Schizophrenia and Major Depressive Disorder: Experience in Developing New Therapeutic Area Standard Data Elements in Mental Health Duke Translational Medicine Institute Meredith N. Zozus1, Amy Palmer2, Rhonda Facile2, Steve Kopko2, Anita Walden1 1Duke Translational Medicine Institute, 2Clinical Data Interchange Standards Consortium Abstract Methods Results Two new standard data element sets, one in schizophrenia and the other in major depressive disorder (MDD) have recently been published. These data element sets represent priority areas listed in the FDA’s Therapeutic Area Data Standardization program goals, and the FDA supported their development. The Clinical Data Interchange Standards Consortium (CDISC), under the Coalition for Accelerating Standards and Therapies (CFAST) Initiative, is translating the schizophrenia data element sets into CDISC submission standards and plans to publish a Schizophrenia Therapeutic Area User Guide (TAUG) in early 2015; in addition, there are plans for developing an MDD TAUG. This collaboration entailed the Duke team working within Health Level 7 (HL7) to develop the initial data element sets (94 total data elements for MDD; 85 for schizophrenia), which were then delivered to CDISC to develop the required submission metadata. Candidate data elements were identified from 4 sources: 4. Data collection forms from clinical studies funded by the National Institute of Mental Health (NIMH) 1. Existing standards 2. Diagnostic and Statistical Manual of Mental Disorders IV and 5 (DSM-IV-TR and DSM 5) Candidate data elements were compared to identify semantically equivalent/ similar concepts. Semantic analysis provided a list of distinct concepts to become data elements. Definitions and 3. Data collection forms from phase III pivotal trials submitted for marketing authorization Figure 1. Relationships Between Data Elements: CDISC & HL7 Models Inform Information Models Research Representation (CDISC SDTM) Implementable Specifications CDISC ODM Standard Data Elements HL7 CDA Healthcare Representation (HL7 Domain Model) HL7 Message HL7 EHR Profile CDASH is the CDISC standard that specifies data elements; HL7 documents data elements in Domain Analysis Models (DAM). Both CDISC and HL7 rely on controlled terminologies, utilize the data or information model as the middle layer, and use the information model (SDTM for CDISC and DAM for HL7) to document relationships between data elements. While an information model may be used to specify data storage, or views upon which to facilitate reporting, information models are not the “terminal point” for CDISC or HL7. Both groups use technical specifications for data exchange (ODM for CDISC and CDA or messages for HL7). enumerated permissible values were drafted from the DSMs and from form context. Draft data elements were reviewed by a committee including clinical experts from industry, academia, and clinical professional societies. Elements were represented in the ISO 11179 model and a UML class diagram. UML use cases were written and corresponding use case and activity diagrams were created. These artifacts were balloted through Health Level Seven (HL7) at the Informative level. Data elements and other artifacts were then passed to CDISC to begin work on the Schizophrenia TAUG. The majority of CDISC’s work began with the development of draft standards (Stage 2 of CFAST development process), which builds on the provided data In September 2013, the schizophrenia and MDD data elements became HL7 standards. For each therapeutic area, an estimated 11,000 data elements were reviewed (Table 1). The final data element sets include 85 data elements for schizophrenia, 62 of which are designated and defined as common data elements that will be used in other mental health disorders. The final data element set for MDD contains 94 data elements, 57 of which are from the common data element set. The number of comment rounds and ballots is shown in Table 2 along with comment counts and dispositions at each round/ ballot. The TAUG-Schizophrenia v1.0 includes the following: • Overview of schizophrenia • Trial design (diagrams, textual explanations, and data examples) • Brief overview of schizophrenia-related differences between DSM-IV and DSM 5 (diagnosis data examples) • Disease assessments (instruments used to assess schizophrenia patients, data examples for psychotic episode and worsening of symptoms, and clinical studyspecific discontinuation data) • Routine data (concomitant medications, labs of interest, and pharmacokinetic data examples) • Concept maps (Figure 3) and a list of references The schizophrenia and MDD data standards exist in the context of larger initiatives to standardize clinical data elements that include FDA efforts to standardize 60 therapeutic areas over 5 years and the creation of performance measures and associated data elements to serve Meaningful Use requirements. To meet these national goals, both CDISC and HL7 have ongoing data element standardization programs, and a number of therapeutic area standards have already been released (Tables 3 and 4). Next Steps for Standards 1. Release of CDISC Schizophrenia TAUG v1.0 for public comment in late 2014 Figure 3. Concept Map for Schizophrenia Diagnosis 2. Testing of data standards/ public notice announcing a comment or testing period 3. Once standards are deemed acceptable by the FDA, a guidance discussing their use will likely be produced Table 3. CDISC/CFAST Therapeutic Area Standards Therapeutic area Version Status Date Alzheimer’s disease 2.0 Provisional Dec 16, 2013 Tuberculosis 1.0 Provisional Jun 29, 2012 Pain 1.0 Provisional Aug 07, 2012 Virology 1.0 Provisional Dec 06, 2012 Parkinson disease 1.0 Provisional Dec 18, 2012 Polycystic kidney disease 1.0 Provisional Feb 26, 2013 Asthma 1.0 Provisional Nov 26, 2013 Multiple sclerosis 1.0 Provisional May 05, 2014 Release Status Date Tuberculosis+ R1 Published Feb 2009 Cardiology+ R2 Published Mar 2012 Vital records+ (VR DAM) R1 Published Apr 2011 Immunization+ R1 Published May 2012 Allergy and intolerance+ R1 Published Mar 2014 Data elements for emergency department systems R1-US Published Oct 2013 Body weight and body heightD R1 Published Jan 2013 R1-US Published May 2012 Preoperative anesthesiology+ R1 Published May 2013 Emergency medical services+ R1 Published May 2013 Family history/pedigree interoperability IG R1 Published Apr 2013 Blood, tissue, organ; donation† R1 DSTU Jul 2013 Implantable device cardiac — follow-up summary† R2 Published Oct 2013 Pressure ulcer prevention+ R1 Published Aug 2013 Trauma registry data submission+ R1 Balloted Sep 2013 Schizophrenia+ R1 Balloted Sep 2013 Major depressive disorder+ R1 Balloted Sep 2013 Table 1. Metrics from Schizophrenia and MDD Data Element Standardization Figure 2. Data Standardization Process YES Schizophrenia Major Depressive Disorder (MDD) 7 7 Number of compounds Scope of effort decided 1. Identify sources of candidate data elements (DEs) 2. Synthesize candidate DEs to into a set of distinct concepts 3. Harmonize candidate DEs with existing standards 6. Curate standard DEs in public data element registry (caDSR, USHIK) 4. Define & vet candidate DEs with Clinical Experts Change needed? NDA trial CRFs reviewed Funding Acknowledgment Ballot passes? YES 7. Finalize 2° data use representation, e.g., CDISC SDTM Secondary use representation, e.g., SDTM public comment NO Changes Needed The schizophrenia standard data elements were funded under grants R24FD004271 and 1R24FD004655 to Duke University and CDISC, respectively. The major depressive disorder (MDD) standard data elements are funded under grant R24-FD004656 to Duke University. These grants were funded by the United States Food and Drug Administration (FDA). The contents of this poster reflect the opinions of the authors and do not necessarily represent those of the FDA. Stage 0 START Stage 1 Scoping & Planning Inform Governance Committee Approval 01 SRC Approval 04 CDISC POP-001 Draft Educational Materials Team Comment Tracker Internal Review Checklist Draft Standards Package SRC Approval 05 CDISC POP-001 Public Comment Tracker Public Posting Process Checklist Draft Standard Package Number of data elements abstracted 4156† TA specific candidate data elements 212† 584 466 85 94 Final number of TA specific 26 39 Number of common data elements used 62 57 Rating scales & questionnaires 154 87 *Estimated assuming 550 data elements per CRF. Estimated counts do not include data elements from non-NDA sources, e.g., NIMH funded trials or the DSM. do not include data elements from rating scales and questionnaires. Schizophrenia Number of CERC reviews* Number of comments: Stage 4 Sept 2012 ballot/CERC review 2 Maintenance and Education 06 CDISC POP-001 CDISC Website Announcements Checklist Lessons Learned Templates Final Education Materials Provisional/Final Standard Document, Education Package Archival Checklists and Artifacts 11,000 Total number of data elements CERC review 1 Public Release 5 Table 2. Metrics for Clinical Reviews & Ballots CDISC POP-001 SHARE Metadata Templates Controlled Terminology TAUG Document Template SRC QC Checklist Draft TAUG Stage 3c Public Review 11,000 11 Development of Draft Standards 03 CDISC POP-001 BRIDG Gap Assessment Concept Listing Template, Concept Modeling Training, Concept Maps, Check of Concepts List of Concepts TAUG Document Template Stage 3b Internal Review Governance Committee Approval 3 Number of NDA data elements reviewed* †Counts 02 CDISC POP-001 Project Proposal Template, Charter Template Project Plan Template Survey Template Scoping Checklist Template, Concept Listing Template Lessons Learned Template Stage 3a Stage 2 Identification/Modeling of Research Concepts 20 NIMH trial CRFs reviewed HL7 Informative standard 5b. Create/ update DAM, initiate HL7 Public Ballot Meredith N. Zozus, PhD Associate Director for Clinical Research Informatics Biomedical Informatics Core Duke Translational Institute DUMC Box 3850 Durham, NC 27710 [email protected] Both Health Level 7 (HL7) and CDISC approaches adhere to a 3-level structure in which data elements are the most granular level of concept description (Figure 1). CDISC also requested copyright permission to develop supplements outlining the mappings of prioritized clinical outcomes assessment instruments used to evaluate schizophrenia patients. These supplements are developed independently of the TAUG and are maintained on the CDISC 5a. Draft 2° data use representation, e.g., CDISC SDTM Contact Information website at http://www.cdisc.org/ ft-and-qt. element list to develop examples and metadata that enhance and finalize concepts. Using these mappings, data examples were created to illustrate these concepts (medical and family history; characterization of current episode; relapse information). The draft TAUG then cycled through Internal Review (allowing relevant CDISC teams, collaborative groups, and subject matter experts to review the new standards) and Public Review (to facilitate broad comment by the general public). Discussion CERC review 3 07 Issue Tracker Capture Feedback Education Package CERC response, remission, relapse 1 CERC response, remission, relapse 2 Sept 2013 ballot/CERC review 6 Number of HL7 ballots Major Depressive Disorder (MDD) 6 4 751 689 395:144/157/094 590:290/187/113 188: NA/105/083 081: 052/016/013 31 comments 32 comments NA NA 32 comments 23 comments 024: 004/018/002 044: 002/039/003 2 1 *Counts include initial CERC reviews, CERC reviews done during HL7 ballots, and 2 additional review cycles that were done to define and vet response, remission, and relapse concepts Table 4. HL7 Domain Model Standards Therapeutic area# Summary behavioral health record (BHCCD DAM+) #Pharmacy & Lab Data Elements not listed because they apply to all therapeutic areas +HL7 Version 3 Domain Analysis/Information Models DHL7 Version 3 Detailed Clinical Models IGHL7 Version 3 Implementation Guide †HL7 Version 3 Specifications Conclusions Development of data standards is an iterative process, one followed by an equally iterative maintenance process. As data element sets are released, organizations will be able to evaluate what efforts will be required to implement them internally. Likewise, the release of the TAUG offers a similar opportunity to evaluate how the therapeutic area data elements should be represented in the CDISC SDTM model. Organizations will be able to maximize their input into these data standards by becoming involved in reviewing and evaluating them as early as possible. DCRI Communications • September 2014
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