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ゆきひらよどぎみ
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1 FDA EOP2A 1

2 21 21 Clin Pharmacol Ther 2007; 81:

3 Critical Path Opportunities for Clinical Pharmacologists Disease model Phase 3 TDM Clin Pharmacol Ther 2007; 81:

4 M&S 1. review team

5 M&S

6 M&S

7 M&S

8 FDA 1. EOP2A 2. FDA 8

9 Draft Guidance for End of Phase 2A Meetings Table of contents Introduction Background A. Strategies for early dose selection B. EOP2A Pilot Program The EOP2A meeting A. Objectives of an EOP2A meeting B. EOP2A meeting requests C. Useful information for an EOP2A meeting Package D. EOP2A meeting arrangements 9 / 38

10 II. Background Dose selection for phase 2 and phase 3 studies is a challenge in many drug development programs and may lead to trial failure. FDA recognizes trial planning may be improved by clinical trial simulations. FDA would like to encourage the best use of modeling and simulation to increase the likelihood for successful trials. Cited from Guidance for Industry: End-of-Phase 2A Meetings 10

11 Phase 3 50% Science 309:726,

12 III-A. Objectives of an EOP2A Meeting To help select the dosing regimens for the next phase by best incorporating prior quantitative knowledge. Cited from Guidance for Industry: End-of-Phase 2A Meetings 12

13 II-A. Strategies for Early Dose Selection Existing meetings do not allow for the in-depth discussion for dose estimation and selection. Guidance for Industry: End-of-Phase 2A Meetings 13

14 III-B. EOP2A Meeting Requests 1. FDA resource 2. Unmet therapeutic need 3. High clinical trial failure rate 4. FDA experience 5. Benefit from M&S Guidance for Industry: End-of-Phase 2A Meetings 14

15 FDA HIV 2 Disease Model 15 Clin Pharmacol Ther 2007; 81:170-77

16 III-C. Useful Information for an EOP 2A Meeting Package Questions about drug development issues Proposed trial designs Investigator s s brochure Analysis and interpretation of available exposure-response response data supporting the proposed trial designs. The conditions and methods used for modeling and simulation. Guidance for Industry: End-of-Phase 2A Meetings 16

17 Phase 2A M&S M&S 17

18 Modeling & Simulation Influences All Lives Today etc... Rx patients (MRI, ) (hip, knee,..) Drugs 18 From Dr. Powell, FDA

19 Model Based Drug Development DISEASE MODEL Relative Risk [HbA1c] MI & STROKE RETINOPATHY NEPHROPATHY [HbA1c] DRUG MODEL Toxicity [HbA1c] Toxicity [Drug] [TIME (WEEKS)] CLINICAL TRIAL INFO BASELINE PLACEBO EFFECT DROP-OUT RATE ADHERENCE [Drug] Time [Drug] Dose Clinical Trial Simulation Go / No go etc. 19 From Dr. Powell, FDA

20 We know too much and feel too little. Bertrand Russell (English philosopher, ) 20

21 Opinion is ultimately determined by the feelings, not by the intellect. Herbert Spencer (English naturalist and philosopher, ) 1903) 21

22 History of Pharmacometrics 1962 Approval = two confirmatory study 1997 FDA Modernization Act of 1997 Approval = causal evidence one confirmatory study 2001 EOP2a Meeting idea emerged CDDS meeting Clinical pharmacology subcommittee emphasizing pharmacometrics solutions Drug approval decision based on pharmacometric analysis (Gabapentin( Gabapentin?) 2003 Exposure-Response Guidance In some cases this information could support approval. (Page 5) 2003 Hypothesis: A single clinical trial plus causal evidence of effectiveness is sufficient for drug approval Carl Peck et al. Clin Pharm Ther 73, , 490, Critical Path Initiative 2004 EOP2a pilot program 2006 Critical Path Report and List Review articles for pharmacometrics 2008 EOP2a Meetings Draft Guidance 22

23 Gabapentin M&S M&S mg Package Insert states... PK/PD modeling provided confirmatory evidence of efficacy across all doses. J Pharmacokinet Pharmacodyn 2005, 32,

2000-2004 2004 244 NDA Cardio-renal, renal, Oncology

24 NDA Cardio-renal, renal, Oncology Neuropharmacology Pharmacometric The AAPS Journal 2005; 7: E503-E512

25 M&S 4 Busulfan, Sotalol FDA M&S Oxcarbazepine M&S Zoledronic acid PK M&S 25 The AAPS Journal 2005; 7: E503-E512

FDA 31 12 Pharmacometric Introduction of 6 case studies evidence of effectiveness dose optimization by quantifying exposure-response response prophylaxis of

26 FDA Pharmacometric Introduction of 6 case studies evidence of effectiveness dose optimization by quantifying exposure-response response prophylaxis of organ rejection Micafungin (esophageal candidiasis; ) Varenicline (smoking cessation) improvement in future trial design 26 Clin Pharmacol Ther 2007; 81:213-21

27 Impact of FDA Pharmacometrics Analyses (N = 31) Impact Discipline PM Reviewer Clin Pharmacology Reviewer Team Leader Medical Reviewer Approval 95% 95% 90% 90% Labeling 100% 100% 94% 90% Pivotal: 30-40% Supportive: 50-60% Clin Pharmacol Ther 81: ,

28 FDA 2006 FDA 200 PM 5 28 Clin Pharmacol Ther 2007; 82:

29 Five Focal Points for Pharmacometric Work at FDA 1. NDA 85% PM 2. QT Concentration-QT thorough QT 3. ex. Busulfan, Oxycarbazepine 4. EOP2A 5. Disease modeling project 29 Clin Pharmacol Ther 2007; 82:

30 Last paragraph in the article We encourage sponsors to more routinely use quantitative methods and PM thinking in their regulatory submissions. 30 Clin Pharmacol Ther 2007; 82:

31 Phase 2b or Phase 3 31

32 2004 FDA EOP2A FDA EOP2A J Clin Pharmacol 2008;48:

33 FDA M&S 11 BIG SUCCESS!! 33 J Clin Pharmacol 2008;48:

Value of Pilot EOP2A Meetings Average score on a 1 (no value) to 5 (pivotal) scale for the overall value of the EOP2A meeting to discuss dose and trial

34 Value of Pilot EOP2A Meetings Average score on a 1 (no value) to 5 (pivotal) scale for the overall value of the EOP2A meeting to discuss dose and trial design selections based on quantitative analyses. Overall scores indicate that the meetings were very helpful (score of ~4). 34 J Clin Pharmacol 2008;48:

35 Average response from the sponsors to the question Did the interaction with the FDA lead to a change in the drug development plan? The score was averaged across yes (treated as 1) and no (treated as 0) answers. For example, an average response of 1 indicates all and 0.5 indicates 50% of the sponsor representatives concluded that the meeting changed the development d plan. 35 J Clin Pharmacol 2008;48:

36 Acknowledgements Bob Powell, PharmD Director (2/05-1/07), Pharmacometrics, Office Clinical Pharmacology, Office of Translational Sciences, CDER, FDA Lawrence J. Lesko,, Ph.D. FCP Director of the Office of Clinical Pharmacology, CDER, FDA 36

FIBA In Memoriam

FIBA In Memoriam 第 37 回 ICH 即時報告会 ICH E8(R1) 医薬品医療機器総合機構新薬一部伊熊睦博 2017.12.15 経緯 / 背景 1997:E6( 医薬品の臨床試験の実施の基準 GCP) 施行 E8( 臨床試験の一般指針 ) 策定, 国内通知は1998 発出. 2014-2016: E6(R2) addendum 追加, 2016.11 ステップ4. 2016 パブコメ外部コンソーシアムからの