We present our evaluation of existing data standards for clinical trials. For this purpose a survey about the importance of data standards for clinical trials centers and EDC software companies were conducted. Electronic data capture in clinical trials uses a computerized system designed for the collection of clinical data in electronic form in Case Report Forms (CRF). It also covers medical data captured during clinical trials, safety data related to clinical trials, and patient reported outcome. The degree of implementation of standards, like CDISC ODM in available EDC software products was evaluated. Failure to establish data standards will make it difficult or impossible to connect data between different systems for efficient clinical study execution. The next step after purchasing a software solution is the computer system validation. Validation is about bringing computerized systems into regulatory compliance and making them compliant with GCP, GLP and GMP and other regulations (e.g. data protection). The basis standard for validation is provided by the GAMP Good Practice Guide, which provides a framework of best practices to ensure that computer systems are suitable for use and compliant with the legislation. The newest version uses a risk-based approach to computer system validation A system is evaluated and assigned to a predefined category based on its intended use and complexity. For validation one should define how all elements of the computer system are supposed to work (functional requirements), develop corresponding scripts and test routines to validate it is functioning as it should.

1. Importance of Data Standards and System
Validation for Software for Clinical Research
TELEMED 2005
9.4.2005 in Berlin
Wolfgang Kuchinke
Uni Düsseldorf, Düsseldorf, Germany

2. System Validation
Project
 Evaluation of existing data
standards for clinical trials
 Survey about the importance of
data standards for clinical trials
centers
 Degree of implementation in
available EDC software products
 Evaluation of the requirement for
computer system validation of EDC
system
 Preparation of the complete
validation of EDC systems used by
research networks in the TMF
network

3. Aim of project
• Development of process descriptions, as well
as necessary documents and checklists for any GCP-
compliant system validation
• Provided to all research associations of the TMF platform
for Medical Research Networks
• Research networks should be made aware of the necessity
and importance of system validation
• Provision of the validation documents to all interested by
TMF

4. Telematics
Plattform (TMF)
Growing importance of
standards for data and
metadata exchange
• Overarching problems of
networked working
• Merger of research associations
• Competence networks in
medicine
• Coordination centers for clinical
studies
• National Genome Research
Network
• Networks for rare diseases
• Further medical research
collaborations
• Importance of data standards

5. EDC (Electronic
Data Capture)
Need for
implementation
in research
networks
• Electronic recording of
patient data in clinical
studies
• Internet
• Increased efficiency
• Improved quality
• Integration between
different data collection
system
• Data sharing

6. What is
electronic data
capture clinical
trial?
• A computerized system
designed for the collection of
clinical data in electronic
format using Case Report
Forms (CRF) for use in
human clinical trials
• Recording of different types
of clinical trial data, such as:
– Medical data captured during
clinical trials
– Safety data related to clinical
trials
– Test results from labs
– Information from patients
(Quality of Life), PRO
– Patient information recorded
by apps and devices

7. Beginning as RDC
●
EDC started as ‘Remote Data
Capture’ (RDC)
●
Patient data were recorded
electronically at clinical study
sites, but often offline with
isolated systems
●
Recently, daat collection systems
have become more sophisticated,
and web-based systems such as
electronic case report forms
(eCRFs) and patient-reported
outcome (PRO) systems are being
increasingly used

8. Data exchange
• XML-based data exchange supports cooperation in
scientific research networks
• Clinical data acquisition and study execution
• Patient examinations
• Electronic data (ECG, ...)
• Laboratory data, lab notebook
• X-ray images
• Formats of clinical study data are different
• The way of documentation is different
 Restrictions due to software used

9. Importance of
Patient Reported
Outcomes
(PRO)
●
Is a valuable tools to collect
patient-centered data
●
Is included in clinical trials as
primary or secondary endpoints
●
It gives unique information on
the impact of a medical
condition and its treatment from
the patient’s perspective
●
Validated PRO measures are
used in clinical trials to ensure
that the response options, and
the general approach to
assessment are standardized

10. Infrastructure
Topology of
collaboration
Coordination Centres
of Clinical
Trials
Medical Research
Networks
Cooperation
EDC
Additional
cooperating partners
Improving Cooperation by using EDC
EDC PRO
Lab

11. Data standards
for clinical trials
 Adoption of data standards are
necessary to guarantee correct
clinical study processes, high data
quality, efficiencies and the
integration of applications across
the complex clinical research
processes
 Clinical trials are operating under
the observance of global regulatory
agencies that demand data
standards for the submission of
clinical trials data
 It has become necessary to collect
data in a standardized way
 Failure to establish data standards
will make it difficult or impossible to
connect data between different
systems for efficient clinical study
execution

12. Focus on
XML for
exchange
of study data
• New possibilities for
integrating data and
metadata
• Possibilities for
standardization
• Automation of processes
• Improving of cooperation
• Use of different EDC
system in a single clinical
trial
• Easy way of clinical
document archiving

13. XML
eXtensible Markup
Language
 XML is a text-based mark-up
language for structuring data
content with self-describing
metadata tags
 XML is independent of software and
hardware for storing and
transfereing data
 XML was designed to create
documents, and data records that
are fully portable

14. Survey among the TMF network members
• 42 Associations of the TMF
• Standardized questionnaire
• 32 answered questionnaires
• 11 questions on the exchange of
clinical data and the importance of
standards
• Senior IT or data manager of the
networks
 5-values answer scale, ranging from
"very important (=1)" to "useless
(=5)

15. Survey
Clinical Study Centres
and other
members of TMF
42
participants
EDC software
companies
5
participants

16. Survey about data standards
• Members of Research Networks
• Metadata
• Type of data and metadata exchanged by the TMF
consortia
• Type of study partners mainly involved in data exchange
• Importance of the CDISC standards (ODM, SDM, LAB) for
the research networks
 Degree of implementation of CDISC in study software
solutions of research networks

17. Survey of EDC software companies
 7 questions on the degree of implementation
of CDISC in the study software solutions of
the associations
 Answers from "fully implemented" to "neither
implemented nor planned”
 Strategy for the use of data standards by the
EDC developers
 Five software companies included: eResearch
Network by eDataCapture and
eResearchNetwork by eResearch Technology,
MACRO by InferMed, secuTrial by iAS, PhOSCo
by Guillemot Design, CAP-Netz by CAP-Netz

18. Question about
importance
Questionnaire
How important do you consider the use of ODM or SDM in
your association?

19. Frage nach
Wichtigkeit
Questionnaire
How do you rate the importance of sharing data and metadata
with one of the following study partners?

20. Results
• 90% possibility of data exchange very important / important
• 80% Exchange of metadata very important / important
• Partners for data exchange
• universities = 91%
• Partners within the respective network = 81%
• study group = 78%
• Competency networks and PPS = 78%
• Exchange of laboratory data = 88%
• Patient data = 78%.
Requirements for data exchange

21. CDISC, the standard for clinical research
• CDISC Consortium
• Developed a standard for the collection, exchange,
submission of data to authorities
• Standard for archiving of data from clinical studies
• CDISC is global, vendor neutral, platform and software
independent
• XML-based standard for study content and metadata
• ODM (Operational Data Model), SDS (Submission Domain
Standard) and LAB (Laboratory Data Standard)
• Broad support and approval in the pharmaceutical industry
• But largely unknown in the academic world

22. ODM
• ODM (Operational Data Model) for clinical study data
• Completely XML-based
• Maps the entire clinical study
• Main modules.
• Study metadata
• administrative data
• Reference data
 Clinical data
• EDC Software should support ODM standard for data sharing

23. Modules of ODM

24. Data
Harmonization
Efforts
• Consolidation of data acquisition on the
supply and research level through
harmonized XML standards
• HL7: leading standard for electronic
exchange of supply data
• HL7 "supports" XML as a technology
standard from V3 Reference Information
Models (RIM)
• ICH Electronic Common Technical
Document (eCTD)
• Technical Committee for HL7 Regulated
Clinical Research and Information
Management (TC:RCRIM)
• Representatives of HL7 / Pharma, FDA
and CDISC
• Harmonization of standard development
between research and supply

25. Situation in
Germany
Information technology
networking in the
health care system in
Germany
Merging of the xDT
standard for general
practitioners with the
HL7 standard in the
hospital sector
SCIPHOX

26. Next step: Validation
EDC Software
Purchase
●
Use in clinical
●
trials
●
Training of
investigators
Installation
System Validation
Training of users
Regulatory compliant use

27. What is
Computer
System
Validation?
 Computerized systems, including all
instrumentation and software used
to create, modify, transmit, or
archive data associated with work
subject to federal regulations (GCP,
GLP, and GMP)
 Bringing standard computerized
systems into regulatory compliance
 Making computerized systems
compliant with GCP, GLP and GMP
and other regulations (e.g. data
protection)

28. Working
packages
 KKS Düsseldorf (Tracebilitymatrix,
Validation Master Plan, Validation
Plan, SOPs)
 KKS Mainz/KKS Heidelberg
(Evaluation of legal foundations
and guidelines, Glossary)
 KKS Leipzig (security infrastructure,
security SOPs, security plan,
security policy, risk analysis)
 KKS Tübingen (test study and test
cases, test plan, test evaluation)
 KKS Marburg
Validation project

29. Definition of
Computer
System
 Any programmable device
including its software, hardware,
peripherals, procedures, users,
interconnections and inputs for the
electronic processing and output of
information used for reporting or
control
 It is important to determine how to
validate, and what is the extent of
validation required, for computer
systems
 Compliance with the validation
requirements documented in the
Validation Master Plan (SDMP)

30. Traceability
Matrix
• Based on user requirements
• Considers the complete course of
clinical studies
• GCP Impact (high, medium, low)
according to the risk to the data
• Connect regulatory and functional
requirements with validation scripts
for testing
• Should include validation for CDISC
data standards
The most important
validation document

31. IQ
Validation process: Scripts to test data entry
Action to do Expected result Result
IQ

32. OQ
Test Script Example
Validation requirement Did expected result occur?

33. • Need for Computer System Validation
• Requirement of regulatory compliance
• Improvement of quality of clinical studies in the university
environment
• GCP-compliant studies and/or studies relevant to
marketing authorization
• GCP and quality assurance
• EDC software that will be validated: MACRO, eResNet, CAP
network, PhOSCo, secuTrial
Importance of System Validation

34. GAMP
●
Defines a standard for computer
system validation
●
Provides a framework of best
practices to ensure that computer
systems are suitable for use and
compliant with the legislation
●
Newest version provides a risk-
based approach to computer
system validation
●
A system is evaluated and
assigned to a predefined category
based on its intended use and
complexity
●
Compatible with IEEE, ISO 9001
and 12207, ITIL and other
international standards
GAMP Good Practice Guide

35. 21CFR Part11
●
Part 11 of Title 21 of the Code of
Federal Regulations
●
It describes how a company
operating in the US can use
electronic quality records and
digital signatures in place of
paper based documentation
compliant with FDA regulations
●
It is the regulatory response to
security concerns about
managing the distribution,
storage and retrieval of digital
records by drug and medical
equipment manufacturers

36. 21CFR Part11
Guidance
document

37. Innovations from
FDA
• “Validation of systems to ensure
accuracy, reliability, consistent
intended performance’
• Overall approach by FDA: „Part 11
will be interpreted narrowly“
• Validation: „The Agency intends to
exercise enforcement discretion
regarding the specific Part 11
requirements for validation of
computerized systems (§ 11.10(a)
and corresponding requirements“

38. Critical
requirements
• Validation of the computer system
• One should define how all elements of
the computer system are supposed to
work, develop corresponding scripts and
test routines to validate it is functioning
as it should
• Digital record generation and search
functions
• Implementation of an Audit Trail
• Operational Controls exist
• Security Controls exist
• Training
• Digital Signatures
• Set of rules so that the identity of the
signer and the integrity of the data can
be verified
When using digital
documents in clinical trials

39. Validation
Training
• Training is an important
topic
• Participation in training
– 3. CSVHC Conference
software validation in the
health care (SQS in
Cologne)
– Workshop Computer
Validation (Kendle)
– PTS-Workshop 6.5.03

40. Contact
Wolfgang Kuchinke
University Duesseldorf,
Duesseldorf, Germany
Further info: www.tmf-ev.de
wolfgang.kuchinke@uni-
duesseldorf.de
wokuchinke@outlook.de
This presentation is a translation from German and
contains additional explanatory material for the
workshop and Q&A session.