sNDA 20221

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sNDA 20-221

• ETHYOL
• FOR RADIATION INDUCED XEROSTOMIA

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REVIEW TEAM
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WR-0038

• A Phase III Trial of Radiation Therapy ?
  Amifostine in Patients with Head and Neck Cancer

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PRETREATMENT CHARACTERISTICS

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

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INTENDED RADIATION DOSEType of Radiation

• Inoperable 66-70 Gy
• Post-Operative, High-Risk 60-66 Gy
• Post-Operative, Low-Risk 50-60 Gy

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ACTUAL RADIATION RECEIVED

• Overall p0.056

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PRIMARY ENDPOINTS
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PRIMARY ENDPOINTAcute Xerostomia

• Applicant
• Significant Reduction of Grade 2 Xerostomia
• ART (51) vs. RT (78) (plt0.0001)

• FDA
• Agree
• No difference in overall incidence (Gr 1 2)
• ART (90) vs. RT (94) (p0.07)

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PRIMARY ENDPOINT Late Xerostomia

• Applicant
• 365 ? 31 days
• Significant Reduction in Grade 2 or greater
• ART (34) vs. RT (57) (plt0.0019)

• FDA Comments
• Disagree with applicants definition
• Reanalysis necessary

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FDA Review (revised)Late Xerostomia
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LATE XEROSTOMIA vs. TOTAL RADIATION DOSE
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PRIMARY ENDPOINT Acute Mucositis

• No difference (Grade 3 or greater)
• ART (35) vs. RT (39) (p0.48)

• Grade 1 to 4
• ART (95) vs RT (99)

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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

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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

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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

• Applicant
• Significant difference in unstimulated saliva at
  one year (gt 0.1 gm)
• ART (72) vs. RT (49) (p0.003)
• Not confirmed by stimulated saliva collections
• ART (33) vs. RT (41) (p0.3)

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FDA ANALYSISChange from Baseline
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SUMMARY OF SECONDARY EFFICACY ENDPOINT
FINDINGSSaliva Measurements
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SECONDARY ENDPOINTPatient Benefit Questionnaire

• Reasons for Different Analyses
• FDA Analysis
• Results
• Summary

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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

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FDA Analysis of PBQ Data

• Cutoff value in defining dropouts and completers
  1 year
• Number of Patients
• Method Longitudinal analysis with GEE quadratic
  models

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Functional Well-beingCompleters Dropouts
GEE quadratic model
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General Condition Completers Dropouts
GEE quadratic model
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Use of External Aids Completers Dropouts
GEE quadratic model
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Functional Well-beingAll Patients
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General Condition All Patients
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Use of External Aids All Patients
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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 ?

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SECONDARY ENDPOINTTumor Control

• Applicant
• Primary no difference in locoregional control at
  one year (72 vs. 71, p1.0)
• 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

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SAFETY

• Significantly greater frequency of known adverse
  events
• Large number of dropouts in ART
• 29/150 (19)
• More radiotherapy doses missed in ART
• More hospitalizations in ART
• ART101 vs. RT63

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CONSIDERATIONS FOR APPROVAL

• Well-designed, well-controlled trials
• Substantial evidence of efficacy and safety

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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

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Efficacy

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

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• Adequate and well controlled clinical trials

• Single phase 3 trial

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