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Meeting Agenda

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. Presentations . Regulatory background General regulatory requirements

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Meeting Agenda

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  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 trial1: “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.” • 1Efficacy 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 1Draft 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

  11. 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

  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

  13. New Drug Approval Efficacy Requirement • 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

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

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

  16. DODP Accelerated Approvals

  17. 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

  18. 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

  19. 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)

  20. Endpoints and Issues

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

  22. 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

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

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

  25. TTP: Problems • 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

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

  27. 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

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

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

  30. 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?

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

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

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

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

  35. 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)

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