LYs QALYs Life years: LY Quality of life: 100 Kaplan-Meier s curve Cost effectiveness Cost/LY Cost utility Cost/QALY (Quality-Adjusted Life Year) s s

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1 Dept. of Healthcare and Social Services, Univ. of Marketing and Distribution Sciences PHRF CSPOR/CSP-HOR Kojiro Shimozuma CRC Seminar March 11, 1 Quality of Life () Patient- Reported Outcome (PRO) /PRO /PRO Appendix: /PRO 2 CRC Donabedian - structure process MSW (HR)(PRO) CR, PR, SD outcomes (HR) 5 HR() 6

Seminar March 11, 2006 @Tokyo 1 Quality of Life () Patient- Reported Outcome

2 LYs QALYs Life years: LY Quality of life: 100 Kaplan-Meier s curve Cost effectiveness Cost/LY Cost utility Cost/QALY (Quality-Adjusted Life Year) s s clinical research clinical trials trials for approval 9 HR RCT) Phase I, II: Phase II, III: HR (HR) etc. 10 Quality of Life () How is your quality of life today? Quality of Life () Patient- Reported Outcome (PRO) /PRO /PRO Appendix: /PRO 11 12

for approval 9 HR RCT) Phase I, II: Phase II, III: HR (HR) etc.

3 Multidimensionality (Multidomain concept) Multidimensionality (Multidomain concept) Subjectivity (HR) 1948WHO 15 WHO Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity WHO WHO 1998 Health is a dynamic state of complete physical, mental, spiritual and social well-being and not merely the absence of disease or infirmity. dynamic spiritual Dynamic, spiritual 17 dynamic 18

4 WHO WHO EU Subjectivity (HR) Patient-based outcomes Patient-reported outcomes: PRO reliability validity Psychometry 23 24

html 20 Subjectivity 21 22 (HR) Patient-based

5 CSPOR N-SAS BC 02 (2000-) Reporting Impairment Litwin, MS: J Urol, 159: , n HER2 AC4 Paclitaxel4 AC4 Docetaxel4 Paclitaxel8 Docetaxel8 30

6 / NCI-CTC PNQ PNQ PNQ Shimozuma K, et al: 27 th 32 San Antonio Breast Cancer Symposium 2004 Shimozuma K, et al: 27 th San Antonio Breast Cancer Symposium 2004 etc Patient-Reported Outcome (PRO) - Guidance for Industry by FDA - A PRO is a measurement of any aspect of a patient s health status that comes directly from the patient (i.e., without the interpretation of the patients responses by a physician or anyone else). Patient-Reported Outcome (PRO) - Guidance for Industry by FDA In clinical trials, a PRO instrument can be used to measure the impact of an intervention on one or more aspects of patients health status, hereafter referred to as PRO concepts, ranging from the purely symptomatic (response of a headache) to more complex concepts (e.g., ability to carry out activities of daily living), to extremely complex concepts such as quality of life, which is widely understood to be a multidomain concept with physical, psychological, and social components. PRO PRO PRO 35 36

33 34 Patient-Reported Outcome (PRO) - Guidance for Industry by FDA - A PRO is a measurement of any aspect of a patient s health status that comes directly from the patient (i.e., without the interpretation of the patients responses by a physician or anyone else).

7 Quality of Life () Patient- Reported Outcome (PRO) /PRO /PRO Appendix: /PRO etc. -ACD ACD FWB 1 to 6 PWB 7 to 11 EWB 12 to (RS) 0 1 (SG) P 1-P or P i SWB 17 to 21 GQL (TTO) x / t i h i i t x x 0 x t 42

-ACD 39 40 -ACD FWB 1 to 6 PWB 7 to 11 EWB 12 to 16 0.

8 SF-36 Medical Outcome Study (MOS) 36 item Health Survey LY, cost EORTC QLQ, FACT, -ACD Cost/QALY LY, cost KD Asthma- symptom index, symptom checklist N-SAS BC 01 study Module subscale for additional concerns FACT-B, EORTC QLQ-BR23, -ACD-B FACT-Ntx, EORTC CIPN20 FACT-ES 45 Design: Non inferiority of UFT compared to CMF Primary endpoint: Disease-free survival Secondary endpoints: Overall survival Adverse events Direct costs Breast cancer (I - IIIA) Surgery Eligibility (1) Pathological: Node negative, high nuclear grade (2) Clinical: age, organ function, etc. Eligible Informed consent Randomization UFT p.o. 2 yrs. CMF 6 cycles Tamoxifen p.o. 5 yrs. 46 assessment points was assessed at baseline, 1, 4, 12, and 27 months after the start of adjuvant chemotherapy. CMF 2 Y UFT mos. assessment 47 Score EORTC < > Pre 4M 12M Higher score indicates higher Mean +- S.E. 27M UFT CMF Time ANOVA P=0.025 Shimozuma K, et al: ASCO Proc, , 2001

Overall survival Adverse events Direct costs Breast cancer (I - IIIA) Surgery Eligibility (1) Pathological: Node negative, high nuclear grade (2) Clinical: age, organ function, etc.

9 (missing data) Quality of Life () Patient-Reported Outcome (PRO) /PRO (CRC) ( /PRO Appendix: /PRO 49 Missing at random (MAR) missing not at random (MNAR) RCT 50 score - Missing not at random (MNAR) time 51 HR Yes No N/A* Yes No Yes No Yes No N/A** 3 Yes No Yes No Yes No Yes No Yes No Yes No Yes No 3 * ** Efficae F, et al J Clin Oncol 21: ,

2 3 time 51 HR Yes No N/A* Yes No Yes No Yes No N/A** 3 Yes No Yes No Yes No Yes No Yes No Yes No Yes

12 2800 Quality of Life Assessment in Clinical Trials Methods and Practice Staquet MJ, Hays RD, and Fayers PM Oxford University Press 9730 Multidimensionality (Multidomain concept) Subjectivity Appendix /PRO 71 72

Multidimensionality (Multidomain concept) 2002 http://www.jbcs.gr.

13 NSABP-P1 BCPT Day R, et al: J Clin Oncol, Day R, et al: J Natl Cancer Inst, FACT-B Shimozuma K, et al: ISO, % % % % Shimozuma K, et al: Breast Cancer Res Treat 1999 Shimozuma K, et al: Breast Cancer Res Treat 1999

70 1 45-59% 1 45-48% 1 79-84% 1 42-46% 77 78 Shimozuma K, et al:

14 % 40-42% 25-37% Shimozuma K, et al: Breast Cancer Res Treat Shimozuma K, et al: Breast Cancer Res Treat 1999 Shimozuma K, et al: ISO, 2005 UFT vs. CMF* 83 * 5-FU 84

15 (I IIIA) N-SAS BC 01 CMF UFT (1) (2) UFT 2 CMF Shimozuma K, et al: ASCO Proc, , 2001 N-SAS BC 01 EORTC QLQ-C30 (version 2.0) -ACD : Shimozuma K, et al: ASCO Proc, , 2001 Score 100 EORTC < > Mean +- S.E. Score 50 EORTC < > Mean +- S.E UFT CMF UFT CMF Pre 4M 12M Higher score indicates higher 27M Time ANOVA P= Pre 4M 12M Lower score indicates higher 27M Time ANOVA P=0.024 Shimozuma K, et al: ASCO Proc, , 2001 Shimozuma K, et al: ASCO Proc, , 2001 Score 100 -ACD < > Mean +- S.E Pre 4M 12M Higher score indicates higher 27M UFT CMF Time ANOVA P=0.014 vs. Shimozuma K, et al: ASCO Proc, ,

RTC < > Mean +- S.E. Score 50 EORTC < > Mean +- S.E. 90 80 40 30 UFT CMF 70 60 UFT CMF 20 10 50 Pre 4M 12M Higher score indicates higher 27M Time ANOVA P=0.

16 FACT-B (FACT-G + BCS) Jones SE, et al: J Clin Oncol: Jones SE, et al: J Clin Oncol: Jones SE, et al: J Clin Oncol: ATAC vs. (A) (T) (C) 95 FACT-B + ES Fallowfield LJ, et al: J Clin Oncol

SE, et al: J Clin Oncol: 2005 93 94 ATAC vs.

17 17% FACT-B TOI 38% FACT-ES Fallowfield LJ, et al: J Clin Oncol Fallowfield LJ, et al: J Clin Oncol CMF LH-RH Fallowfield LJ, et al: J Clin Oncol (chemofog) (chemobrain) 1040% LH-RH Matsuda T, et al: Breast Cancer

Fallowfield LJ, et al: J Clin Oncol 2004 99 100 (chemofog)

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untitled 19 CSPOR CRC/2009.8.8-9 2009 8 8 ( ) - CSPOR CRC SEMINAR- [email protected] http://www.oncoloplan.com - Toru Watanabe MD - 2 Phase I: Dose Finding trial Phase II : Efficacy and Safety trial Phase