This presentation describes Identification & differentiation of Protocol deviation & violation; Different methods of RCA & best suitable method for Multiregional Clinical Trial; CAPA management and CAPA application to other trial sites/CRO/SMO/ Country that is involved in same trial (Strategic Management and application of CAPA in MRCT)

1. Root cause Analysis (RCA) & Corrective and
Preventive action (CAPA) in MRCT
Identifying & Managing Protocol deviation, Protocol
violation, RCA & CAPA from Global Regulatory Perspective
Prof (Dr.) Bhaswat Chakraborty
On 11th May 2019, Ahmedabad, India
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2. Contents
• Identification & differentiation of Protocol deviation & violation
• Different methods of RCA & best suitable method for Multiregional
Clinical Trial
• CAPA management
• CAPA application to other trial sites/CRO/SMO/ Country that is
involved in same trial (Strategic Management and application of
CAPA in MRCT)
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3. Totality of Product Quality, Clinical Performance and
TPP
• Quality of a drug product, be it a formulation or a device, that has to
be designed in such a way that it delivers the target product profile
(TPP)
• TPP Consists of quality efficacy and safety and just not quality
• However when we talk about CAPA, Usually the quality concerns and
the corrective and preventive action is related to manufacturing
• However quality concerns and building of quality spans throughout
the development cycle and subsequent commercialisation and
distribution cycle of the product
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4. Protocol Deviation Risk Ctegories
High Risk
Low Risk Grade 5Grade 4Grade 3Grade 2Grade 1
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5. Protocol Deviation & Violation
• Grade 1: No impact on data quality or patient safety
• Grade 2: Minor impact on data quality
• Grade 3: Minor impact on patient safety
• Grade 4: Major impact on data quality or patient safety
• Grade 5: Leading to patient/(s) death
Ghooi et al., Perspect Clin Res. 2016 Jul-Sep; 7(3): 132–136.
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6. Protocol Aspects that are Critical to Quality (CTQ)
• Eligibility Criteria
• Randomization
• Masking
• Types of Controls
• Data Quantity
• Endpoints
• Procedures Supporting Study Endpoints and Data Integrity
• Investigational Product (IP) Handling and Administration
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7. RCA & CAPA
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8. Root Cause Analysis
• Five Whys
• Cause of causes
• Ishikawa Diagram
• Also known as the fishbone diagram or cause-and-effect diagram
• Cause-and-effect diagrams can reveal key relationships among various
variables, and the possible causes provide additional insight into process
behavior
• Failure Mode and Effects Analysis (FMEA)
• Analysis of potential failure modes by the severity and likelihood of the
failures
• Often based on past experience with similar products or processes 8

9. Collect Detailed
Information
1. Event/Issue
identification and
description.
2. RCA participant
selection.
3. Define the
issue/problem.
Corrective and
Preventive Action
1. Prioritize root
causes by
identifying which
one contributed
most to the
undesirable event.
2. Develop
corrective and
preventive action
plan.
Rao N., PharmaSUG 2017 - Paper MS09
Analyze Inforation to
get Root Cause
1. Identify various
causal factors
2. Analyze causal factors
to 'dig' root cause(s)
by going through
causal chain.
3. Utilize various RCA
tools like 5-Why, Fish-
Bone etc.
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10. CAPA Management & Application
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13. CAPA & QbD in Clinical Trials
• CAPA is part of a good quality system applicable to regional and multi-
regional clinical trials
• One of the problems of applying impactful CAPA to clinical trials is
that the quality attributes and their associated risks in clinical trials
are not as clear as those in pharmaceutics or analytical development
• We know that lin manufacturing slight changes in critical excipients,
API, manufacturing process, controls and conditions can lead to a
faulty product not delivering the TPP
• Actually this is also true for the components of clinical trials
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14. Clinical Trials: Study Site Considerations Critical to
Quality (CTQ)
• Consider both the countries/regions in which the trial will initially be
conducted and those that might be added to bolster enrollment. If the
trial could not be conducted in these regions, would there be an
impact on the trial completion or conclusions?
• Discuss the standard of care for the therapeutic area/indication in the
different countries/regions in which the trial will be conducted.
• Are established research networks for the therapeutic area available?
• Evaluate the level of clinical experience with the trial interventions that
will be needed at the clinical sites.
CTTI, Duke University 14

15. Clinical Trials: Study Site Considerations Critical to
Quality (CTQ)..
• Consider site‐level infrastructure, resources, and any specific certification
or training necessary to carry out the planned study visits and procedures
and to collect and report data in a timely manner.
• Will the protocol design be pretested with investigators, site staff, and/or
PPAO during development?
• Consider the reimbursement issues that impact conduct of the study at the
site:
• Will unmasking of the control arm become an issue to secure reimbursement for trial
participants in the control arm?
• Will use of the investigational product in the post-‐marketing setting affect
reimbursement?
CTTI, Duke University 15

16. CT Endpoints in Evaluating Risks to CTQ Factors
• Does the primary endpoint address the study aims? Is it accepted by regulators, payers,
and clinicians?
• Are assessments related to the endpoint complex and/or subject to variable
interpretation?
• If it is a “soft” endpoint, is there the potential for bias to be introduced? How and by
whom? What might minimize this potential for bias?
• What measures are necessary to ensure appropriate endpoint ascertainment and
reporting, particularly if an endpoint occurs external to the site?
• If a third-‐party adjudicator is involved:
• In what aspects of the adjudication process would a failure undermine evaluability?
• By whom and by when will adjudication rules and required training be developed and delivered?
CTTI, Duke University 16

17. CT Endpoints in Evaluating Risks to CTQ Factors..
• If a third-‐party adjudicator is involved:
• How will the team ensure that events are appropriately sent for adjudication?
• Are adjudicators masked to treatment assignment? If so, by what method?
• For event-‐driven endpoints, how will the study team monitor the
rate of reporting of key study outcomes?
• If the event rate is below a specified threshold, are there remedial
measures that will be taken to preserve the power or integrity of the
study?
• If the study is not blinded, are there special considerations for
reducing bias?
CTTI, Duke University 17

18. Summary
• Like API, manufacturing or product development, quality has to be
built in a clinical trial by design
• Deviations from protocol in a CT or MRCT can be classified according
to their disassociated with them
• All aspects of a clinical trial have factors that are critical to quality
• When a clinical trial fails or doesn’t go according to plan or protocol,
then a systematic route cause analysis needs to be performed to go to
the actual cause or causes
• The more accurate RCA is, the more effective the CAPA will be
• Once a CAPA is implemented look for its affectedness. Ineffective
Kappa is counter-productive.
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Any Questions?