEIVED Overall : p=0.056

7. PRIMARY ENDPOINTS

8. PRIMARY ENDPOINT: Acute Xerostomia 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)

9. PRIMARY ENDPOINT: Late Xerostomia 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

10. FDA Review (revised): Late Xerostomia

11. LATE XEROSTOMIA vs. TOTAL RADIATION DOSE

12. PRIMARY ENDPOINT: Acute Mucositis 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%)

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) SECONDARY ENDPOINT Saliva Measurements FDA Comments: Longitudinal analysis of unstimulated saliva production non-confirmatory Retrospective definition of time point comparisons Retrospective definition of clinically significant cut-off values

16. FDA ANALYSIS: Change from Baseline

17. SUMMARY OF SECONDARY EFFICACY ENDPOINT FINDINGS: Saliva Measurements

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

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-being Completers & Dropouts GEE quadratic model

22. General Condition Completers & Dropouts GEE quadratic model

23. Use of External Aids Completers & Dropouts GEE quadratic model

24. Functional Well-being All Patients

25. General Condition All Patients

26. Use of External Aids All 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. 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 SECONDARY ENDPOINT Tumor Control 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. 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 SAFETY

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

31. !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 i Safety

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

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