ObTiMA: a new ontology-driven tool for managing multi-site trials

1. ObTiMA: a new ontology-driven tool for managing multi-site trials Norbert Graf, Fatima Schera, Micke Kuwahara University of the Saarland, Germany; IBMT, Germany; University of Hokkaido, Japan

2. CT in Europe: away forward? In Europe, it is a legal requirement to conduct clinical trials in accordance with the International Conference on Harmonisation’s guidelines on good clinical practice (see http://www.ich.org/) We develop a data management system for clinical trials that adheres to evolving standards such as those set by CDISC (Clinical Data Interchange Standards Consortium; http://www.cdisc.org). We believe that an open-source approach is needed[1]. [1] Greg W. Fegan, Trudie A. Lang, Could an Open-Source Clinical TrialData-Management System be whatwe have all been looking for?PLoS Medicine, March 2008, Volume 5, Issue 3, e6

4. Why ObTiMA? The conduct of clinical trials in Europe is characterized by Redundant paperwork Liability tangle (sponsor, insurance, contracts, …) Complicated legal and ethical regulations causing an unending bureaucracy Assessment of Clinical Trial Applications (CTA) differs from country to country European Sponsor + ‚Satellite Sponsors‘? … 24. April 2009 http://www.eu-starc.org

5. Relevance • A continuous decline in the number of trials being conducted in Europe by independent academic groups is observed [1]. • One possible reason for this is that reporting and documentation requirements are now so burdensome that the process has become unnecessarily complicated [2] Keim B: Tied up in red tape, European trials shut down. Nature Medicine 13:110, 2007 [1] Hemminki A, Kellokumpu-Lehtinen PL (2006) Harmful impact of EU clinical trials directive. BMJ 332: 501-502. [2] Grimes DA, Hubacher D, Nanda K, Schulz KF, Moher D, et al. (2005) The Good Clinical Practice guideline: a bronze standard for clinical research. Lancet 366: 172-174.

6. Data Flow within clinical trials Int. Centre Participating Centers SAE / SUSAR Legal Authorities SAE / SUSAR Clinical data Data transfer Local Hospital Trial Centre registration Follow-up Follow-up Patient Long term follow-up Ca Registry registration Long term Follow-up Research data Imaging, tumor material, … Research Centers Reference Centers Statistical Center

7. Trial outline Registration CRF Treatment A CRF Treatment 1 CRF Diagnostic CRF irradiation CRF on a regular basis imaging CRF Treatment B CRF stratification randomisation surgery Follow-up CRF … CRF Treatment 2 CRF Treatment C CRF SUSAR CRF at any time possible SUSAR CRF relapse CRF death CRF timeline diagnosis start of treatment end of treatment

8. stage I-III stage IV stage V AV 4 weeks AVD 6 weeks AV/AVD individual surgery surgery surgery histology tumor- Volume stage I stage II stage III CR Non-CR postoperative treatment according to the highest local stage and histological subtype nothing AV-2 AV-2 low risk AV-2 AV-2 + irradiation epithelial predominant AV-1 AV-2 randomization Irradiation of metastases in case of Non-CR andhigh risk treatment at least stage II no randomization intermediate risk < 500 ml AVD AVD + irradiation AVD other subtypes AVD HR + irradiation HR + irradiation HR > 500 ml high risk +/- irradiation SIOP 2001/GPOH

9. Roles & Rights Communication ObTiMA Masterprotocol administrative templates Repository Ontology submission Trial Outline Builder Ontology based CRF Creator general view graphical schema Trial Builder patient specific view Patient Data Management System Security Data export Queries Reports ACGT Mediator

10. Physician Patient Therapy plan Personal data Trial chairman Administration Trial Trial outline Researcher (person, tool) Metadata Hospital CRF CRF CRF Constraints User Clinical data (CRF) Clinical data (CRF) Clinical data (CRF) ACGT ObTiMA System Trial and CRF Repository User roles and rights Manage- ment Web application Trial registration • ACGT Trial Builder: • Trial outline builder • CRF creator Patient data management SAE/SUSAR registration Report Data export module Statistical centre Consultant Communication/ consultation ACGT mediator OGSA DAI Service Patient

11. Value conflicts Individual interest Collectiveinterests conflictbetween Data Access Privacy Balance?

12. User Roles & Rights ObTiMA is a clinical trial management system accessed by many users with heterogeneous responsibilities. A Role Based Access Control approach provides a satisfactory solution in regulating the various tasks performed by users. Each user is assigned to one or more roles that characterize his/her purpose and function in ObTiMA. Roles control user access to different parts of ObTiMA according to the rights assigned to them.

13. Ontology Integration • During the design of CRFs relational metadata in terms of the ACGT Master Ontology are created • Items are described by a path from the ontology starting with the class Patient • Descriptions are stored in mapping-files • data collected in databases of the Clinical Data Management System can be transformed to instantiation of the ACGT Master Ontology • data can be queried with SPARQL in terms of the ACGT Master Ontology • Allowing flexibility in item creation

14. Different possibilities to create items from ontology • Items that query values of „attributes“ • Gender • Name of mother • Items that query if an instance for a selected class exists for the patient (yes/no) • Has infectious disease? • Has tumour? • Items that query how many instances for a selected class exist for a patient • How many siblings does patient have?

15. ACGT MO Submission Tool The Submission Tool is a system designed to support maintenance of the ACGT Ontology and answer to the Ontology Expert’s needs by: • gathering the requests for changes on the Ontology, • feed them to the Ontology Expert in a manageable way, • keeping version history of the Ontology • informing the interested parties about the changes in the Submissions and the Ontology versions by sending notifications (e-mails).

16. Main Aims of ObTiMA Data Management System CRF Creator Ontology based Ontology Submission system Trial Outline Builder Trial Protocol Builder Templates Master Protocol Contracts Communication with regulatory bodies, ethics committees, … Administrative § Security Issues Roles & Rights Management Anonymization / Pseudonymization Pharmacovigilance SAEs, SUSARs Communication Data transmission Consultation Queries & Data export

17. Technical Details • Web Application • Jakarta Struts (open-source framework to develop Java EE web applications), Java Server Pages, Java Server faces • Apache Tomcat Webserver • Backend • Persistence Layer: Spring Framework (Hibernate) • Postgres database • XML format for study metadata, clinical data, administrative data and ontology mapping • CDISC ODM (extended to comprise ontology mapping)

18. FHG-IBMT (main development/coordination) UdS (design/user requirements) UHokk (Trial outline Builder) Forth (roles and rights/secure access) (Ontology Submission System integration) Custodix (security solutions) IFOMIS (ontology/testing) UPM (Mediator integration) Philips (Data access services) Partners involved

21. Laws on good clinical practice Information about laws on clinical practice. EUR-Lex 2001/20/EC: principles and detailed guidelines for good clinical practice EUR-Lex 2005/28/EC: principles and detailed guidelines for good clinical practice JURIS: Information about laws on clinical practice (German) Arzneimittelgesetz (German)

23. Trial Outline Builder

24. CRFs

25. Editing & operation levels • Level 1 (Template) • events that can be used for any trial • Level 2 (Trial Outline) • events belonging to a specific trial • some properties specified • timing defined relative to a timeline • Level 3 (Individual Patient) • events belonging to a specific patient • properties are linked to CRFs for this patient • given absolute dates • Level 4 (Query/Analysis) • treatments and results from one or more trials • various visualisations possible

26. C S 6 15 4 9 Event appearance Chemotherapy Randomisation Stratification Supportive therapy Shortening Radiotherapy Delay Communication Surgery SAE /SUSAR Diagnostics Reporting S

27. ICE ICE 50 Gy 50 Gy 50 Gy 50 Gy 50 Gy 50 Gy 50 Gy I C Scratchboard Events I I I I I I I S S C C C C C C C II II II II II II S S C C C C C C drag & drop C C C C copy CE CE CE CE C C C C I II II S S C C C II S I I S II II C C C C C S 0 Trial 9

28. ICE ICE ICE 50 Gy 50 Gy 50 Gy 50 Gy 50 Gy I C Scratchboard Events I I I I S C C C C II II II II II S C C C C C C C C C C C CE CE CE CE C C C C I II II S S C C C II S I I S II II C C C C C S 0 Trial 9

29. ICE 50 Gy 50 Gy I I I I I C C C C C Scratchboard Trials Queryboard Tools Trial 1 Query Query I II Descriptive Statistics Correlations Cox-Regression Descriptive Statistics Correlations Cox-Regression Multivariate Analysis Life-Table Analysis …… C C Trial 2 II I C C Trial 3 Visualisation C Trial 4 Report CE C Trial 5 I Trial 6 II II S C C C II II I S I C C C C Trial 7 Trial 8 0 Trial 9 Trial 8

30. Scratchboard Trials Queryboard Tools ICE Trial 1 Query Query I II Descriptive Statistics Correlations Cox-Regression Descriptive Statistics Correlations Cox-Regression Multivariate Analysis Life-Table Analysis …… C C Trial 2 II I C C Trial 3 50 Gy 50 Gy Visualisation C Trial 4 Report CE C Trial 5 I I I I I I Trial 6 II II S C C C C C C C C II II I S I C C C C Trial 7 Trial 8 0 Trial 9 Trial 8

31. ICE 1,0 ,9 ,8 50 Gy 50 Gy 50 Gy 50 Gy ,7 relapse free survival ,6 ,5 ,4 I C ,3 ,2 ,1 0,0 0 1 2 3 4 5 6 7 8 9 10 time [years] Scratchboard Trials Queryboard Results Trial 1 I I I S C C C Trial 2 Histogram II II II S C C C Trial 3 Life table C Trial 4 Cox- Regression CE C Trial 5 … I Trial 6 II S C C II II I S C C C Trial 7 Visualisation Board Trial 8 0 Trial 9 Trial 8

32. Validation • Rhabdoid clinical trial • A new clinical trial for the European Registry for Rhabdoid tumors. • CRFs for this trial have been designed ontology based • SIOP 2001/GPOH • An ongoing trial with its own database for clinical data management without an ontology. • CRFs of this trial were partly created ontology based and anonymized patient data were imported.

33. Demonstration • Administration module including the role based secure access • Set up of the Rhabdoid clinical trial with the Trial Builder (incl. Ontology viewer) • Patient management • Data export module (SIOP 2001/GPOH trial)

34. Future work • ACGT Portal Integration • Customizing of trials, CRFs, etc. • Constraints, edit checks, validation of data, etc. • Enhancing functionalities • Roles & Rights; Ontology submission system • Automatic pseudonymization of personal data • Module development • SAE/SUSAR, Communication, imaging data, etc. • Tutorial, Help menu, etc. • Audit trail, Certification process Research tool  productive tool

35. Clinical data

36. The ACGT architectural framework From the technical point of view, the requirements can be met using a federated, multi-layer, service oriented, grid enabled, and ontology driven architecture. User Access Layer DomainSpecific (Pseudo-Anonymization, etc.) Bioinformatics and Knowledge Discovery Services Layer Security Services Layer Clinical Data Management and Trial Builder Computational Biology Master Ontology VO Management Semantic Mediator Portal Knowledge Discovery Services Data Browsers Workflow Authoring Visualization tools Data Wrappers (OGSA-DAI) Mediator Query Interface Workflow Management and Enactment RFT Mobile GAS GDMS GridFTP GRAM MDS Generic Security Services (Access & Identity Control) GRMS Advanced Grid Middleware Layer Common Grid Infrastructure Layer

37. Centre for Data Protection https://cdp.custodix.com/index.php

38. Ontologies and Metadata Master Ontology for Cancer Enable semantic data integration Ontology maintenance Ontology viewer Submission system Service Ontology has been specified providing: Metadata for Data (formats, role in data mining, statistical information, etc.) Metadata for Operators and Models (required input, parameters, etc) Metadata for Services and Workflows (publisher/creator, service quality, etc.)

39. encrypting Patient A Database Data processing Anonymous or pseudonymous Data Patient A Database Non-personal data Data processing making anonymous Personal data Dataset 1 encrypting Non-personal data making pseudonymous Pseudonym Personal data 5P67z6r4 Trust Center

40. Main Components Patient Data Management System TrialBuilder Administration Master Protocol Personal Data Clinical Data Treatment Plan User, Roles and Rights,.. Trial Outline Builder Trial Database setup automatically CRFBuilder Ontology Viewer Wrapper Services (SPARQL ) Mapping file setup automatically Data Export Module (CDISC ODM) CRF Repository ACGT Master Ontology ACGT Mediator Tool

41. Ontology Viewer http://62.103.163.162/OntologyViewer/

42. Roles & Rights Communication ObTiMA Masterprotocol administrative templates Repository Ontology submission Trial Outline Builder Ontology based CRF Creator general view graphical schema Trial Builder patient specific view Patient Data Management System Security Data export Queries Reports ACGT Mediator

43. The Tower of Babel Pieter Brueghel the Elder (1563)