Clinical Research and Healthcare – Where is the Link? 24 February 2004 Orlando, FL

Healthcare Delivery Patient Information Treatment, Insurance Basic Clinical Research Investigator-Sponsored Data Acquisition, Analysis Lab Notebooks, Files Insurance Claims Protocol-driven Clinical Trials Biopharmaceutical Industry-Sponsored Data Acquisition, Analysis Multiple databases EDC, CDMS, CTMS SAE… Publications Regulatory Drug Approval Medical Records Paper Charts EMR

Current State of Clinical Data Transfer Lab Submission Data Submission Operational Data Operational Data Medical Records C CRF

Current State: Costly and Time-consuming Pharma 1 Pharma 2 Pharma N... CRO 1 CRO 2 CRO M... Investigator 1 Investigator 2 Investigator K... Lab 1 Lab 2 Lab L... Regulatory

The Current State of Clinical Information Healthcare information is found in paper medical records, in disparate databases, in hospital- based information systems--- there are islands of data Clinical research data may exist in additional databases and/or research notebooks Clinical trial data is collected on 3-part NCR forms (~90% of trials) or via a multitude of electronic data capture applications

Current Technology Issues in Conducting Clinical Trials Electronic Data Capture (EDC) and/or eClinical Trials and new technologies are being piloted (if not adopted) by the major pharma companies. Sources for electronic data are many and varied (e.g. EDC, IVRS, hand-held diaries, clinical laboratories, AE databases); ready retrieval of electronic data is very important. Investigative sites are dealing with multiple and varied systems and interfaces.

Many industry stakeholders have realized that proprietary data structures are not necessarily of value….instead, focus should be on the molecule---the therapy. Innovation depends upon standardization. –Dr. Bob ONeill, Director, Office of Biostatistics, CDER, FDA

The Future: Standards to Facilitate Data Flow ….from Source to Reviewers Operational Database SDS ADaM ODM LAB eSubmission for Regulatory Review CRO EDC LAB ECG Sources of electronic data

Clinical Data Interchange Standards Consortium CDISC is an open, multidisciplinary, non-profit organization committed to the development of worldwide industry standards to support the electronic acquisition, exchange, submission and archiving of clinical trials data and metadata for medical and biopharmaceutical product development. The CDISC mission is to lead the development of global, vendor-neutral, platform-independent standards to improve data quality and accelerate product development in our industry.

CDISC History Started as grass roots volunteer group in Fall 1997 with 25 attendees at first meeting Invited to form DIA SIAC in 1998 Independent, non-profit organization in February 2000 ~130 Corporate Memberships, of which ~50 are Corporate Sponsors (e.g. global pharmaceutical companies, CROs and technology providers) Originally two working teams (Nomenclature and Modeling); Modeling split modeling into four teams; Nomenclature to Glossary Group Models developed by consensus-based process

Data Sources Site CRFs Laboratories Contract Research Organizations Development Partners Operational Database Study Data Audit Trail Metadata Operational Data Interchange & Archive: ODM, LAB Submission Data CRT/Domain Datasets Analysis Datasets Metadata Submission Data Interchange & Archive: SDS, ADaM Evolution of CDISC Standards ODM = Operational Data Model/Std SDS = Submission Domain Standards LAB = Laboratory Data Model/Std ADaM = Analysis Data Models

Progress on the Standards LAB Standard: Production Version available; approved HL7 RIM message –V1.0 plus microbiology extension –Four methods of implementation ODM Standard: Production Version 1.2 available as an XML schema –Define.xml in progress with SDS metadata SDS Standard: Version 3.0 available –Version 3.1 anticipated to be HL7 Informative Document referenced by FDA Guidance by Q ADaM: Selected analysis dataset models

CDISC SDS Standard Submission Domain Standards Version 3.1 –Incorporates changes based upon results of Version 3.0 FDA pilot –Scheduled to be balloted through HL7 and referenced in FDA Guidance as of April 2004; final documents anticipated by June 2004 –Provides means to submit Case Report Tabulation data to FDA in standard form, thus facilitating Review of submissions using standard tools Population of cross-trial database (Janus model) Plan is to reference as specification (HL7-approved CDISC SDS V3.1) in Guidance for FDA Implementation of International Conference on Harmonization (ICH) eCommon Technical Document (eCTD).

Transmitting and Using Data: Current Approach - FDA Data on Physical Media Tabulation Datasets Analysis Datasets Data Listings Datasets Metadata Files Subject Profiles Summary Tables and Graphs Datasets Text Electronic Document Room SubmissionStorageReview F.E. Wood, CDISC Interchange 2003 SAS Tx File v5

Transmitting and Using Data: Study Data Repository - FDA Electronic Message Standard Tabulations Analysis Datasets? Electronic Document Room Study Data Repository* Tools Datasets Summaries Profiles SubmissionStorageReview F.E. Wood, CDISC Interchange 2003 *Planned and Actual Future-XML

Patient Profile Viewer: example of standard tool for reviews (CRADA)

Interchange Standards: Long-term Desired Outcomes A holistic approach to standards, facilitating data interchange from sites through regulatory submission, utilizing XML Standards for data acquisition supporting the population of a cross-trial warehouse within FDA HL7-CDISC models harmonized to yield value for both clinical research and healthcare – sharing of information between EMR and clinical trials Global adoption of CDISC data standards CDISC Meeting with FDA Commissioner, April 2003

Data Sources Site CRFs Laboratories Contract Research Organizations Development Partners Operational Database Study Data Audit Trail Metadata Operational Data Interchange & Archive: ODM, LAB Submission Data CRT/Domain Datasets Analysis Datasets Metadata Submission Data Interchange & Archive: SDS, ADaM Evolution of CDISC Standards ODM = Operational Data Model/Std SDS = Submission Domain Standards LAB = Laboratory Data Model/Std ADaM = Analysis Data Models Future Uniform Standard

ODM Operational Data Model XML format for clinical study data and metadata Supports regulatory-compliant e-Archive format SDS Submission Data Standards *Describes content, structure and attributes of data for regulatory submissions *Defines metadata content for standard domains *Facilitates regulatory reviews LAB Laboratory Data Model Defines standard content for transferring clinical laboratory data from Labs to sponsors ASCII, SAS, XML, and HL7 implementations available ADaM Analysis Dataset Models Provides models for commonly used statistical analyses. Operational Data ModelingSubmission Data Modeling ODM values can be expressed via SDS metadata Data Sources Regulatory Reviewers LAB data can be mapped into ODM XML Applies submission model for analysis datasets ODM can be used to represent and archive submission data Define.xml

CDISC and HL7 Formal Association as of 2001 Technical Committee (Regulated Clinical Research and Information Management – RCRIM) co-chaired by FDA, CDISC and HL7 Benefits Capitalizes on HL7 standards development experience base Leverages HL7 accreditation and HHS acknowledgement as SDO; FDA support Expands value and influence of clinical trials standards efforts through harmonization Provides opportunity for common informatics platform for healthcare and clinical research

Shared Goals; Individual Contributions Shared Purpose (CDISC, FDA/HHS and HL7) –To improve the quality of public health –To have one overarching standard model for data interchange for healthcare information and clinical trial/clinical research data Domain Expertise –CDISC, FDA and the Pharmaceutical Industry – Regulated clinical research data acquisition, review and archive requirements –HL7 – Healthcare information exchange standards and methodology; accreditation processes

Initiated as Clinical Trials SIG in Jan TC approved in April 2002 Joint Leadership: HL7, CDISC, FDA Active Membership: FDA, CDISC, HL7 & others Regulated Clinical Research Information Management TC (RCRIM) Facilitates development of common standards across variety of organizations to improve information management during clinical research and regulatory evaluation Defines messages, document structures, and terminology to support collection, storage, distribution, integration and analysis of clinical research data Assures related or supportive standards produced by other HL7 groups are robust enough to be used in regulated clinical research

RCRIM: Current Initiatives Research Process Standardized representation of clinical trial protocol Research Data Periodic reporting of clinical trial laboratory data Annotation of ECGs Clinical trial data for regulatory submission (Informative Doc) Define.xml (Informative Doc) Non-clinical data for regulatory submissions (SEND) Surveillance Individual Patient Safety Reports (eMedWatch) Regulatory Information Structured Product label eStability data HL7 Ballots Approved Direct CDISC Involvement

CDISC and RCRIM Standards (Collaborative Groups ~ FDA, CDISC, HL7, SEND, CDC, NIH, LOINC, etc.) ADaM Protocol Elements LAB SDS ODM HL7 Reference Information Model RIM Patient Safety Report Product Label eStability Data CDA CDISCFDA Regulated Clinical Research Information Management Technical Committee ECG SEND Non-Clin SDS V3 RIM Inf.Doc Collaborative Groups Inf.Doc HL7 RCRIM TC Inf.Doc Define.xml V3 RIM CDA V3 RIM V3 RIM

Leverages HL7 accreditation and HHS acknowledgement as SDO; FDA support Capitalizes on HL7 standards development experience base Expands value and influence of clinical trials standards efforts through harmonization Benefits of CDISC-HL7 Alliance Provides opportunity for common informatics platform for healthcare and clinical research

Proof-of Concept Project Designed to demonstrate compatibility between HL7 RIM-derived Clinical Document Architecture (CDA) and CDISC Operational Data Model (ODM) –Single source entry for medical records and clinical trials –eSource documentation contributes to patient chart, not the reverse (i.e. extraction from EMR); reduces regulatory issues –Minimizes redundancy in data entry, thus improving data integrity/quality –Can potentially be driven from electronic protocol First stage POC initiated through Duke Hospital and DCRI Have commitments from two major technology partners, an academic institution and an academic research organization; establishing more pharma support for this breakthrough project (five interested in ringside seat)

Single Source Proof-of-Concept Clinical Database ePatient Record Leverages healthcare (HL7) and research (CDISC) data interchange standards; tool interoperability Facilitates investigator workflow; eliminates transcription steps Compliance with 21CFR11 and HIPAA feasible Enables online monitoring Single Source CDA ODM

CRT/Analysis Datasets ePatient Record Leverages healthcare (HL7) and research (CDISC) data interchange standards; tool interoperability Facilitates investigator workflow; eliminates transcription steps Compliance with 21CFR11 and HIPAA feasible Enables the protocol (PLAN) to drive the entire process Single Source CDA ODM Define.xml

Agreement w/ statement Standards should be extended to facilitate data collection at investigative sites… % Agree * Source: CDISC-CenterWatch Research Project

InternationalN. America Sponsor should collaborate in the standardization of EDC practices and systems for sites CDISC-CenterWatch 2003 International Project Regional Comparisons

Healthcare Delivery Patient Information Basic Clinical Research Investigator-Sponsored Data Acquisition, Analysis Insurance Claims Protocol-driven Clinical Trials Biopharmaceutical Industry-Sponsored Data Acquisition, Analysis Publications Regulatory Drug Approval Medical Records

Insurance Claims Biopharmaceutical Industry-Sponsored Data Acquisition, Analysis Publications Regulatory Drug Approval Protocol-driven Clinical Trials Basic Clinical Research Investigator-Sponsored Data Acquisition, Analysis Healthcare Delivery Patient Information

Information and Contacts For standards and information, see Quarterly updates available via ; contact Shirley Williams Technical questions: Julie Evans or Public Discussion Forum Education and Membership: Frank Newby Rebecca Kush:

Knowing is not enough; we must apply. Willing is not enough; we must do. - Goethe- CDISC could not be what it is without all of our kind supporters who apply and do…. THANK YOU!

The CDISC Vision The exchange of all clinical trial data between any two parties will be achieved by the application of the appropriate CDISC data models and standards.

HL7 RCRIM Standards Process Flow HL7 Membership Accredited Standard Working group e.g. CDISC, FDA, RCRIM RCRIM Proposed standard Public Draft FDA Guidance Final FDA Guidance FDA

External Focused Review CDISC Standards Development Process (COP-001) Need for Specific Standard(s) Identified (any stakeholder) Proposal to Board of Directors (via OIS) Working Plan (timelines, deliverables communication mech., resources reqd) (Team ) Consensus (Initial) Version Harmon- ized Version Team Leader ID And Team Formation (multidisciplinary) (OIS) Review per strategy, budget priorities Approved Annual Review of Released Version (comments, chg reqsts, tests, plans) (Team) Released (Production) Version 1.0 Review Version Stage I: Standard Definition/Team Initiation Stage III: Education & Support Stage IV: Standards Update & Maintenance Stage II: Standards Development/Review/V 1.0 Release Working Plan (timelines, deliverables, communication mech., resources reqd) (Team) Consensus (Revised) Version Respond To Comments And Questions Educational Programs (EDU, OIS) Not Approved TCC Review Comments to address by team Public Review Comments addressed New Released (Production) Version Harmon- ized Version TCC Review Ex Focused Review Public Review as needed Optional Testing Note: Occasional bug fix releases may be issued as needed with team review only.

Standard data models are very important so that there can be efficient interchange of clinical data between my company and…other parties % Agree * 2003 Results; Respondents (n=750), Pharma (n = 211) CRO (n= 146) Tech Provider (n=38)

Sponsors Should Collaborate in the Standardization of EDC Practices and Systems for Investigative Sites Percent of Investigative Sites

Do you advocate the usage of eSource now or in the future? BioPharmaCRO

Formed DIA eClin/Stds SIAC Volunteer CDISC Group Initiated 1997 Formed DIA SIAC 1998 CDISC Incorporated: Independent Non-Profit Organization CDISC Timeline CDISC Europe Intiated CDISC Japan Initiated Initial CDISC Model (SMM) V3.x SDS FDA Guidance (Projected) V2.0 SDSV1.0 SDS Nomenclature & Modeling Groups V0.8 ODMV3.0SDSV1.0 ODMV1.1 ODM SDS = Submission Domain Standards ODM = Operational Data Model LAB = Laboratory Data Model ADaM = Analysis Dataset Models ADaM Models Formal Agreement with HL7; CT-SIG HL7 RCRIM TC* LAB & SDS models passed HL7 ballot * RCRIM TC: Regulated Clinical Research and Information Management Technical Committee; Co-chaired by HL7, CDISC and FDA 2004 V1.0LAB

Standards: HL7, XML Dictionaries: MedDRA, LOINC Clinical Trials CDISC in the World of Standards 2000 US FDA EU EMEA Japan MHW REGULATORY AUTHORITIES Health Care Providers & Pharmacies Models: NCI, OMG, RIM ICH Pharmaceutical Industry EU USA Japan EFPIA PhRMA JPMA SDSODM ADaMLAB

Protocol Std Clinical Document Architecture DICOM ADaM CDISC in the World of Standards 2003 International Conference on Harmonization (ICH) U.S. Dept. of Health and Human Services (HHS) Health Level 7 (HL7) U.S. FDA CDISC TC: RCRIM NIH/NCINLM EFPIA EMEA MHLW KIKO PhRMAJPMA CDC Reference Information Model RIM LAB eCTD LOINC ISO SNOMED MedDRA ODMSDS = Organization = Dictionary, Codelist = Standard = Model = Document Standard, or Architecture

Speaking of health benefits/opportunities to be realized from making more effective use of IT…. I think that CDISC will be a big part of moving FDA onto an electronic information architecture where we can realize all of these opportunities. I think this will have a profound and positive impact on our drug review process, allowing us to design trials that can be less expensive and still tell us more about the risks and benefits of a new medical product. And I think that the most significant and perhaps enduring legacy to your efforts could be the very immediate and significant impact it has on improving the lives of patients. –Mark B. McClellan, MD, PhD, FDA Commissioner

Single Source: Potential Flow for Clinical Trial Data Clinical Trial eSource Document (w/ required CRF fields identified) eCRF Data (Document) Central LAB Data Transfers Hospital Lab data Operational HL7 CDA CDISC ODM Interchange Maps to CDA, includes ODM support of Regulated Clinical Research data interchange and archive; uses SDS metadata FDA Submission Database CDISC SDS HL7 Messaging EMR Database eVerification/Audit Data Entry [or Dictation] by Investigator or CRC

Submission Domain Standards (SDS) Version 3 * New in Version 3 Interventions Events ConMeds ExposureAE MedHist Disposition Findings ECGPhysExam Labs Vitals Demog Other Subj Char* Subst Use* Incl Excl* RELATES* Extra Data* Study Sum* Study Design* QS*, MB* Comments* CP*, DV*