1. Accenture Life Sciences Rethink Reshape Restructure… for better patient outcomes CDISC Journey in Lymphoma using Cheson 2007 Kevin Lee CDISC NJ meeting April 17th, 2014

2. Disclaimer Any views or opinions presented in this presentation are solely those of the author and do not necessarily represent those of the company. 2

3. Agenda 1.Introduction of Oncology 2.Introduction of Lymphoma Studies 3.Introduction of Cheson 4.CDISC SDTM 5.CDISC ADaM 6.Conclusion 7.Questions 3

4. Cancer Trivia 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. Cancer is the leading cause of death in developed countries. 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. There are 28 million cancer survivors worldwide. Men who have never married are up to 35% more likely to die from cancer than those who are married. 4

5. FDA New Drug Approval 2012 –37 Approval –12 Oncology (32 %) 2013 –27 Approval –8 Oncology (30 %) 5

6. Oncology Study How are the oncology studies different from other studies? –Tumor measurements and their response to drug –Toxicity (Lab and AE) –Time to Event Analysis What tumor studies and response guidelines? –Solid Tumor : RECIST 1.1 –Lymphoma : Cheson 2007 –Leukemia : IWCLL 2008 6

7. What is Lymphoma Cancer that starts in lymph nodes Type of Lymphoma –Hodgkin lymphoma (HL) : lymphoma in the presence of a specific type of abnormal cell called a Reed-Sternberg cell –Non-Hodgkin lymphoma (NHL) : lymphoma not in the presence of a specific type of abnormal cell called a Reed-Sternberg cell Guidelines for response : Cheson 2007 7

8. Cheson 2007 History –IWG (International Working Group) 1999 and Cheson 2007 Lesions (tumors) –Type : Enlarged Lymph Nodes (long axis > 15 mm or its greatest perpendicular axis > 10 mm by CT scan) Nodal Masses Extra Nodal Masses (> 10 mm ) 8

9. Lymphatic System 9 A Nodal Mass is the conglomerate of several enlarged nodes touching one another which are not distinguished from individual nodes any more.

10. Extra Nodal Site 10 Extra nodal – a lymphoma that is detected outside of lymphatic system.

11. Cheson 2007 Two-dimensional measurement - product of longest diameter and its greatest perpendicular axis (e.g., 40 mm * 15 mm = 600 mm^2) 11

12. What is to measure in Lymphoma according to Cheson 2007 Tumor measurements in CT / MRI –Lymph Node, Nodal Masses and Extra Nodal Masses PET scan on lesions (to distinguish viable tumor from fibrosis) Bone Marrow Assessment Spleen and Liver Enlargement Assessment 12

13. Target Lesions according to Cheson 2007 Normally 6 lesions –lymph nodes or nodal masses –Two perpendicular diameters should be clearly measurable Quantitative measurements –Longest diameter and its greatest transverse perpendicular diameter –Products of the diameters –Sum of the products of the diameters (SPD) up to 6 target lesions 13

14. Non-Target Lesions according to Cheson 2007 All other lesions beside target lesions Extra nodal (i.e., Liver, Spleen) Quantitative measurements –Longest diameter and its greatest transverse perpendicular diameter –Products of the diameters Qualitative measurements – present, absent, increased or decreased. 14

15. New Lesions according to Cheson 2007 Any lesions that are newly found at post- baseline Either quantitative or qualitative measurements 15

16. Lesions at baseline 16 Lesions Measurable Lymph Node or Nodal Masses Non-Measurable or Extra Nodal Masses Targets Non-Targets

17. Response Criteria Complete Response(CR) : Disappearance of all evidence of disease Partial Response(PR) : Regression of measurable disease and no new sites Progressive Diseases (PD) : Any new lesions or any increase by 50% from nadir in SPD Stable Disease (SD) : Fail to CR/PR or PD Not Evaluable (NE) 17

18. Complete Response (CR) Nodal Masses Typically FDG-avid lymphoma - if PET is positive in screening, PET is negative for all lesions. Variably FDG-avid lymphoma - all the lymph nodes/nodal masses regress to normal size (<= 15 mm in their greatest transverse diameter or < 10 mm in short axis if their greatest transverse diameter is between 10 and 15) Spleen and Liver – Not palpable, nodules disappeared Bone Marrow – Infiltrate cleared; if indeterminate by morphology, immunohistochemistry should be negative 18

19. Partial Response (PR) Nodal Masses A 50% decrease in the sum of the product of diameters (SPD) of six target lesions No increase in any lesions Typically FDG-avid lymphoma - if PET is positive in screening, PET is positive at least one lesion. Variably FDG-avid lymphoma - all the lymph nodes/nodal masses regress. Spleen and Liver – Not palpable, nodules regressed by 50 % in SPD. Bone Marrow – Irrelevant 19

20. Progressive Disease (PD) Nodal Masses Any new lesions (more than 15 mm in any axis) An increase by 50% in SPD from nadir of any involved lesions An increase by 50% in the longest diameter from nadir of any involved lesions Positive PET. Spleen and Liver – nodules increase by 50 % in SPD. Bone Marrow – New or recurrent involvement 20

21. CDISC Domains or Datasets for Lymphoma Studies SDTM –TU : Tumor Identification –TR : Tumor Results –RS : Response –LB / FA : Bone Marrow –PE : Liver and Spleen Palpable assessment ADaM –-TTE : Time to Event Analysis Datasets 21

22. Efficacy Evaluation in Lymphoma Primary –Overall Survival : Death as event. –Progression-free survival : Disease Progression or death as a event. preferred end point in Lymphoma studies. Secondary –Event-free survival –Overall Response Rate : Phase II trials of novel new agents –Time to Progression –Disease Free Survival 22

23. Example Randomized and open label Phase II Study Lymphoma following Cheson 2007 5 cycles 3 target and 2 non-target lesions at screening Primary Efficacy – Overall Survival and Progression Free Survival 23

24. SDTM TU (Tumor Identification) USUBJI D TULIN KID TUTESTC D TUTESTTUORRESTULOCTUMETHO D 001-01- 001 T01TUMIDENTTumor Identification TARGET NODAL PELVIC LYMPH NODE CT SCAN 001-01- 001 T02TUMIDENTTumor Identification TARGET NODAL AXILARY LYMPH NODE CT SCAN 001-01- 001 T03TUMIDENTTumor Identification TARGET NODAL CERVICAL LYMPH NODE CT SCAN 001-01- 001 NT01TUMIDENTTumor Identification NON-TARGET EXTRA NODAL LIVERCT SCAN 001-01- 001 NT02TUMIDENTTumor Identification NON-TARGET EXTRA NODAL SPLEENCT SCAN 001-01- 001 T01TUMIDENTTumor Identification TARGET NODAL PELVIC LYMPH NODE FDGPET 001-01- 001 T02TUMIDENTTumor Identification TARGET NODAL AXILARY LYMPH NODE FDGPET 001-01- 001 T03TUMIDENTTumor Identification TARGET NODAL CERVICAL LYMPH NODE FDGPET 24 Key points to note: Subject 001 has 3 target and 2 non-targets TU.TULINKID is connected TR.TRLINKID using RELREC.

25. SDTM TR at Screening USUBJ ID TRGRI D TRLIN KID TRTE STCD TRTESTTRCATTROR RES TROR RESU VISITTRME THOD 001-01- 001 TargetT01LDIAMLongest Diameter Measure ment 20mmScreeningCT SCAN 001-01- 001 TargetT01LPERPLongest Perpendicular Measure ment 15mmScreeningCT SCAN 001-01- 001 TargetT01AREAAreaMeasure ment 300mm^2ScreeningCT SCAN 001-01- 001 TargetT01TUMST ATE Tumor StateQualitati ve POSITI VE ScreeningFDGP ET 001-01- 001 TargetSUMAR EA Sum of Products of Perpendicular Diameters Qualitati ve 2560mm^2Screening 001-01- 001 Non- Target NT01TUMST ATE Tumor StateQualitati ve PRESE NT ScreeningCT SCAN 001-01- 001 Non- Target NT02TUMST ATE Tumor StateQualitati ve PRESE NT ScreeningCT SCAN 25 Key points to note: Area and Sum of Area were collected SPD at screening for 001 is 2,560 mm^2

26. SDTMTR at Cycle 1 USUBJ ID TRGRI D TRLIN KID TRTE STCD TRTESTTRCATTROR RES TROR RESU VISITTRME THOD 001-01- 001 TargetT01LDIAMLongest Diameter Measure ment 15mmVisit 1CT SCAN 001-01- 001 TargetT01LPERPLongest Perpendicular Measure ment 10mmVisit 1CT SCAN 001-01- 001 TargetT01AREAAreaMeasure ment 150mmVisit 1CT SCAN 001-01- 001 TargetT01TUMST ATE Tumor StateQualitati ve NEGATI VE Visit 1FDGP ET 001-01- 001 TargetSUMAR EA Sum of Products of Perpendicular Diameters Qualitati ve 1200mmVisit 1 001-01- 001 Non- Target NT01TUMST ATE Tumor StateQualitati ve PRESE NT Visit 1CT SCAN 001-01- 001 Non- Target NT02TUMST ATE Tumor StateQualitati ve PRESE NT Visit 1CT SCAN 26 Key points to note: SPD at visit 1 for 001 is 1,200, more than 50 % decrease. FDGPET is negative from positive.

27. Bone Marrow - SDTM LB and FA USUBJI D LBCATLBSPECLBSPIDLBTESTLBORR ES LBOR RESU VISIT 001-01- 001 HEMATO LOGY BONE MARROW BR01Bone Marrow Infiltrate 35%Screening 001-01- 001 HEMATO LOGY BONE MARROW BR01Bone Marrow Infiltrate 9%Visit 1 27 Key points to note: LB.LBSPID is connected to FA.FASPID We can also use BR (Biopsy) domain following SDTM terminology Row 1: Bone Marrow Infiltration (i.e., 35%) and its result (i.e., POSITIVE) are collected, so the example has infiltration number in LB and results in FA. USUBJIDFACATFASP ID FATESTFAORRESVISIT 001-01-001BONE MARROW BIOPSY BR01Bone Marrow Biopsy ResultsPOSITIVEScreening 001-01-001BONE MARROW BIOPSY BR01Bone Marrow Biopsy ResultsPOSITIVEVisit 1

28. Liver and Spleen Palpable Assessment - SDTM PE USUBJI D PECATPEMETHODPETESTCDPETESTPEOR RES VISIT 001-01- 001 PHYSICAL EXAMINATION PALPATIONSPLEENENSpleen Enlargement YESScreening 001-01- 001 PHYSICAL EXAMINATION PALPATIONSPLEENENSpleen Enlargement NOVisit 1 001-01- 001 PHYSICAL EXAMINATION PALPATIONLIVERENLiver Enlargement YESScreening 001-01- 001 PHYSICAL EXAMINATION PALPATIONLIVERENLiver Enlargement NOVisit 1 28 Key points to note: Subject 001 was palpable at Screening, but not palpable at Visit 1

29. SDTM RS (Response) USUBJI D RSTESTC D RSTESTRSCATRSORRESVISITRSDTCRSSE Q 001-01- 001 OVRLRESPOverall ResponseCHESON 2007 PRCycle 1 2011-03- 01 1 001-01- 001 OVRLRESPOverall ResponseCHESON 2007 SDCycle 2 2011-06- 01 2 001-01- 001 OVRLRESPOverall ResponseCHESON 2007 PRCycle 3 2011-09- 01 3 001-01- 001 OVRLRESPOverall ResponseCHESON 2007 PDCycle 4 2011-12- 01 4 001-01- 001 OVRLRESPOverall ResponseCHESON 2007 PDCycle 5 2012-03- 01 5 29 Key points to note: Overall Response for each visit was collected.

30. Response Assessment at given visit 30 Response (RS) Tumor measurement in SPD by CT SCAN (TU) Tumor Assessment by PET (TU) Bone Marrow Infiltrate (LB, FA) Spleen and Liver Enlargement (PE)

31. ADaM : Overall Survival (OS) USUBJI D TRTPPARAM AVA L STARTDTADTCNSREVNTDESC 001-01- 001 Study Drug 1 Overall Survival (Days) 4522011-01-012012-03-011PROGRESSION DISEASE 001-01- 002 ControlOverall Survival (Days) 3382011-02-012012-01-051LOST TO FOLLOW-UP 001-01- 003 ControlOverall Survival (Days) 2122011-02-052011-09-050DEATH 001-01- 004 Study Drug 1 Overall Survival (Days) 4632011-03-202012-06-251COMPLETED STUDY 001-01- 005 Study Drug 1 Overall Survival (Days) 672011-03-262011-06-011PROGRESSION DISEASE 31 Key points to note: DEATH is NOT censored.

32. ADaM : Progression Free Survival (PFS) USUBJIDTRTPPARAM AVAL STARTDTADTCNSREVNTDESC 001-01-001Study Drug 1 Progression Free Survival (Days) 4522011-01-012012-03-010PROGRESSION DISEASE 001-01-002ControlProgression Free Survival (Days) 3382011-02-012012-01-051LOST TO FOLLOW-UP 001-01-003ControlProgression Free Survival (Days) 2122011-02-052011-09-050DEATH 001-01-004Study Drug 1 Progression Free Survival (Days) 4632011-03-202012-06-251COMPLETED STUDY 001-01-005Study Drug 1 Progression Free Survival (Days) 672011-03-262011-06-010PROGRESSION DISEASE 32 Key points to note: In PFS, DEATH and PD are NOT censored.

33. Conclusion Standard for Lymphoma Studies 1.Cheson 2007 : Tumor Measurements and Responses 2.CDISC SDTM : submission data 3.CDISC ADaM : analysis data 33

34. 2014 Summer Preview Blockbuster Movies Webinar : FDA Electronic submission Guidance PharmaSUG (June 1 st to 4 th ) –CDISC Electronic Submission 34

35. Contact Information 35 © 2014 Accenture All Rights Reserved. Email address : kevin.s.lee@accenture.com Linkedin Profile : www.linkedin.com/in/HelloKevinLee/Profile : www.linkedin.com/in/HelloKevinLee/ Tweet : @HelloKevinLee Slide share : http://www.slideshare.net/KevinLee56 Blogs : HiKevinLee.tumbrl.com

36. Questions and Discussion 36 © 2014 Accenture All Rights Reserved.