Happy New Year in 2017!!! Year of Rooster

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2 Happy New Year in 2017!!! Year of Rooster

3 The Agenda Introduction of Oncology Why Standards? Oncology-specific Standards: Response Criteria guideline and CDISC Standards-driven Oncology Studies Final Thoughts / Q&A

4 Cancer Facts The word cancer is related to the Greek word crab because its finger-like projections were similar to the shape of the crab In 2010, the economic cost of the disease worldwide was estimated at $1.16 trillion. One in eight deaths in the world are due to cancer. WHO predicts new cancer cases of 14 million in 2012 to 22 million in 2030 and cancer deaths from 8.2 million a year to 13 million annually. Men who are married are up to 35% less likely to die from cancer than those who are not married.

5 FDA CDER NMEs and BLAs Approval Approval 13 Oncology (33 %) Approval 8 Oncology (30 %) Approval 9 Oncology (22%) Approval 13 Oncology (29%) Note: based on the reports of NMEs and BLAs approved by CDER

6 Big Pharma Turns Its Focus to Cancer A cornerstone to the success Unmet medical needs Profitable

7 TOP Oncology Companies J&J $4.1B BMS $4.5B Celgene $8.5B Novartis $10.4B Roche $25.7B $107B in 2015 to +$150B in 2020 Global oncology revenue by top ten pharmaceutical companies 2015

8 We live in the oncology drug development environment.

9 What do we feel about oncology studies? Different Complex Difficult

10 Difference in Oncology Studies Tumor measurements and their response to drug Oncology-specific measurements for response criteria (e.g., Liver and Spleen Enlargement, Bone Marrow Infiltrate and Blood Counts) Oncology-diagnosis measurements (e.g., immunophenotype, performance status by ECOG, staging) Toxicity (Lab and AE) Time to Event Analysis (e.g., OS, PFS, TTP and ORR)

11 Houston, we have a problem!!!

12 How to scale for oncology studies How to do complex oncology studies

13 The more complex problem is, the easier the winner be distinguished. Do your biometric department want to be a winner?

14 Complex problem for 6 th grader If ( x + 2 ) = 1000, what is x 2 4 =?

15 How can we solve the complex problem? Complex Standards Simple

16 Oncology specific Standards Response Criteria Guidelines CDISC Analysis

17 Oncology specific Standards Response Criteria Guideline What to collect How to measure How to determine responses from measurements CDISC How to store/submit the data Analysis How to analyze/report the data

18 Response Criteria Guidelines Solid Tumor RECIST (Response Evaluation Criteria in Solid Tumor) 1.1 irrc(immunerelated RECIST) 2009 Lymphoma Cheson 2007 Cheson 2014 (2014 Lugano classification) Leukemia IWCLL 2008 IWAML 2003 NCCN Guideline 2012 on ALL CML ESMO Guidelines

19 CDISC Oncology specific Standards SDTM TU : Tumor Identification TR : Tumor Results RS : Response ADaM -TTE : Time to Event Analysis Datasets

20 CDISC Oncology specific Standards CT Response Criteria : CR, PR, PD, SD, ircr, irpr, irpd, irsd Tumor Measurements : LDIAM, SUMDIA, LPERP, AREA, SUMAREA, TUMSTATE Response : TRGRESP, NTRGRESP, NEWLPROG, OVRLRESP, BESTRESP

21 Oncology specific Analysis OS Overall Survival PFS Progression Free Survival ORR Objective Response Rate

22 Standards Implemented Oncology Studies Study Types Response Criteria Guidelines CDISC

23 Solid Tumor Studies based RECIST 1.1 measurements Tumor measurements in CT / MRI Target Non-target New

24 RECIST 1.1 driven Response Assessment at given visit Target lesions assessment (TR) Non-target lesions assessment (TR) New lesions (TR) Response (RS)

25 Response Assessment at Cycle 1 for RECIST 1.1 (TR to RS) USUBJID TRGRID TRLI NKID TRTESTC D TRTEST TRORRE S TROR RESU VISIT Target T01 LDIAM Longest Diameter 10 mm Cycle Target T02 LDIAM Longest Diameter 10 mm Cycle Target T03 LDIAM Longest Diameter 15 mm Cycle Target SUMDIAM Sum of Diameter 35 mm Cycle Non-Target NT01 TUMSTATE Tumor State PRESENT Cycle Non-Target NT02 TUMSTATE Tumor State PRESENT Cycle Non-Target NT03 TUMSTATE Tumor State PRESENT Cycle 1 USUBJID RSTESTCD RSTEST RSCAT RSORRES VISIT TRGRESP Target Response RECIST 1.1 PR Cycle NTRGRESP Non-target Response RECIST 1.1 NonCR/NonPD Cycle NEWLPROG New Lesion Progression RECIST 1.1 N Cycle OVRLRESP Overall Response RECIST 1.1 PR Cycle 1

26 Lymphoma Studies based Cheson measurements Tumor measurements (Lymph Node, Nodal Masses and Extra Nodal Masses) in CT / MRI PET scan on lesions (to distinguish viable tumor from fibrosis) Bone Marrow Assessment Spleen and Liver Enlargement Assessment

27 Cheson driven Response Assessment at given visit Tumor Assessment by PET (TR) Bone Marrow Infiltrate (LB, FA) Tumor measurement by CT SCAN (TR) Response (RS) Spleen and Liver Enlargement (PE)

28 Leukemia Studies based IWCLL 2008 measurement Tumor measurements in CT / MRI Spleen and Liver Enlargement Assessment Bone Marrow Assessment Blood Count Assessment Lymphocytes, Neutrophils, Platelets, and Hemoglobin.

29 IWCLL 2008 drvien Response Assessment at given visit Bone Marrow (LB, FA) Spleen and Liver Enlargement (PE) Tumor measurement by CT SCAN (TR) Response (RS) Blood Counts (LB)

30 Tumor Measurement in Oncology Studies Solid Tumor Studies (RECIST 1.1) > 10 mm by CT Scan One-dimensional measurement (longest diameter) 25 mm Sum of Diameters

31 Tumor Measurement in Oncology Studies Lymphoma (Cheson 2014) and Leukemia (IWCLL 2008) Enlarged Lymph Nodes (Long axis > 15 mm) Two-dimensional measurement : product of longest diameter and its greatest perpendicular axis (e.g., 25 mm * 15 mm =375 mm^2) Sum of Products of Diameters (SPD)

32 Tumor measurements Examples SDTM TR Solid Tumor according to RECIST 1.1 USUBJID TRLI NKID TRTESTC D T01 LDIAM Longest Diameter T02 LDIAM Longest Diameter T03 LDIAM Longest Diameter SUMDIAM Sum of Diameter TRTEST TRCAT TRO RRES TRO RRE SU VISIT Measurement 23 mm Screening Measurement 22 mm Screening Measurement 25 mm Screening Measurement 70 mm Screening

33 Tumor measurements Examples SDTM TR Lymphoma according to Cheson 2014 USUBJI D TRL INKI D TRTE STCD TRTEST TRCAT TRO RRES T01 LDIAM Longest Diameter Measureme nt T01 LPER P Longest Perpendicular Measureme nt T01 AREA Area Measureme nt SUMA REA Sum of Area Measureme nt TRO RRE SU VISIT 25 mm Screening 15 mm Screening 375 mm^2 Screening 1060 mm^2 Screening

34 Time to Event Analysis in ADaM USUBJID TRTP PARAM AVAL START DT Study Drug 1 Study Drug 2 Study Drug 2 Study Drug 1 Study Drug 1 Time to Death (Days) Time to Death (Days) Time to Death (Days) Time to Death (Days) Time to Death (Days) ADT CNSR EVNTDESC COMPLETED THE STUDY 1 LOST TO FOLLOW-UP 0 DEATH 1 ONGOING 1 ONGOING Overall Survival analysis by Kaplan Meier plot, log rank test or Cox Regression Analysis.

35 Standards Driven Oncology Studies

36 ncology-specific Standards Library Response Criteria Guidelines Collection CDISC Analysis Documents RECIST 1.1 Tumor Measurement SDTM : TU, TR, RS OS, PFS,TTP, ORR, DFS Links Cheson 2011 Bone Marrow Assessment ADaM : --TTE Reporting Tables, Listings and Graphs Traceability IWCLL 2008 Spleen and Liver Enlargement Assessment Blood Counts CT : CR, PR, PD, SD, ircr, irpr, irpd, irsd, LDIAM, SUMDIA, LPERP, AREA, SUMAREA, TUMSTATE, TRGRESP, NTRGRESP, NEWLPROG SAS Macros / R Packages Algorithms (Industry, Company) Introduction SOP / WG Response Assessment

37 E2E Standards-driven Oncology Studies Protocol Collection SDTM ADaM Analysis Cheson 2014 Tumor Measurement Bone Marrow Assessment TR TU ADTTEPFS Progression Free Survival Time to Even Analysis Report Spleen and Liver Enlargement LB Response FA PE RS

38 Why Standards driven process in oncology studies? Regulatory compliance Easy to understand Scalable 20/80 Time Saving Cost Effective Less Human Errors

39 Standardized way to solve the complex problem If ( x + 2 ) = 1000, what is x 2 4 =? ( x - 2 ) ( x + 2 ) = 996,000

40 Final Thoughts Benefics of Standards in Oncology Studies Oncology-specific standards E2E Standardsdriven process

41 About Clindata Insight CDISC Gold Member Provider CDISC Implementation CDISC Roadmap FDA esubmission Biostatistics & Programming

42 Contact Us! Contact Clindata Insight to learn more about Oncology. Youtube in UCK1H3T0w1S_qOe5bKVh0bYw us at Like us on Facebook.com/clindatainsight Clindata is a CDISC Gold Member Clindata Insight Inc. 2016