System validation at the KKS Cologne a practical approach

1
System validation at the KKS Cologne a
practical approach

• MACRO User Group Meeting
• 26.-27. Mai 2004Edinburgh, Scotland
• Thomas Bratke, Andreas Gassmann, Ingrun
  Leyendecker Coordination Centre for Clinical
  Trials Cologne,University Hospital Cologne,
  Germany

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List of Abbreviations

• KKS Coordination Centre for Clinical Trials
• BMBF German Ministry of Education and Research
• TMF Telematics Platform for German Medical
  Research Networks
• GCP Good Clinical Practice
• GMP Good Manufacturing Practice
• ER Electronic Record
• ES Electronic Signature

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Content

• German KKS general background information
• Regulatory affairs a short overview
• Practical approach to system validation
• Discussion

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German KKS general background information
- scope -

• supporting scientifically-driven ("investigator
  sponsored") non-profit clinical trials
• initiating, planning and performing innovative
  and competitive national and international
  clinical trials
• implementation of harmonized quality management
• training related to scientific and organizational
  aspects of trials (e.g. study nurse courses,
  investigator courses)
• long-term establishment of the coordination
  centres with universitysupport and
  pharmaceutical industry cooperation

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German KKS general background information
- locations -
Government funding
BMBF
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German KKS general background information
- modules available for profit and non-profit
organizations -

• project management
• monitoring
• clinical trail assistance (i.e. study nurses)
• statistics
• data management

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Content

• German KKS general background information
• Regulatory affairs a short overview
• Practical approach to system validation
• Discussion

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Regulatory affairs a short overview
- imposed regulations -

• ICH GCP (International Conference on
  Harmonization), 1996 E6 Guideline for Good
  Clinical Practice
• EU Guide to Good Manufacturing Practice, Volume
  4
• Annex 11 Computerized Systems, 1998
• Annex 15 Qualification and Validation, September
  2001
• EU Directive 2001/20/EC
• FDA 21 CFR Part11 Electronic Records Electronic
  Signatures Final Rule, Federal, March 20, 1997

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Regulatory affairs a short overview
- EU Directive 2001/20/EC -

• standardization of procedures for ethical and
  competent authority consideration and
  authorization
• GCP standards for commencing and conducting
  clinical trials
• Good Manufacturing Practice (GMP) standards for
  medicines used in clinical trials
• inspections against internationally accepted
  principles and standards of GCP and GMP,
  supported by enforcement powers

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Regulatory affairs a short overview
- EU Directive 2001/20/EC implementation -

• United Kingdom
• 'the Medicines for Human Use (Clinical Trials)
  Regulations 2004' (SI 2004 No. 1031) that
  implement the Clinical Trials Directive were laid
  before both Houses of Parliament on 1 April 2004
  and came into force on 1 May 2004.
• Germany
• the 12th amendment of the German Medicines Law
  was not accepted by the Federal Council
  (14.5.2004)
• further modifications will be discussed at the
  Arbitration Commission (before summer 2004)

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Regulatory affairs a short overview
- FDA 21 CFR Part 11 -

• Draft Guidance for Industry 21 CFR Part11 ERES,
  Validation, August 2001
• Draft Guidance for Industry 21 CFR Part11 ERES,
  Glossary of Terms, August 2001
• Draft Guidance for Industry 21 CFR Part11 ERES,
  Time Stamps, February 2002
• Draft Guidance for Industry 21 CFR Part11 ERES,
  Maintenance of ER, July 2002
• Draft Guidance for Industry 21 CFR Part11 ERES,
  Electronic Copies of ER, August 2002
• Draft Guidance for Industry Part 11 ERES, Scope
  and Application, February 2003
• Guidance for Industry Part 11 ERES, Scope and
  Application, August 2003
• risk based approach

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Regulatory affairs a short overview
- leading questions -

• How can a small organization fulfill its
  responsibility to the various regulatory
  requirements?
• Specifically, how can a validated computer
  system in data management be implemented and
  maintained?
• available time period
• available qualified employees
• total costs

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Content

• German KKS general background information
• Regulatory affairs a short overview
• Practical approach to system validation
• Discussion

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Practical approach to system validation
- local interpretation of computer system
validation -

• computer system validation will be restricted to
  the usage and requirements of the MACRO computer
  system
• whole System Life Cycle of the MACRO computer
  system must be considered (planning, development,
  implementation, documentation, operation,
  inspection, changing)
• emphasis on usage of the MACRO computer system in
  central operational business (i.e. data
  management in clinical trials and patient
  registers)
• In-house data management
• EDC online data management
• EDC offline data management

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Practical approach to system validation
- the validation project (validation master plan)
-

• EDC computer software evaluation and
  recommendations
• EDC computer software development
• EDC computer software usage
• risk based analyses
• change management (in planning)

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Practical approach to system validation
- EDC computer software evaluation and
recommendations -

• procedure (performed by TMF and KKS Duesseldorf)
• evaluation of 40 EDC software products
• vendor presentations and detailed analysis of 15
  EDC software products
• recommendation of 3 EDC software products
• recommended software products (open source and
  commercial)
• PhOSCo (Pharma Open Source Community)
• eResearch Network, eResearch Technology,
  Philadelphia
• MACRO, InferMed, London

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Practical approach to system validation
- EDC computer software development -

• commercial EDC computer software is developed and
  documented according to a quality assurance
  process
• audit at software vendor
• software vendor promotes exchange of experience
  in computer system software (workshops, training,
  hotline, support)
• limitations on EDC computer software will be
  communicated and addressed by local SOPs or
  working instructions

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Practical approach to system validation
- EDC computer software usage -

• Risk based approach
• The risk-based approach refers to the application
  of risk analysis principles to manage inspection
  programs. It has been used in the nuclear power
  generation industry for some time and is also
  employed in refineries and petrochemical plant.
  The ultimate goal is to develop a cost-effective
  inspection and maintenance program that provides
  assurance of acceptable integrity and
  reliability.
• Risk is defined as the combination of probability
  and consequence. Probability is the likelihood of
  a failure occurring and consequence is a measure
  of the damage that could occur as a result of the
  failure.
• An increased risk is resulting from an increased
  probability and a higher degree of consequence.

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Practical approach to system validation
- EDC computer software usage -

• Risk based approach
• process field and function description
• description of (system) failure or error
• error causes
• risk level (1low, 2medium, 3high) depending on
• occurrence (A)
• GCP relevance (B)
• time interval between occurrence and detection
  (E)
• measures (standard operating procedures, working
  instructions, manuals, logs, etc.)

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Practical approach to system validation
- risk based approach example 1 -
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Practical approach to system validation
- risk based approach example 2 -
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Practical approach to system validation
- change management (in planing) -

• What can change during EDC computer software
  usage?
• personal
• hardware
• project specifications
• MACRO software versions
• MACRO software patches
• What are the differences between new and running
  EDC computer software projects?
• Thank you for your attention !

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Discussion
- System validation at the KKS Cologne a
practical approach -

• Thank you for your attention