trial design model tutorial -...
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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