GCP Session1 SineadCurran PDF
GCP Session1 SineadCurran PDF
GCP Session1 SineadCurran PDF
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ICH GCP (E6) – Guideline for Good Clinical Practice
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Ethical
Satisfactory quality
Conduct
GCP
assurance
Credible
Data Fit for purpose
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GCP – A review of recent and future changes
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Why the need for an addendum?
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Risk based approaches
Regulatory development and implementation
of ICH GCP E6(R2) addendum
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
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Structure: GCP E6(R1)
1. Glossary: terms and definitions
2. Set of 13 overarching principles
3. Requirements specific to ethics committee (IRB/IEC)
4. Requirements specific to investigator
5. Requirements specific to sponsor
6. Clinical trial protocol and amendments
7. Investigator brochure
8. Essential documents
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Structure: GCP E6(R2) addendum*
1. Glossary: terms and definitions *
2. Set of 13 overarching principles *
3. Requirements specific to ethics committee (IRB/IEC)
4. Requirements specific to investigator *
5. Requirements specific to sponsor *
6. Clinical trial protocol and amendments
7. Investigator brochure
8. Essential documents *
Interpretation: in the event of conflict between R1 and R2, the R2 addendum text should take priority
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GCP – A review of recent and future changes
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R2 addendum: Key Themes
Prioritized,
Additional
Quality risk risk-based Investigator
text on use of
management approach to oversight/
computerised
for sponsors monitoring supervision
systems
clinical trials
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Quality Risk Management, Sponsors
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Traditional phases of clinical development
Phase
Phase IV
Phase III
II
Phase
I
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Quality Risk Management (ICH Q9)
• ‘some examples of use of quality risk management in the
pharmaceutical industry….limited and do not represent the
full contributions that risk management has to offer’
• ‘valuable component of an effective quality system’
• ‘systematic processes designed to coordinate, facilitate and
improve science-based decision making with respect to risk’
• ‘understood that risk is….combination of the probability of
occurrence of harm and the severity of that harm’
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E6(R2): Quality Risk Management - GCP
• Using the principles of quality management, identify those
aspects that are critical to generating reliable data and
providing appropriate protections for research participants
• Develop strategies and actions to effectively & efficiently
support quality in these critical areas
• Move away from ‘one size fits all’, with over reliance on
checklists/monitoring/auditing for quality
• Move to critical thinking with proactive and prospective
designing of quality measures into clinical trials to manage
risks
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Examples of Trial Related Risk Factors
Sponsor
& Service Provider(s)
Facilities Human
Organisation and Quality Resources/ Compliance
Roles & computer System and monitoring
Processes Qualified
Responsibility systems Personnel
GCP E6(R2)
QRM process
Risk
Risk Review
Evaluation
Methods
Operationally
proportionate
feasible,
to the risks &
avoid
importance of
unnecessary
Risk Risk the information
complexity
Communication Control collected
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What are the challenges?
• Converting principles into clearly defined processes, with
well considered and understood criteria, for the discipline of
clinical trials
• Cultural change & compliance confidence
• Misconceptions
– QRM is not a segue to justify non-compliance, cherry pick GCP
requirements or obviate obligations
– Not mitigating the risk of non-compliance
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Considerations for implementation
Prioritized,
Additional
Quality risk risk-based Investigator
text on use of
management approach to oversight/
computerised
for sponsors monitoring supervision
systems
clinical trials
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Traditional approach
GCP E6(R1),5.18.3: Extent and nature of monitoring should be based on
considerations such as the objective, purpose, design, complexity, blinding, size and
endpoints of the trial.
***********
Traditional monitoring:
• Reliant upon on-site monitoring, and good monitor-site relationship
• Often focused upon 100% source data verification of case report forms
• Higher risk study/problematic site; typically higher frequency of visits
Issue management:
• Largely dependent on monitoring visit report review & trending of common issues
• Periodic feedback from data monitoring committees and other trial monitoring
committees
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Centralized monitoring: analysis of accumulating data
Help to understand the
Describe variability
underlying causes of
between investigator Unusual patterns
variability and therefore
sites, regions, groups of highlighted in real time
highlight priorities for
sites managed by for further investigation…
additional
different organisations
control/monitoring
Complement on-site
Help to implement
monitoring and better
measurements that can
focus resource to
describe the quality and
activities of greater added
reliability of a trial…
value to trial quality
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On-site monitoring: important aspects
IMP management,
Investigator oversight
including storage and
and resources
accountability
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5.18.3 Extent and nature of monitoring
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5.18.3 Extent and nature of monitoring
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5.18.6 Monitoring report
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5.20.1 Noncompliance
• Necessary to have a process to manage noncompliance:
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R2 addendum: Key Themes
Prioritized,
Additional
Quality risk risk-based Investigator
text on use of
management approach to oversight/
computerised
for sponsors monitoring supervision
systems
clinical trials
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Shift in clinical trial organisation…
• Increased fragmentation and distribution of tasks
• Multiple parties involved
• Investigator site e.g.
– Specialised clinical trial facility
– Third party pharmacy
– Third party laboratory
– Homecare nursing organisation
• Investigator site – sponsor e.g.
– Site management organisation
– Provision of archive facilities
– IT vendors
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4.2.5-6: Adequate resources
• Clarity with respect to expectations for investigator/institution
oversight:
4.2.5 The investigator is responsible for supervising any individual or party
to whom the investigator delegates trial-related duties and functions conducted at
the trial site.
4.2.6 If the investigator/institution retains the services of any individual or party to
perform trial-related duties and functions, the investigator/institution should ensure
this individual or party is qualified to perform those trial-related
duties and functions and should implement procedures to ensure the
integrity of the trial-related duties and functions performed and any data
generated.
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R2 addendum: Key Themes
Prioritized,
Additional
Quality risk risk-based Investigator
text on use of
management approach to oversight/
computerised
for sponsors monitoring supervision
systems
clinical trials
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Computerised systems
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Direct
Access
Data
Integrity
IT vendor
Oversight
&
ALCOAC
Technology
& GCP
Computer
Data
System
control
Validation
Data
Protection
&
Ethics
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2.10: Updated principle for clinical trial data
R2 Addendum
This principle applies to all records referenced in this guideline,
irrespective of the type of media used
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1.63, 65: Certified copies & CSV
• New definitions
1.63 Certified Copy
A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by
a dated signature or by generation through a validated process) to have the same
information, including data that describe the context, content, and
structure, as the original
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4.9.0: Records and reports
• Investigator: data integrity rules strengthened e.g. ‘ALCOAC’
4.9.0
The investigator/institution should maintain adequate and accurate source
documents and trial records that include all pertinent observations on each
of the site’s trial subjects. Source data should be attributable, legible,
contemporaneous, original, accurate, and complete. Changes
to source data should be traceable, should not obscure the original entry,
and should be explained if necessary (e.g., via an audit trail).
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5.5.3: Electronic trial data handling
• Introduction of risk assessment, SOP scope and roles
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5.5.3: Electronic trial data handling
• Introduction of risk assessment, SOP scope and roles
(b) Maintains SOPs for using these systems: The SOPs should cover system
setup, installation, and use. The SOPs should describe system
validation and functionality testing, data collection and handling, system
maintenance, system security measures, change control, data backup, recovery,
contingency planning, and decommissioning. The responsibilities of
the sponsor, investigator, and other parties with respect to the
use of these computerized systems should be clear, and the users should be
provided with training in their use.
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5.5.3: Electronic trial data handling
• Concept of data integrity – including for metadata
(h) Ensure the integrity of the data including any data that
describe the context, content, and structure. This is
particularly important when making changes to the computerized
systems, such as software upgrades or migration of data.
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8.1: Essential documents
• ISF/TMF: Traceability, as well as access and control rights
addressed
Prioritized,
Quality risk Additional
risk-based Investigator
management text on use of
approach to oversight/
computerised
for sponsors monitoring supervision
systems
clinical trials
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Signposting /
Useful resources
ICH GCP E6 Guideline for Good Clinical Practice
• ICH GCP E6 (R2):
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Product
s/Guidelines/Efficacy/E6/E6_R2__Addendum_Step2.pdf
• GCP Renovation package:
http://www.ich.org/products/gcp-renovation.html
• ICH E17 Multi Regional Clinical Trials:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Pr
oducts/Guidelines/Efficacy/E17/E17EWG_Step_4_Presen
tation_2018_0114.pdf
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Clinical Trial Regulation no. 536/2014
- Implementation:
http://www.ema.europa.eu/ema/index.jsp?c
url=pages/regulation/general/general_cont
ent_000629.jsp
- European Commission:
https://ec.europa.eu/health/human-
use/clinical-trials/regulation_en
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Eudralex Volume 10 (Clinical trial guidelines)
• https://ec.europa.eu/health/docum
ents/eudralex/vol-10_en
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Irish Legislation
• www.irishstatutebook.ie
• http://health.gov.ie/wp-content/uploads/2014/03/Informal-Codification-Text.pdf
• S.I. No. 190 of 2004 European Communities (Clinical Trials on Medicinal Products for Human
Use) Regulations, 2004, As amended by
– European Communities (Clinical Trials on Medicinal Products for Human Use) (Amendment)
Regulations 2004 (S.I. No. 878 of 2004)
– European Communities (Clinical Trials on Medicinal Products for Human Use) (Amendment
No. 2) Regulations 2006 (S.I. No. 374 of 2006)
– Medicinal Products (Control of Manufacture) Regulations 2007 (S.I. No. 539 of 2007)
– Medicinal Products (Control of Placing on the Market) Regulations 2007 (S.I. No. 540 of 2007)
– European Communities (Clinical Trials On Medicinal Products For Human Use) (Amendment)
Regulations 2009 (S.I. No. 1 of 2009)
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GDPR
• Question and Answers on the interplay between the
Clinical Trials Regulation and the General Data Protection
Regulation – expected from EC
• Data Protection Act 2018 (Section 36(2)) (Health Research)
Regulations 2018
• Health Research Regulations 2018 -
https://www.hrb.ie/funding/gdpr-guidance-for-
researchers/gdpr-and-health-research/health-research-
regulations-2018/
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HPRA GCP Inspections & Topics of Interest
• General information:
https://www.hpra.ie/homepage/medicines/regulatory-
information/clinical-trials/good-clinical-practice-(gcp)-
inspections
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GCP Inspections
• Procedures:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regu
lation/document_listing/document_listing_000136.jsp
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