A Complex ADaM dataset? Three different ways to create one.

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 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 Agenda 1. 2. 3. 4. 5. 6. 7. Introduction of Oncology Introduction of Lymphoma Studies Introduction of Cheson CDISC SDTM CDISC ADaM Conclusion Questions 3 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 FDA New Drug Approval 2012 37 Approval 12 Oncology (32 %) 2013 27 Approval 8 Oncology (30 %) 5 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 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 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 Lymphatic System A Nodal Mass is the conglomerate of several enlarged nodes touching one another which are not distinguished from individual nodes any more. 9 Extra Nodal Site Extra nodal a lymphoma that is detected outside of lymphatic system.

10 Cheson 2007 Two-dimensional measurement - product of longest diameter and its greatest perpendicular axis (e.g., 40 mm * 15 mm = 600 mm^2) 11 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 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 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 New Lesions according to Cheson 2007 Any lesions that are newly found at postbaseline Either quantitative or qualitative measurements 15 Lesions at baseline Lesions Measurable Lymph Node or Nodal Masses Targets Non-Measurable or Extra Nodal Masses Non-Targets 16 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 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 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 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 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 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

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 SDTM TU (Tumor Identification) USUBJI D TULIN KID TUTESTC D TUTEST TUORRES TULOC TUMETHO D 001-01001 T01 TUMIDENT Tumor Identification TARGET

NODAL PELVIC LYMPH NODE CT SCAN 001-01001 T02 TUMIDENT Tumor Identification TARGET NODAL AXILARY LYMPH NODE CT SCAN 001-01001 T03 TUMIDENT Tumor Identification TARGET NODAL CERVICAL LYMPH NODE CT SCAN

001-01001 NT01 TUMIDENT Tumor Identification NON-TARGET EXTRA NODAL LIVER CT SCAN 001-01001 NT02 TUMIDENT Tumor Identification NON-TARGET EXTRA NODAL SPLEEN CT SCAN 001-01001 T01 TUMIDENT Tumor

Identification TARGET NODAL PELVIC LYMPH NODE FDGPET 001-01001 T02 TUMIDENT Tumor Identification TARGET NODAL AXILARY LYMPH NODE FDGPET 001-01001 T03 TUMIDENT Tumor Identification TARGET NODAL CERVICAL

LYMPH NODE FDGPET Key points to note: Subject 001 has 3 target and 2 non-targets TU.TULINKID is connected TR.TRLINKID using RELREC. 24 SDTM TR at Screening USUBJ ID TRGRI D TRLIN KID TRTE STCD TRTEST TRCAT TROR RES TROR RESU VISIT TRME THOD 001-01001

Target T01 LDIAM Longest Diameter Measure ment 20 mm Screening CT SCAN 001-01001 Target T01 LPERP Longest Perpendicular Measure ment 15 mm Screening

CT SCAN 001-01001 Target T01 AREA Area Measure ment 300 mm^2 Screening CT SCAN 001-01001 Target T01 TUMST ATE Tumor State Qualitati ve

POSITI VE Screening FDGP ET 001-01001 Target SUMAR EA Sum of Products of Perpendicular Diameters Qualitati ve 2560 001-01001 NonTarget NT01 TUMST ATE Tumor State Qualitati ve PRESE

NT Screening CT SCAN 001-01001 NonTarget NT02 TUMST ATE Tumor State Qualitati ve PRESE NT Screening CT SCAN Key points to note: Area and Sum of Area were collected SPD at screening for 001 is 2,560 mm^2 mm^2 Screening 25 SDTMTR at Cycle 1

USUBJ ID TRGRI D TRLIN KID TRTE STCD TRTEST TRCAT TROR RES TROR RESU VISIT TRME THOD 001-01001 Target T01 LDIAM Longest Diameter Measure ment

15 mm Visit 1 CT SCAN 001-01001 Target T01 LPERP Longest Perpendicular Measure ment 10 mm Visit 1 CT SCAN 001-01001 Target T01 AREA

Area Measure ment 150 mm Visit 1 CT SCAN 001-01001 Target T01 TUMST ATE Tumor State Qualitati ve NEGATI VE Visit 1 FDGP ET 001-01001 Target

SUMAR EA Sum of Products of Perpendicular Diameters Qualitati ve 1200 001-01001 NonTarget NT01 TUMST ATE Tumor State Qualitati ve PRESE NT Visit 1 CT SCAN 001-01001 NonTarget

NT02 TUMST ATE Tumor State Qualitati ve PRESE NT Visit 1 CT SCAN mm Visit 1 Key points to note: SPD at visit 1 for 001 is 1,200, more than 50 % decrease. FDGPET is negative from positive. 26 Bone Marrow - SDTM LB and FA USUBJI LBCAT D LBSPEC LBSPID LBTEST LBORR ES

LBOR RESU VISIT 001-01001 HEMATO LOGY BONE MARROW BR01 Bone Marrow Infiltrate 35 % Screening 001-01001 HEMATO LOGY BONE MARROW BR01 Bone Marrow Infiltrate 9

% Visit 1 USUBJID FACAT FASP FATEST ID FAORRES VISIT 001-01-001 BONE MARROW BIOPSY BR01 Bone Marrow Biopsy Results POSITIVE Screening 001-01-001 BONE MARROW BIOPSY BR01 Bone Marrow Biopsy Results POSITIVE Visit 1

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. 27 Liver and Spleen Palpable Assessment - SDTM PE USUBJI D PECAT PEMETHOD PETESTCD PETEST PEOR RES VISIT 001-01001 PHYSICAL EXAMINATION PALPATION SPLEENEN Spleen Enlargement

YES Screening 001-01001 PHYSICAL EXAMINATION PALPATION SPLEENEN Spleen Enlargement NO Visit 1 001-01001 PHYSICAL EXAMINATION PALPATION LIVEREN Liver Enlargement YES Screening 001-01001 PHYSICAL EXAMINATION

PALPATION LIVEREN Liver Enlargement NO Visit 1 Key points to note: Subject 001 was palpable at Screening, but not palpable at Visit 1 28 SDTM RS (Response) USUBJI D RSTESTC D RSTEST RSCAT RSORRES VISIT RSDTC RSSE Q 001-01001 OVRLRESP

Overall Response CHESON 2007 PR Cycle 1 2011-0301 1 001-01001 OVRLRESP Overall Response CHESON 2007 SD Cycle 2 2011-0601 2 001-01001 OVRLRESP Overall Response CHESON

2007 PR Cycle 3 2011-0901 3 001-01001 OVRLRESP Overall Response CHESON 2007 PD Cycle 4 2011-1201 4 001-01001 OVRLRESP Overall Response CHESON 2007 PD

Cycle 5 2012-0301 5 Key points to note: Overall Response for each visit was collected. 29 Response Assessment at given visit Tumor Assessment by PET (TU) Tumor measuremen t in SPD by CT SCAN (TU) Bone Marrow Infiltrate (LB, FA) Response (RS) Spleen and Liver Enlargement (PE) 30 ADaM : Overall Survival (OS) USUBJI D TRTP

PARAM AVA L STARTDT ADT CNSR EVNTDESC 001-01001 Study Drug 1 Overall Survival (Days) 452 2011-01-01 2012-03-01 1 PROGRESSION DISEASE 001-01002 Control Overall Survival (Days) 338

2011-02-01 2012-01-05 1 LOST TO FOLLOW-UP 001-01003 Control Overall Survival (Days) 212 2011-02-05 2011-09-05 0 DEATH 001-01004 Study Drug 1 Overall Survival (Days) 463 2011-03-20 2012-06-25

1 COMPLETED STUDY 001-01005 Study Drug 1 Overall Survival (Days) 67 2011-03-26 2011-06-01 1 PROGRESSION DISEASE Key points to note: DEATH is NOT censored. 31 ADaM : Progression Free Survival (PFS) USUBJID TRTP PARAM AVAL STARTDT ADT

CNSR EVNTDESC 001-01-001 Study Drug 1 Progression Free Survival (Days) 452 2011-01-01 2012-03-01 0 PROGRESSION DISEASE 001-01-002 Control Progression Free Survival (Days) 338 2011-02-01 2012-01-05 1 LOST TO

FOLLOW-UP 001-01-003 Control Progression Free Survival (Days) 212 2011-02-05 2011-09-05 0 DEATH 001-01-004 Study Drug 1 Progression Free Survival (Days) 463 2011-03-20 2012-06-25 1 COMPLETED STUDY

001-01-005 Study Drug 1 Progression Free Survival (Days) 67 2011-03-26 2011-06-01 0 PROGRESSION DISEASE Key points to note: In PFS, DEATH and PD are NOT censored. 32 Conclusion Standard for Lymphoma Studies 1. Cheson 2007 : Tumor Measurements and Responses 2. CDISC SDTM : submission data 3. CDISC ADaM : analysis data 33 2014 Summer Preview Blockbuster Movies Webinar : FDA Electronic submission Guidance PharmaSUG (June 1st to 4th) CDISC Electronic Submission

34 Contact Information Email address : [email protected] Linkedin Profile : www.linkedin.com/in/HelloKevinLee/ Tweet : @HelloKevinLee Slide share : http://www.slideshare.net/KevinLee56 Blogs : HiKevinLee.tumbrl.com 2014 Accenture All Rights Reserved. 35 Questions and Discussion 2014 Accenture All Rights Reserved. 36

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