1. Elke Sennewald, 22 September 2011 Trial Design Introduction

2. Information about study design – No subject data Describe the overall trial design and plan via data representation Trial Design Domains

3. Why Do Trial Design Rapidly understanding the design of the study Standard and relatively simple data structures Relatively small number of rows of data and easy to comprehend Useful for both FDA reviewers and internal sponsor use Information can be centrally accessible and searchable

4. Trial Design Datasets Trial Arms (TA) Trial Elements (TE) Trial Visits (TV) Trial Inclusion /Exclusion (TI) Trial Summary (TS) Start thinking about this before you start the other SDTM datasets! 4

5. Trial Summary (TS) Dataset Summary of trial information No link to subject-level data in SDTM TSGRPID used to group multiple related parameters such as Dose, Units, Frequency etc TSSEQ used as a key for multiple records with the same parameters Common questions: – What need to be included? – Why are we generating this? 5

6. Trial Inclusion/Exclusion (TI) Not subject-oriented Link to IE domain – STUDYID, IECAT, IETESTCD, IETEST – Subject IETEST/IETESTDC must match Trial Inclusion/Exclusion IETEST/IETESTCD – Best to create TI first, before you tackle IE Common questions: – How to truncate if >200 characters? – Truncation – potential for duplicate IETEST values – Protocol amendment: do we need to add to TI only the changed criteria or all criteria? – Local amendment 6

7. TA / TE / TV datasets A data representation on the different epochs, arms and visit structure in the study Where to start? Is there a systematic approach? 7

8. Example 1 – Trial Design Schema 8 Screen Drug A Drug B Follow-up

9. Epoch 9 Screen Drug A Drug B Follow-up Screening Treatment Follow-up EPOCH

10. Arm / Treatment Strategy 10 Screen Drug A Drug B Follow-up Screening Treatment Follow-up ARM (Treatment Strategy) 1 2

11. Arm / Treatment Strategy 11 Screen Drug A Drug B Follow-up Screening Treatment Follow-up Study Cell 1 2 Screen Drug A Drug B Follow-up

12. Trial Design Matrix 12 Screening Treatment Follow-up A B Screen Drug A Drug B Follow-up

13. TE (Trial Elements) What are the elements? – Unique study cell values (=ELEMENT) 13 Screen Drug A Drug B Follow-up

14. Trial Visits describes the planned Visits for each Arm, and any start and end rules. ScreenRun-InDrug AScreenRun-InDrug B Screening ScreenRun-InPlacebo Drug A Drug B Trial Arms describes the Elements in each Arm, their order and Epoch, and any branching or transition rules. ScreenRun-inPlacebo Drug ADrug B Trial Elements describes the Elements and the rules for the start and end of each. Placebo Run-InTreatment Epochs are described only in Trial Arms, and have no separate table. Visit 1Visit 2Visit 3Visit 4Visit 5 Trial Arms and Elements Overview

15. Trial Design Matrix 15 ScreeningRun-inTreatment A B Screen Run-in Drug A Drug B P Screen Run-in Placebo

16. Creating Trial Elements (1) Usually the most challenging dataset Not a duplication of EX (Exposure) Assign an element code (ETCD) to each value, define the start of each element (TESTRL) and end of each element (TEENRL or TEDUR) Start rules are the most important – Subject data must exist to support the creation of these – Start of next element defines end of previous

17. ScreenRun-inPlacebo Drug ADrug B Trial Elements describes the Elements and the rules for the start and end of each. STUDYIDDOMAINETCDELEMENTTESTRLTEENRLTEDUR 1999001TESCRNScreenInformed consent signed Start of next element or date subject dropped P2W 1999001TERUNINRun-inFirst dose of run-in drug Start of next element or date subject dropped P1W 1999001TEPLACPlaceboFirst dose of placeboStart of next element or date subject dropped or completed P2W Creating Trial Elements (2) Example pseudocode: DSSTDTC where DSDECOD = INFORMED CONSENT Example pseudocode: EXSTDTC where EXTRT = RUN-IN DRUG

18. TE -> SE (Subject Elements) Shows the trial progress of each subject – Whether a subject passes through each element – Timing of each element 18

19. STUDYIDDOMAINUSUBJIDSESEQETCDELEMENTSESTDTCSEENDTCSEUPDES 1999001SE145-0111SCRNScreen2003-04-012003-04-15 1999001SE145-0112RUNINRun-In2003-04-152003-04-22 1999001SE145-0113PLACPlacebo2003-04-222003-05-06 Creating Subject Elements DSSTDTC where DSDECOD = INFORMED CONSENT EXSTDTC where EXTRT = RUN-IN DRUG

20. Trial Arms (TA) Dataset High level treatment plan Composed of Elements from Trial Elements Go back to the Trial Design Matrix 1 study cell = 1 row of record in TA So in our example we expect 9 rows of record Planned ARM values in DM correspond to ARM values in Trial Arms Names of ARM should reflect the protocol 20

21. ScreenRun-InDrug AScreenRun-InDrug BScreenRun-InPlacebo Drug A Drug B Placebo STUDYIDDOMAINARMCDARMTAETORDETCDTABRANCHEPOCH 1999001TAPPlacebo1SCRNScreen 1999001TAPPlacebo2RUNINRandomized to Placebo Run-In 1999001TAPPlacebo3PLACTreatment 1999001TAADrug A1SCREENScreen 1999001TAADrug A2RUNINRandomized to Drug A Run-In 1999001TAADrug A3DRUGATreatment 1999001TAADrug B1SCREENScreen 1999001TAADrug B2RUNINRandomized to Drug B Run-In 1999001TAADrug B3DRUGBTreatment Creating Trial Arms

22. Trial Visit (TV) Dataset Describe the planned visits in a trial VISITNUM and TRSTRL is required ARMCD expected VISIT and VISITDY permissible 1 record per planned visit per arm – A visit may span over several days (eg screening visit) What is really the start and end of a visit? Create Subject Visits dataset from Visit based SDTM datasets 22

23. TV -> SV (Subject Visits) Shows the actual visits of each subject – Compare against the scheduled/planned visits or assessments in TV – Include unscheduled visits Designation of VISITNUM becomes crucial – Whole number for planned visits – Decimals for unscheduled visits in SV – and slot into right place 23

24. STUDYIDDOMAINVISITNUMVISITVISITDYARMCDARMTVSTRLTVENRL 1999001TV1Visit 1Signing of informed consent Completion of lab draw 1999001TV2Visit 230 minutes before receipt of Run-In drug 1999001TV3Visit 330 minutes before receipt of blinded treatment 30 minutes after receipt of blinded treatment 1999001TV4Visit 41 week after receipt of blinded treatment 1999001TV5Visit 52 weeks after receipt of blinded treatment Completion of final disposition page Creating Trial Visits Planned schedule of Visits Challenge is in defining start and end of a visit ARM/ARMCD can be used if schedule varies by Arm

25. Summary Construction of TA/TE/TV – Study Schema Epoch Arm Study Cells – Unique study cells = rows in TE – All study cells = rows in TA – If all arms have same visits, then 1 set of visits for all arms. Otherwise 1 set of visits for each arm. Complex study designs – Systematic approach will make life easier – Think at protocol/CRF design stage – dont wait till the end – Details vs ease of use 25