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FUTURE of PHASE 1, 2, and 3 TRIALS

FUTURE of PHASE 1, 2, and 3 TRIALS. Philip Colangelo, Pharm.D., Ph.D. Office of Clinical Pharmacology & Biopharmaceutics FDA / CDER. FDA Review Division Organization. Office of Drug Evaluation IV (ODE IV) Division of Anti-Infective Drug Products Division of Anti-Viral Drug Products

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FUTURE of PHASE 1, 2, and 3 TRIALS

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  1. FUTURE of PHASE 1, 2, and 3 TRIALS Philip Colangelo, Pharm.D., Ph.D. Office of Clinical Pharmacology & Biopharmaceutics FDA / CDER

  2. FDA Review Division Organization • Office of Drug Evaluation IV (ODE IV) • Division of Anti-Infective Drug Products • Division of Anti-Viral Drug Products • Division of Special Pathogen & Immunologic Drug Products • Division Review Teams • Medical Officers • Statistics • Microbiology • Clinical Pharmacology and Biopharmaceutics • Pre Clinical Pharmacology and Toxicology • Chemistry

  3. OUTLINE • General Overview of Clinical Studies • Example - Antibiotic X (Ab-X) • Dose-Response in Phase 2 for Efficacy/Safety • PK/PD in Phase 3 for Efficacy • Exposure-Response in Phase 1 for Safety • Future of Phase 1, 2, and 3 Trials for Anti-Infective Drug Development • Key Considerations • Other Considerations/Tools for the Future

  4. CAUTION ! • This talk contains no hard and fast answers • Many questions remain regarding how clinical trials should be performed in the future to expeditiously obtain information • However, for a given patient with a given infection and pathogen, we all want to know: • Right Drug? • Right Dosage Regimen? • Right Duration?

  5. General Overview: Phase 1 PK Studies • Goal: Understand the PK and Identify Possible Sources/Determinants of PK Variability • Healthy Subjects and Patients (Phase 3) • Oral Absorption • Distribution and Disposition • In Vitro and In Vivo Metabolism • Excretion

  6. Phase 1 Clinical Pharmacology • Special Populations (Intrinsic Factors) • Renal Impairment • Hepatic Impairment • Age (Elderly; Pediatrics) • Gender • Race

  7. Phase 1 Clinical Pharmacology • Drug - Drug Interactions (Extrinsic Factors) • Based on In Vitro Studies • Based on Drug Class (e.g., chelation effects on fluoroquinolones by cations) • Special Safety Studies • Further Investigation of AE’s Observed in Clinical Trials (e.g., phototoxicity, skin rash, QT effects, hypo- / hyperglycemia)

  8. Phase 2 Trials • Goal: Right Dose and Right Duration • Proof of Concept (in vitro/pre clinical) • Exploration of Exposure-Response Relationship • “Exposure” = drug input, i.e., dose; plasma conc. (e.g., Cmax, Cmin, Css, AUC) • “Response” = drug effect, i.e., desired (e.g., clinical / bacteriological cure) or undesired (e.g., QT prolongation)

  9. Phase 2 Trials (cont.) • Limitations: • For anti-infectives dose-response difficult to do over broad range of doses (>2-3 doses) for ethical reasons (sub-therapeutic doses) • Small N • When May Dose-Response be Appropriate: • No Active Control Exists • No approved agent • No recognized standard of care • Treatment Failure  Mortality or Serious / Irreversible Morbidity

  10. Phase 2 Trials (cont.) • Information from Dose-Response • Assess Activity Over Several Doses • Minimal Effective Dose • Maximal Beneficial Dose • Safety Information Over Several Doses • PK/PD Information (Exposure-Response) • Identify appropriate parameter(s) to predict outcomes and design dosage regimen in Phase 3 • Define magnitude of the parameter - ideally want lower dose to be sufficiently distinct from higher dose

  11. Phase 3 Trials • Primary Goal: Confirmation of the Right Dose and Duration by Demonstration of Adequate Efficacy and Safety • Benefit vs. Risk

  12. Phase 3 Trials (cont.) • Secondary and Potentially Useful (?) Information: PK/PD • PK in Target Patient Population(s) via Sparse Sampling and Pop PK Approach • Most often retrospective analysis • Often combined with Pop PK from Phase 1 healthy subjects • Assessment of systemic exposure and PK variability in patients vs. healthy subjects • Exploration of covariates that may influence PK variability in patients

  13. Phase 3 Trials (cont.) • PK/PD in the Target Population(s) • A Good Way to Present Raw Data • Individual Patient MIC Values and Pathogen ID • Individual Post-Hoc Bayesian PK Estimates • Calculated PK/PD Parameters • Individual Outcomes (Clinical and Bacteriological) • Relationship between PK/PD Parameter(s) and Outcomes; Preferably Both Successes and Failures • Relationship between PK Parameters and AE’s (incidence and/or severity)

  14. EXAMPLE • NDA - Antibiotic X (Ab-X) • Dose-Response for Efficacy & Safety in Phase 2 • 2 Trials (R, DB/DD, MC, Parallel Group): • (1) RTI @ Daily Doses 0.25X, 0.5X, 1X Proposed Clinical Dose (N=200) vs. Comparator (N=70) x 10 Days • (2) SSSI @ Daily Doses 0.5X, 1X proposed Clinical Dose (N=72) vs. Comparator (N=37) x 10 Days • Clinical & Bacteriological Efficacy @ End of Therapy (EOT) & Post Therapy Follow-Up Visits (TOC)

  15. EXAMPLE • NDA - Ab-X • Dose-Response for Efficacy & Safety-Phase 2 • Overall Efficacy Results @ TOC • RTI • Clinical Efficacy: 0.5X and 1X doses equivalent; 0.25X dose success rates lower • Bacteriological Efficacy: 0.5X and 1X doses equivalent; 0.25X dose not equivalent • SSSI • Clinical Efficacy: 0.5X and 1X doses equivalent (0.5X success rate less vs. comparator) • Bacteriological Efficacy: 0.5X and 1X doses equivalent (inconclusive vs. comparator) • Overall Safety/AE Results (RTI + SSSI) • Approximately equal % of AE’s across all doses • Patient withdrawals due to AE’s greater @1X dose vs. 0.5X and 0.25X doses

  16. EXAMPLE • NDA - Ab-X • PK/PD Relationships for Efficacy in Phase 3 • 3 Trials for Respiratory Tract Infections using Proposed Clinical Dosage Regimen • Post-Hoc Bayesian Estimates of AUC • Individual Patient MIC and Pathogen ID • Individual AUC/MIC Ratios • Outcomes at End of Therapy (EOT) Visit and Post Therapy Follow-Up Visit for Test of Cure (TOC) • Clinical Success and Failure • Bacteriological Success and Failure

  17. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

  18. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

  19. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

  20. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

  21. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

  22. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

  23. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

  24. Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections • Conclusions • Majority of patients attained AUC/MIC >150 • Majority of patients had clinical and/or bacteriological successes at the proposed clinical dosage regimen • Data suggested AUC/MIC >50 for successful outcome • Limitations • Small numbers of patients with AUC/MIC ratios <100 • Not able to assess Cmax/MIC because of limitations to sparse sampling design (Pop PK) • Limited and widely overlapping AUC/MIC ratios for failures vs. successes • No PK/PD data for other dose regimens (lower dose)

  25. EXAMPLE • NDA - Ab-X • Exposure-Response Relationships for Safety • Meta Analysis of Dose-QTc Response from 5 Phase 1 Clinical Pharmacology Trials (Sponsor) • Healthy Young Males and Females • Healthy Elderly Males and Females • Healthy Young Japanese • Multiples of Clinical Dose: 0.5X, 1X, 1.5X, 2X; Placebo • Regression Analyses of Cp-QTc Response (FDA Request) • Regression 1: Delta QTc at Time of Observed Cmax (QTc vs. Cmax) • Regression 2: Maximum Delta QTc and Corresponding Cp (MaxQTc vs. Cp)

  26. Ab-X: Meta Analysis of QTc

  27. Ab-X: Regression Analyses of QTc

  28. Ab-X: Regression Analyses of QTc

  29. Ab-X: Regression Analyses of QTc

  30. Ab-X: Exposure-QTc Response • Conclusions • Meta Analysis of Dose-Response • No clear trend with single doses • Some trend with repeat doses • Regression Analyses of Cp-Response • Weak (if any) relationship for QTc vs. Cmax or for MaxQTc vs. corresponding Cp with either single or repeat doses • MaxQTc occurred, on average, between 5 to 10 hrs postdose in the majority of subjects after both single and repeated doses – substantially longer than the Tmax (i.e., ~1.0 hr); suggesting lag-time for the occurrence of maximum QTc changes

  31. Ab-X: Exposure-QTc Response • Limitations • Studies not designed to specifically evaluate QT effects • Relatively sparse data for repeated dosing vs. single dosing • Sparse data in elderly • Timing of ECG’s varied with study; did not always correspond with actual observance of Cmax • Lack of evaluation of exposure-response at higher doses (up to 3X clinical dose) • Lack of comparison with other FQ

  32. Future of Clinical Trials:Key Considerations • Challenge the drug development program by asking the “tough” questions • Does the drug fill a current (or future) unmet medical need? (e.g., treatment of infection(s) due to resistant pathogen(s); serious/life-threatening infection) • Is there enough evidence to demonstrate that the drug fills this need? • What are the safety issues and can they be adequately managed?

  33. Future of Clinical Trials:Key Considerations (cont.) • What are important PK and PK/PD issues? • Variability in Systemic Exposure (PK) and MIC (PD) • Exposure-Therapeutic Response Relationships • Exposure-Toxicity/Safety Relationships • Drug-Drug / Drug-Food Interaction Potential • Other Intrinsic and Extrinsic Factors

  34. Future of Clinical Trials:Key Considerations (cont.) • Greater integration and use of information obtained from in vitro/pre clinical evaluations and early phase clinical trials • Continuum of learning and confirming throughout all phases of drug development • Knowledge Based Development

  35. Future of Clinical Trials:Key Considerations (cont.) • In the End: What is the Benefit vs. Risk? • Proven Benefit for indication(s) for which there is an unmet medical need? • Proven Benefit for indication(s) for which acceptable therapeutic agents already exist? • Is there less Risk over existing therapies? • Risk Management Strategy?

  36. Future of Clinical Trials: Other Considerations/Tools • Develop labeling at the outset of development; Targeted Product Information (TPI) document • Pilot in ODE IV (FDA & PhRMA) • Evolving version of proposed labeling that can be used throughout all phases of development • Embodies the notion of beginning development with the end in mind (approval and final labeling) • Can be used by sponsor to: • guide design, conduct, and analysis of clinical trials • facilitate communication between FDA and sponsor • promote shared understanding of the development program • http://www.fda.gov/cder/tpi

  37. Future of Clinical Trials: Other Considerations/Tools • Pop PK & PK/PD Approaches/Analyses • Prospectively designed into Phase 3 trials (vs. after thought) • Exploration of other PK/PD Indices • How important are unbound drug concentrations? • Computer Assisted Trial Design (CATD) and Simulation • Monte Carlo Simulation • Probability Functions for PK and MIC Values • Estimating Susceptibility Breakpoints - Maybe?

  38. Future of Clinical Trials: Other Considerations/Tools • Present and Future Initiatives at FDA • Resistant Pathogens Guidance (Draft) • Exposure-Response Guidance (Draft) • CATD/Modeling & Simulation Research (OCPB/Biostats) • PK/PD Database for Anti-Infective Classes (Clin Pharm, Micro, Medical)

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