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Effective clinical trial design

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IPHARMA Clinical Trials Russia Forum

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Effective clinical trial design

  1. 1. EFFECTIVE CLINICAL TRIAL DESIGN Natalia Vostokova Chief Operating Officer IPHARMA LLC November 24, 2015
  2. 2. 2 WORKSHOP SUBJECT • Effective phase 2 and 3 clinical study design • Adaptive design implementation in local clinical studies
  3. 3. 3 WORKSHOP AGENDA • Phase 2 and 3 study concepts • What is adaptive design? • Adaptive design advantages and risks • Next-in-class drugs • Examples of successful adaptive design implementation
  4. 4. 4 SCIENTIFIC EXPERIMENT Objective ResultDesign
  5. 5. 5 PHASE 2 = pilot trial • Objectives  Results • works or doesn’t work • optimum dosing schedule • preliminary efficacy data for planning phase 3 • Design – fast and demonstrative
  6. 6. 6 PHASE 2 Randomization Dose 1 Dose 2 Dose 3 Placebo Response
  7. 7. 7 PHASE 3 = pivotal trial • Objectives  Results • Hypothesis testing with pre-defined predictable result • Design – with minimal risk
  8. 8. 8 PHASE 3 Randomization Investigational product «Gold standard» Response
  9. 9. 9 STUDY DESIGN DEVELOPMENT PRINCIPLES • Primary endpoint • Binary (response rate) • Continues (change of parameter) • Hypothesis • Non-inferiority • Equivalence • Superiority Study objective Drug mode of action Primary endpoint Hypothesis H0 ↔ Hа Sample sizing calculation Treatment length and procedures Data collection Decision-making algorithm Control group expected value
  10. 10. 10 CLINICAL STUDY DESIGN Adaptive design Classic design«Prehistoric design»
  11. 11. 11 ADAPTIVE DESIGN • Study that allows modifying any design or hypothesis aspect based on the interim data analysis • in accordance with a pre-defined plan • in preselected timepoints • blinded or unblinded • with or without a hypothesis testing
  12. 12. 12 WELL-UNDERSTOOD ADAPTIVE DESIGNS • Adaptation of study eligibility criteria based on analyses of pretreatment (baseline) data • Adaptations to maintain study power based on blinded interim analyses of aggregate data • Adaptations based on interim results of an outcome unrelated to efficacy • Adaptations using group sequential methods and unblinded analyses for early study termination because of either lack of benefit or demonstrated efficacy • Adaptations in the data analysis plan not dependent on within study, between-group outcome differences
  13. 13. 13 LESS-UNDERSTOOD ADAPTIVE DESIGNS • Adaptations for dose selection studies* • Adaptive randomization based on relative treatment group responses • Adaptation of sample size based on interim-effect size estimates • Adaptation of patient population based on treatment-effect estimates • Adaptation for endpoint selection based on interim estimate of treatment effect • Adaptation of multiple-study design features in a single study* • Adaptations in non-inferiority studies
  14. 14. 14 ADAPTIVE DESIGN ADVANTAGES • More efficient data collection • Shorter study duration • Less number of patients • Increasing a probability of success in achieving the study objectives • Improved understanding of the investigational product’s effects Optimization of drug development compared to the classic non-adaptive methodology
  15. 15. 15 ADAPTIVE DESIGN RISKS • Risks of bias • Misinterpretation of the interim analysis • Non-achievement of the study objectives
  16. 16. 16 ADAPTIVE DESIGN RISKS MITIGATION • Well-planned study • Well-considered statistical validity • α-adjustment for a multiplicity • Minimal clearly planned adaptation • Pre-scheduled modification of the study parameters • Without correction of the statistical methods • Appropriate use • Data Monitoring Committee (DMC)
  17. 17. 17 NEXT-IN-CLASS DRUGS • Original patented drugs • Affects the well-known biotargets • Similar to the existing drugs in structure and mode of action • High predictability of effects in humans • Possible achievement of better results owing to «improvement» of the original molecule • Less expensive and shorter timelines for development  Low-risk R&D strategy
  18. 18. 18 MINISTRY OF INDUSTRY AND TRADE PROGRAM DRAFT Government of the Russian Federation Regulation as of _______ 2015 № _______ Concerning approval of the rules of granting subsidies from the federal budget to Russian organizations on partial reimbursement for implementation of the projects in development of innovative analogues of pharmaceuticals similar in pharmacotherapeutic action = separate block of the MIT projects oriented on the next-in-class drugs development
  19. 19. 19 STUDY PLANNING FOR NEXT-IN-CLASS DRUGS • Possible use of data of other drugs of the same pharmacological class for planning the study (hypothesis, sample calculation, endpoints) • Comparison with the best-in-class drug • Non-inferiority study • Possible adaptive design
  20. 20. 20
  21. 21. EFFICACY ASSESSMENT OF DIFFERENT DRUG DOSING REGIMENS Mono- and combination therapy
  22. 22. 22 TYPE 2 DIABETES MELLITUS DPP-4 INHIBITOR Screening Monotherapy 12 weeks Combination therapy 24 weeks Follow-up Gosogliptin  Gosogliptin+Metformin Vildagliptin  Vildagliptin+Metformin STAGE 1 STAGE 2 Interim analysis Final analysis
  23. 23. 23 PATIENTS ALLOCATION Stage 2 Combination therapy Stage 1 Monotherapy Randomization 299 treatment naïve patients with T2DM Gosogliptin N=149 Gosogliptin + Metformin N=122 Vildagliptin N=150 Vildagliptin + Metformin N=114 ~ 20% didn't roll-over to Stage 2
  24. 24. 24 INTERIM AND FINAL ANALYSIS ∆HbA1c, % Gosogliptin Vildagliptin Monotherapy (W12-W0) -0.93% -1.03% ∆ [97.5% CI] 0,104% [-0,133 to 0,342] upper bound of 97.5% CI < 0.4 Combination (W36-W0) -1.29% -1.35% ∆ [97.5% CI] 0,057% [-0,187 to 0,300] upper bound of 97.5% CI < 0.4
  25. 25. DOSE FINDING AND EFFICACY ASSESSMENT Interim analysis using statistics for small sample size
  26. 26. 26 PREVENTION OF TROMBOSIS DIRECT FACTOR Xa INHIBITOR Screening Randomization Kneereplacement Hospital treatment Endoftreatment Follow-up Day D-14…-1 D0 D1 D4 D7 D12±2 D21 D42 1) Tearxaban twice a day (morning and evening) (first dose in the evening > 10 hours after surgery) - 50 mg - 100 mg optimal daily dose selection at Stage 1 - 150 mg 2) Enoxaparin 40 mg s/c (1st dose in the evening before the surgery)
  27. 27. 27 PATIENT ALLOCATION Stage 2 Efficacy assessment Stage 1 Dose-finding Randomization 190 patients with knee replacement (prevention of VTE) Tearxaban 50 mg N=21 Tearxaban 100 mg N=21 Tearxaban 100 mg N=21+52=73 Tearxaban 150 mg N=20 Enoxaparin 40 mg N=22 Enoxaparin 40 mg N=22+54=76 Interim analysis Final analysis
  28. 28. 28 INTERIM ANALYSIS (80 PATIENTS, VTE, SIMON'S MINIMAX) Tearxaban Enoxaparin N = 2250 mg N = 21 100 mg N = 21 150 mg N = 20 Cumulative VTE 5 (23.8%) 3 (14.3%) 1 (5.0%) 5 (22.7%) DVT frequency 5 (23.8%) 3 (14.3%) 1 (5.0%) 4 ( 18.2%) Symptomatic VTE frequency (DVT, PE) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (9.1%) Non-fatal PE frequency 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.5%) Cumulative hemorrhagic complications frequency 3 (14.3%) 1 (4.8%) 4 (19.0%) 1 (4.5%) Major and clinical significant non-major bleeding frequency 2 (9.5%) 0 (0.0%) 1 (4.8%) 1 (4.5%)
  29. 29. 29 FINAL ANALYSIS (150 PATIENTS, VTE, NON-INFERIORITY) TeaRX 100 mg N = 73 Enoxaparin N = 76 Cumulative VTE 14 (19.2%) 21 (27.6%) ∆ [97.5% CI] 8.45% [-3.01%; 19.59%] Lower bound of 97.5% CI > -5.00% DVT frequency 14 (19.2%) 20 (26.3%) Symptomatic VTE frequency (DVT, PE) 0 (0.0%) 2 (2.6%) Non-fatal PE frequency 0 (0.0%) 1 (1.3%) Cumulative hemorrhagic complications frequency 1 (1.4%) 2 (2.6%) Major and clinical significant non-major bleeding frequency 0 (0.0%) 2 (2.6%)
  30. 30. DOSE FINDING AND EFFICACY ASSESSMENT Interim analysis with a surrogate endpoint
  31. 31. 31 HIV, NNRTI SCREENING Investigational therapy administration Follow-up VM-1500 20 mg + ART VM-1500 40 mg + ART Efavirenz 600 mg + ART V1 B2 V6 V8 V10 B11 W-2 W0 W12 W24 W48 W52 ↑ ↑ ↑ ↑ Randomization Surrogate endpoint (interim analysis) Primary endpoint (final analysis) End of treatment
  32. 32. 32 PATIENTS ALLOCATION Stage 2 Efficacy assessment Stage 1 Dose-finding Randomization 150 treatment naïve patients with HIV VM-1500 20 mg N=30 VM-1500 40 mg N=30 VM-1500 40 mg N=30+30=60 Efavirenz 600 mg N=30 Efavirenz 600 мг N=30+30=60 Interim analysis Final analysis
  33. 33. 33 INTERIM ANALYSIS (90 PATIENTS, HIV RNA< 400 COPIES/ML ON WEEK 12, NON-INFERIORITY) Patients with HIV RNA < 400 copies/ml Week VM-1500 20 mg N=30 VM-1500 40 mg N=29 EFV 600 mg N=27 W12 28 (93.3%) 25 (86.2%) 22 (81.5%) ∆ [97.5% CI] 11.85% [-2.59%; 26.92%] 4.73% [-11.50%; 20.83%] Lower bound 97.5% CI > -15.00% * Final analysis at Q1 2016
  34. 34. 34 CONCLUSION • Implementation of adaptive design provides an opportunity to improve timeline and resources when developing next-in-class innovative drugs
  35. 35. 35 THANK YOU FOR YOUR ATTENTION Natalia Vostokova Chief Operating Officer 7 Nobel street «Skolkovo» Innovation Center Moscow, 143026, Russia Mobile: +7 (926) 098-3633 Phone: +7 (495) 276-1143 Fax: +7 (495) 276-1147 E-mail: nv@ipharma.ru Web-site: www.ipharma.ru

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