Clinical Trial Management System Working Group Meeting City of Hope National Medical Center

1. Clinical Trial Management SystemWorking Group MeetingCity of Hope National Medical Center Joyce C. Niland, PhD Chair, Information Sciences February 19, 2004

2. Dr. Joyce Niland Dr. Doug Stahl Dr. David Ikle Dr. Hemant Shah Cindy Stahl Joycelynne Palmer Amy Cox Stacy Berger Tremon White Tuong Tieu Chair, Information Sciences Director, Biomedical Informatics Associate Director, Biostatistics Information Scientist Systems Analyst Systems Analyst Systems Analyst Database Architect Application Developer Application Developer Development Team

3. Outline of Today’s Talk • Past Experience in Clinical ResearchSystem Development • Current Approach: Fully Integrated Research Standards & Technology (FIRST) • Proposed Future Approach: Year One

4. City of Hope’s Experience inClinical Trials System Development

5. Eligibility Screening Protocol Monitoring Patient Tracking Protocol Tracking Outcomes Data Research Protocol Lifecycle Results Research Idea <---Protocol Data---> <----Patient Data---->

6. Computerized SystemYear Deployed Biostatistics Information Tracking System (BITS) 1989 Frozen Tumor Bank Specimen Tracking System 1992 NCCN Web-based Outcomes Research System 1996 Forms Tracking System 1997 Clinical Trials On-Line Protocol Delivery System 1998 Clinical Pathways Patient Management System 1999 Web-enabled Genotype-Phenotype Database 2000 Guideline Graphical Decision Support Interface 2001 GCRC Protocol & Patient Administrative System 2002 Web-based Services for Protocol Data Integration 2002* Metadata Repository System 2003* *Prototype City of Hope Experience in Clinical Research System Development and Deployment

7. Clinical Trials System at COH • Over 400 ongoing trials at City of Hope • 30-40% of COH patients enroll on one or more trials • 1/3 pharma, 1/3 cooperative group, 1/3 intramural • Data Coordinating Center for ~60 multi-center trials • Created centralized clinical trials database • Biostatistics Information Tracking System (BITS) • In continual use for all COH trials since 1989 • Over 500,000 records on more than 20,000 patients • Migrated to MS SQL server, building web interfaces • Also deploying scannable forms

8. BITS & Clinical Trials On-Line support: >400 clinical trials >110 investigators

9. Features of BITS • Protocol accessions, demographics, labs, and relapse survival on all patients • Detailed case report form (CRF) data for patients on in-house trials • Export to NCI CDUS application • Mirrored copy of Oacis to import • A2K demographics • Sunquest labs • Cytogenetics • HLA data

10. Deployed for all Pediatric protocol patients Clinical Pathways System

11. All Clinical Trial and Observational Study Data Lessons Learned.... • Architecture must support within trial and cross-protocol analyses Study-Specific Model for: Unified Data Model for: T R I A L 1 T R I A L 2 T R I A L 3 T R I A L 4 T R I A L 5 T R I A L 6 Case Series, outcomes research, meta analysis, data mining Case series, outcomes research, meta analysis, data mining

12. Lessons Learned…. • ‘Metadata’ are critical! • Data about the data themselves • Technical directory: system perspective • Business directory: user perspective • Required for critical database functionality: • Merging in legacy electronic data • Data directory to facilitate data mining • Management of data derivation and logic rules • Preparing summary versions of massive data sets (‘data marts’) • Documenting creation and “sunset” dates of data elements & codes

13. Creation of an Effective Metadata Repository • Building an interactive Web-based metadata repository (ISO/IEC 11179 compliant) • Will be the “driver” of future systems • Technical metadata populated from ‘feeder’ systems • Detailed analysis of business metadata of all fields underway by full-time Metadata Analyst

14. Root Cause of Data Managementand Integration Problems • Lack of a unified information architecture • Requires standard • Data model • Vocabularies • Data interfaces • Improved information technology infrastructure and toolsneeded to exploit significant investments in biomedical data • Formidable task • Becomes more intractable and costly as time goes on

15. FIRST:Fully Integrated ResearchStandards & Technology

16. FIRST • 3-year GCRC supplement grant funded by the NCRR • Goal: Develop a fully integrated information management and decision support environment • Facilitate all phases of clinical research • Support research infrastructure of the GCRCs • Development group: COH Division of Information Sciences • Input and testing from USC and CHLA • Collaboration with Dr. David Forslund, Advanced Computing Lab, Los Alamos National Laboratory

17. Objectives of FIRST • Create a clinical research environment to support the wide range of clinical research activities across the protocol life cycle • Bring together enabling technologies: • Standardized information modeling • Object-oriented distributed architecture • Advanced graphical user interfaces • Ultimate goal: scalable interoperable system

18. caBIG ‘Desiderata’ • Open access, open source • Derived from common information models • Standards for data exchange formats • Data and metadata following ISO/IEC 11179 • Consume appropriate public, open access standards when available All of these principles are being followed in FIRST

19. Through FIRST… • A common standardized UML model for clinical research will be made publicly available • Semantic analysis will yield common standards and mapping among vocabularies • Integration of existing data sources will be facilitated • Prototype applications that support the clinical research life cycle are being developed and tested

20. Eligibility Screening Protocol Monitoring Patient Tracking Protocol Tracking Outcomes Data Functionality to be Supported in FIRST Results Research Idea

21. Principles in Developing FIRST • Computational and semantic standards • Information integration • System interoperability • Workgroup collaboration • Sufficiently flexible methods to: • Scale over time • Adapt to unanticipated needs • Accommodate multiple disease entities • Adopt to different research environments • Exploit major advances in science and technology

22. FIRST Unifying Information Architecture • Enforce both technological and lexical standards through: • Standardized Data Model • Semantic Standards • Technical Interoperability

23. FIRST Schematic Diagram

24. FIRST Modeling Process

25. Standardized Data Model • Requires clear understanding of the environment • FIRST Advisory Group of senior investigators • Clinical trialists, biostatisticians, research staff, informaticists • Originally envisioned “units of application functionality” as shown in protocol life cycle • Actual components of model far less orderly, organized, and separated in practice • Much time and effort required to: • Separate, document, and specify units of application functionality • Define interrelationships sufficiently begin application development

26. Form B Form C 30,000 Foot View of FIRST Information Model ProtocolRegistered Available for Accrual Available for Accrual ProtocolStatus: SAE onProtocol ReportedSAE N – 1Slots Available Registration Conditions met,N slots available Suggestedfor Protocol First Study ParticipantStatus: FullyEligible Registered Consented RXHeld On-Study . . . Treatment SAE Eligibility Screening ConsentingProcesses AccessioningProcesses Eligibility Filtering SAEForm ConsentForm Data CollectionProcess: Eligibility Checklist Form A

27. FIRST Modeling Process • Requirements analysis and documentation conductedin a uniform manner • Unified Modeling Language (UML)-based clinical research domain model • Maintains consistency among model, metadata,and technology • Assures architectural soundness • Improves communication between domain & technical experts • Facilitates translation into an executable program • Promotes platform independence • City of Hope members of HL7 working group • Expert consultant: Gunther Schadow, Regenstrief Institute

28. Eligibility Filtering Use Case • Use Case 20.0 Protocol Abstraction for Eligibility Filtering • Description • The protocol abstractor entered data about the protocols eligibility and exclusion criteria into the system. • Actor • Protocol Abstractor • System • Pre-Conditions • Protocol is registered into the system. • Basic Course • .The actor has logged into the system (See Use Case 1.0), searched and selected the desired protocol (See Use Case10.0) (example screen # 3) • .The system displays a page (example screen # 4) that allows the actor to select ‘Eligibility Criteria’ within the ‘Protocol Abstraction’ function. • .The system displays the protocol abstraction – eligibility filtering criteria page (example screen #22, #27, #23, #32). The following information is requested about the protocols eligibility and exclusion criteria. All criteria are required. NA is used if the protocol does not specify. • Gender* (^Alternate Course 8.0.3 Add a value to any of the pick lists) • Minimum age and unit* • Maximum age and unit* • Functional status* • Minimum life expectancy* • Disease* • Measurable disease* • Disease status* • Evaluable disease* • Metastases* • Minimum tumor size* • Maximum tumor size*

29. HL7 RIM 2.01 Class Diagram

30. HL7 Reference Information Model(RIM 2.01) Backbone

31. HL7 Block Diagram

32. FIRST Block Diagram:Protocol Registration

33. FIRST Semantic Standards

34. No Single VocabularyCan Meet All Needs • More than one vocabulary system required for FIRST • SNOMED, LOINC, RX-NORM • caDSR Common Data Elements (CDEs) • External standards can be represented as CDEs (e.g. ICD-O-3) • Still may need to additional terms/concepts • Utilize UMLS to search for terms

35. Concept 1 Term 1 Concept 2 Term 2 Term 3 Concept 4 Term 4 UMLS for Mapping AcrossTerms and Concepts UMLS Metathesaurus Vocab. Source A Concept 1 Term 1 Concept 2 Term 2 Vocab. Source B Concept 3 Term 3 Concept 4 Term 4

36. Without proper metadata…

37. Source HL7 Ref Sample Master Data Elements

38. FIRST Technologies

39. FIRST Technologies • Object Management Group (OMG) International Standards Organization • Develops technically integrated, commercially viable, vendor independent specifications for software industry • Achieved international consensus on Common Object Request Broker Architecture (CORBA) • Facilitates technical interoperability among disparate information systems • Recognized as a potential solution in healthcare informatics • Has not been operationalized in clinical research context

40. FIRST Technologies • Software architecture based on international standards &interoperable components • Leveraging existing standardsor help expand/ build new ones • Systems are “future proof” if retain CORBA-compliant interfaces

41. OpenEMed (formerly TeleMed) • An intuitive patient-record system that supports, image, audio, and graphical data • Open-source, interoperable components based on OMG Healthcare Domain Taskforce interface standards • Enables multiple databases to be integrated together to create a virtual patient record • Individual healthcare facilities still own and manage their own data • Data accessible to others who have treated the same patient • Security of the data is maintained, patient privacy and confidentiality is ensured

42. OpenEMed (formerly TeleMed) • CORBA “Services” used in FIRST • PIDS: Person Identification Service • Correlate health records among multiple institutionbased on a "core" set of profile elements, whileprotecting confidentiality • COAS:Clinical Observation Access Service • Interface to supply clinical observations, includingraw data recordings, and derived judgmentsor knowledge

43. Form B Form C Applying OpenEMed to FIRST Global Model PIDS ProtocolRegistered Available for Accrual Available for Accrual ProtocolStatus: SAE onProtocol COAS ReportedSAE N – 1Slots Available Registration Conditions met,N slots available Suggestedfor Protocol PIDS First Study ParticipantStatus: FullyEligible Registered Consented RXHeld On-Study . . . Treatment SAE COAS Eligibility Screening ConsentingProcesses AccessioningProcesses Eligibility Filtering COAS SAEForm ConsentForm Data CollectionProcess: Eligibility Checklist Form A

44. Significance of FIRST Technologies • Technology behind FIRST application prototypesmuch more significant than their applied functionality • Significant advantages through flexibility and re-usability of CORBA services • Minimizes additional development later (e.g. security and auditing capability) • Places emphasis on knowledge representation, rather than database construction

45. Graphical Representation of PIDS XML configuration files <Trait Type = "HL7" Name="Patientt”<Value> Hasman^Arie^^^^ </Value></Trait> <Trait Type="HL7" Name="PhoneNumber_Home"> <Value>(505)672-1200 </Value> </Trait> <Trait Type="HL7" Name="SSNnumber"> <Value>111-222-3333 </Value> </Trait> Defines relationships among data elements Tells service what the data is • Data • patient PIDS DB PIDS (service) Entity-Attribute-Value (EAV) structural independence Stores data & preserves relationships defined by the configuration file, maintained by PIDS service Can be HL-7, flat files, etc

46. Protocol Abstraction UnderliesAll FIRST Applications • Abstraction Categories: • Administrative Overview • Study Personnel • Protocol Entities / Organizations • Study Design • Scientific Objectives • Eligibility Criteria • Statistical Approach • Treatment Roadmap • Toxicity Monitoring • Outcomes Assessment • Data Collection Expectation • Obvious logical extension: protocol authoring via FIRST

47. Sample FIRST Application

48. months months Female years Example Screen # 22 Protocol Abstraction - Eligibility Filtering Criteria pg 1 Protocol Participant Reports Other Main Menu Exit Overview Information Related Entities, Committees & Organizations Protocol Personnel Scientific Abstraction Eligibility Criteria Statistical Approach Protocol Registration Protocol Abstraction Protocol Management Tasks Eligibility Filtering Criteria Oncologic Studies Demographics Minimum Maximum 18 3 Age:* Gender: *note: If physiologic age is used, enter the upper limit +5 years for the maximum Status Check all eligible functional status descriptions: Able to carry on normal activity and to work; no special care needed X Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed X Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly 3 And above Minimum life expectancy: Click here to communicate with the System Administrator

49. OK Clear Example Screen # 27 - Edit/View Protocol Abstraction - Participant Characteristics for Eligibility Filtering - Disease List Protocol Participant Reports Other Main Menu Exit Overview Information Committees & Organizations Protocol Personnel Scientific Abstraction Eligibility Criteria Statistical Approach Protocol Registration Protocol Abstraction Protocol Management Tasks FIRSTSM Unique Protocol ID: Prefill from search This protocol is ‘available’ for accrual NCI Disease List: Check all eligible Any Diagnosis Any Hem Any Solid X Hematologic: Solid Tumors: Esophagus Prostate Hematopoietic, other Anus Eye and Orbit Rectum Leukemia, Lymphoid Respiratory & intrathoracic Organs, other Bones & Joint Genital - Female, other Leukemia, Monocytic Skin Melanoma Brain & Nervous System Genital - Male, other Leukemia, Myeloid Breast - Female Skin, other Ill-defined Sites Leukemia, not otherwise specified Small Intestine Breast - Male Kaposis Sarcoma Lymphoma, Hodgkin’s Soft Tissue Buccal Cavity & Pharynx Kidney Lymphoma, Non-Hodgkin's Larynx Cervix Stomach Mycosis Fungoides Thyroid Colon Liver Multiple Myeloma Unknown Sites Corpus Lung Urinary Bladder Digestive Organ, other Ovary Urinary, other Endocrine System, other Pancreas Click here to communicate with the System Administrator

50. Example Screen # 50 - Protocol Filtering Search Results Protocol Participant Reports Other Main Menu Exit Protocol Matches for : FIRSTSM Unique Person ID: 46586 Name: Kelly M Clarkson Status Age Gender Min Life Expect Evaluable Measurable Diagnosis Metastasis F 20 No Assist Lymphoma Yes Yes 6 mo Pt ID:(Prefill pt ID #) Protocol Information N/A to 18yrs No Assist; Some Assist Lymphoma Yes Yes 3 mo N/A #113 N/A 18yrs to 70yrs No Assist; Some Assist All Hem N/A N/A 3 mo N/A #540 N/A 18yrs to 65yrs No Assist; Some Assist All Hem N/A N/A N/A N/A #700 N/A 18yrs to No Assist; Some Assist Any Cancer N/A N/A N/A N/A #003 Filter Summary: 15 protocols in FIRST;10 available for searching; 5 matched your query Click here to communicate with the System Administrator