Clinical_Data_Management

ICH E8 (R1)
General Considerations for Clinical

Studies: Impact on Data Management
ACDM DMEG: Regulatory
Introduction
• The key focus of the latest revision of ICH GCP documents (E6, E8) is embedding
‘Quality by Design’ into clinical research
• Focus on critical to quality factors
• Protection of subjects
• Generation of reliable and meaningful results
• Management of risks to the above
• The approach is supported by the establishment of an appropriate framework
for the identification and review of critical to quality factors (Section 3.3) at the
time of design and planning of the study, and throughout its conduct, analysis,
and reporting
• “Activities such as document and data review and monitoring, where conducted
retrospectively, are an important part of a quality assurance process; but, even
when combined with audits, they are not sufficient to ensure quality of a clinical
study” (ICH R8(R1) 3.1)
Reflection paper on risk based quality management in
clinical trials EMA/269011/2013
“The general problem can be summarised by stating that current practices in
clinical research are not proportionate to risk nor well adapted to achieving the
desired goals. The origins of the problem are multifactorial and include: …
• poor design of studies and study processes, often being much more complicated
than necessary to achieve what is required, thus diminishing focus and resource
available to achieve the quality necessary for the more important objectives;
• failure to identify priorities. Both study and process design is often cluttered by
data collection requirements or quality control activities (e.g. monitoring etc.) of
limited importance that distract greatly from the most important issues;
• poor risk identification and poor risk mitigation – a lack of use or understanding
of risk- management tools and techniques, is often associated with a reactive,
fire-fighting approach to problem management. This results in processes largely
based on corrective rather than preventive action; “*
• *Reflection paper on risk based quality management in clinical trials

EMA/269011/2013 - > https://www.ema.europa.eu/en/documents/scientific-
guideline/reflection-paper-risk-based-quality-management-clinical-trials_en.pdf
The Paradigm Shift
Traditional Data Review and Cleaning Risk Based Approach
Data checks driven by technical feasibility (if we can program Data checks driven by category (critical, supportive, other)
it, we put it in the validation plan)
Quality Checks: Quality Assurance

Queries from edit checks Quality by Design
Retrospective verifications on static data Key Performance Indicators/Dashboards
Monitoring/SDV – point2point visual inspection Continuous re-evaluation of KPIs, longitudinal analysis
Audits/Inspections (‘external’) Integrated and Continuous Risk Management (‘self

starting’)
Transactional: Integrated:
Systems and processes for each department/function Data Visualisation systems with multiple roles and
(seprate and disparate = siloed) collaborative reviews. Cross functional processes and
SOPs, enterprise level TMF documentation, no gaps and
overlaps
Checklist driven, reactive, passive and segmented data Conscious, validated and transparent evaluations.
reviews: importance on ‘How?’ and ‘By When?’ Clinical Study Team: importance on ‘Why?’ and ‘Event
Driven/Proactive’
How does E8(R1) look to address
this?
E8 (R1) Section 3
Designing Quality into Clinical Studies
• Section 3 has been dedicated to defining how to design quality into clinical
studies
• 3.1 Quality by Design of Clinical Studies

• 3.2 Critical to Quality Factors
• 3.3 Approach to identifying the Critical to Quality Factors
• 3.3.1 Establishing a Culture that Supports Open Dialogue
• 3.3.2 Focusing on Activities Essential to the Study
• 3.3.3 Engaging Stakeholders in Study Design
• 3.3.4 Reviewing Critical to Quality Factors
Identifying Critical to Quality factors
(3.2 & 3.3)
• A basic set of factors relevant to ensuring study quality should be identified for
each study at the point of study design
• The risks that threaten their integrity should be determined and probability and
impact assessed
• Pro-active communication of critical to quality factors and risk mitigation
activities should be in place
• Proactive, cross functional discussions and decision making is required at the
time of study planning
Establishing a culture (3.3.1)
Speak Up!! Open dialogue about quality
Create a culture that values and rewards

critical thinking – lose the reliance on
checklists (AGILE)
Choose quality measures and performance

indicators that are aligned with proactive
approach to design
Focus on activities essential to the
study (3.3.2)
• Focus effort on activities that are essential to the reliability and
meaningfulness of study outcomes and safe ethical conduct
Ø Risk based methodologies will be applied to data cleaning to ensure
that data cleaning approaches for critical data are interrogated to
identify and mitigate risks
Ø Non-critical data could be subject to reduced data cleaning ie;
Reducing low value queries
• Evaluate the study design to verify that planned activities and choice of data
to be collected are essential
• Study designs should be operationally feasible
• Avoid unnecessary complexity
• Avoid unnecessary data collection
Engaging Stakeholders in Study Design (3.3.3)
• Clinical investigators and potential subjects have valuable insights into

feasibility of a study
• Are visits/procedures overly burdensome?
• Are the end points relevant?
• Value of the treatment within targeted population
• If there are novel elements early engagement with regulators should be

considered
Reviewing Critical to Quality Factors (3.3.4)
• Periodic review of critical to quality factors is essential to determine if

adjustment to risk controls are needed – new or unanticipated issues may arise
once the study has started
• For adaptive design studies, interim decision points ensure proactive planning
and ongoing review of critical to quality factors and risk management (ICH E9
Statistical Principles for Clinical Trials)
Other points of interest
Data Management
Understanding data classifications
• Primary Data Collection
• Data collected for study purposes using processes that ensure a sufficient
level of quality
• Secondary Data Collection
• Use of data that was collected for other purposes and not collected just for
the study
• National Death Databases
• Disease/drug registries
• Medical and admin records from routine medical practice
• Absence of affirmative info does not mean the condition is not
present..
Data Standards
• Use of data standards supports the reliability of the data, facilitates correct
analysis and proper interpretation of the data as well as promoting data
sharing.
• International data standards exist for many sources of study data and should
be used wherever possible.
• Early identification of new data types/forms
• Early identification of data sources
• For all data sources procedures to ensure the confidentiality of pt data

should be followed
• Ensure we know and follow the chain of custody for the study data
Data Management (6.1.3)
• Manner and timelines of data collection are critical components of overall
study quality
• Operation checks and statistical surveillance can identify quality issues at a
point where corrective action is feasible
• Instream data collection
• Ongoing review of KRIs
• Data management procedures should account for diversity of data sources
• Access to data: Inappropriate access to data during the conduct may
compromise study integrity. Attention should be given to who has access to
data and results (ICH GCP E6 6.1.4)
What’s next…
• Reflection paper on modernisation of E8 and E6
• ICH_Reflection_paper_GCP_Renovation_Jan_2017_Final.pdf
• ICH GCP E8 (R1) released this 06OCT2021 –
• E8-R1_Guideline_Step4_2021_1006.pdf (ich.org)
• ICH E6 (R3) Undergoing revision
• Alignment with E8 (R1) – release planned end 2022
• Updates to data management sections to reflect changing landscape of
technologies used in clinical trials

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ICH E8 (R1)

General Considerations for Clinical

• *Reflection paper on risk based quality management in clinical trials

Quality Checks: Quality Assurance

Audits/Inspections (‘external’) Integrated and Continuous Risk Management (‘self

• 3.1 Quality by Design of Clinical Studies

Speak Up!! Open dialogue about quality

Create a culture that values and rewards

Choose quality measures and performance

• Clinical investigators and potential subjects have valuable insights into

• If there are novel elements early engagement with regulators should be

• Periodic review of critical to quality factors is essential to determine if

• For all data sources procedures to ensure the confidentiality of pt data

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