From PDF to RDF – Representing the CDISC Foundational Standards Geoff Low Frederik Malfait, IMOS Consulting Scott Bahlavooni, d-Wise Mitra Rocca, FDA CTS Ontology Workshop, 2015

Agenda Regulatory Submissions Overview CDISC Foundational Standards PhUSE Computational Science Symposium Working Groups CDISC Foundational Standards in RDF Further PhUSE Semantic Technologies Projects

Regulatory Submissions, Current State DM: - USUBJID: 101 - SEX: F - BRTHDTC: 1975-02-22 Demog: - SUBJ: 101 - GENDER: FEMALE - DOB: 02/22/1975 Pharma Co. BioTech Inc. Current state of regulatory submissions - Standards are encouraged, but not required - Data can be provided electronically or submission can be all paper-based.

Regulatory Submissions, Future State 06-Feb-2014, FDA issues (draft) Guidance for Industry: Providing Regulatory Submissions in Electronic Format 06-Feb-2014, FDA issues (draft) Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Standardized Study Data Standards requirements per FDA Data Standards Catalog CDISC tabulation, analysis, and terminology standards are the current supported standards for study data Required 24 months after final guidance (~2017/2018) Discuss guidance. - Note that industry has been expecting this for YEARS. - Note that majority of industry provide subject data in CDISC format; however, non-clinical data is currently not provided in standard format. - Highlight that supported standards are per FDA Data Standards Catalog and that catalog is subject to change. - Note that in addition to guidance, FDA issued a Study Data Technical Conformance Guide that provides sponsors additional information relating to the implementation of CDISC standards.

CDISC Foundational Standards Clinical Data Interchange Standards Consortium (CDISC) Mission: “…to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research…” Provide an overview of CDISC and the different standards - Mention SDTM, SEND, ADaM, and CT are the standards in the referenced in the FDA Data Standards Catalog At the end, say…but…

CDISC Foundational Standards Provide an overview of CDISC and the different standards - Mention SDTM, SEND, ADaM, and CT are the standards in the referenced in the FDA Data Standards Catalog - Metadata Registry At the end, say…but…

Machine-Processable CDISC Foundational Standards? CDISC Foundational Standards are not machine processable Note the types of docs CDISC publishes…model docs, IGs, supplements, Excel workbooks of metadata (not always published) CPATH initiative to develop 55 TA standards in 5 years This requires industry to separately develop their own “machine-processable” representations of CDISC Foundational Standards. CDISC SHARE is supposed to provide a machine-processable representation of CDISC FS, but this is still 2 to 4 years away from a full-production implementation and initial output of SHARE R1 will be CSV. This is where PhUSE CSS comes in

PhUSE CSS Working Groups PhUSE Computational Science Symposium (CSS) Mission: “…bring together academia, industry, technology providers and the FDA to collaborate on projects to address unmet computational science needs.” Overview of CSS collaborations noting “unmet computational science needs” 4 WGs PhUSE website and dashboard Overview of ST project - Note how representation of CDISC standards in RDF helps to address unmet computational science need for machine-processable representation of CDISC standards.

PhUSE CSS Working Groups Semantic Technologies Project: Investigate the application of W3C semantic standards to support the clinical and non-clinical data life-cycle from protocol development to submission to regulatory agencies http://www.phusewiki.org/wiki/index.php?title=Semantic_Technology Overview of CSS collaborations noting “unmet computational science needs” 4 WGs PhUSE website and dashboard Overview of ST project - Note how representation of CDISC standards in RDF helps to address unmet computational science need for machine-processable representation of CDISC standards.

Representation of CDISC Foundational Standards in RDF Project Overview: Representing existing CDISC standards in RDF provides a foundation for interoperable end-to-end data standards in clinical and non-clinical research Separate sub-teams represented individual standards and leveraged CDISC community standards SMEs as needed Separate models were consolidated, vetted within the sub-team co-leadership, and a draft posted to GitHub Collaborate with CDISC to have the RDF representations adopted as CDISC standards

Representation of CDISC Foundational Standards in RDF Data Capture Data Tabulations Data Analysis CDASH v1.1 SEND IG v3.0 SDTM v1.2, v1.3 SDTM IG v3.1.2, v3.1.3 ADaM v2.1 ADaM IG v1.0 CDISC Controlled Terminology Note that NCI publishes CT in RDF already.

CDISC Foundational Standards: RDF Walkthrough Based on ISO-11179 standard for metadata registries Schemas define classes and predicates for ontology to represent CDISC standards RDF datasets in Turtle (ttl) for each CDISC data standard and terminology standard The core element of the Metadata Model is that of an Administered Item, which may represent any item that is managed in an MDR. An administered item must be named and defined within a Context that defines the scope within which the administered item has meaning. A key administered item is that of Data Element that represents a generic unit of data. A Classifier or a defined subclass thereof offers a generic way to classify administered items. This applies in particular to data elements, e.g. an SDTM data element may be classified as Character or Numeric, or also according to compliance classifiers such as Required, Expected, or Permissible. A term of the controlled terminology of a data element is defined by a Permissible Value that is part of an Enumerated Value Domain. Walk through this on the next slide using SDTM.

CDISC Foundational Standards: RDF SDTM IG v3.1.2 Walkthrough

CDISC Foundational Standards: RDF SDTM IG v3.1.2 Walkthrough

CDISC Foundational Standards: RDF SDTM IG v3.1.2 Walkthrough Explain attributes and context

CDISC Foundational Standards: RDF SDTM IG v3.1.2 Walkthrough Explain…relationship btw. Item and controlled terminology At the end explain that other CDISC standards are modeled similarly to SDTM and segue into PRM/SDM

Step 1: Publication Standards available on Github https://github.com/phuse-org/rdf.cdisc.org

Step 2: Documentation

Step 3: Acceptance The CDISC SHARE Metadata Registry will support export of RDF representations matching those developed within the PhUSE ST Foundational Standards workgroup. The NCI controlled terminology representation was updated to match the schema developed.

PhUSE ST Working Groups Activities Representation of Analysis Results Metadata to Support Clinical and Non-Clinical Applications Representing a Clinical Development Plan in RDF Representation of Regulations and Guidance in RDF Representation of the Protocol using RDF Schedule of Activities model in RDF (using the SDM) Representation of Eligibility Criteria in RDF Structured Document Representation using RDF Document Use Cases for Linked Data in the Clinical Trial Life-Cycle keyCRF – semantically rich CRFs for EHR integration determining the logical model for the representation of analysis results and their associated metadata for clinical and non-clinical applications – using RDF Data Cube Develop an RDF information model to capture, retain, reuse and share the design of clinical programs: Design inputs such as claims, target product profile, development plans etc. Design elements such as objectives, endpoints, treatments, patient population, etc. Options being considered for each design decision Rationale for each design decision, including related information, guidance, best practice Various sources (e.g. CDISC standards) refer to regulations and guidance documents. Representing the regulations and guidance documents in RDF enables the linking of said documents to RDF sources Protocol Study Design Model – data and metadata about a study design (includes activities, trial parameter, transitions, etc) Evaluate existing models for Eligibilty Criteria - Eligibility Criteria Model (ECM) described in the TRANSFoRm Project "D6.2 Clinical Research Information Model” Evaluate structured document representations (eg DITA, DocText) – specifically looking at the representation of the common protocol template – developed by TBI Flat tables are boring, and mostly ineffective – how can we use linked data to improve the way we capture, represent and analyse clincal trial data Using the SALUS RDF Metadata repository

Conclusions We have been able to bring industry and standards development organizations around to the value of Semantic Technologies. There are a number of interesting projects (with active communities) ongoing looking at how we can use Semantic Technologies to improve the way clinical research is done. Better trials, better drugs and better Patient Outcomes