1. July 20011 FUTURE of PHASE 1, 2, and 3 TRIALS Philip Colangelo, Pharm.D., Ph.D. Office of Clinical Pharmacology & Biopharmaceutics FDA / CDER

2. July 20012 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. July 20013 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. July 20014 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. July 20015 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. July 20016 Phase 1 Clinical Pharmacology Special Populations (Intrinsic Factors) –Renal Impairment –Hepatic Impairment –Age (Elderly; Pediatrics) –Gender –Race

7. July 20017 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. July 20018 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. July 20019 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. July 200110 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. July 200111 Phase 3 Trials Primary Goal: Confirmation of the Right Dose and Duration by Demonstration of Adequate Efficacy and Safety –Benefit vs. Risk

12. July 200112 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. July 200113 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. July 200114 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. July 200115 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. July 200116 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. July 200117 Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

18. July 200118 Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

19. July 200119 Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

20. July 200120 Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

21. July 200121 Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

22. July 200122 Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

23. July 200123 Ab-X: PK/PD in Phase 3 Trials for Respiratory Infections

24. July 200124 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. July 200125 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. July 200126 Ab-X: Meta Analysis of QTc

27. July 200127 Ab-X: Regression Analyses of QTc

28. July 200128 Ab-X: Regression Analyses of QTc

29. July 200129 Ab-X: Regression Analyses of QTc

30. July 200130 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. July 200131 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. July 200132 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. July 200133 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. July 200134 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. July 200135 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. July 200136 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. July 200137 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. July 200138 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)