1. CDISC Protocol Representation Model: Structuring the Content
Art Gertel
VP, Strategic Regulatory Consulting,
Medical Writing, & QA
Beardsworth Consulting Group

2. ICH GCP Protocol
“A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial.”
This is the ICH definition of a protocol
Thanks to ICH, we already have some guidelines, like the E6, E3, and E9 that help to shape our clinical trial protocols… however, there is still much room for variation of interpretation and implementation of these guidelines

3. The Protocol as Tree Trunk
This is the ICH definition of a protocol
Thanks to ICH, we already have some guidelines, like the E6, E3, and E9 that help to shape our clinical trial protocols… however, there is still much room for variation of interpretation and implementation of these guidelines
Critical Source of Information that is Mapped to Many Other Documents

4. The Clinical Trial Protocol Lifecycle
Drug Approval
Data Archiving
Trial Sponsor; Sites
Regulatory Submission
Trial Sponsor to Agency
Research Hypothesis
PI or Trial Sponsor
Protocol Development
PI or Trial Sponsor
Data Analysis
Reporting of Results
Trial Sponsor
Site/Trial Preparation
Sites;Trial Sponsor; IRB
Trial Management
Trial Sponsor; Sites
Subject Enrollment
Sites
Data Collection,
Monitoring, Processing
Trial Sponsor; Sites

5. Today’s Clinical Trial Protocol
Sponsor-/investigator-specific format
Highly variable in:
Content
Organization
Representation of information
Despite ICH guidelines, Today’s Clinical Trial Protocol is…
TRANSITION:
This variability limits the usefulness of this document and the information that it contains.

6. Today’s Clinical Trial Protocol Limitations
Time-consuming for authoring & review functions
Error-prone
Omission
Corrections/revisions
Lack of coordination/consistency with other parts of submission; i.e., CSR, study data
Each is unique in presentation of information
Applications/use of information are/is limited
Options for access/storage of information is limited
Today’s Protocol is time consuming to author and review…
THIRD BULLET:
Although many companies have created their own templates for the sake of efficiency within their own company, if you think from the perspective of an investigator, IRB, or Regulatory Agency, who receive numbers of protocols from many different companies, it can be a nightmare to navigate through the document to find what you’re looking for
FOURTH AND FIFTH:
These last two points address limitations of today’s protocol that result from the fact that the information is buried within the document itself.
As a result, the usefullness of that data is limited as well as access and storage of that data

7. Tomorrow’s Clinical Trial Protocol
A data layer in the full-text source
Full-text protocol
Database
Data layer
…documents can be married with technology because a data layer is introduced within the full-text source.
This data layer can then be used to feed downstream activities within the trial.
TRANSITION:
This has been the vision for the future of protocols and has been the objective of a standards developing group called…

8. Protocol Representation Project Description
Project Objective(s): Publication of a standard, machine- and human-readable model for protocol representation that will enable interchange of data among systems and stakeholders.
Support the entire life-cycle of clinical research protocols to achieve semantic interoperability (the exchange of content and meaning) among systems and stakeholders

9. Interoperability Main Entry: in·ter·op·er·a·bil·i·ty:
ability of a system ... to use the parts or equipment of another system
Source: Merriam -
Webster web site
Interoperability:
ability of two or more systems or components to
exchange information and to use the information that
has been exchanged.
Syntactic
Semantic
interoperability
interoperability
Source: IEEE Standard Computer Dictionary: A Compilation of
IEEE Standard Computer Glossaries, IEEE, 1990

10. Protocol Representation Project Description
Protocol Representation will identify standard elements of a clinical trial protocol that can be further clarified and codified to facilitate:
study design,
regulatory compliance,
project management,
trial conduct,
data interchange among consumers and systems.
This work will be based upon the needs of protocol “consumers”.
Analysis/interpretation of clinical data
Management of clinical trial 10 10

11. Protocol Representation Group Approach
Content 1st - Implementation 2nd
Elements were defined in a glossary
CDISC Glossary, Applied Clinical Trials, published annually
Identified core set of elements initially
Source references
ICH E6 - Basis for the development and organization
ICH E3 - Terms & definitions
21CFR
FDA/EU Guidance
EudraCT (EMEA)
Subject Matter Experts

12. Modeling the Clinical Trial Protocol Standard
We did developed initial model through HL7
Based on HL7 Reference Information Model (RIM)
Uses HL7 Version 3 information model and data types
Based on the HL7 Clinical Document Architecture (CDA)
XML schema
Why XML?
Application independent
Preserves human readability of documents
And the Semantic markup of documents facilitates machine processability, e.g.:
Extraction
Storage in a database
Re-use (including combination from multiple sources)
Interchange
Automation
Re-ordering

13. Clinical Trial Registry Information
PRM v1.0 includes
WHO Trial Registration Data Set
ClinicalTrials.gov Registration Data Elements for Interventional Studies
Study Summary
Title, Short Title, Acronym, ID
Study Type, Phase, IND/IDE
Sponsors, Investigators
Interventions
Oversight, IRB, Data Safety Monitoring
Eligibility Criteria
Protocol Tracking
Status, Recruitment Status, Location 13

14. Eligibility Criteria Minimum Age Maximum Age Gestational Age
Subject Gender
Pregnancy
Nursing
Current Population Disease Condition
Past Population Disease Condition
Prior and Concomitant Medication(s)
Subject Ethnicity
Subject Race(s)
Special Populations
Ethical Considerations (e.g. informed consent)
BMI
Lifestyle Choices
Substance Use 14 14

15. Protocol Identification
Protocol Elements
Protocol Identification
CT.gov
CSR
Protocol Title
table of studies
synopsis

16. Protocol Identification
Protocol Elements
Protocol Identification
CT.gov
CSR
Protocol Identifying
Number
synopsis
ISE/ISS

17. Protocol Elements Study Population CT.gov CSR table of studies
Subject Ethnicity
synopsis
label
ISE/ISS

18. Protocol Identification
Protocol Elements
Protocol Identification
Protocol Title – CSR, table of studies, synopsis, CT.gov
Protocol Short Title – Internal reference, CT.gov
Protocol identifying number – CSR, table of studies, synopsis, ISE/ISS, CT.gov
Regulatory Investigational Product Number – Regulatory Correspondence
Protocol Approval Date – appendix to CSR, perhaps CSR text
Amendment Number – appendix to CSR, perhaps CSR text
Amendment Date – appendix to CSR, perhaps CSR text
Confidentiality Statement - CSR

19. Protocol Elements Study Population
Target patient population – CSR, table of studies, synopsis, labeling, BG/introduction, NDA summary, ISE/ISS, benefit/risk, and similar sections of Module 2 of CTD, label, CT.gov
Subject Age Range(s) – CSR, table of studies, synopsis, NDA, label. summary, ISE/ISS, and similar sections of Module 2 of CTD, CT.gov
Subject Gender – CSR, table of studies, NDA summary, ISE/ISS, and similar sections of Module 2 of CTD, label, CT.gov

20. Protocol Elements Study Population
Population Disease Condition – CSR, synopsis, labeling, BG/introduction, NDA summary, ISE/ISS, benefit/risk, and similar sections of Module 2 of CTD, label, CT.gov
Subject Ethnicity – CSR, synopsis, ISE/ISS, label, CT.gov
Subject Race(s) – CSR, synopsis, ISE/ISS, CSE/CSS, label, CT.gov
Special Populations – labeling, NDA summary, ISE/ISS, benefit/risk, and similar sections of Module 2 of CTD, label, CT.gov

21. Protocol Element Standards
Study
Mgmt
Medical
Records
Regulatory
Review
IND
‘Use Cases’
Source
Documentation
Regulatory
Submission
Cross-trial DB
Submissions
CT DB
Clinical
Trial
Data
Fields
(CRF)
Operational
Database
(Data Mgmt,
Analyses)
SDS*
Clinical
Trial
Protocols
HL7 CDA*
ODM*
Set-up
CRFs
ADaM*
CTD *
LAB *
This slide captures many of those downstream systems and stakeholders
Trial
Reports
Analysis
Plans
Clinical
Laboratory
IRB

22. Protocol Representation Model - Development
XML Schema Development (ODM Extension)
Protocol Representation
Excel Spreadsheet
BRIDG Mapping; Harmonization
PRM v1.0 Standard
Documentation
Clinical Trial Tracking,
Study Summary (SDTM)
Clinical Trial Registry
Eligibility Criteria
(most common)
PRM
V 1.0
Q2 2009
CDISC Trial Design Part I
(arms, elements, visits)
CDISC Trial Design Part II
Planned assessments
& interventions
(NCI Study Calendar)
CDISC Statistics
PRM
V 1.x
(2010)
Other Protocol
Template Sections
and Attachments

23. Constant Vigilance and Updating are Required
Glossary Team
The CDISC Glossary contains the definitions for protocol elements, either as definitions from another source (e.g. ICH, FDA, ACT, HL7) or as definitions developed by the CDISC Glossary Group, which collaborated closely with the PR Group.
Constant Vigilance and Updating are Required

24. Registry Information

25. Protocol Representation

26. Semantic Interoperability - a Portal to Healthcare
BRIDG
The Biomedical Research Integrated Domain Group (BRIDG) Model is a domain analysis model representing protocol-driven biomedical/clinical research.
It was developed to provide an overarching model that could readily be understood by domain experts and would provide the basis for harmonization among standards within the clinical research domain and between biomedical/clinical research and healthcare.
Semantic Interoperability - a Portal to Healthcare
The BRIDG Model serves to bridge standards, as well as organizations and various communities, including academic research institutions and pharmaceutical product development organizations and related service and technology providers. It is also bridging the gap between clinical research and healthcare.

27. BRIDG Sponsors

28. What is a Domain Analysis Model (DAM)?
An implementation-independent view of the Problem Space
from the Domain Expert’s perspective
A DAM must be readable by ‘the domain expert on the street’
A DAM defines ‘what’ (static and dynamic aspects)
A design model defines ‘how’
The most important feature is that it separates the semantics of analysis (“the Problem Space”) from those of design (“the Solution Space”) – “what” vs “how” 28
Source: Charlie Mead 28

29. 29 29

31. Mapping to BRIDG

32. Section hierarchy groups the elements based on ICH.
Definition Source indicates the glossary, dictionary, or other source where the element definitions come from
Element Names are the names of the common protocol elements identified by the PRG.
BRIDG Mapping indicates the name of the BRIDG element to which each PR element is mapped.
Figure : Partial view of PR Elements Spreadsheet. The spreadsheet helps define and elaborate on the standard elements, and maps them to elements in the BRIDG model.

33. The protocol includes 2 views of a study: The experimental design
Study Design
The protocol includes 2 views of a study:
The experimental design
Often represented in a study schema
The schedule of activities
Often represented as a time & events table
Source: Diane Wold

34. Representation of the Experimental Design
Main BRIDG experimental design concepts:
Arm – a planned path through the study
Epoch – one of a sequence of time periods into which a subject’s participation in the study in divided
Study Cell – the “intersection” of an Arm and an Epoch
Study Segment – a re-usable set of activities that represents a treatment strategy (or part of one)
Study Cell “contains” one or more study segments
Source: Diane Wold

35. Study Design Diagram Run-in Epoch First Treatment Epoch
Second Treatment
Epoch
Follow Up
Epoch
Run-in
A 5 mg
A 10 mg
B 5 mg
B 10 mg
Follow Up
Arm AB
Run-in
B 5 mg
B 10 mg
A 5 mg
A 10 mg
Follow Up
Arm BA
NB: Some features are based on best guesses from original diagrams
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 study segments.
Source: Diane Wold

36. Representation of the Schedule of Activities
Main BRIDG concepts
Activities
Subject Study Encounters, planned times in which a subject is involved in study activities
More general than clinic visits
SoA Cells (schedule of activities cells) connect an Activity to a Subject Study Encounter
Complexities are handled with relationships between activities
Allow composition of complex activities
Provide “rules” that allow performance of activities to depend on the timing or results of other activities
Source: Diane Wold

37. Connecting the Two Views
The experimental design is driven by the objectives of the study
The activities planned to achieve the purposes of the study are linked to Study Segments
Administration and assessment of treatments
Determination of eligibility in screening epochs
Assessment of post-treatment effects in follow-up epochs
The timing and conditions for performing the study procedures are detailed in the schedule of activities
Source: Diane Wold

38. How will the SCTP change what You do?
Less wordsmithing and haggling over terminology
Increased collaboration among Data Management, Statistics, Medical Writing, and others.
Reduced preparation and review time for applications
Increased automation of study processes through enhanced use of technology
Development of the protocol
Conduct of a trial
Preparation of data
Visualization of results
Analysis and reporting
Structured authoring and structured content aren’t new concepts –authors already structure content
Templates
Guidelines from agencies
Community “best practices” and implementation guides
Tool features and limitations

39. Implementations of the Protocol Model
CDISC SDTM standard*
Trial summary and text eligibility criteria
Study design schema and visits
CDISC ODM Study Design extension
Trial summary and text eligibility criteria, complete study design
HL7 Clinical Trial Registration and Results message
HL7 Study Design message
Related messages for Study Participation and Subject Data
caBIG® Patient Study Calendar (PSC) application*
Schedule of activities
ASPIRE
Eligibility criteria
IHE Retrieve Protocol for Execution profile
Allows EHR systems to “consume” standard protocol data
* In production, others in development

40. Next Steps Addressing over 250 comments received
Plan to publish next version Q4
Additional information
Archived webcast at BetterManagement.com
Standards Aren’t Just for Data Anymore: Reap Benefits from a Standards-based Approach to Study and Protocol Design (audio seminar)

41. This slide is just a snapshot of the CDISC Website where there are links to most of the work products of the PR Group.
This work has been the bulk of the PR Group effort to date. It has been important because these elements serve as the foundation for the modeling efforts.

42. Thank You! www.cdisc.org Art Gertel
VP, Strategic Regulatory Consulting, Medical Writing, & QA
Beardsworth Consulting Group
70 Church Street
Flemington, NJ USA
(908) 42 42