UC5:Assigning of Epoch after treatment discontinuation (NS) Screening Treatment Follow up Study epochs per protocol: Randomization, Treatment start End of treatment, Date of last trt End of study, consent withdraw

UC5: (cont.) subject information CRF pages: end of treatment, FU, end of study Subject has got 2 cycles. Last TRTDTC=2014-02-01 Cycle 3 should start at 2014-02-21, but subject has AE, thus treatment delay, No bettering after 14 days, Lab visit, EG Visit performed. => Physician decision to discontinue treatment Subject comes to visit and decide not to go to FU, but to withdraw consent at 2014-03-14, so no FU observation and data collection, end of study. Q: Which epoch and VISITNUM to assign to LB and EG visit in delay period?

Question On which level should we handle treatment delay period: EPOCH or ELEMENT?

Definition from CDISC SDTM Epoch: As part of the design of a trial, the planned period of subjects' participation in the trial is divided into Epochs. Each Epoch is a period of time that serves a purpose in the trial as a whole. That purpose will be at the level of the primary objectives of the trial. Typically, the purpose of an Epoch will be to expose subjects to a treatment, or to prepare for such a treatment period (e.g., determine subject eligibility, wash out previous treatments) or to gather data on subjects after a treatment has ended.

Definition from CDISC SDTM Element: An Element is a basic building block in the trial design. It involves administering a planned intervention, which may be treatment or no treatment, during a period of time. Elements for which the planned intervention is "no treatment" would include Elements for screening, washout, and follow-up.

Definition from CDISC SDTM “If TAETORD and/or EPOCH are added, then the values must be those at the start of the visit” Chapter 5, “SV”, P3 5. Judgment will also have to be used in deciding how to represent a subject's experience if an Element does not proceed or end as planned. For instance, the plan might identify a trial Element which is to start with the first of a series of 5 daily doses and end after 1 week, when the subject transitions to the next treatment Element. If the subject actually started the next treatment Epoch [see Section 7 - Introduction: 7.1.2, Definitions Of Trial Design Concepts] after 4 weeks, the sponsor will have to decide whether to represent this as an abnormally long Element, or as a normal Element plus an unplanned non-treatment Element. Chapter 5, “SE”, P3

Handling on EPOCH level Screening Treatment Follow up Study epochs per protocol: Randomization, Treatment start End of treatment, Date of last trt End of study, consent withdraw

Epoch Level: Subject time axis No FU information collected in Original EDC DB Last treatment 2014-02-01 Consent W. 2014-03-14 Screening Treatment Follow up? LB and EG visit Randomization Treatment start End of treatment, Date of last trt End of study, consent withdraw

How it looks in the data (Option 1) SE ROW ETCD SESTDTC SEENDTC SEUPDES EPOCH 1 SCR 2014-01-01 2014-01-10 SCREENING 2 TRT 2014-02-01 TREATMENT 3 FU 2014-03-14 FOLLOW UP

How it looks in the data (cont.) ROW EPOCH VISIT VISITNUM LBDTC 1 TREATMENT Cycle 2 2 2014-02-01 FOLLOW UP Cycle 3 3 2014-03-07 LB ROW EPOCH VISIT VISITNUM SVDY SVDTC 1 TREATMENT Cycle 2 2 2014-02-01 FOLLOW-UP Cycle 3 3 2014-02-21 ??? End of Treatment 99 2014-03-14 4 End of Study 999 SV Date, where decision to stop treatment and study was made (last subject visit) ROW DSCAT DSSCAT DSDECODE EPOCH DSSTDTC 1 PROTOCOL MILESTONE RANDOMIZATION SCREENING 2013-11-11 2 DISPOSITION EVENT END OF TREATMENT AE ??? 2014-02-01 3 END OF STUDY CONCENT WITHDRAWL FOLLOW-UP 2014-03-14 DS Date of last medication administration

Question to team How to populate EPOCH for „End of Treatment“ (SV obs 3, and DS obs 2) for that case: „FOLLOW UP“ in SV and DS (discrepancy with protocol schedule and SDTM IG as end of treament closed to treatment epoch)? „TREATMENT“ in SV and DS (discrepancy by date and sorting order for SV, discrepancy to SE)? „FOLLOW UP“ in SV and „TREATMENT“ in DS (agreement with SE based on date, but different EPOCH description for same event)? Leave blank?

Element level: Subject time axis No FU information collected in Original EDC DB Last treatment 2014-02-01 Consent W. 2014-03-14 Screening Treatment Unplanned SE, Treatment delay? LB and EG visit Randomization Treatment start End of treatment, Date of last trt End of study, consent withdraw

How it looks in the data (Option 2) SE ROW ETCD SESTDTC SEENDTC SEUPDES EPOCH 1 SCR 2014-01-01 2014-01-10 SCREENING 2 TRT 2014-02-01 TREATMENT 3 UNPL 2014-03-14 Treatment delay 4 FU FOLLOW UP

How it looks in the data (cont.) ROW EPOCH VISIT VISITNUM LBDTC 1 TREATMENT Cycle 2 2 2014-02-01 Cycle 3 3 2014-03-07 LB ROW EPOCH VISIT VISITNUM SVDY SVDTC 1 TREATMENT Cycle 2 2 2014-02-01 Cycle 3 3 2014-02-21 End of Treatment 99 2014-03-14 4 FOLLOW-UP End of Study 999 SV Date, where decision to stop treatment and study was made (last subject visit) ROW DSCAT DSSCAT DSDECODE EPOCH DSSTDTC 1 PROTOCOL MILESTONE RANDOMIZATION SCREENING 2013-11-11 2 DISPOSITION EVENT END OF TREATMENT AE TREATMENT 2014-02-01 3 END OF STUDY CONCENT WITHDRAWL FOLLOW-UP 2014-03-14 DS Date of last medication administration

Questions to team Can we consider Treatment delay as Unplanned Element if it is acceptable according to Protocol Do we need to define „FU“ Element /Epoch for this case in SE and other domains?

Questions to FDA Is variable EPOCH expected in SV and DS domains as well? Is discrepancy between scheduled visit number and EPOCH acceptable if described in RG? (considering option 1 as for other subjects Cycle 3 will correspond to „TREATMENT“ EPOCH) Would it be acceptable to have EPOCH blank with description in Reviewer Guide?