Elke Sennewald, 22 September 2011

Trial Design Introduction

• Information about study design

– No subject data

• Describe the overall trial design and plan via data representation

Trial Design Domains

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!

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?

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

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?

8

Example 1 – Trial Design Schema

ScreenDrug A

Drug B

Follow-up

Follow-up

9

Epoch

ScreenDrug A

Drug B

Follow-up

Follow-up

Screening Treatment Follow-upEPOCH

10

Arm / Treatment Strategy

ScreenDrug A

Drug B

Follow-up

Follow-up

Screening Treatment Follow-up

AR

M(T

rea

tme

nt

Str

ate

gy)

1

2

11

Arm / Treatment Strategy

ScreenDrug A

Drug B

Follow-up

Follow-up

Screening Treatment Follow-up

Study Cell

1

2

Screen

Screen

Drug A

Drug B

Follow-up

Follow-up

12

Trial Design Matrix

Screening Treatment Follow-up

A

B

Screen

Screen

Drug A

Drug B

Follow-up

Follow-up

13

TE (Trial Elements)

• What are the elements?

– Unique study cell values (=ELEMENT)

Screen

Drug A

Drug B

Follow-up

Trial Visits describes the planned Visits for each Arm, and any start and end rules.

Screen Run-In Drug A

Screen Run-In Drug B

Screening

Screen Run-In Placebo

Drug A

Drug B

Trial Arms describes the Elements in each Arm, their order and Epoch, and any branching or transition rules.

Screen Run-in Placebo

Drug A Drug B

Trial Elements describes the Elements and the rules for the start and end of each.

Placebo

Run-In TreatmentEpochs are described only in Trial Arms, and have no separate table.

Visit 1

Visit 2

Visit 3

Visit 4

Visit 5

Trial Arms and Elements Overview

15

Trial Design Matrix

Screening Run-in Treatment

A

B

Screen

Screen

Run-in

Run-in

Drug A

Drug B

P Screen

Run-in

Placebo

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

Screen Run-in Placebo

Drug A Drug B

Trial Elements describes the Elements and the rules for the start and end of each.STUDYID DOMAIN ETCD ELEMENT TESTRL TEENRL TEDUR

1999001 TE SCRN Screen Informed consent signed

Start of next element or date subject dropped

P2W

1999001 TE RUNIN Run-in First dose of run-in drug

Start of next element or date subject dropped

P1W

1999001 TE PLAC Placebo First dose of placebo

Start 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

STUDYID DOMAIN USUBJID SESEQ ETCD ELEMENT SESTDTC SEENDTC SEUPDES

1999001 SE 145-011 1 SCRN Screen 2003-04-01 2003-04-15

1999001 SE 145-011 2 RUNIN Run-In 2003-04-15 2003-04-22

1999001 SE 145-011 3 PLAC Placebo 2003-04-22 2003-05-06

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

Screen Run-In Drug A

Screen Run-In Drug B

Screen Run-In Placebo

Drug A

Drug B

Placebo

STUDYID DOMAIN ARMCD ARM TAETORD ETCD TABRANCH EPOCH

1999001 TA P Placebo 1 SCRN Screen

1999001 TA P Placebo 2 RUNIN Randomized to Placebo

Run-In

1999001 TA P Placebo 3 PLAC Treatment

1999001 TA A Drug A 1 SCREEN Screen

1999001 TA A Drug A 2 RUNIN Randomized to Drug A

Run-In

1999001 TA A Drug A 3 DRUGA Treatment

1999001 TA A Drug B 1 SCREEN Screen

1999001 TA A Drug B 2 RUNIN Randomized to Drug B

Run-In

1999001 TA A Drug B 3 DRUGB Treatment

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

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

STUDYID DOMAIN VISITNUM VISIT VISITDY ARMCD ARM TVSTRL TVENRL

1999001 TV 1 Visit 1 Signing of informed consent

Completion of lab draw

1999001 TV 2 Visit 2 30 minutes before receipt of Run-In drug

1999001 TV 3 Visit 3 30 minutes before receipt of blinded treatment

30 minutes after receipt of blinded treatment

1999001 TV 4 Visit 4 1 week after receipt of blinded treatment

1999001 TV 5 Visit 5 2 weeks afterreceipt 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 – don’t wait till the end

– Details vs ease of use