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Tipranavir NDA 21-814: Efficacy Evaluation

Tipranavir NDA 21-814: Efficacy Evaluation. Rafia Bhore, Ph.D. Statistician Reviewer Division of Antiviral Drug Products Food and Drug Administration. May 19, 2005 FDA Antiviral Drugs Advisory Committee Meeting. Outline of Efficacy Presentation. Study Design of Phase 3 Trials

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Tipranavir NDA 21-814: Efficacy Evaluation

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  1. Tipranavir NDA 21-814:Efficacy Evaluation Rafia Bhore, Ph.D. Statistician Reviewer Division of Antiviral Drug Products Food and Drug Administration May 19, 2005 FDA Antiviral Drugs Advisory Committee Meeting

  2. Outline of Efficacy Presentation • Study Design of Phase 3 Trials • Patient Disposition • Demographics and Baseline Characteristics • Evaluation of Open-Label Design • Efficacy Evaluation • Primary Efficacy (FDA Analysis) • Subgroup Analyses by PI resistance, T-20 use • Head-to-head comparison of TPV vs PIs • Summary of Efficacy FDA Antiviral Drugs Advisory Committee Meeting

  3. Study Design of RESIST* Trials (Studies 1182.12 and 1182.48) *Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir FDA Antiviral Drugs Advisory Committee Meeting

  4. Yes No No Yes STUDIES 1182.12 (RESIST 1) and 1182.48 (RESIST 2) Open-label, Controlled, Highly ARV-experienced patients RESIST 1: USA, Canada, Australia RESIST 2: Europe, Latin America SCREENING 3 ARV class and dual PI-experienced Genotype Resistance Testing At least 1 primary protease resistance mutations at codons: 30N, 46I/L, 48V, 50V, 82 A/F/L/T, 84V, or 90 M ? Screening Failure  2 mutations at codons 33, 82, 84, or 90 ? Enroll in Trial 1182.51 Enroll in RESIST Trial Go to A 4

  5. A Pre-select PI (Protease Inhibitor) based on genotypic resistance test Select OBR (OPTIMIZED BACKGROUND REGIMEN) based on screening genotype test and ARV medication history Week 8 Week 8 Week 24 Week 24 Week 48 Week 48 Week 96 Week 96 TPV 500 mg bid + RTV 200 mg bid + OBR RANDOMIZE to either or PI + RTV + OBR APV/RTVSQV/RTVIDV/RTVLPV /RTV Amendment # 2 Allowed patients with highly PI resistant virus to be treated with PI-based regimen. Open-label Roll-over Trial 1182.17 NOTES: PI=Protease Inhibitor TPV=tipranavir, RTV=ritonavir APV=amprenavir, SQV=saquinavir IDV=indinavir, LPV=lopinavir Patients in comparator PI/RTVgroup with lack of initial virologic response or confirmed virologic failure willroll-over to TPV/RTV group inRoll-Over Trial 1182.17 5

  6. Patient Disposition FDA Antiviral Drugs Advisory Committee Meeting

  7. Patient Disposition FDA Antiviral Drugs Advisory Committee Meeting

  8. Demographics and Baseline Characteristics FDA Antiviral Drugs Advisory Committee Meeting

  9. Demographics • RESIST 1 (N=620) • USA (80%), Canada (13%), Australia (7%) • RESIST 2 (N=539) • Europe (85%), Latin America (15%) • France 26%, Germany 19%, Italy 16%, Spain 7%, Greece 4%, Belgium 3%, UK 3%, Denmark 3%, Portugal 2%, Netherlands 2%, Switzerland 1%, Sweden <1%, Austria <1%, Luxembourg <1% • Argentina 14%, Brazil 2%, Mexico (not completed 24 weeks treatment yet) FDA Antiviral Drugs Advisory Committee Meeting

  10. Demographics (contd) • Age [Mean (range)] • RESIST 1: 45 years (24 to 80 yrs) • RESIST 2: 43 years (17 to 76 yrs) • Gender • RESIST 1: 91% male, 9% female • RESIST 2: 84% male, 16% female • Race • RESIST 1: 77% Caucasian, 22% Black, 1% Asian • RESIST 2: 68% Caucasian, 5% Black, 1% Asian, 26% Missing (France) FDA Antiviral Drugs Advisory Committee Meeting

  11. Baseline Disease Characteristics FDA Antiviral Drugs Advisory Committee Meeting

  12. Baseline Disease Characteristics FDA Antiviral Drugs Advisory Committee Meeting

  13. Protease Inhibitor Stratum FDA Antiviral Drugs Advisory Committee Meeting

  14. Evaluation of Potential Biases due toOpen-Label Design FDA Antiviral Drugs Advisory Committee Meeting

  15. Pre-determined T-20 Stratum versus Actual T-20 use • Mismatches between Pre-determined vs Actual * McNemar’s test p-value < .001 FDA Antiviral Drugs Advisory Committee Meeting

  16. Pre-determined vs Actual Background Regimen • Total # of pre-determined regimen = 155 • Total # of actual regimen = 161 • Mismatches between Pre-determined vs Actual FDA Antiviral Drugs Advisory Committee Meeting

  17. Commonly Used Background Antiretroviral Regimen • Balanced across TPV/r and CPI/r groups • 3TC + TDF (11%), • ddI + TDF (8%), • 3TC + ddI + TDF (7%), • 3TC + TDF + ENF (4%), • 3TC + ddI + TDF + ENF (3%), 3TC + ABC + TDF (3%), d4T + TDF (3%) FDA Antiviral Drugs Advisory Committee Meeting

  18. Protocol Violations in RESIST 1 and RESIST 2 trials • Unique patients with protocol violations • 51% in TPV/r and 56% in CPI/r group • Patients had 1 or more protocol violations of same or different type • Types of protocol violations • Screening (Entry Criteria) violations • Treatment Regimen violations during study • Other violations with use of concomitant drugs FDA Antiviral Drugs Advisory Committee Meeting

  19. Screening Violations • 29% TPV/r vs 32% CPI/r unique patients with screening violations • E.g., no protease gene mutations at codons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M • Less than 2 PIs or less than 3 mos. of trt on historical therapy • Screening viral load < 1,000 copies/mL, etc. FDA Antiviral Drugs Advisory Committee Meeting

  20. Treatment Regimen Violations • 24% TPV/r vs 25% CPI/r unique patients with treatment regimen violations • E.g., Dual-boosted PIs used • Randomized to CPI/r group and pre-specified PI not taken or changed • No new or recycled ARV in optimized background regimen, etc. FDA Antiviral Drugs Advisory Committee Meeting

  21. Initial Lack of Virologic Response by Week 8 • Viral load has not dropped 0.5 log10 HIV RNA copies/mL after 8 weeks of treatment • Failure to achieve a viral load <100,000 copies/mL after 8 weeks, despite a 0.5 log10 drop after 8 weeks of treatment • Patients in CPI/r group may discontinue and roll-over to Study 1182.17 and receive tipranavir/ritonavir • Escape clause may create bias in efficacy after Week 8 FDA Antiviral Drugs Advisory Committee Meeting

  22. Efficacy Evaluation Primary Efficacy (FDA Analysis) FDA Antiviral Drugs Advisory Committee Meeting

  23. Efficacy Endpoint at 24 Weeks • Proportion of patients with confirmed ≥1 log reduction from baseline in HIV RNA without prior evidence of treatment failure, i.e., • Death • Confirmed virologic failure • Permanent discontinuation of study drug • Introduction of a new ARV drug for reasons other than toxicity to background ARV FDA Antiviral Drugs Advisory Committee Meeting

  24. Efficacy Outcomes at 24 Weeks(Intent-to-Treat Analysis) FDA Antiviral Drugs Advisory Committee Meeting

  25. Efficacy Outcomes at 24 Weeks (contd.) FDA Antiviral Drugs Advisory Committee Meeting

  26. Sensitivity Analyses addressing Open-Label Biases • Bias at Week 8 due to initial lack of virologic response • incorporated into ITT analysis • Probability of response (>=1 log reduction in HIV RNA) was 0.5% in TPV/r vs 1.5% in CPI/r if lack of virologic response (>= 0.5 log reduction) by Week 8 • Bias due to Wrong T-20 stratum • Bias due to each type of protocol violation FDA Antiviral Drugs Advisory Committee Meeting

  27. Sensitivity AnalysisEfficacy Results 18%(13%, 23%) 22%(16%, 27%) 23%(17%, 29%) FDA Antiviral Drugs Advisory Committee Meeting

  28. Subgroup Analyses • By T-20 stratum • By Control Protease Inhibitors adjusting for Resistance and Experience FDA Antiviral Drugs Advisory Committee Meeting

  29. Subgroup-Analysis by T-20 use stratum FDA Antiviral Drugs Advisory Committee Meeting

  30. New Definition of Combined Resistance & Experience Patterns • Susceptible Naïve • Not resistant and prior duration of exposure to PI is <=1 month • Susceptible Experienced • Not resistant and prior duration of exposure to PI is 1-<6 month or >=6 months • Resistant • Possibly resistant or Resistant according to TruGene or Virtual Phenotype assay regardless of prior duration of exposure to PI FDA Antiviral Drugs Advisory Committee Meeting

  31. Baseline Resistance Patterns in PI Strata FDA Antiviral Drugs Advisory Committee Meeting

  32. Confidence Intervals on Treatment Differences (TPV/r – CPI/r) FDA Antiviral Drugs Advisory Committee Meeting

  33. Summary of Efficacy • FDA analysis confirmed that tipranavir was statistically significantly better than the control with respect to the surrogate endpoint of percent with at least 1 log decrease in viral load at 24 weeks. • Efficacy of tipranavir/ritonavir was shown when the best available comparator protease inhibitor was sub-optimal. • Sensitivity analyses adjusting for open-label biases in RESIST trials • Results were consistent with the efficacy shown • Net treatment benefit will range from 13% to 29%. FDA Antiviral Drugs Advisory Committee Meeting

  34. Summary of Efficacy (contd.) • Efficacy of tipranavir/ritonavir was demonstrated regardless of T-20 use, but the efficacy was significantly greater when combined with T-20 • Boosted tipranavir is not proven to be better than boosted lopinavir, or amprenavir, or saquinavir, if patients are naïve and not resistant to respective protease inhibitors. • No data available on indinavir on susceptible naïve patients. FDA Antiviral Drugs Advisory Committee Meeting

  35. Acknowledgment • FDA colleagues • Greg Soon, Ph.D., Statistics Team Leader • Andrea James, M.D., Medical Reviewer • Rosemary Johann-Liang, M.D., Medical Team Leader • Tom Hammerstrom, Ph.D., Statistician Reviewer FDA Antiviral Drugs Advisory Committee Meeting

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