QUALITY MANAGEMENT IN CLINICAL

RESEARCH/TRIALS

Sucheta Banerjee Kurundkar, Ph.D., MBA

Director Training
Clinical Development Services Agency, Translational Health Science & Technology Institute,
Department of Biotechnology, Ministry of Science & Technology, Government of India
NABL & NABH Assessor; FERCAP-SIDCER Surveyor, GCP, GCLP, GLP Auditor
Disclaimer: My personal views are expressed in this talk
GCP MARCH 02, 2022
 Disclaimer
The views and opinions expressed in this presentation (PowerPoint slides) are those of the individual presenter and should not
be attributed to CDSA, THSTI, DBT officers, employees, volunteers, members, chapters, councils, special interest area
communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are
the intellectual property of the individual presenter and are protected under the copyright laws. Used by permission. All rights
reserved. All other trademarks are the property of their respective owners.

Additional disclaimer: This presentation supports an oral briefing and should not be relied upon solely on its own to support
any conclusion. The names, places, all details are purely fictitious. Any similarity to actual persons, living or dead, or actual
events, is purely coincidental. These slides are intended to provide general educational information and are not intended to
convey any legal advice.

GCP MARCH 02, 2022

 Monitori
ng
Common
observations

• Rights
Audit Quality Ethics • Safety
• Well-being

Quality
Experience Management
• Credible
sharing Data &
• Accurate
Results

GCP MARCH 02, 2022

 What is quality?

❖Quality is a set of characteristics that a product or

service must have to satisfy needs and
expectations of the customer [ISO 9000]
❖Conformance to standards

What is quality in clinical trials/research?

❖Compliance to Protocol
❖Compliance to GCP
❖Compliance to applicable regulations
❖Compliance to SOPs

GCP MARCH 02, 2022

 Where is
GCP quality in
GCP?

It is an International standard for clinical studies or trials that encompasses the design,
conduct, monitoring, termination, audit, analyses, reporting and documentation of the
studies. It ensures that the studies are implemented and reported in such a manner that
there is public assurance that the data are credible, accurate and that the rights,
integrity and confidentiality of the subjects are protected.

GCP aims to ensure that the studies are scientifically authentic and that the clinical
properties of the “Investigational Product” are properly documented.

GCP MARCH 02, 2022

What is GCP non-compliance?
 Rights, safety and well being
Data – credible and of all study subjects
accurate (ALCOA-C) /participants
are well protected

Good Clinical Practice (GCP)

GCP MARCH 02, 2022

GOOD CLINICAL PRACTICE 12 FEBRUARY 2021
 Consequences of Non-compliance

Jeopardizes data integrity Risk to patient safety

Undermines regulatory Inaccurate product

authorities' mission approval or labeling

➢ To investigator: Reputation damage, Debarment, Imprisonment, Fines

➢ To Sponsor: Negative media attention, large fines, loss of trust

GCP MARCH 02, 2022

GCP MARCH 02, 2022
 GCP Violations
(5 most common)

OCTOBER 05, 2021

 CDSCO GCP
CONTENTS
1. Definition
ICH GCP E6: 13th Principle
2. Pre-requisites for the study
Systems with Procedures that
3. Responsibilities Assure the Quality of every aspect
4. Record Keeping and Data Handling of the trial should be Implemented
5. Quality Assurance
6. Statistics
7. Special Concerns

GCP MARCH 02, 2022

 Quality Assurance (QA) & Quality Control (QC)

QA: All those planned and systematic actions that are established to ensure
that the trial is performed, and the data is generated, documented
Quality means Good ?…….
(recorded), and reported in compliance with Good Clinical Practice (GCP)
and the applicable regulatory requirement(s). Good Clinical Practice
(GCP)
QC: The operational techniques and activities undertaken within QA system
to verify that the requirements for quality of the trial-related activities have
been fulfilled.
(ICH-GCP 1.46 & 1.47)

GCP MARCH 02, 2022

 Auditing Function Monitoring Function

1) Monitoring is a QC function where study

1) Auditing, a QA function, is an independent,
conduct is routinely assessed on an on-going basis
top-down, systematic evaluation of trial
at every step of the trial. Preventive Process
processes. Verification Process
2) Done continuously
2) Compliance Snapshots in time
3) Regulatory authority has access to monitoring
3) Regulatory authority do not have access to
report
auditor’s findings
4) In tree analogy, a monitor looks in detail at each
4) In tree analogy, auditing involves looking at
leaf on the tree. During a monitoring visit, all
the forest as a whole.
aspects of the study at a specific site will be
checked in accordance with a monitoring plan

GCP MARCH 02, 2022

 Project
QC
Study Start-up
Feasibility Plan Management
Plan
Plan

Training
Monitoring Safety Communication
• Therapeutic area Plan Reporting Plan Plan
• Protocol
• CRA Data
IP Management Laboratory
Management
Plan Manual
Meeting Plan
• Investigator
• Initiation Statistical Medical
Analysis Plan Writing Plan

GCP MARCH 02, 2022

 QA spectrum

Document Study Start-up and

Reporting
Development Conduct
Process Audits Process Audits Process Audits
Document Audits TMF Audits Tables and Graphs Audits
Vendor Evaluations Investigator Site Audits Clinical Study Report Audits
Vendor Audits
Data Management File
(DMF) Audits
Database Audits

GCP MARCH 02, 2022

 Audit Plan Audit Conduct

CAPA Audit Report

QA process
GCP MARCH 02, 2022
 What is Monitoring?
❑Although an extensively written guidance can assure
appropriate conduct of the study, the sponsor
should ensure that the studies are adequately
monitored.

❑Determination of extent & nature of monitoring

should be based ---- objective, purpose, design,
complexity, blinding, size & endpoints of the study.

❑Sponsor must appoint adequately trained monitors

or CRO to supervise an ongoing study [CDSCO GCP
3.1.13]
 Audit
A systematic and independent examination of trial related activities and
documents to determine whether the evaluated trial related activities were
conducted, and the data was recorded, analyzed and accurately reported
according to the protocol, sponsor's standard operating procedures (SOPs),
Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

(ICH-GCP 1.6)

GCP MARCH 02, 2022

 What is Audit?
CDSCO GCP (3.1.14)
✓Sponsor should perform an audit as a part of QA
system.
✓Audit should be --- Independent & separate from
routine monitoring (QC functions).
✓Audit should evaluate ----study conduct &
compliance with protocol, SOPs, GCPs and
applicable regulatory requirements.
✓Sponsor may appoint individuals qualified by
training & experience to conduct audits.
✓The Auditors should be independent of the parties
involved in the study & their qualifications should
be documented.

GOOD CLINICAL PRACTICE APRIL 20, 2021

 Inspection

The act by a regulatory authority(ies) of conducting an official review of

documents, facilities, records, and any other resources that are deemed by
the authority(ies) to be related to the clinical trial and that may be located at
the site of the trial, at the sponsor's and/or contract research organization’s
(CRO’s) facilities, or at other establishments deemed appropriate by the
regulatory authority(ies).

(ICH-GCP 1.29)

GCP MARCH 02, 2022

 Monitor QC

Document Study Start-up and

Reporting
Development Conduct

QA

Auditor Auditor Auditor

Standards

GCP MARCH 02, 2022

 Audits Vs Inspections
Sponsor
Can be Done by
Audits Auditor
by
CRO

Advance notice will always be given prior to an Audit

Will always Regulatory bodies Done

Inspections Inspector
be by e.g. US-FDA, EMA by

Advance notice may/ may not be given prior to an Inspection

GCP MARCH 02, 2022

GCP MARCH 02, 2022
 Quality Assurance [CDSCO GCP 5]

The Sponsor is responsible for the implementation of a system

of Quality Assurance in order to ensure that the Study is
performed, and the data is generated, recorded and reported in
compliance with the Protocol, GCP and other applicable
requirements. Documented SOPs are a prerequisite for quality
assurance.

All observations and findings should be verifiable, for the

credibility of the data and to assure that the conclusions
presented are correctly derived from the Raw Data. Verification
processes must therefore be specified and justified.

GCP MARCH 02, 2022

 Quality Assurance [CDSCO GCP 5]

Statistically controlled sampling may be an acceptable method of

data verification in each Study.
Quality control must be applied to each stage of data handling to
ensure that all data are reliable and have processed correctly.

Sponsor’s audits should be conducted by persons independent of

those responsible for the Study. Investigational sites, facilities, all
data and documentation should be available for inspection and
audit by the Sponsor’s auditor as well as by the Regulatory
Authority(ies).

GCP MARCH 02, 2022

 Pre-requisites for the study --- QC & QA
[CDSCO GCP 2.3.1.11]
a. A meticulous and specified plan for the various steps and procedures for the purpose of
controlling and monitoring the study most effectively.
b. Specifications and instructions for anticipated deviations from the protocol.
c. Allocation of duties and responsibilities with-in the research team and their coordination
d. Instructions to staff including study description (the way the study is to be conducted and
the procedures for drug usage and administration)
e. Addresses and contact numbers etc. enabling any staff member to contact the research
team at any hour
f. Considerations of confidentiality problems, if any arise
g. Quality control of methods and evaluation procedures
GCP MARCH 02, 2022
 Responsibilities --- Study management, data handling and
record keeping [CDSCO GCP 3.1.5]

h. Quality Assurance and Quality Control systems with written SOPs to

ensure that the Study is conducted, and data are generated,
documented (recorded), and reported – in compliance with the
Protocol, GCP and the applicable regulatory requirement(s)

It shall be the responsibility of Sponsor.

GCP MARCH 02, 2022

 Sponsor may transfer any/all of
Ethics Committee
the Sponsor’s study related duties
Investigator Study Co-ordinator
& functions to a CRO but the
ultimate responsibility for the
QUALITY & integrity of the Study
data shall always reside with the
Sponsor [ CDSCO GCP 3.1.17]
Sponsor
Monitor
Lab
Who is
responsible?
Auditor Regulator
GCP MARCH 02, 2022
Quality Management System (QMS)

Quality Manual

Standard Operating Procedures

Work Instructions

Forms and Templates

 Quality
• PRotocol • Process & procedures
• INvestigator’s Brochure • Regulatory approval
• Case Report Form • INformed consent process
• Essential documents • Clinical study report
• Ethics approval
• Source data
• SOPs + Surveillance

GCP MARCH 02, 2022

 Quality: Documentation

Source Data CRF

• Attributable • Accurate
• Legible • Legible
• Contemporaneous • Contemporaneous
• Original • Complete
• Accurate
• Complete

GCP MARCH 02, 2022

 Is it necessary?
Monitoring and Auditing of Records [CDSCO GCP 3.3.3]
• The investigator / institution shall allow monitoring &
auditing of the records, procedures and facilities, by the
sponsor, the ethics committee, CRO or their authorised
representative(s) or by the appropriate regulatory
authority.

GCP MARCH 02, 2022

GCP MARCH 02, 2022
 Types of Audits in Clinical Research

Systems Audits Data Audits

Routine Study Specific

Sponsor Vendor Other
Investigator Site CSR

Database
ECG Lab CRO

Full Safety
Monitoring Biometrics IMP
Service Reporting
GCP MARCH 02, 2022
 Audits-Sponsor Responsibility

Evaluate trial conduct

and compliance with
Independent of
the protocol, SOPs, ICH Auditor Qualification Written SOPs
operations
GCP and applicable
regulations

Audit Plan Audit Report Audit Certificate

ICH GCP Section 5.19

GCP MARCH 02, 2022

 Document Auditor
Interviews Facility Review
Reviews Auditor Auditee
▪ Informed Consents ▪ PI ▪ Patient Registration
▪ Subject recruitment ▪ Sub-I ▪ OPD
▪ Subject source data ▪ Study Co- ▪ Informed Consent
▪ Protocol specific procedures ordinators ▪ Physical Exam
▪ Regulatory and Ethics ▪ Phlebotomist ▪ Vital Signs
submissions and approvals ▪ Pharmacists ▪ Study specific procedures
▪ Investigator Site File ▪ Archivist ▪ IMP Storage
▪ IMP receipt, storage, ▪ Others, as ▪ IMP Dispensation
dispensation, return and applicable (eg: ▪ IMP Return
accountability Radiologist etc) ▪ Sample Collection
▪ Sample collection records ▪ Sample Storage/Shipment
▪ Laboratory reports ▪ Clinical Trial Supplies
▪ Medical oversight storage (For example -
▪ Safety reporting Sample collection kits), etc
▪ Archival records
Investigator Site
GCP MARCH 02, 2022
 Document Auditor Auditor
Interviews Facility Review
Reviews Auditee Auditee
▪ Organization Chart ▪ QMS Team ▪ Clinical Trial
▪ Personnel & Training Records ▪ Training Team Supplies storage
▪ SOPs/QMS ▪ Project ▪ Document
▪ Project Management Managers Storage
▪ Document Development ▪ Medical ▪ Document
▪ Study Start-up Monitors Archival
▪ Monitoring and Site Management ▪ Clinical Research ▪ IT (Server Room)
▪ Safety Reporting Associates (CRA)
▪ Protocol Deviation Management ▪ Clinical Trial
▪ Issue Escalation Process Assistants
▪ Medical Oversight ▪ Database
▪ IMP Management Designer
▪ Vendor Selection, Management ▪ Clinical Data
and Oversight Manager
▪ Data Management & Reporting ▪ Medical Writers
▪ IT and Computer System ▪ Biostatisticians
Validation ▪ Internal QC
▪ Document Management, Storage ▪ IT Personnel
and Archival Sponsor/CRO
▪ QA
 Access to audit reports

To preserve independence and value of Regulatory authority(ies) may seek access

the audit function, the regulatory to an audit report on a case-by-case basis
authority(ies) should not routinely when evidence of serious GCP non-
request the audit reports. compliance exists or in course of legal
proceedings
ICH GCP Section 5.19.3 (d)

GCP MARCH 02, 2022

 Classification of findings
• CRITICAL: - Conditions, practices or processes that adversely affect the rights, safety or
wellbeing of the subjects and/or the quality and integrity of data. Possible consequences:
rejection of data and/or legal action required.

• MAJOR: - Conditions, practices or processes that might adversely affect the rights, safety or
well-being of the subjects and/or the quality and integrity of data. Possible consequences:
data may be rejected and/or legal action required.

• MINOR: - Conditions, practices or processes that would not be expected to adversely affect
the right, safety or well-being of the subjects and/or the quality and integrity of data. Possible
consequences: observations classified as minor, indicate the need for improvement of
conditions, practices and processes.

GCP MARCH 02, 2022

Let’s discuss….
 Monitoring: Which areas are selected for?
All areas in monitoring scope

Auditing/Inspection:
• Highest enrolling sites
• Large no. of screen failures
• High patient drop-out rates
• Large no. of S/AEs at only 1-2sites
• Under reporting of S/AEs
• Sites with some type of financial conflict of interest

GCP MARCH 02, 2022

 Checklist (Records/Procedures/Facility):
• Essential Documents (Before/During/After) What to check ?
• Study documents/TMF (Protocol, IB, CRF, SOPs, etc.)
• Regulatory /EC approval
• Delegation Log
• IC procedure and documentations
• Investigators/study team (CV/Training)
• IMP
• Safety Reporting
• Monitoring
• Insurance
• Regulatory/EC communication
• Data (retrospective assessment of data quality)

GCP MARCH 02, 2022

 Outcome
• What happens if …………all is well
• Gives assurance that system & procedures are in place

• What happens if ……… serious/persistent NC are observed

• Sponsor takes prompt action (CAPA, Notification, Termination)

GCP MARCH 02, 2022

 US FDA Inspections-India Investigators

14 13
12
12
10
8
#Investigators

6
6
4
2 2
2 1
0
02-Failure to 04-Inadequate 05-Failure to 06- Inadequate 15-Failure to 18- Other
obtain and/or drug follow and inaccurate notify IRB of
document accountability investigational records changes, failure
subject consent plan to submit
progress reports
Discrepancy Codes

GCP MARCH 02, 2022

 FDA observations
• Protocol Deviations-Inclusion/Exclusion.;
• schedules- dosing, lab tests, return visits; meds.
• Failure to report Adverse Events
• Poor record keeping -- missing source docs
• Informed Consent issues-wrong version
• IRB issues-Approvals; reports SAEs/deviations
• Test Article Accountability (CI responsible) COMMON OBSERVATIONS
• PI’s failure to adequately supervise the study: CLINICAL INVESTIGATORS
• -- staff errors, training lapses

Source document issues ranked 5th among the top 10 findings from
European Medicines Agency (EMA) inspections of investigator sites
Source: Nancy A. Bellamy,Bioresearch Specialist/ BIMO Monitor,US Food & Drug Administration,Office of Regulatory Affairs,Detroit District Office, May 2013

GCP MARCH 02, 2022

 Most common audit findings

GCP MARCH 02, 2022

 Most common investigator site audit findings
• Inadequate Source Data
• Protocol Non-Compliance
– Eligibility
– Visit Windows
– Protocol specific tests and procedures
• Non-compliance to administration of updated informed consent forms
• Non-compliance to safety reporting timelines
• EC Issues
• Inadequate IMP Management
• Inadequate facilities
GCP MARCH 02, 2022
 Most common Sponsor / CRO audit findings

• Inadequate issue escalation process

• Non-compliance to monitoring plan
• SOP non-compliance
• Inadequate vendor surveillance
• Inadequate document translation process

GCP MARCH 02, 2022

 What to check?
Informed Consent Process & documentation
• Incorrect version
• Consent not dated by subject
• Original consent missing
• Re‐consent missing, wherever applicable.

Protocol non-adherence
• Non-adherence to protocol procedure/schedule
• Lack of clarity in protocol & Sponsor’s communication
• Protocol amendments without EC approvals

GCP MARCH 02, 2022

 What to check?
Eligibility & I/E criteria AE noted in medical record but not on CRF, or vice versa ??

• SD non-compliance with eligibility criteria

• Failure to conduct all tests needed to satisfy eligibility, I/E
criteria
• Inadequate PI’s review of eligibility, I/E criteria
• No documentation of sponsor waiver of eligibility, I/E
requirement

Inadequate & inaccurate records

SAE Reporting
• Inadequate source documents (SD)
• Failure/Delay in SAEs Reporting (Sponsor, EC, Regulatory)
• Discrepancies between CRFs and SD • Discrepancy in CRFs & SD
• Incomplete CRFs + Improper Error Correction • S/AEs not signed/graded/attributed in a timely manner

GCP MARCH 02, 2022

 What to check?
IP Accountability
• Poor documentation that IPs was provided to subject and/or
returned by subject with pill count
• Expired IPs under subject’s custody
• Poor documentation regarding IPs diaries

ISF/Documentation
• No/Inadequate delegation of duties log
• No up‐to‐date folder with CVs, licensing info,
• No SOPs for Institution, Site, EC etc.
• Missing EC communication
• Missing Regulatory communication + Poor record storage
GCP MARCH 02, 2022
 Possible reasons

Multicentre studies across

Complex protocols
various continents

Inefficient practices that

Multiple outsourcing consume valuable resources
partners & inadvertently detract
from quality

GCP MARCH 02, 2022

Possible solutions
 Shift from Quality Assurance via audits and inspections to
Quality by Design (QbD) and
Risk based approach

1. Quality adds ‘Good’ to GCP

2. Always ENSURE, Never ASSUME
3. Compliance is Organizational responsibility &
mandatory act
4. Compliance is every body’s responsibility
5. Integrity as a culture Take Home
Message
6. Document properly what you did correctly &
completely (C2) + Document what was not done
also. (don’t leave to your memory)
7. Training… training …. and training
8. Do it right at for the first time, at right time, in
right manner
GCP MARCH 02, 2022
How to manage quality?
Say What You Do Do What You Say

Follow
SOPs Processes

PDCA Cycle

Identify Demonstrate
Improvements Compliance

Improve It Prove It
 References

• https://cdsco.gov.in
• https://www.ich.org
• https://www.fda.gov
• https://www.ema.europa.eu/en
• Information Sheet Guidance For IRBs, Clinical
Investigators, and Sponsors FDA Inspections of Clinical
Investigators

GCP MARCH 02, 2022

 It is not enough to do your best; You must
know what to do and then do your best.
Let difficulties know that you too are difficult (Dr W. Edwards Deming)
(Dr A. P. J. Abdul Kalam)

We should not give up and we should not allow the

problem to defeat us
(Dr A. P. J. Abdul Kalam)
Failing to plan is planning to fail
(Alan Lakein)

GCP MARCH 02, 2022