1. eSource
June 7, 2006.
EMEA, London
Dave Iberson-Hurst, Assero
Co-lead, CDISC eSDI Group
© Assero Ltd & CDISC, 2006

2. Agenda
CDISC
Background
Method & Analysis
User Requirements
Scenarios
Benefits
Next Steps
Summary
EMEA. June 7th, 2006 2

3. The CDISC Mission
Clinical Data Interchange Standards
Consortium
The mission of CDISC is to develop and
support global, platform-independent data
standards that enable information system
interoperability to improve medical research
and related areas of healthcare.
EMEA. June 7th, 2006 3

4. CDISC Organisation
CDISC Coordinating Committee CDISC Board Committees
Leaders, Japan & Europe
Board of Directors • Executive
• Financial Oversight
• Governance
Industry Advisory Board • Global Strategy
• Global Communications
President
Global Operations
Board and IAB Support International Operations Support
Member Services New Opportunity Exploration
PR/Communications Program Management
Business Case Alliance Management
Website/IT; Interchanges Member Services
Technical Advisory Committee
Production Standards Implementation Services Innovation Initiatives
• Production Standards Updates • Education Courses • BRIDG Modeling
(SDTM, SEND, define.xml, ODM, • Global User Network Support • SDTM-ADaM Pilot
LAB, ADaM, Glossary) • Regional CDISC Coordinating Comm. • Submission in ODM XML
• End-to-end Documentation (Japan, Europe) • eSource Data Interchange
• Implementation Guide/Std • U.S. Networks • Terminology and NIH Grants
Enhancement (e.g. TDM, PK, • Implementation Enablers ( proto- • Protocol Representation
device, vaccine) tools ) • Healthcare Link
• Help Desk • Industry Architecture Proposal
EMEA. June 7th, 2006 4

5. History
CDISC Volunteer CDISC CDISC SDTM into
Group Europe Japan guidance
DIA SIAC CDISC Define.XML
Formed Incorporated guidance
1997 1998 1999 2000 2001 2002 2003 2004 2005
ODM V1.1 LAB V1.0 ODM V1.2
ODM V1.0 SDS V2.0 SDS V3.0 SDTM V1.0
(*) (*) (*)
* Note: SDS became SDTM
EMEA. June 7th, 2006 5

6. Standards
CRO Sponsor
Investigator
Subject LABs
EMEA. June 7th, 2006 6

7. Standards
CRO Sponsor
ODM
Archive
ODM
SDTM
ODM ADaM
Investigator ODM
Define.XML
Archive
Subject LABs
Protocol
EMEA. June 7th, 2006 7

8. Operational Data Model
CRO Sponsor
ODM
Archive
ODM
SDTM
ODM ADaM
Investigator ODM
Define.XML
• Exchange & Archive of
clinical data
Archive
Subject
• Production Version 1.2.1
LABs
• Protocol
XML Schema
EMEA. June 7th, 2006 8

9. Laboratory Data Model
CRO Sponsor
ODM
Archive
ODM
• Exchange of LAB
data SDTM
ODM ADaM
• Production ODM
Investigator
Version 1.0.1 Define.XML
• Implementations
through SAS,
Archive
ASCII, XML/ODM
Subject LABs
and HL7 V3 RIM Protocol
message
EMEA. June 7th, 2006 9

10. Study Data Tabulation Model
CRO Sponsor
ODM
Archive
ODM
SDTM
• Submission data (Case Report
ODM ADaM
Tabulations; analysis data)
Investigator ODM
Define.XML
• Production Version 1.1
• Referenced as a specification in
Archive
FDA Guidance - 21 July 2004
Subject LABs
Protocol
EMEA. June 7th, 2006 10

11. Standards for the Exchange of Non-clinical
Data (SEND)
CRO Sponsor
ODM
Archive
ODM
• Non-clinical (animal) data SDTM
ODM ADaM
• Based upon CDISC SDS V3.1
Investigator ODM
• Included in SDTM model now Define.XML
referenced in FDA Guidance
Archive
Subject LABs
Protocol
EMEA. June 7th, 2006 11

12. Analysis Dataset Models
CRO Sponsor
ODM
Archive
ODM
• General Considerations
Document and Examples of
ODM
SDTM
ADaM
Standard Analysis Datasets ODM
Investigator
for Submissions Define.XML
Archive
Subject LABs
Protocol
EMEA. June 7th, 2006 12

13. Protocol Representation
CRO Sponsor
ODM
Archive
ODM
SDTM
ODM ADaM
• HL7-CDISC-NCI Collaboration
Investigator ODM
• Objective to develop a standard,
Define.XML
structured, machine-readable clinical
Archive
protocol representation
Subject LABs
Protocol
EMEA. June 7th, 2006 13

14. Terminology
CRO Sponsor
ODM
Archive
ODM
SDTM
ODM ADaM
Investigator ODM
Define.XML
• Covers the work of all teams
Archive
Subject LABs
Protocol
EMEA. June 7th, 2006 14

15. CDISC Projects - A Sample
• End-to-End Production Use
– How are the models used end-to-end in detail
• Device Domain
– SDTM Domain
• SDTM-ADaM Pilot
– In conjunction with the FDA
• Submission in ODM XML
– Removal of SAS Transport Files
• The Link with Healthcare
– Integrating the Healthcare Enterprise (IHE)
Profile
EMEA. June 7th, 2006 15

16. Background
• FDA Presentation, August 2004 - Reviewers
– Operational Data Model (ODM)
– The Archive Use Case
– Define.xml
• FDA Presentation, November 2004 - DSI
– ODM
– Regulations
• Suggested changes to CSUCT guidance
document
EMEA. June 7th, 2006 16

17. eSDI Group
• The electronic Source Data
Interchange (eSDI) initiative
• Started in November 2004 with the
encouragement from the Food and
Drug Administration (FDA)
EMEA. June 7th, 2006 17

18. eSDI Mission
Produce a document that would benefit
industry and FDA by providing
recommendations for the use of the
CDISC standards with associated
processes that can promote the
enhanced use of eSDI within the context
of the existing regulations for regulated
clinical research.
EMEA. June 7th, 2006 18

19. Issues
• How to transition from the paper world to the
e-World in terms of audits, reviews,
compliance to regulations
• No regulatory basis for Trusted Third Parties
• Concern about Interim Analysis
• Collection of data without adequate
psychometric validation
• Inadequate validation and control of systems
used for data collection
EMEA. June 7th, 2006 19

20. History
• Expert Focus Groups Invited for Comment
– 23rd February, Philadelphia
– 7th March, Lisbon
• 1st Draft 14th March 2005
– 4th & 5th April, DIA ePRO Conference, Arlington
– 11th April, SAS Users Forum
• 2nd Draft 25th May 2005
• 3rd Draft 11th August 2005
• 4th Draft 29th August 2005
• 5th Draft 16th September 2005
• 500+ individual comments
• 6th Draft Q2 2006
EMEA. June 7th, 2006 20

21. Content
• Psychometric validation not in document
– Now being looked at by a DIA group
• Interim Analysis
– Small reminder of current regulations and
guidance
• eSource
– Main focus of document
– How standards can help
EMEA. June 7th, 2006 21

22. Motivation and Aims
• Motivation
– Desire to solve the issue and increase adoption
• Aims
– Something tangible to shoot at, detailed enough
to allow debate and be practical
– Simple check list, well understood (a what not
how)
– Allows all stakeholders (FDA, Sponsors, Vendors
& Investigators) to assess current and future
technologies
EMEA. June 7th, 2006 22

23. Method
• Examine the paper process; if well executed,
it meets the regulatory requirements
• What are the requirements that source
documents must meet?
• What do the FDA, Sponsors and
Investigators need (key requirements) from
source documents?
• Consider
– Regulations
– Data Quality & Integrity
– Subject Safety
EMEA. June 7th, 2006 23

24. Outcome
• Checklist
– A checklist that allows industry to assess any
technology and process now or in the future
• Scenarios
– Suggested ways to move forward
EMEA. June 7th, 2006 24

25. Criticism of Approach
• Criticisms
– We don’t want to preserve paper
– Why look at the paper process
• Fundamental Question
– Why do we have source documents and data?
EMEA. June 7th, 2006 25

26. Fundamental Questions
• How do we ensure that the data submitted
are the data captured?
• How do we ensure the data captured is
accurate?
• How do we ensure the subject's safety?
EMEA. June 7th, 2006 26

27. User Requirements
• 12 in total
• As they stand today
• Open for review, discussion and debate
• The detail is in the white paper
• All are mapped to regulations
EMEA. June 7th, 2006 27

28. Requirement 1 (Old Text)
An instrument used to capture source
data shall be an accurate representation
of the protocol ensuring that the data as
specified within the protocol is captured
correctly.
EMEA. June 7th, 2006 28

29. Requirement 1 (New Text)
An instrument used to capture source
data shall ensure that the data is
captured as specified within the protocol
EMEA. June 7th, 2006 29

30. Requirement 2
Source data shall be Accurate, Legible,
Contemporaneous, Original, Attributable,
Complete and Consistent (the ALCOA
and Data Integrity requirement).
EMEA. June 7th, 2006 30

31. Requirement 3
An audit trail shall be maintained as part
of the source documents for the original
creation and subsequent modification of
all source data.
EMEA. June 7th, 2006 31

32. Requirement 4
The storage of source documents shall
provide for their ready retrieval.
EMEA. June 7th, 2006 32

33. Requirement 5
The investigator shall store the original
source document or a certified copy.
EMEA. June 7th, 2006 33

34. Requirement 6
The mechanism used to maintain source
documents shall ensure that source data
cannot be modified without the
knowledge or approval of the investigator.
EMEA. June 7th, 2006 34

35. Requirement 7
Source documents and data shall be
protected from destruction.
EMEA. June 7th, 2006 35

36. Requirement 8
The source document shall allow for
accurate copies to be made.
EMEA. June 7th, 2006 36

37. Requirement 9
Source documents shall be protected
against unauthorised access.
EMEA. June 7th, 2006 37

38. Requirement 10
The sponsor must never have exclusive
control of a source document.
EMEA. June 7th, 2006 38

39. Requirement 10
The sponsor must never have exclusive
control of a source document.
“Comments were also made
indicating that this was not a new
requirement, but intrinsic to
complying with FDA regulations
regarding clinical trials.”
EMEA. June 7th, 2006 39

40. PRO Guidance Document
• FDA Guidance for Industry.
– Patient-Reported Outcome Measures: Use in
Medical Product Development to Support
Labeling Claims
• Lines 848 & 849
– Sponsors should also plan to avoid the following:
• Direct PRO data transmission from the PRO data
collection device to the sponsor (i.e., the sponsor
should not have exclusive control of the source
document)
EMEA. June 7th, 2006 40

41. Requirement 11
The location of source documents and
the associated source data at all points
within the capture process shall be clearly
identified.
EMEA. June 7th, 2006 41

42. Requirement 12 (Old Text)
When source data are copied, the
process used shall ensure that the copy
is an exact copy having all of the same
attributes and information as the original.
EMEA. June 7th, 2006 42

43. Requirement 12 (New Text)
When source data are copied, the
process used shall ensure that the copy
is an exact copy preserving all of the data
and metadata of the original
EMEA. June 7th, 2006 43

44. Recommendations (1)
• Source at Site
– Electronic equivalent of paper
– Must be easy (practical) for the investigator
– The CDISC Operational Data Model (ODM) can
assist greatly
Source
Data
Investigator ODM
Sphere of investigator Sponsor
control
EMEA. June 7th, 2006 44

45. Recommendations (2)
• eSource System Provider
– Works on behalf of the investigator
– Must document how the 12 core requirements
are met
– This document must be open to inspection by
the FDA
Investigator
eSource System
Provider
Sponsor
EMEA. June 7th, 2006 45

46. Recommendations (3)
• Single Source Concept Sponsor
Sponsor
Database
– Single entry of data
using an EHR
– Data used, as required,
in both healthcare and
clinical research ODM
– Use of “ODM Store”
helps facilitate
compliance with the
Source
regulations EHR
Data
ODM
EMEA. June 7th, 2006 46

47. Recommendations (4)
• EHR Extraction and Sponsor
Sponsor
Investigator Verification Database
– Data extracted from the
EHR database
– Investigator verifies the
data
– Protects against 21 CFR
11 “creep”
EHR EHR
Database
EMEA. June 7th, 2006 47

48. Recommendations (5)
• Direct Extraction Sponsor
Sponsor
– Data extracted from the Database
EHR database
– EHR must be 21 CFR
Part 11 Compliant
EHR
Database
EHR
EMEA. June 7th, 2006 48

49. Next Steps - The Ideal Picture?
eSource System Provider
Investigator Sponsor
Source
Doc
EMEA. June 7th, 2006 49

50. Next Steps - The Ideal Picture?
eSource System Provider
• Read
• Create
• Read
• Update
Investigator Sponsor
Source
Doc
• Read
• Update With
Approval
EMEA. June 7th, 2006 50

51. Fundamental Questions
• How do we ensure that the data submitted
are the data captured?
• How do we ensure the data captured is
accurate?
• How do we ensure the subject's safety?
EMEA. June 7th, 2006 51

52. Output From Work
• 12 User Requirements
• 5 Scenarios
• Recommendations
• Checklist for Investigators
• Sponsor Audit Report Template
EMEA. June 7th, 2006 52

53. Summary
• The work of the eSDI group provides a clear
way forward in the use of eSource
• Core requirements and recommendations
provide the foundation stone for the building
of true e-Clinical systems
• Draft 6 being worked on, will be released via
the CDISC website, www.cdisc.org
EMEA. June 7th, 2006 53

54. Information and Contacts
• eSDI Group Leaders
– Rebecca Kush
rkush@cdisc.org
– Dave Iberson-Hurst
dave.iberson-hurst@assero.co.uk
EMEA. June 7th, 2006 54

55. Contributors
• Ethan Basch • Michael Noonan
Memorial Sloan-Kettering Cancer Asthma Research
Center
• Lisa Olson
• Peter Black SEC Associates
Scirex
• Shaghig Palanjian
• David Detoro Perceptive Informatics
Schering Plough
• Jay Pearson
• Hugh Donovan Merck & Co.
Siemens
• David Reasner
• Greg Fromell Sepracor
University of Pennsylvania
• Dana Stone
• Ed Helton Merck & Co.
SAS
• Mark Weiner
• John Jordon University of Pennsylvania
Schering Plough
• Wallace Wormley
• Suzanne Markel-Fox University of Pennsylvania
GSK
EMEA. June 7th, 2006 55

56. FDA Liaisons
• Laurie Burke
Director Study Endpoints and Label Development, Office of New Drugs
CDER
• Joanne Rhoads
Director, Division of Scientific Investigations, CDER
• Joe Salewski
Deputy Director, Division of Scientific Investigations, CDER
• Jane Scott
Study Endpoints and Label Development, Office of New Drugs, CDER
• Steve Wilson
Deputy Director, Division of Biometrics II, CDER
EMEA. June 7th, 2006 56

57. Discussion
EMEA. June 7th, 2006 57