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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 21-399ZD1839 for Treatment of NSCLCFDA ReviewDivision of Oncology Drug Products
FDA ZD1839 NDA Review Team ODAC Presentation: NDA 21-399
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
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
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
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
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
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
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
DODP Accelerated Approval Using Response Rates ODAC Presentation: NDA 21-399
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
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
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
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
Medical Review Findings Martin Cohen, MD
First line - paclitaxel/cisplatin gemcitabine/cisplatin vinorelbine + cisplatin Second line - docetaxel FDA Approved Drugs: NSCLC Stage IIIB/IV ODAC Presentation: NDA 21-399
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
Trial Designs Phase II, Randomized, Double-Blind ZD1839 250 mg/day versus ZD1839 500 mg/day
Trial 39 - Efficacy Endpoints Co-primary: Response rate Disease related symptom improvement (Assessment difficulty was recognized)
Trial 39 ITT Population n=216 ODAC Presentation: NDA 21-399
Trial 39 Pts refractory or intolerant ODAC Presentation: NDA 21-399
Trial 39 Responder Characteristics ODAC Presentation: NDA 21-399
Trial 39 Responder Characteristics ODAC Presentation: NDA 21-399
Symptom Assessment Problems - Patients and caregivers are unblinded - Patients are informed of response - No prospective plan for managing concomitant medication
Concomitant Medication Narcotics Bronchodilators Antidepressants/Anxiolytics Oxygen Prednisone Transfusions/Erythropoietin Antibiotics Cough Syrup
Trial 16 ITT Population n=209 ODAC Presentation: NDA 21-399
Trial 16: Prior Chemotherapy ODAC Presentation: NDA 21-399
Trial 16 Objective Response Rate ODAC Presentation: NDA 21-399
Responder Characteristics ODAC Presentation: NDA 21-399
Response Rate and Chemotherapy Progression ODAC Presentation: NDA 21-399
Trials 39 & 16 AE’s ODAC Presentation: NDA 21-399
Response Rates ODAC Presentation: NDA 21-399
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
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
NDA 21-399: ZD1839 for NSCLC Statistical Review Findings Rajeshwari Sridhara, Ph.D.
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
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
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
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
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
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
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
Patient LCS Profile - An Example ODAC Presentation: NDA 21-399
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
% of Patients Evaluated Over Time ODAC Presentation: NDA 21-399
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
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
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
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
Tumor Response and One-year Survival Rates in Trial IL0014 ODAC Presentation: NDA 21-399