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Development of New Drugs: Lessons from Clinical Trials

Development of New Drugs: Lessons from Clinical Trials

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Development of New Drugs: Lessons from Clinical Trials

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  1. Development of New Drugs:Lessons from Clinical Trials Paul A. Meyers, MD Vice-Chair, Pediatrics Memorial Sloan-Kettering Professor of Pediatrics Weill Cornell Medical College

  2. Combining biological agents with chemotherapy • Phase 1 • Safety profile • Pharmacology • Active dose/MTD • Phase 2 • Preliminary efficacy • Design considerations • Phase 3 • Design considerations • Choice of outcome variable • Statistical considerations • Duration of followup • Benefit-risk ratio & regulatory considerations

  3. Phase 1 • First-in-man • Few anti-cancer agents are tested in healthy volunteers • Pharmacokinetics, pharmacodynamics, metabolism • Toxicity/ active dose/MTD

  4. Phase 1: Biologics/BRMs • Studies in patients with a variety of cancers, usually late stage. • Clinical activity may be rare in patients with bulky disease • Pharmacology • Non-linear dose/response (threshold doses, tachyphylaxis) • Biologic activity – passive/active

  5. Phase 1: MTP • Phase 1 studies in patients with late stage cancers • Anecdotal responses • Optimal biologic activity .5-2mg/m2 • MTD (<grade 3 events) 4-6mg/m2

  6. Phase 1: IGF1R Inhibitors • Few dose limiting toxicities (antibodies) – dosing based on biomarkers? • Clinical activity

  7. Phase 2 • Larger group of patients (usually 50-200) • Obtain evidence of efficacy in target indication • Extend safety information • Obtain information needed to plan randomized efficacy studies

  8. Phase 2: Biologics/BRMs • Bulk disease vs minimal residual disease • Animal models • Mechanism of action (passive/active) • Activation of host immune system • Synergy/antagonism with chemotherapy • Preclinical data

  9. Phase 2: MTP in osteosarcoma • Impact of data from canine OS • Expectation of benefit in mrd • In vivo evidence of anti-tumor activity

  10. Phase 2: MTP and osteosarcoma • Planning for Phase 3 • With/without chemotherapy • Proposed mechanism of action a) activation of macrophages b) fas/fas-ligand interaction • Administer with chemotherapy • Role of adjuvant phase 2 design

  11. Phase 2: IGF1R inhibition in sarcoma • Single agent vs chemo combination • Outcome: objective response, PFS, survival • Randomized trial or historical control • Use of phase 2 data impact design

  12. Phase 3 • Confirmation studies: prove that the promising effects seen in Phase II are real (usually 100-1,000 people) • Safety

  13. Phase 3: Biologics/BRMs • Design considerations • In combination with other agents • Timing of introduction • Timing of randomization

  14. Phase 3: Design Considerations MTP and Osteosarcoma • Timing of introduction • Phase I/II trials suggest use in mrd • Introduce after surgical resection of clinically detectable disease

  15. Phase 3: Design Considerations MTP and Osteosarcoma • Timing of introduction • Delayed introduction of new agent will be ineffective • Failure in osteosarcoma: appearance of metastatic nodules • Reflects events months earlier • Timing of randomization

  16. Phase 3: Design Considerations Osteosarcoma Survival DFS

  17. A+ Cisplatin, Doxorubicin, HDMTX, MTP Cisplatin, Ifosfamide,Doxorubicin, HDMTX, MTP B+ Phase 3 Study Design INDUCTION DEFINITIVESURGERY MAINTENANCE A Cisplatin Doxorubicin HDMTX A Cisplatin, Doxorubicin, HDMTX Cisplatin, Ifosfamide, Doxorubicin, HDMTX B Ifosfamide Doxorubicin HDMTX B 20 27 36 Weeks R Introduction of MTP

  18. Phase 3: Design ConsiderationsIGF R Inhibitors • Timing of introduction • Phase II trials show objective responses • Synergy with chemotherapy

  19. Phase 3: Biologics/BRMs • Statistical considerations • Study design • Sample size • Interim analyses • Choice of outcome variable (endpoints) • Duration of follow up • Post hoc analyses

  20. Phase 3: Statistical ConsiderationsStudy Design • Factorial Design • Address two questions in one clinical trial • Marginal analysis • Interaction • test for interaction • proof of no interaction: trial sizing

  21. A+ Cisplatin, Doxorubicin, HDMTX, MTP Cisplatin, Ifosfamide,Doxorubicin, HDMTX, MTP B+ Phase 3 Study Design INDUCTION DEFINITIVESURGERY MAINTENANCE A Cisplatin Doxorubicin HDMTX A Cisplatin, Doxorubicin, HDMTX Cisplatin, Ifosfamide, Doxorubicin, HDMTX B Ifosfamide Doxorubicin HDMTX B 20 27 36 Weeks

  22. Phase 3 Statistical Considerations: Sample size • Sample size:population ratio • Impact on magnitude of error • Regulatory issue: need for confirmatory study

  23. Phase 3 Statistical Considerations: Sample size • Jar holding 1,000 marbles, 700 red, 300 blue • Sample: 50 marbles • Mean: 35 red, 15 blue (70% red) • Standard error of the mean: 6.3%

  24. Phase 3 Statistical Considerations: Sample size • Jar holding 1,000 marbles, 700 red, 300 blue • Sample size: 500 marbles • Mean: 350 red, 150 blue (70% red) • Standard error of the mean: 1.5%

  25. Phase 3 Statistical Considerations: Sample size for MTP in Osteosarcoma • INT0133 777 patients/48 months • Osteosarcoma incidence 350-400/year • Sample size 48-55% of population • Effect estimate robust, smaller error

  26. Phase 3 Statistical Considerations:Interim analyses • Timing of interim analyses • Pre-defined by events not elapsed time • Danger of looking too often

  27. Phase 3 Statistical Considerations:Interim analyses and MTP/Osteosarcoma • Futility • Safety • Three interim analyses • Modified p-value

  28. Phase 3 :Statistical ConsiderationsChoice of outcome variable • Progression free survival • Event free survival • Median survival • 80th percentile survival • Overall survival • Quality of life

  29. Pediatric oncology endpoint:NCI position (I) • Strength of Study Design • 1. Randomized controlled clinical trial • i. Double-blinded • ii. Non-blinded http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment

  30. Pediatric oncology endpoint:NCI position (II) • Strength of Endpoints • A. Total mortality • B. Cause-specific mortality • C. QOL • D. Indirect surrogates • i. EFS • ii. DFS • iii. PFS • iv. Response

  31. Pediatric oncology endpoint:FDA Position • Patient Access to New Therapeutic Agents for Pediatric Cancer December 2003 • Report to Congress • “Surrogate markers could be considered as an early means of identifying efficacy, but the use of surrogates requires validation of these markers and correlation with clinical benefit.” http://www.fda.gov/cder/Pediatric/BPCA-ReportDec2003.pdf

  32. Phase 3 Statistical Considerations: Outcome variableProgression free survival (PFS) • Wide applicability in sarcoma • Not widely used in “pediatric” sarcomas • Result available relatively quickly • Ascertainment bias • Predetermined evaluation schedule • Central review of imaging • Regulatory considerations

  33. Phase 3 Statistical Considerations: Outcome variableEvent free survival (EFS) • Widely employed surrogate for survival • Includes secondary malignancy, toxic deaths • Ascertainment bias • Predetermined evaluation schedule • Central review of imaging

  34. Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP • Interaction between assigned chemotherapy and MTP was assessed using the proportional hazards regression. A p-value of 0.10 level or less was considered evidence of a significant interaction.

  35. Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP • Event free survival: • Test of the hypothesis of no interaction (p = 0.102) • MTP Hazard ratio [95% CI] • Regimen A 0.99 [0.69, 1.4] • Regimen B 0.65 [0.45, 0.93] • All patients 0.80 [0.62, 1.0]

  36. By Chemotherapy Assignment By MTP Assignment MTP No MTP Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP

  37. A A + MTP B B + MTP Years Phase 3: Statistical Considerations- Outcome variable Event free survival (EFS) and MTP

  38. Phase 3: Statistical Considerations- Outcome variable Survival • Not subject to ascertainment bias • Many years of followup • Lack of QOL data

  39. MTP MTP Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma

  40. Analysis of Interaction • Overall survival: Test of the hypothesis of no interaction (p = 0.60) • MTP Hazard ratio [95% CI] • Regimen A 0.76 [0.49, 1.2] • Regimen B 0.66 [0.43, 1.0] • All patients 0.71 [0.52, 0.96]

  41. Survival by Chemotherapy Assignment Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma

  42. MTP No MTP Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma Survival by MTP Assignment

  43. Phase 3: Statistical Considerations- Outcome variable Survival and MTP in Osteosarcoma

  44. Phase 3 Statistical Considerations: Outcome variableQuality of life • Incorporates survival • Adds dimension related to non-lethal toxicity • Increasingly considered optimal endpoint

  45. Phase 3: Statistical ConsiderationsDuration of follow-up • Dependent on variable and population • PFS in late stage patients: shorter followup • DFS, EFS in mrd patients – multi year • Survival: need to monitor late effects, need for life time followup

  46. Phase 3: Statistical ConsiderationsDuration of follow-up and MTP/Osteosarcoma • Cooperative group fiscal decision to close study to followup • Difficulty obtaining followup after official study closure • Older study, no social security numbers

  47. Phase 3: Statistical Considerations Duration of follow-up and IGF1R inhibition/sarcoma • Phase II study: PFS, not designed to capture survival • Phase III study: EFS, must be designed to capture survival

  48. Phase 3: Statistical Considerations Post hoc analyses • Analyses of … important subgroups should be a regular part of the evaluation of a clinical study (when relevant), but should usually be considered exploratory, unless there is a priori suspicion that one or more of these factors may influence the size of effect” (CPMP/EWP/908/99).

  49. Favors MTP Hazard Ratio: MTP vs No MTP Phase 3: Statistical Considerations Post hoc analyses and MTP/Osteosarcoma

  50. Subgroup Analysis Caveat “Clearly significant overall results may therefore provide strong indirect evidence of benefit in subgroups where the results, considered in isolation, are not conventionally significant (or even, perhaps, slightly adverse).” ISIS-2 (Second International Study of Infarct Survival) Collaboration Group, The Lancet 1988, 2 (8607):349-360.