1. Meeting Agenda Presentations on endpoints –Regulatory issues –Scientific issues Pros and cons of end points –Classical end points –Non-classical end points End points and trial designs according to lung cancer stage

2. Presentations Regulatory background –General regulatory requirements –US lung cancer approvals –International lung cancer approvals Classical lung cancer end points Non-classical lung cancer end points

3. Outline of Presentation FDA requirements for new drug approval Regular approval of cancer drugs: end points used Accelerated approval Endpoints and issues

4. Requirements for Drug Approval Safety (FDAC, 1933) Efficacy demonstrated in adequate and well controlled studies (1962) Basis for efficacy: –Regular approval Clinical benefit, or Established surrogate for clinical benefit –Accelerated approval Surrogate (reasonably likely to predict CB)

5. How many trials? 505(d) of the Act: Substantial evidence: “Adequate and well- controlled investigations” Single trial 1 : “generally only in cases in which a single multicenter study of excellent design provided highly reliable and statistically strong evidence of an important clinical benefit… and a confirmatory study would have been difficult to conduct on ethical grounds.” – 1 Efficacy Guidance, May 1998

6. Oncology Efficacy Supplements Only one additional trial may be needed for closely related indications: –Advanced cancer and earlier cancer –Different dosing regimens –New combinations of drugs 1 Draft Guidance on New Cancer Treatment Uses, 1997.

7. Regular Approval Endpoints in Oncology

8. Clinical Benefit Endpoints Supporting Oncology Drug Approval Survival Improvement in tumor-related symptoms Disease-free survival (selected settings)

9. Established Surrogates Supporting Approval Complete response rates in some settings (e.g., acute leukemia) Partial response rate in some settings (e.g., hormonal treatment of breast cancer)

10. DODP: Endpoints for Approval (1/1/90 - 11/1/02 ) Approvals not based on Survival : –73% (48/66) of all approvals –67% (37/55) excluding accelerated approvals

12. Examples of endpoints in oncology Idarubicin-Prolonged remission in leukemia Zinecard-Protection from cardiac toxicity Photofrin-Dysphagia scale Aredia-Skeletal morbidity scale Daunozome-Visible lesions of KS Novantrone-Pain

13. 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

14. Regular approval: clinical benefit or established surrogate Accelerated approval (AA):surrogate endpoint reasonably likely to predict clinical benefit. –AA used only when new treatment represents benefit over available therapy –Sponsor must do phase 4 trial showing clinical benefit New Drug Approval Efficacy Requirement

15. Evidence for Accelerated Approval Substantial evidence from well controlled clinical trials regarding a surrogate endpoint NOT: Borderline evidence regarding a clinical benefit endpoint

16. ODAC Meeting on: Accelerated Approvals (March 2003) 19 NDAs or BLAs for new treatment indications (involving 16 drugs)

17. DODP Accelerated Approvals

18. ODAC Meeting on: Accelerated Approvals (March 2003) Confirmatory studies should be part of drug development plan Early discussion of confirmatory studies with Agency ODAC wanted to be consulted on confirmatory study plans

19. Single Arm Trials (SAT) and Accelerated approval (AA) SAT require few patients SAT for AA limit study to refractory disease SAT have limited ability to evaluate valuable endpoints such as TTP, QOL, and Survival

20. Randomized Trials (RT) and Accelerated approval (AA) More patients and time Allows AA at any disease stage (surrogate beats available therapy) Allows “add-on” design (A vs A + B) Allows a variety of endpoints –Time to event (TTP, survival) –Endpoints requiring blinding (symptoms, QOL) Defines individual drug contribution –(oxaliplatin vs 5FU/LCV versus oxaliplatin + 5FU/LCV)

21. Endpoints and Issues

22. Survival Gold standard Superiority design: beat anything The crossover problem Non-inferiority design: problematic with current regimens

24. Tumor Response Rate Can be assessed in single-arm study Documents activity in a subset of patients When can it be considered an established surrogate? –Suggested as such by ODAC for topotecan treatment of refractory small cell lung cancer When can it be considered a “reasonably likely surrogate”? –ODAC, lung cancer discussion 2002

25. Does it measure clinical benefit? Is it reliable? TTP: Critical Regulatory Questions

26. Measured in all patients Measures cytostatic activity Progression is often the basis for change in therapy Assessed before crossover Requires smaller studies ?Face validity TTP: Advantages

27. Indirect measure of patient benefit. Unclear clinical meaning of small TTP difference Expensive to measure carefully Reliability in unblinded setting? Unknown reliability of small TTP difference with usual trial monitoring TTP: Problems

28. Visit 1Visit 2Randomization = Date of Death or actual tumor progression Survival Event Date Visit 1Visit 2Randomization TTP Event Date Survival Analysis TTP Analysis Determining Event Dates

29. Tumor-Related Symptoms Evaluation of patient morbidity has supported many NDA approvals Major impediments –Lack of blinding –Missing data Time to symptomatic progression –Frequently discussed, not yet successful

30. Review of Presentation FDA requirements for new drug approval Regular approval of cancer drugs: end points used Accelerated approval Endpoints and issues

32. Endpoints Discussion Classical end points (pros and cons) Non-classical end points (pros and cons) Discussion according to stage (End points and trial designs)

33. 1. What are the Pros and Cons of each end point: As a regular approval endpoint? (A measure of clinical benefit or a reliable surrogate) As an accelerated approval endpoint? (A surrogate reasonably likely to predict clinical benefit) As a secondary end point for labeling?

34. 2. For each endpoint, what are the important trial design issues?

35. Classical Endpoints Survival Response Rate Time to progression Disease-free Survival

36. Non-classical endpoints Specific quality of life instruments Assessment of tumor-specific symptoms

37. Treatment settings Neoadjuvant Adjuvant First-line therapy Second-line and subsequent therapy

38. Trial designs Superiority design (A beats B) Add-on design (A+B beats A) Non-inferiority design (e.g., A + B is non-inferior to A + C)