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

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

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

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

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.

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

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…

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

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

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

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

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

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

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

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

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

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

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  

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

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

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

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

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

Registry Information

Protocol Representation

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.

BRIDG Sponsors

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

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Mapping to BRIDG

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.

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

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

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

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

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

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

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

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) http://www.bettermanagement.com/seminars/seminar.aspx?l=14998

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.

Thank You! www.cdisc.org Art Gertel VP, Strategic Regulatory Consulting, Medical Writing, & QA Beardsworth Consulting Group 70 Church Street Flemington, NJ 08822 USA artg@beardsworth.com (908)806-5983 42 42