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Good Clinical Practice

Review of recent and future changes

Sinead Curran, GCP/PV inspection manager

HPRA Information Day – GCP for IMP clinical trials

Dublin, 23 October 2018


GCP – A review of recent and future changes

• Objective and purpose of GCP


• Background to ICH GCP E6(R2) addendum
• Key themes of the R2 addendum
• Signposting/useful resources

2
ICH GCP (E6) – Guideline for Good Clinical Practice

‘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 that have their origin in the
Declaration of Helsinki, and that the clinical trial data are
credible’
Ref. ICH GCP E6

3
Ethical
Satisfactory quality
Conduct

GCP
assurance
Credible
Data Fit for purpose

4
GCP – A review of recent and future changes

• Objective and purpose of GCP


• Background to ICH GCP E6(R2) addendum
• Key themes of the R2 addendum
• Signposting/useful resources

5
Why the need for an addendum?

‘Since the development of the ICH GCP Guideline, the scale,


complexity, and cost of clinical trials have increased. Evolutions
in technology and risk management processes offer new
opportunities to increase efficiency and focus on relevant
activities’

Source: Tufts Centre for the Study of Drug Development.

6
Risk based approaches
Regulatory development and implementation
of ICH GCP E6(R2) addendum

EMA RP RBQM EMA RP RBQM ICH E6 (R2)


Draft Publication Draft
August 2011 November 2013 August 2015

2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

FDA GfI RBM FDA GfI RBM ICH E6 (R2)


Draft Procedural In Effect
August 2011 August 2013 June 2017

Ack. Gabriele Schwarz, BfArM


7
GCP Renovation – Future changes
w Meta analysis
• ICH reflection on ‘GCP Renovation’ January 2017 RCTs
• Modernisation of ICH E8, General considerations for Cohort
CTs studies
Cross section
surveys
• Renovation of ICH E6, GCP guideline
Case studies
• To continue the move towards risk based approach Ideas, expert
opinions, editorials
• In recognition that the emerging clinical trial Anecdotal
environment may increasingly serve as an important
adjunct to traditional Randomised Controlled Trials
(RCTs) to support regulatory decisions
• To provide guidance for emerging data streams and
plurality of evidence

8
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

9
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

10
GCP – A review of recent and future changes

• Objective and purpose of GCP


• Background to ICH GCP E6(R2) addendum
• Key themes of the R2 addendum
• Signposting/useful resources

11
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

12
Quality Risk Management, Sponsors

Is management of risk a new concept in clinical


trials?

13
Traditional phases of clinical development

Phase
Phase IV
Phase III
II
Phase
I
14
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’

15
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

16
Examples of Trial Related Risk Factors

IMP Trial Design Operations

• Nature of IMP e.g. • Complexity of design • Resources, inc. third party


advanced therapy, • Trial population involvement
biological, small molecule • Robustness of eligibility • Clinical site setup and
• Properties of active criteria infrastructure, laboratory
ingredient • Endpoint selection setup
• Authorisation status • Sample size calculation • Setup of trial databases,
management of clinical
• Additional diagnostic and
data
monitoring procedures
• Clinical trial supply
• Patient protection/ethics
processes and
management
17
System/infrastructure related risk factors (e.g.)

Sponsor
& Service Provider(s)

Facilities Human
Organisation and Quality Resources/ Compliance
Roles & computer System and monitoring
Processes Qualified
Responsibility systems Personnel

Regulatory & ethical framework of countries & regions


18
Critical
Process and Focus on trial
Data I.D. activities
Applied at all essential to
stages of trial Risk human subject
process Risk I.D protection and
Reporting
reliability of trial
results

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
19
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

20
Considerations for implementation

Leadership Culture Process attributes

• QRM principles provided • Truly understand the • Multidisciplinary approach


for at top of QMS hierarchy purpose of GCP • Stakeholder engagement
e.g. policy level • QRM concept will benefit • Utilise knowledge from
• Implementing QRM from information sharing clinical development
requires upfront time across all stakeholders experience (e.g. ‘lessons
investment….but with a • Support personnel to learned’)
downstream value upskill with appropriate • Iterative process that
training, and, recognise reflects the state of
existing experience in knowledge of risk
managing risk in clinical • Provision for escalation of
trials issues
• Careful consideration of • Good documentation
performance metrics for practices throughout
trial success (e.g. first
patient in)
21
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

22
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
23
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
24
On-site monitoring: important aspects

Verifying protocol Detection of


Investigator site- compliance and data unreported events, e.g.
sponsor relationship quality against source AEs, SAEs, protocol
data deviations

IMP management,
Investigator oversight
including storage and
and resources
accountability

25
5.18.3 Extent and nature of monitoring

• The new addendum emphasises the concept of flexibility


applied to monitoring:

The sponsor should develop a systematic, prioritized, risk-based approach to


monitoring clinical trials. The flexibility in the extent and nature of monitoring
described in this section is intended to permit varied approaches that
improve the effectiveness and efficiency of monitoring.
The sponsor may choose on-site monitoring, a combination of
on-site and centralized monitoring, or, where justified, centralized
monitoring. The sponsor should document the rationale for the chosen
monitoring strategy (e.g., in the monitoring plan)..

26
5.18.3 Extent and nature of monitoring

• Clearly defines different approaches that can be taken:

“On-site monitoring is performed at the sites at which the clinical trial


is being conducted.”

“Centralized monitoring is a remote evaluation of accumulating


data, performed in a timely manner, supported by appropriately qualified
and trained persons (e.g., data managers, biostatisticians).”

27
5.18.6 Monitoring report

• Specifies the need to report on all types of monitoring


activities:

“(e) Reports of on-site and/or centralized monitoring should be


provided to the sponsor (including appropriate management and staff
responsible for trial and site oversight) in a timely manner for review and
follow up.
Results of monitoring activities should be documented in sufficient detail
to allow verification of compliance with the monitoring plan.
Reporting of centralized monitoring activities should be
regular and may be independent from site visits.”

28
5.20.1 Noncompliance
• Necessary to have a process to manage noncompliance:

If noncompliance that significantly affects or has the potential to


significantly affect human subject protection or reliability of trial results is
discovered, the sponsor should perform a root cause analysis and
implement appropriate corrective and preventive actions

29
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

30
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

31
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.

32
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

33
Computerised systems

Equipment and Data Data Capture (& Electronic Records


Processing Management) • eHealth Records
• Analysis instruments • eCase Report Forms • eTrial Master File
and data processing • Patient eDiaries • Management Systems
• Statistical analysis and • Mobile technology (CTMS etc.)
report production • Databases (IRT, PV etc.)
Cloud Technology

34
Direct
Access

Data
Integrity
IT vendor
Oversight
&
ALCOAC

Technology
& GCP

Computer
Data
System
control
Validation

Data
Protection
&
Ethics

35
2.10: Updated principle for clinical trial data

• Concept of equivalence for all data:

2.10 All clinical trial information should be recorded, handled, and


stored in a way that allows its accurate reporting, interpretation
and verification

R2 Addendum
This principle applies to all records referenced in this guideline,
irrespective of the type of media used

36
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

1.65 Validation of Computerized Systems


A process of establishing and documenting that the specified requirements of a computerized
system can be consistently fulfilled from design until decommissioning of the
system or transition to a new system. The approach to validation should be based
on a risk assessment that takes into consideration the intended use of the system and the potential
of the system to affect human subject protection and reliability of trial results.

37
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).

38
5.5.3: Electronic trial data handling
• Introduction of risk assessment, SOP scope and roles

The sponsor should base their approach to validation of such


systems on a risk assessment that takes into consideration the
intended use of the system and the potential of the system to
affect human subject protection and reliability of trial results.

39
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.

40
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.

41
8.1: Essential documents
• ISF/TMF: Traceability, as well as access and control rights
addressed

The sponsor and investigator/institution should maintain


a record of the
location(s) of their respective essential documents including
source documents…..
…….The sponsor should ensure that the investigator has control of and
continuous access to the CRF data reported to the sponsor. The sponsor should
not have exclusive control of those data…..
The investigator/institution
should have control of all essential
documents and records generated by the investigator/institution
before, during, and after the trial
10/24/2018 42
R2 addendum: Key Themes

Prioritized,
Quality risk Additional
risk-based Investigator
management text on use of
approach to oversight/
computerised
for sponsors monitoring supervision
systems
clinical trials

43
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

45
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

46
Eudralex Volume 10 (Clinical trial guidelines)

• https://ec.europa.eu/health/docum
ents/eudralex/vol-10_en

24/10/2018 47
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)

48
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/

49
HPRA GCP Inspections & Topics of Interest
• General information:
https://www.hpra.ie/homepage/medicines/regulatory-
information/clinical-trials/good-clinical-practice-(gcp)-
inspections

• Topics of special interest:


https://www.hpra.ie/homepage/medicines/regulatory-
information/clinical-trials/topics-of-special-interest

50
GCP Inspections
• Procedures:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regu
lation/document_listing/document_listing_000136.jsp

• GCP Inspectors Working Group Q&A:


http://www.ema.europa.eu/ema/index.jsp?curl=pages/regu
lation/q_and_a/q_and_a_detail_000016.jsp&mid=WC0b01a
c05800296c5

51
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