1. eSDI Group
7 March 2005, Lisbon
Becky Kush, CDISC
Jane Scott, FDA
Dave Iberson-Hurst, Assero & CDISC

2. Contents
eSDI Group
Areas of Interest
Work to Date
Psychometric Validation
Interim Analysis
eSource
Next Steps
Discussion

3. eSDI Group
• The eSource Data Interchange Group was
formed to provide a forum for gathering
input from the biopharmaceutical industry
and the development of recommendations
that could help address existing issues with
the collection and use of eSource Data for
clinical trials; the initial focus was on
electronic Patient Reported Outcomes.

4. eSDI Group
• FDA and sponsors currently share a
feeling that there is no clear direction on
regulatory issues related to eSDI/ePRO
• CDISC was asked to initiate the eSDI
group
• It was considered very important for this
group to have a vendor-neutral, platform-
independent perspective.

5. eSDI Group
• Formed in October 2004
• FDA requested input from industry
representatives (specifically trials
sponsors, site representatives and CDISC
representatives) regarding the issues
• Comprised of two representatives from
major pharmaceutical companies, one
validation expert, three representatives of
investigative sites, two CDISC
representatives and five FDA liaisons

6. Areas of Interest
• Interim Analysis
– What are the issues?
• Psychometric Validation
– What are the issues?
– Touch points with System Validation?
• eSource
– How does industry move forward?

7. Progress to Date (1)
• eSDI Group Communications
– Teleconferences ~ every two weeks; minutes/e-mails
to share ideas and identify issues
– Face to face meeting on 31 January
• Development of a Draft White Paper
– Rationale
– eSource Data Interchange
• (issues, relationship to regulations for paper,
recommendations for adherence to regulations for ePRO/
eSource)
– Psychometric and System Validation
– Interim Analyses
– Issues for the Future

8. Progress to Date (2)
• Expert Focus Groups Invited for
Comment
– 23 February, Philadelphia
– 7 March, Lisbon

9. Next Steps
• Revise White Paper and Solicit Broader
Comment
– 4-5 April, DIA ePRO Conference, Arlington
– 11 April, SAS Users Forum
– CDISC Website
• Complete White Paper and Present
Widely with FDA Representatives
– DIA Annual Meeting, Washington DC, June 2005
– Potential Guidance on ePRO
– Webinars, other venues

10. Issues
• Collection of data without adequate
psychometric validation
• Inadequate validation and control of
systems used for data collection
• How to transition from the paper world to
the eWorld in terms of audits, reviews,
compliance to regulations
• No regulatory basis for Trusted Third
Parties

11. Sense of Urgency
• ePRO data going directly from patient to
trial sponsor (bypassing the investigator)
• Investigators not having a copy of or
control of the source data
• Collection of data without Data analysis
on the fly – during the collection
process, without adherence to ICH E9
guidance on interim analyses

12. Interim Analysis
• Present the issues resulting from the
concerns about the introduction of bias
• Detail the guidance
– ICH E9
• Section 4.5 - Interim Analysis and Early Stopping
– FDA Guidance for Clinical Trial Sponsors
(Draft Guidance – November 2001)
• Section 4.2 - Confidentiality of Interim Data and
Analyses

13. Validation
• Examining the touch points between
system and psychometric validation
• Psychometric aspect of ePRO instruments
• System validation aspects of ePRO
systems
• FDA PRO draft guidance coming in April

14. eSource
• Motivation and Aims
• Method
• Analysis
• Recommendations

15. Motivation and Aims
• Motivation
– Desire to solve the issue
– Increase adoption
• Aims
– Something tangible to shoot at
– Detailed enough to allow debate
– Practical
• End Point
– Simple check list, well understood (what not how)
– Allows all stakeholders (FDA, Sponsors, Vendors &
Investigators) to assess current and future
technologies

16. 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?

17. Method
• Examine the life cycle of paper source
documents
• Stand back and extract the requirements
• Consider
– Regulations
– Data Quality & Integrity
– Subject Safety

18. Paper Life Cycle
Select
Make Copy
BLANK
Capture
Create POPULATED
Study Ends
ARCHIVED Clarify, View,
Monitor or Inspect
View or Inspect
Destroy
End of Retention Period
OBSOLETE

19. Analysis of Process
• What are we doing? (The What)
– What is the action?
• Why are we doing it? (The Why)
– What is the purpose?
• What does it achieve?
– What are the drivers?
• What are the regulations?
• How does it contribute to data quality (ALCOA) and integrity?
• What impact on subject safety?
• Purpose is to identify the significant operations
and the core requirements/needs of the various
stakeholders (FDA, Sponsors and Investigator)

20. Paper Life Cycle
Select
Make Copy
BLANK
Capture
Create POPULATED
Study Ends
ARCHIVED Clarify, View,
Monitor or Inspect
View or Inspect
Destroy
End of Retention Period
OBSOLETE

21. Analysis of Process
• What are we doing? (The What)
– What is the action?
• Why are we doing it? (The Why)
– What is the purpose?
• What does it achieve?
– What are the drivers?
• What are the regulations?
• How does it contribute to data quality (ALCOA) and integrity?
• What impact on subject safety?
• Purpose is to identify the significant operations
and the core requirements/needs of the various
stakeholders (FDA, Sponsors and Investigator)

22. Requirements
• Initial analysis resulted in 9 requirements
• Requirements examined in the context of
21 CFR 11
– Additional requirement
• Re-examined in the context of existing
technologies/architectures
– Additional two requirements

23. Architectures/Technologies
• Case Report Form
– Paper CRF
– eCRF (Thin & Thick Client)
• Diaries
– Paper Diary
– eDiary (PDA, IVRS etc)

24. 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

25. Requirement 1
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.

26. Requirement 2
Source data shall be Accurate, Legible,
Contemporaneous, Original,
Attributable, Complete and
Consistent (the ALCOA and Data
Integrity requirement).

27. Requirement 3
Source documents shall provide the
ability to maintain an audit trail for
the original creation and subsequent
modification of the source data.

28. Requirement 4
The storage of source documents shall
provide for their ready retrieval.

29. Requirement 5
The investigator shall store the original
source document or a certified copy.

30. Requirement 6
The mechanism used to hold source
documents shall ensure that source data
cannot be modified without the
knowledge or approval of the
investigator.

31. Requirement 7
The storage of source documents shall
ensure they cannot be destroyed.

32. Requirement 8
The source document shall allow for
accurate copies to be made.

33. Requirement 9
Source documents shall be protected
against unauthorised access.

34. Requirement 10
The sponsor must never have exclusive
control of a source document.

35. Requirement 11
The location of source documents, and the
associated source data, shall be clearly
identified at all points within the capture
process.

36. Requirement 12
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.

37. Example – eDiary
Trusted Third
Party
Data entered by
Data stored by TTP, subject using a PDA
viewed by investigator and is saved to non-
via the web. volatile storage on the
PDA. Sent to TTP
database as and when
communications
available.
Investigator Subject

38. Example – eDiary
Requirement Requirement
An instrument used to capture source data The storage of source documents
shall be an accurate representation of the shall ensure they cannot be
protocol ensuring that the data as specified destroyed.
within the protocol is captured correctly.
The source document shall allow for
Source data shall be Accurate, Legible, accurate copies to be made.
Contemporaneous, Original, Attributable,
Source documents shall be protected
Complete and Consistent (the ALCOA and against unauthorised access.
Data Integrity requirement).
The sponsor must never have
Source documents shall provide the ability exclusive control of a source
to maintain an audit trail for the original
document.
creation and subsequent modification of the
source data. The location of source documents,
and the associated source data, shall
The storage of source documents shall be clearly identified at all points within
provide for their ready retrieval.
the capture process.
The investigator shall store the original
When source data are copied, the
source document or a certified copy.
process used shall ensure that the
The mechanism used to hold source copy is an exact copy having all of the
documents shall ensure that source data same attributes and information as
cannot be modified without the knowledge the original.
or approval of the investigator.

39. Example – eDiary
The investigator Trusted Third
Party
shall store the
original source
document or a
certified copy.
Data entered by
Data stored by TTP, subject using a PDA
viewed by investigator and is saved to non-
via the web. volatile storage on the
PDA. Sent to TTP
database as and when
communications
available.
Investigator Subject

40. Example – eDiary
The mechanism Trusted Third
Party
used to hold source
documents shall
ensure that source
data cannot be
modified without Data entered by
Data stored by TTP,
the knowledge or investigator subject using a PDA
viewed by and is saved to non-
approval via the web.
of the volatile storage on the
investigator. PDA. Sent to TTP
database as and when
communications
available.
Investigator Subject

41. Example – eDiary
The sponsor must Trusted Third
Party
never have
exclusive control of
a source document.
Data entered by
Data stored by TTP, subject using a PDA
viewed by investigator and is saved to non-
via the web. volatile storage on the
PDA. Sent to TTP
database as and when
communications
available.
Investigator Subject

42. Example – eDiary
Requirement Requirement
An instrument used to capture source data The storage of source documents
shall be an accurate representation of the shall ensure they cannot be
protocol ensuring that the data as specified destroyed.
within the protocol is captured correctly.
The source document shall allow for
Source data shall be Accurate, Legible, accurate copies to be made.
Contemporaneous, Original, Attributable,
Source documents shall be protected
Complete and Consistent (the ALCOA and against unauthorised access.
Data Integrity requirement).
The sponsor must never have
Source documents shall provide the ability exclusive control of a source
to maintain an audit trail for the original
document.
creation and subsequent modification of the
source data. The location of source documents,
and the associated source data, shall
The storage of source documents shall be clearly identified at all points within
provide for their ready retrieval.
the capture process.
The investigator shall store the original
When source data are copied, the
source document or a certified copy.
process used shall ensure that the
The mechanism used to hold source copy is an exact copy having all of the
documents shall ensure that source data same attributes and information as
cannot be modified without the knowledge the original.
or approval of the investigator.

43. Example – eDiary
Trusted Third
Party
Data entered by
Data stored by TTP, subject using a PDA
viewed by investigator and is saved to non-
via the web. volatile storage on the
PDA. Sent to TTP
database as and when
communications
available.
Investigator Subject

44. Next Steps
• Experts: Today and DIA Lisbon
– Update in response to comments
– Additional technologies/architectures
• EHR
– Direct from EHR system
– Single-Source
• Public: April, DIA ePRO Conference, Arlington
– Update in response to comments
• Complete White Paper and Present Widely with
FDA Representatives
– DIA Annual Meeting, Washington DC, June 2005
– Potential Guidance on ePRO
– Webinars, other venues

45. Discussion

46. Information and Contacts
• eSDI Group Leaders
– Rebecca Kush
rkush@cdisc.org
– Dave Iberson-Hurst
dave.iberson-hurst@assero.co.uk