NDA 21和-399 ZD1839 for Treatment of NSCLCFDA ReviewD.pptVIP

9/24/02 ODAC Presentation: NDA 21-399 NDA 21-399 ZD1839 for Treatment of NSCLCFDA ReviewDivision 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 Rajeshwari Sridhara, PhD Summary and Introduction of Questions Grant Williams, MD 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? Efficacy requirement for regular approval 1962 law: substantial evidence of efficacy from well controlled clinical trials Efficacy is defined as clinical benefit DODP: Endpoints for Approval Approvals not based on Survival: 67% (37/55) excluding accelerated approvals 73% (48/66) of all approvals 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 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) 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 DODP Accelerated Approval Using Response Rates Evidence for Accelerated Approval Substantial evidence from well controlled clinical trials regarding a surrogate endpoint NOT: Borderline evidence regarding a clinical benefit endpoint Accelerated approval Serious o