Trial Design Model Tutorial

RTP CDISC User’s Group

June 4, 2013

Diane Wold

Overview

• Regulatory basis and scope

• The Study Schema in SDTM

• Trial Visits in SDTM

• Trial Inclusion/Exclusion

• Trial Summary

• Subject Elements and Subject Visits

• Trial Design Template (backup)

Regulatory Basis

ICH Guidance: E3, Section 9.1

• “The overall study plan and design

(configuration) of the study (e.g., parallel,

crossover) should be described briefly but

clearly, using charts and diagrams as needed.”

• Annexes III has “charts and diagrams” for two

studies, namely for each study

– Study design (aka study schema)

– Schedule of assessments (aka schedule of activities)

Study Schema

1st ICH example

Schedule of Activities

1st ICH example

Study schema

2nd ICH example

Schedule of Activities

2nd ICH Example

Regulatory Basis

FDA Requests

• Trial Summary

• Trial Inclusion/Exclusion

• Study Schema

• Schedule of activities i.e.,

– Planned assessments

– Planned interventions

CDISC Standards

For Study Design • SDTM (for human clinical trials)

– FDA proposed structures. Intended to support submission of data in SDTM.

– Summary, Inclusion/Exclusion, and Study Schema covered

– In Schedule of Activities, only Trial Visits covered

• Real world scheduling includes repetitions and contingencies difficult to represent in

SDTM tables

• SEND – adds Trial Sets dataset (fixed-size sub-groups within arms)

• Protocol Representation Model (PRM)

– Worked from ICH guidance. Intended to provide structured representation of

parts of the protocol

– Became a subset of the BRIDG model

– Covers everything, but in UML, in a fairly abstract way

• SDM extension to ODM

– More complete study schema and schedule of activities capability than SDTM

– In xml, not datasets, not part of a submission.

The Study Schema in SDTM

Terminology • Arm: A path through the trial from beginning to end. An

arm is usually associated with a treatment strategy in the study objectives. Each subject is assigned to an arm.

• Epoch: The period of subjects’ participation in the trial is divided into epochs. Each epoch serves a purpose related to the trial’s objectives, usually exposure to a treatment, or preparation for or follow-up after treatment.

• Study Cell: The “intersection” of Arm and Epoch, a cell in the Trial Design Matrix

• Element: A re-usable building block of the trial. Each study cell has a pattern of elements. Many study cells have just one element, but a study cell can have many elements.

Follow Up

Epoch

Treatment Epoch

Screen Epoch

Example showing arms, epochs, trial cells, and elements

Screen

Screen

Follow Up

Follow Up

X P

A two-arm trial comparing Treatment X with and without Pre-treatment P

X

Arm PX

Arm X

Columns shown with large rectangles “in back” are epochs.

Rows marked by arrows are arms.

Rectangles with heavy outlines are study cells.

Rectangles within the trial cells are elements.

Trial of Drug A vs. Placebo

Treatment Epoch

Screen Epoch

Screen

Screen

Drug A

Placebo

Drug A

Placebo

Crossover trial of AB vs. BA

First Treatment

Epoch

Screen Epoch

Screen

Screen

A Arm AB

Arm BA B

Second Treatment

Epoch

B

A

A trial of drug therapy vs. surgical

treatment

Treatment Epoch

Screen Epoch

Screen

Screen

Drug

Surgery

Follow Up

Epoch

Follow Up

Follow Up

Drug

Pre-op Surgery Post-op

Trial with cycles of chemotherapy

Treatment Epoch

Screen Epoch

Screen

Screen

Drug A

Drug B

Cycles of chemotherapy are repeated until disease progression.

The pattern of elements within each of the treatment trial cells is

expressed with a repeating rule; cannot be represented with a fixed

number of elements in this diagram.

Follow Up

Epoch

Follow Up

Follow Up

Cycle A Repeat cycle until

disease progression

Cycle B Repeat cycle until

disease progression

Trial comparing drug and placebo

in treating a disease episode

Treatment Epoch

Screen Epoch

Screen

Screen

Wait Drug A

Placebo

Drug A

Placebo

Subject is randomized at end of screening, but must wait until a

disease episode to administer treatment.

Wait

Titration Trial of A vs. B

Treatment Epoch

Screen Epoch

Screen

Screen

Titrate A Arm A

Arm B Titrate B

Constant Dose A

Constant Dose B

Drug is titrated to a subject-specific dose that meets protocol-defined criteria.

A trial comparing AX to BX,

with switching from X to Y if needed

Treatment Epoch

Screen Epoch

Screen

Screen

AX A

B

AY

BY

If subject does not meet criteria for adequate disease criteria while

treated with the initial combination containing X, they are switched to

the combination containing Y.

BX

Trial Used for SDTM/ADaM Pilot Treatment Epoch

Screen Epoch

Screen

Screen

Placebo

Low

Screen High

Placebo

Low

High

Follow-up

Epoch

Follow-up

Follow-up

Follow-up 2 2

2-week

low-dose

element

2-week

low-dose

element

Transition between elements in the High arm was achieved via distribution of

pre-packaged clinical trial material, which maintained blinding between the arms.

Modeling a Study’s Schema

• Identify the Epochs

– Associated with “treatment strategies” rather than

treatment administration detail

– Start with Screen-Treatment-Followup and add

additional Epochs as needed

• Identify the Arms

– Watch out for

• Multi-stage assignment

• Major path variations within an arm

• Identify Elements within the Study Cells

– Don’t try to model dose modifications within an arm

Example Trial 3: Multiple Branches

Screen

Drug A

Drug B

Open Drug A

Rescue

Open Drug A

Rescue Randomization

Response Evaluation

Example Trial 3: Four Arms

Randomization Response Evaluation

Screen Drug A Open Drug A

Screen Drug A Rescue

Screen Drug B Open Drug A

Screen Drug B Rescue

A/Open A

A/Rescue

B/Rescue

B/Open A

Open

Label

Double

Blind

Screen

Example Trial 3: Arms and Epochs

Randomization Response Evaluation

Screen Drug A Open Drug A

Screen Drug A Rescue

Screen Drug B Open Drug A

Screen Drug B Rescue

A/Open A

A/Rescue

B/Rescue

B/Open A

3-5w

Rest

Example Trial 7, RTOG 93-09:

Open Trial with Dissimilar Arms

Screen

Induction

Chemo + RT

Induction

Chemo + RT

Surgery

Additional

Chemo

Off Treatment

Follow-up

Off Treatment

Follow-up

Additional Chemo

+ RT Boost

Randomization

Evaluation for disease progression

Evaluation/consent for surgery

Off Treatment

Follow-up

Off Treatment

Follow-up

4-6w

Rest Additional

Chemo

Off Treatment

Follow-up

3-5w

Rest

Example Trial 7, RTOG 93-09:

Open Trial with Dissimilar Arms

Screen

Induction

Chemo + RT

Induction

Chemo + RTSurgery

Additional Chemo

+ RT Boost

Randomization

Evaluation for disease progression

Evaluation/consent for surgery

Off Treatment

Follow-up

4-6w

Rest

Additional

Chemo

Off Treatment

Follow-up

Trial Visits

• Trial visit start rule

– Visit starts expressed relative to epoch or element transitions

– In a parallel trial with a single treatment epoch, this means

relative to start of treatment

• Trial visit end rule

– Expressed relative to start of visit

– If epoch/element transition (e.g., start of treatment) is within the

visit, important to note this

– If not specified in the protocol (the usual case), use a descriptive

phrase

• If arms have different visit schedules, include ARM in

dataset

Trial Inclusion/Exclusion

Basically simple, BUT

• Some criteria are long and complex

• Criteria may be revised through protocol

amendments

– Multiple versions can be submitted

– Version for a individual subject not covered

explicitly in SDTMIG

Trial Summary

• Dosing variables may require linking and

this can be challenging

• Revisions in SDTMIG 3.1.3

– Driven by FDA

– Includes some summaries of the performed

study, as well as summaries of the plan

– Requirements for parameters added

SUBJECT ELEMENTS, VISITS

Subject Elements

• Allows reviewer a quick check of whether the subject followed their

assigned arm

• Collected data must include (or allow derivation of) dates of starts of

elements

– Screening starts with informed consent

– EX should provide dates for starts of treatment elements

– Start of wash-out or follow-up elements usually based on ends of

treatment

• End date of one element = start date of next element – NO GAPS!

– End date of last element = date of final disposition

• Assumptions used for subjects lost to follow-up?

• Include unplanned elements only for glaring errors (wrong treatment,

big time gaps)

Subject Visits

• Allows reviewer a quick check of whether the subject followed the

visit schedule

– Implies numbers for unscheduled visits are most useful to a reviewer if

they are consistent with chronological order

• Unplanned visits, multiple dates for a visit force you to make

decisions.

– When does an assessment done on a different date constitute a

separate visit?

• Visit numbers assigned to unscheduled visits in data management

may not be suitable for use in SV

– Using one VISITNUM for all unscheduled assessments (e.g., 99) not

appropriate

– Have to decide whether assessments in different domains made

between a pair of successive planned visits represent one or multiple

visits

TRIAL DESIGN TEMPLATE

Available on the CDISC Members’ website

Trial Design “case studies”

• Posted on CDISC Members’ website

– Select “Case Studies” from left-hand panel

– Scroll down to “Trial Design Examples”

• Includes Excel-based template

– Hasn’t been updated to SDTMIG 3.1.3

• Includes several example studies

An Excel Tool for Creating

SDTM TDM datasets

• Create the Trial Design Matrix – Starts with Screen, Treatment, Follow-up

– Add additional Treatment Epochs as needed

– Add run-ins, wash-outs, etc., if needed

– Starts with 2 Arms, add or drop arms as needed

• Fill in the Study Cells – If more than one element in a study cell, add a

column, “merge cells” in “epoch” row.

– If different numbers of elements in the study cells for an epoch, “merge cells” in the study cells with fewer elements

An Excel Tool for Creating

SDTM TDM datasets (2)

• Macros within the spreadsheet transfer

information to SDTM Trial Arms dataset

• Macros also transfer information to the SDTM

Trial Elements dataset

– Add start rules and end rules for the elements

• Other datasets

– TV: copy visits from schedule of activities, add start

and end rules for visits

– TI: cut and past from protocol

– TS: extract from protoocl