Electronic Systems in Clinical Trials

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Electronic Systems in Clinical Trials

• Lisbeth Bregnhøj
• Medicines Inspector, Medicines Control Division

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Topics

• Definitions, requirements etc.
• Draft reflection paper on expectations for
  electronic source documents
• Inspection issues and focus areas
• Conclusion
• (Authorities attitude towards eCRFs, Source data
  vs. eCRF, Worksheets, Version and User control)

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Definitions, requirements etc.

• Directive 2005/28/EC
• Retention and archiving of essential documents
• The media used to store essential documents
• Eudralex volume 10, chapter 5
• Particular attention regarding storage on certain
  media
• Transfer of records

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Definitions, requirements etc.

• ICH GCP
• Definitions of documentation (1.22), essential
  documents (1.23), source data (1.51) and source
  documents (1.52)
• Use of electronic trial data handling and/or
  remote electronic trial data systems (5.5.3)
• Validation, SOPs, Audit trail, Access control,
  Authorisation to change data, back-up

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Definitions, requirements etc.

• Directive 95/46/EC
• Special protection for medical data
• Directive 1999/93/EC
• on electronic signature

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Draft reflection paper on expectations for
electronic source documents

• Reflection paper issued by the GCP Inspectors
  Working Group
• Released for consultation October 2007 to April
  2008
• Sets out the current thinking of the WG
• 16 organisations responded, 67 pages of comments
• Responses under review. Document will be revised
  and finalised

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Scope of the paper

• Electronic source documents in this context
  includes
• e-CRFs
• e-patient diaries
• Other instruments supplied to investigators or
  patients for recording study data either by data
  entry or by automated capture of events

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General Principles

• Accurate
• Legible
• Contemporaneous
• Original
• Attributable
• Complete
• Consistent
• Enduring
• Available when needed

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Reflection paper requirements

• GCP IWG noted the CDISC Standards
• CDISC 12 user requirements for source data
  irrespective of the media or technology
• Independent of a specific technical solution
• Based on ICH GCP and other recognised
  requirements
• High-level principles
• Internationally applicable

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• Requirement 1
• An instrument used to capture source data shall
  ensure that the data are captured as specified
  within the protocol.
• Should not introduce bias
• Change control
• Documentation for specification, installation,
  tests, release

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• Requirement 2
• Source data shall be Accurate, Legible,
  Contemporaneous, Original, Attributable, Complete
  and Consistent.
• Drop down lists
• Edit checks
• Training
• Log-in, user ID, password

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• 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.
• Changes in data should be documented
• Audit trails should be archived for the same
  period as data
• Authorisation on different levels

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• Requirement 4
• The storage of source documents shall provide for
  their ready retrieval.
• Availability for investigators, inspectors and
  other relevant parties.

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• Requirement 5
• The investigator shall maintain the original
  source document or a certified copy.
• Related to 6 and 10
• Investigator should retain control over source
  documents

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• Requirement 6
• Source data shall only be modified with the
  knowledge or approval of the investigator.
• Describe in procedures how this is ensured
• Process in place with queries, obvious data
  modifications etc.

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• Requirement 7
• Source documents and data shall be protected from
  destruction.
• Back up
• Appropriate archiving
• Change control

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• Requirement 8
• The source document shall allow for accurate
  copies to be made.
• Data should be printable for audit or inspection
  purposes

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

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• Requirement 10
• The sponsor shall not have exclusive control of a
  source document.
• NB! Web based systems
• Investigators control (5 and 6)
• Describe in procedures how this is ensured
• Potential tightening in reflection paper
• Contracts with third parties

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• Requirement 11
• The location of source documents and the
  associated source data shall be clearly
  identified at all points within the capture
  process.
• There is only one source
• Source data in CRFs

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• Requirement 12
• 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.
• Method of certification should be described

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Most frequent comments from the consultation

• Reflection paper is generally appreciated
• Request to expand the scope to electronic medical
  records
• Need for definitions and clarifications (source
  (ePROs), certified copies, instrument,
  appropriate archiving etc.)
• Request for more detailed guidance

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Most frequent comments from the consultation

• Real e-source data vs. data entry from other
  source documents
• Relationship/alignment between the reflection
  paper and other guidances (FDA, Japan etc.)
• Apparently still not crystal clear guidance
  regarding investigators control and sponsor not
  having exclusive control

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Inspection issues and focus areas

• Considerations
• Fundamental requirements apply irrespective of
  the media
• Additional challenges!

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Inspection issues and focus areas

• Source is not clearly identified and documented
• Change control is not appropriate
• Instrument is not in place at trial initiation
• Relevant persons do not have access
• No back-up plan is in place
• Sponsor staff insists on participation during
  data entry

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Inspection issues and focus areas

• Data entry at site without appropriate QC
• Data entry from paper work sheets, inconsistent
  corrections
• Central monitoring cannot replace on-site
  monitoring

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Inspection issues and focus areas

• Electronic source data are not available to the
  investigator
• Investigator does not have control over data
• Sponsor has exclusive control of the source
  documents
• Obvious data modifications are not obvious

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Inspection issues and focus areas

• Data delivered to the investigator are not
  endurable
• Passwords are shared
• Essential systems have not been audited
• Electronic medical records are not QCed
• Training at investigator site is not appropriate

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Conclusions

• Responses to reflection paper are under review
• The final document and the comments received will
  be published
• Fundamental requirements apply irrespective of
  the media
• Electronic systems in clinical trials should not
  result in a decrease in data quality or data
  integrity
• Consider the intentions behind the requirements

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