Data Integrity

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Data Integrity

• Impact of Validation in Data Management and
  Statistics

Joanne Malia Associate Director,
Medical Research
Process Management
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Agenda
1. Brief Review of GCPs Part 11
2. Data Integrity
3. Validation
4. Data Management and Statistics
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International GCPs

• Good Clinical Practice (GCP) is an international
  ethical and scientific quality standard for
  designing, conducting, recording and reporting
  trials that involve the participation of human
  subjects.
• ?Compliance with this standard provides public
  assurance that the rights, safety and well-being
  of trial subjects are protected consistent with
  the principles of the Declaration of Helsinki and
  that clinical trial data are credible.
• Guidance for Industry E6 Good Clinical Practice
  Consolidated Guidance

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Principles of ICH GCPs (E6)

• 1. Trials should be conducted in accordance with
  the ethical principles originating from the
  Declaration of Helsinki and consistent with GCP
  and applicable regulatory requirements.
• 2. Before a trial starts, risks and
  inconveniences should be weighed against
  anticipated benefits for the subjects and
  society. Only trials where benefits justify the
  risks should be initiated.
• The rights, safety and well-being of the subjects
  are the most important and should be considered
  over science and society.
• 4. Available pre-clinical and clinical
  information on an investigational product should
  be adequate to support the proposed clinical
  trial.

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Principles of ICH GCPs (E6)

• 5. Clinical trials should be scientifically
  sound and described in a clear, detailed
  protocol.
• A trial should be conducted in compliance with
  the protocol that has received prior
  institutional review board approval.
• 7. Medical care given to and medical decisions
  made on behalf of subjects should always be the
  responsibility of a qualified physician or a
  qualified dentist.
• Each individual involved in conducting a trial
  should be qualified by education, training, and
  experience to perform his or her respective
  task(s).
• 9. Freely given informed consent should be
  obtained from every subject prior to clinical
  trial participation.

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Principles of ICH GCPs (E6)

• 10. All clinical trial information should be
  recorded, handled, and stored in a way that
  allows its accurate reporting, interpretation,
  and verification.
• 11. Confidentiality of records that could
  identify subjects should be protected, respecting
  the privacy and confidentiality rules in
  accordance with the applicable regulatory
  requirements.
• 12. Investigational products should be
  manufactured, handled, and stored in accordance
  with applicable good manufacturing practice
  (GMP). They should be used in accordance with
  the approved protocol.
• 13. Systems with procedures that assure the
  quality of every aspect of the trial should be
  implemented.

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ICH E6 Guidance

• Data Handling and Record Keeping
• The sponsor should utilize appropriately
  qualified individuals to supervise the overall
  conduct of the trial, to handle the data, to
  verify the data, to conduct the statistical
  analyses, and to prepare the trial reports.
• E6 Section 5.5.1

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ICH E6 Guidance

• When using e-data handling and/or remote e-data
  systems, sponsor should
• Ensure and document that the electronic data
  processing system(s) conforms to the sponsors
  established requirements for completeness,
  accuracy, reliability, and consistent intended
  performance (I.e. validation)
• Maintain SOPs for using these systems
• Ensure that the systems are designed to permit
  data changes in such a way that the data changes
  are documented and that there is no deletion of
  entered data (I.e. maintain audit trail).
• Maintain a security system that prevents
  unauthorized access to the data.
• Maintain list of individuals who are authorized
  to make data changes
• Maintain adequate backup of the data
• Safeguard the blinding (I.e. maintain the
  blinding during data entry and processing).
• E6 Section 5.5.3

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ICH E6 Guidance

• If data are transformed during processing, it
  should always be possible to compare the original
  data and observations with the processed data.
  E6 Section 5.5.4
• Essential documents should be retained until at
  least 2 years after the last approval of a
  marketing application in an ICH region and until
  there are no pending or contemplated marketing
  applications in an ICH region or at least 2 years
  have elapsed since the formal discontinuation of
  clinical development of the investigational
  product. E6 Section 5.5.11

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ICH E6 Guidance

• Requirements of Content
• Identification of any data to be recorded
  directly on the CRFs (I.e. no prior written or
  electronic record of data), and to be considered
  to be source data. E6 Section 6.4.9
• Protocol or written agreement that
  investigator/institution will permit
  trial-related monitoring, audits, IRB review and
  regulatory inspections by providing direct access
  to source data and documents. E6 Section 5.15.1

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Summary of ICH Data Expectations

• Data should be traceable and have integrity
• Systems handling data should be validated

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FDA Regulations

• - in 21 CFR Part 312.62 (b)
• An investigator is required to prepare and
  maintain adequate and accurate case histories
  that record all observations and other data
  pertinent to the investigation on each individual
  administered the investigational drug or employed
  as a control in the investigation. Case
  histories include the case report forms and
  supporting data including, for example, signed
  and dated consent forms and medical records
  including, for example progress notes of the
  physician, the individuals hospital chart(s) and
  the nurses notes. The case history for each
  individual shall document that informed consent
  was obtained prior to participation in the study.

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Electronic Records

• Scope of 21 CFR Part 11
• Applies to records in electronic form that are
  created, modified, maintained, archived,
  retrieved, or transmitted, under any records set
  forth in agency regulations.
• To ensure that electronic records are
  trustworthy, reliable and generally equivalent to
  paper records.
• Allows use of electronic records if they comply
  with part 11.

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Definitions

• Closed system - an environment in which system
  access is controlled by persons who are
  responsible for the content of the electronic
  records that are on the system.
• Open system - an environment in which system
  access in not controlled by persons who are
  responsible for the content of electronic records
  that are on the system.

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Electronic Records - Closed

• Validation of systems
• Ability to generate human readable and electronic
  copies for inspectors
• Protection of records throughout retention time
• Use of secure, computer generated, time-stamped
  audit trails
• Use of operational checks to enforce sequencing
  of steps
• Access restricted to authorized users and checked
• Use of device checks to determine validity of
  source of data input
• Users are trained
• Policies that define accountability
• Controls over system documentation (e.g.
  distribution, use of, and version control, etc.)

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Electronic Records - Open

• Same as for closed plus
• Document encryption
• Authentication verification
• To ensure the authenticity, integrity and
  confidentiality of electronic records from their
  creation to their receipt.

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Inspection Expectations

• FDA needs to be able to verify the quality and
  integrity of the data during inspections.
• Data needs to meet ALCOA elements of quality
• Computerized Systems Used in Clinical
  Investigations

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Data Integrity and Quality

• ALCOA?
• Attributable data are identified with a
  specific subject and a specific observer and
  recorder. (Password, audit trail and e-signature)
• Legible data are readable and understandable by
  humans (reports, tables, and listings)
• Contemporaneous - data are recorded at the time
  they are generated or observed. (Time stamps and
  time-limited entry)
• Original data are recorded for the first time.
  (Source data and meta data)
• Accurate data are correct (Calculations,
  algorithms, analyses, and transmissions)

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Integrity

• More or ethical strength
• The quality of being honest
• The condition of being free from defects or flaws
• The state of being whole
• According to Rogets

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Data Integrity

• Information that is accurate, complete and
  truthful.

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Evidence Change of Custody

• Real world analogy
• Consider the chain of custody which must be
  maintained for a jury to be confident that
  evidence has not been tampered.

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Validation

• Establishing documented evidence which provides a
  high degree of assurance that a specific process
  will consistently produce a product meeting its
  predetermined specifications and quality
  attributes.
• According to FDAs Glossary of Computerized
• System and Software Development Terminology

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Better Definition?

• Software Validation means confirmation by
  examination and provision of objective evidence
  that software specifications conform to user
  needs and intended uses, and that the particular
  requirements implemented through the software can
  be consistently fulfilled.
• According to FDAs Guidance on Computerized
• Systems Used in Clinical Investigations

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System Life Cycle

• One of the main principles of validation involves
  the system life cycle
• The course of developmental changes through which
  a system passes from its conception to the
  termination of its use, e.g. The phases and
  activities associated with the analysis,
  acquisition, design, development, test,
  integration, operation, maintenance, and
  modification of a system.
• FDAs Glossary of Computerized System and
• Software Development Terminology

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FDA Expectations

• Each company should have its own procedure on
  system lifecycle and follow it whether for
  off-the-shelf or in-house developed software
• Many methodologies available through ISO, IEEE,
  etc. most common is the waterfall methodology

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Sample SLC
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Meaning?

• Basically,
• System performs as intended

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Define System

• People, machines, and methods organized to
  accomplish a set of specific functions.
• FDAs Glossary of Computerized System and
• Software Development Terminology
• FDA considers a system more than the computer!

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Additional Terms

• Software Verification In general the
  demonstration of consistency, completeness and
  correctness of the software at each stage and
  between each stage of the development life cycle.
• Qualification (installation) Establishing
  confidence that process equipment and ancillary
  systems are compliant with appropriate codes and
  approved design intentions, and that
  manufacturers recommendations are suitably
  considered.
• FDAs Glossary of Computerized System and
  Software Development Terminology

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Expectations

• Computerized System
• Requirements for the computerized system which
  are used to develop or purchase the software
• Evaluation of vendor to ensure they have produced
  a quality product and will continue to support it
• If developed in-house, evidence that developer
  has qualifications to create this software
  support it
• A plan to describe what will be done and how
• Testing documentation and traceability to
  requirements
• People are trained to carry out their
  responsibilities
• Procedures are in place which describe what will
  be done by whom and how it will be done

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Data Management

• Most companies have purchased or commercialized
  off the shelf software as their system.
• Some companies have developed their own software
  and supporting system.
• What is expected of each?
• Basic system is validated
• UAT testing done of both paper based and EDC
  systems

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CDM Computer Systems

• Qualification of System Developer
• Internal training records / experience
• External vendor due diligence
• Process for system lifecycle
• System requirements
• Validation Plan
• Testing and traceability of requirements
• Summary Report
• Support and changes

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Computer System Maintenance

• Access and privilege controls
• Change management
• Virus protection
• Audit trail
• Disaster Recovery / Business Continuity
• Archival

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People and Processes

• People have experience and training to fulfill
  their responsibility
• Internal CVs and Training records
• External CVs of key personnel and evidence of
  due diligence
• Study specific training
• Procedures
• SOPs and work instructions
• Protocol
• Study specific plans

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Key Opportunities

• Transmission of data from CROs, labs, ecgs,
  e-diaries, etc.
• Secure and confidential transmission expected
• Standard e-mail is not acceptable for final
  official transmission not secure or
  confidential (antivirus?), easy to delete /
  modify, not typically part 11 compliant
• Formats (truncation of results, differing of
  transmission formats any qc checks)
• All data for all patients?

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Key Opportunities

• Integration of data
• Different formats from different vendors
• Not all accept / work with CDISC standards
• Difference between paper and electronic
• Lab reports
• ECGs
• Protection of cells and functions in Excel
• Unblinding
• Modifications after study is unblinded
• Queries from PK analyst

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Statistics

• Current situation
• Some companies have developed systems for
  generating tables, listings and graphs
• Most just program using SAS

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Expectations

• People
• Qualified programmers
• Process
• Programming standards
• Process for SAS program verification / validation
  
• Computerized System
• Qualification of SAS (includes vendor due
  diligence)
• Requirements for programs in clinical protocol
  and statistical analysis plan

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Detailed Expectations

• Programming standards are followed a reviewer
  checks!
• Programs are access and versioned controlled
• Output from programs meet requirements
• Programs and output are verified based on
  procedure
• Algorithms are documented and tested to provide
  traceability of data

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Key Opportunities

• Review of SAS output is just as important as
  programming
• Acceptance of CDISC standards
• Standards for tables, listings and graphs
• Documentation of definitions / algorithms
• Study Day (count the first day or not)
• Time recording
• Mapping of data
• Dealing with missing data
• What to do with changes to legacy data
• Emailing results

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Data Integrity and Quality

• Remember the data and the chain of custody.
• Want to ensure that no doubts
  can be raised.

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Data Integrity Quality

• Data integrity must be maintained across the
  entire process
• Remember that data are our evidence in chain of
  custody of a submission
• People
• Process
• Computerized systems

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Thank you for listening!