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NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products

NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products. FDA ZD1839 NDA Review Team. Outline of FDA Presentation. Regulatory Overview and Critical Issues Grant Williams, MD Medical Review Findings Martin Cohen, MD Statistical Review Findings

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NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products

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  1. NDA 21-399ZD1839 for Treatment of NSCLCFDA ReviewDivision of Oncology Drug Products

  2. FDA ZD1839 NDA Review Team ODAC Presentation: NDA 21-399

  3. Outline of FDA Presentation • Regulatory Overview and Critical Issues Grant Williams, MD • Medical Review Findings Martin Cohen, MD • Statistical Review Findings Rajeshwari Sridhara, PhD • Summary and Introduction of Questions Grant Williams, MD ODAC Presentation: NDA 21-399

  4. Study Results 1. Claim of symptom improvement from a study without a control arm 2. Response rate (RR) of 10% in 139 patients with refractory NSCLC 3. No clinical benefit in two large controlled studies of first-line treatment of NSCLC 4. In view of #3, is the 10% RR in refractory NSCLC reasonably likely to predict clinical benefit? ODAC Presentation: NDA 21-399

  5. Efficacy requirement for regular approval • 1962 law: substantial evidence of efficacy from well controlled clinical trials • Efficacy is defined as clinical benefit ODAC Presentation: NDA 21-399

  6. DODP: Endpoints for Approval Approvals not based on Survival: • 67% (37/55) excluding accelerated approvals • 73% (48/66) of all approvals ODAC Presentation: NDA 21-399

  7. Examples of Approvals Based on Tumor-Related Symptoms • Symptoms from obstructive esophageal cancer or lung cancer • Symptomatic prostate cancer • Symptomatic cutaneous KS or CTCL • Bone morbidity from metastatic cancer ODAC Presentation: NDA 21-399

  8. Problems with AZ symptom benefit claims • No concurrent control • Confounding palliative medications • Response correlation: • Patient and observer bias • Assessment bias • Shared baseline prognostic factors (known and unknown) ODAC Presentation: NDA 21-399

  9. Accelerated approval • Serious or life-threatening disease • Drug must provide benefit over available therapy • Surrogate endpoint may be used • Surrogate endpoint must be reasonably likely to predict clinical benefit • Post marketing studies must verify clinical benefit ODAC Presentation: NDA 21-399

  10. DODP Accelerated Approval Using Response Rates ODAC Presentation: NDA 21-399

  11. Evidence for Accelerated Approval • Substantial evidence from well controlled clinical trials regarding a surrogate endpoint • NOT: Borderline evidence regarding a clinical benefit endpoint ODAC Presentation: NDA 21-399

  12. Accelerated approval • Serious or life-threatening disease • Drug must provide benefit over available therapy • Surrogate endpoint may be used • Surrogate endpoint must be reasonably likely to predict clinical benefit • Post marketing studies must verify clinical benefit ODAC Presentation: NDA 21-399

  13. Drug must provide benefit over available therapy • Single arm trial design (all patients receive ZD1839) dictates study of patients with no available therapy • Drugs are currently available for first-line and second-line treatment of NSCLC • The single arm design of Study 039 restricts the accelerated approval analysis to third-line NSCLC (139 patients) ODAC Presentation: NDA 21-399

  14. Reasonably likely to predict clinical benefit • This is a judgement based on all available evidence • A response rate of about 10% has supported some AA’s (e.g., irinotecan) • Lack of clinical benefit in large, randomized first-line studies must be considered ODAC Presentation: NDA 21-399

  15. Medical Review Findings Martin Cohen, MD

  16. First line - paclitaxel/cisplatin gemcitabine/cisplatin vinorelbine + cisplatin Second line - docetaxel FDA Approved Drugs: NSCLC Stage IIIB/IV ODAC Presentation: NDA 21-399

  17. NSCLC Stage IIIB/IVSubmitted ZD1839 Clinical Trials Trial 39 - Third-line trial for accelerated approval Trial 16 - Supporting second-line trial INTACT 1 and 2 - First-line trials to demonstrate clinical benefit

  18. Trial Designs Phase II, Randomized, Double-Blind ZD1839 250 mg/day versus ZD1839 500 mg/day

  19. Trial 39 - Efficacy Endpoints Co-primary: Response rate Disease related symptom improvement (Assessment difficulty was recognized)

  20. Trial 39 ITT Population n=216 ODAC Presentation: NDA 21-399

  21. Trial 39 Pts refractory or intolerant ODAC Presentation: NDA 21-399

  22. Trial 39 Responder Characteristics ODAC Presentation: NDA 21-399

  23. Trial 39 Responder Characteristics ODAC Presentation: NDA 21-399

  24. Symptom Assessment Problems - Patients and caregivers are unblinded - Patients are informed of response - No prospective plan for managing concomitant medication

  25. Concomitant Medication Narcotics Bronchodilators Antidepressants/Anxiolytics Oxygen Prednisone Transfusions/Erythropoietin Antibiotics Cough Syrup

  26. Trial 16 ITT Population n=209 ODAC Presentation: NDA 21-399

  27. Trial 16: Prior Chemotherapy ODAC Presentation: NDA 21-399

  28. Trial 16 Objective Response Rate ODAC Presentation: NDA 21-399

  29. Responder Characteristics ODAC Presentation: NDA 21-399

  30. Response Rate and Chemotherapy Progression ODAC Presentation: NDA 21-399

  31. Trials 39 & 16 AE’s ODAC Presentation: NDA 21-399

  32. Response Rates ODAC Presentation: NDA 21-399

  33. Trial 39 Responding Patients • Responders constitute a patient population enriched for slowly growing, relatively non-biologically aggressive cancers. • Median time from diagnosis to randomization was 19.5 months • Responders were predominantly P.S. 0-1 females with adenocarcinomas. ODAC Presentation: NDA 21-399

  34. Symptom Improvement Problems in Interpretation • Not blinded (no comparator regimen) • Concomitant medications Drug dose and schedule information not collected • ? bias in responders ODAC Presentation: NDA 21-399

  35. NDA 21-399: ZD1839 for NSCLC Statistical Review Findings Rajeshwari Sridhara, Ph.D.

  36. Major Concerns in Trial IL0039 • Trial Design: Single Arm Trial to Eliminate < 5% Response; Trial sized to independently evaluate efficacy in the two ZD1839 treatment arms (250 mg and 500 mg) • Heterogeneity of patient population (third and second line patients) • No Comparative Control Arm (no non-ZD1839 arm) ODAC Presentation: NDA 21-399

  37. Objective Tumor Response • 250 mg + 500 mg ZD1839 Treatment Arms (Third Line Patients Only): • Total 14/139 ( 10.1 %) responses 95% C.I.: 5.6 %, 16.3% ODAC Presentation: NDA 21-399

  38. Symptom Improvement - LCS Score Not at A little Some- Quite Very all bit what a lot much 1. I have been short of breath 0 1 2 3 4 2. I am losing weight 0 1 2 3 4 3. My thinking is clear 0 1 2 3 4 4. I have been coughing 0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4 ODAC Presentation: NDA 21-399

  39. Symptom Improvement - LCS Score Not at A little Some- Quite Very all bit what a lot much 1. I have been short of breath 0 1 2 3 4 2. I am losing weight 0 1 2 3 4 3. My thinking is clear 0 1 2 3 4 4. I have been coughing 0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4 028 ODAC Presentation: NDA 21-399

  40. Symptom Improvement - LCS Score Baseline Score = 24 Not at A little Some- Quite Very all bit what a lot much 1. I have been short of breath0 1 2 3 4 2. I am losing weight 0 1 2 3 4 3. My thinking is clear 0 1 2 3 4 4. I have been coughing0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4 028 ODAC Presentation: NDA 21-399

  41. Symptom Improvement - LCS Score Baseline Score= 24 Improved Score = 26 Not at A little Some- Quite Very all bit what a lot much 1. I have been short of breath0 1 2 3 4 2. I am losing weight 0 1 2 34 3. My thinking is clear 0 1 2 34 4. I have been coughing0 1 2 3 4 5. I have a good appetite 0 1 2 3 4 6. I feel tightness in my chest 0 1 2 3 4 7. Breathing is easy for me 0 1 2 3 4 028 ODAC Presentation: NDA 21-399

  42. Symptom Improvement Rate • 250 mg and 500 mg ZD1839 Treatment Arms (Third line patients only): • 45/139 (32.4 %) with symptom improvement per sponsor definition of improvement on the LCS scale ODAC Presentation: NDA 21-399

  43. Patient LCS Profile - An Example ODAC Presentation: NDA 21-399

  44. Patient LCS Profile - An Example 1. Short of Breath 2. Losing Weight 3. Thinking is Clear 4. Been Coughing 5. Good Appetite 6. Tightness in Chest 7. Breathing Easy ODAC Presentation: NDA 21-399

  45. % of Patients Evaluated Over Time ODAC Presentation: NDA 21-399

  46. Critical Issues • Efficacy with respect to Objective Tumor Response with ZD1839 could be as low as 5.6% (lower 95% CL = 5.6%). • Symptom Improvement not interpretable without control data. • Symptom Improvement possibly confounded by concomitant medication effect and patient characteristics ODAC Presentation: NDA 21-399

  47. Results of Randomized, Controlled, Phase III Studies in First-line NSCLC Patients • Study IL0014: • Gemcitabine + Cisplatin + ZD1839 250 mg; N = 365 • Gemcitabine + Cisplatin + ZD1839 500 mg; N = 365 • Gemcitabine + Cisplatin + Placebo; N = 363 ODAC Presentation: NDA 21-399

  48. 250 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.4382 500 mg vs. Placebo: HR 1.1 (0.9, 1.3), P-value 0.3041 ODAC Presentation: NDA 21-399

  49. 250 mg vs. Placebo: HR 1.0 (0.8, 1.2) 500 mg vs. Placebo: HR 0.9 (0.8, 1.1) ODAC Presentation: NDA 21-399

  50. Tumor Response and One-year Survival Rates in Trial IL0014 ODAC Presentation: NDA 21-399

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