The document discusses quality assurance in clinical trials. It begins by outlining key frameworks for quality like GCP and ISO standards. It emphasizes that quality assurance requires understanding critical parameters, incorporating quality by design principles, and addressing practical challenges in data collection and documentation. The document then provides examples of risk-based quality management, highlighting the importance of identifying, assessing, and mitigating risks at various stages of a clinical trial's lifecycle. Finally, it presents two case studies, one on a large heart failure trial and another on a global respiratory trial, to demonstrate operationalizing quality assurance practices.

1. QUALITY
ASSURANCE OF
CLINICAL TRIALS
A culture of checks and examinations
ensuring the quality of clinical trials
1
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd., Ahmedabad

2. 2

3. CONTENTS
 Quality Framework
 Understanding the critical parameters that need
to be taken care of while conducting a trial
 Developing practical techniques to ensure the
incorporation of Quality by Design (QbD) in the
design trials
 Dealing with practical challenges in data capture
and documentation design to ensure flawless
execution of your clinical trials
 Case Studies
 Concluding remarks
3

4. International Standards Organization
Quality Framework
4
©2010 by Oxford University Press Kleppinger C F , Ball L K Clin Infect Dis. 2010;51:S111-S116

5. GCP
 Good clinical practice (GCP) is a set of internationally
recognized ethical and scientific standards for the
following aspects of clinical trials:
 Design
 Conduct
 Performance
 Monitoring
 Auditing
 Recording
 Analysis, and
 Reporting
5

6. ICH GCP ◊5.1.1
 The sponsor is responsible for implementing and
maintaining quality assurance and quality control
systems with written SOPs to ensure that trials are
conducted and data are generated, documented
(recorded), and reported in compliance with the protocol,
GCP, and the applicable regulatory requirement(s).
The aim: providing assurance of protection of the rights, safety
and well-being of trial subject; and credibility of CT results
Also applicable to CROs, vendors or other delegated service
providers
However, the sponsor remains responsible for the
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quality of the trial.

7. KEY ELEMENTS OF THE
QUALITY SYSTEM
 Documented procedures are developed, implemented
and kept up-to-date
 Training of sponsor personnel as well as of the
personnel in affiliates, at CROs and at trial sites
 Validation of computerised systems
 Monitoring of trial sites and technical facilities on-site
or by using centralised monitoring techniques
 Data management and quality control
 Internal and external audits performed by
independent auditors 7

8. WHAT QUALITY & AT WHAT
COST?
 The most pragmatic definition of quality is “fitness
for purpose”
 Simply striving for the “highest level” of quality has
little practical meaning
 Current practices: either success at an [unnecessarily]
high cost or failure also very costly
 A practical & cost effective paradigm:
“Adequate quality of a CT should be such that the
decisions made would have been no different had the
quality of data and information generated been perfect”
EMA reflection paper on risk based quality management in clinical trials 8

9. CURRENT CLINICAL TRIALS
(CTS)
 Current CT design, implementation and oversight
 Expensive, outmoded and unsustainable in a global,
complex trial environment
 Especially existing monitoring models do not optimally
address the most critical risks to trial integrity
 They rely on frequent, on-site monitoring visits by sponsor
personnel
 Monitoring is only one component of an overall quality
framework
 Trial personnel agree that widespread adoption of an
enlightened “quality-by-design” approach to trial planning,
conduct, and oversight is needed to ensure trial quality and
efficiency
 Such an approach would apply risk management principles 9
to the design and execution of CTs

10. THE CURRENT QUALITY
CHALLENGE
 The ongoing challenge in managing the quality of clinical data is to
continually monitor data collection procedures and data management
practices at every level of the study. This includes:
 Ensuring that data generated during the study reflect what is specified
in the protocol (case report form[CRF] vs. protocol)
 Comparing data in the CRF and data collected in source documents for
accuracy (CRF vs. source documents)
 Ensuring that the data analyzed are the data recorded in the CRF
(database vs. CRF).Quality surveillance continues after the trial has
ended and plays an important role in ensuring that:
 Data presented in tables, listings, and graphs (TLGs) correctly match
data in the database (TLGs vs. database)
 Data reported in the clinical study report (CSR) are the data analyzed
(CSR vs. TLGs)
 All aspects of the data management processes are compliant with SOPs
and GCPs. 10

11. QUALTY BY DESIGN
(QBD)
 QbD is based on 2 basic principles:
1. Clinical insight: link between the product
and its safety and efficacy in humans
and
2. Process understanding: link between the
drug product and process attributes
11

12. A RISK BASED QUALITY
MANAGEMENT PROCESS FOR
CTS
Initiate
Risk Identification
Review & Assessment
Risk
Communicatio
Risk Control n
Implementation 12

13. RISK BASED QUALITY
MANAGEMENT
 Key idea & practice:
 Identify, assess, control & mitigate, communicate,
and review [both risks & remedies]
 All risks [low, mid & high grade] associated with the
clinical trial during its lifecycle
 RBQM facilitates better and more informed
decision making and makes best use of the
available resources
 Should be appropriately documented and
integrated within existing quality systems
 Responsibility of all involved parties to
contribute to the delivery of an effective RBQM
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14. RBQM
 Initiate
 Information on Systems and Project
 Risk Identification and Assessment
 What may go wrong? Chance of occurrence? What
would be in particular the impact on trial subjects’
rights/well being/safety and/or on the reliability of
the trial results?
 Risk Control
 Decision made to reduce and/or accept risks
 Where risks are to be mitigated, the methodology
adapted to conventional GCP should be defined
 (e.g. intensive, regular or reduced on-site monitoring
and/or central monitoring, targeted SDV on primary 14
endpoint variable etc)

15. RBQM CONTD..
 Risk Communication
 Documentation of Process (e.g., Risk management
measures) with reviews of the measures as necessary
 Communication to all stake holders/decision makers
 Implementation
 Putting in place the actions identified, particularly
for high risks, but conversely there may be
implication on low risks
 Review
 Results and new Information (e.g. new pre-clinical
data, new safety data, updated Investigator
Brochure, Protocol Amendment) and ongoing review
(e.g. Data Monitoring Committee Meeting Output,
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Audit Report concerns)

16. QUALITY TOLERANCE
LIMITS
 Establish the acceptable variation or
tolerance limits for the clinical trial
procedures involved.
 Bearing in mind the statistical design of
the trial and the potential impact of the
different levels of variability on the power
of the trial.
a) Trial data
b) Trial protocol procedures and GCP
c) Trial management procedures 16

17. REPORTING QUALITY
 RBQM in clinical research revolves around the
following cycle:
1. establishment of the priorities (protection of trial subjects
and to its scientific objectives)
2. identification of the risks associated with the study
3. setting of the tolerance limits and the documentation of
the processes for mitigation of risks associated with the
priorities
4. the review of the results and data associated to the risk
identified and the documentation of the actions needed
A clear qualitative and quantitative way to report on
the extent to which a trial has operated within the
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tolerance limits of an acceptable level of quality

18. PROPOSED
APPROACHES
Regulatory
Submissions
and/or
Publication
s
The key issues of trial and protocol design, data collection, monitoring
and data management (both centralised & on-site activities), data
quality tolerances, and record keeping for the study should be 18
addressed.

19.  Prioritization and risk mitigation approaches across
several dimensions:
 Protection of trials subjects - Rights and Integrity, Safety
 Credibility of data and results
 Stratified according to knowledge of product (MA
status)
 Customized approach depending on:
 Protocolcomplexity
 Therapeutic indication and nature of endpoints, including
population and co-medications
 Administration of the product, dose, formulation
 Complexity of study procedures and measurement,
including the nature of the intervention
 Vulnerability of the study population
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20. OPERATIONAL DELIVERABLES
OF RBQM
 Overall QC plan
 Sampling plan to be used (if applicable)
 Data source to be used for QC at each operational stage
 Metrics to be documented
 Acceptable quality levels
 Management of compliance with the protocol, SOPs, and GCPs
 Resolution of system problems prior to the end of the study
 Reduction of data queries
 Identification of ways to reduce cycle times for various processes
 Ensuring data integrity throughout the study's course and that
the data collected are the data required by the protocol
 Ensuring the accuracy and consistency of data from entry into the
CRF to final datasets reported in the final CSR
 Dealing with instances of nonconformity while carrying out
clinical trials
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 Delivering an accurate and complete report (final CSR)
 …

21. CASE STUDIES
21

22. CS 1: ASCEND-HF, STUDY DESIGN
 RCT, Double Blind, in acute Heart Failure (HF)
patients
 3500 Nesiritide, 3500 Placebo
 Randomize <48 hours from hospitalization, <24 hours
from IV RX for HF
 Co-Primary Endpoint Dyspnea index at 6/24hrs
 Co-Primary Endpoint 30-day Death/HF
rehospitalization and secondary endpoints
 All-cause Mortality at 180 days
22

23. CS 1: ASCEND-HF, BUILDING & DEFINING
QUALITY
 Building
 Building Establish principles for quality operations/data before trial
begins
 Integrate principles throughout trial operations
 Communicate expectations to sites and trial teams
 Implement surveillance plans and provide feedback
 Adhere to pragmatic principles
 Efficient, effective (& hopefully economical)
 Defining
 Enrolled the right participants according to the protocol with adequate
consent?
 Did participants receive the assigned treatment and did they stay on the
treatment?
 Was there complete ascertainment of primary and secondary efficacy
data?
 Was there complete ascertainment of primary and secondary safety data?
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 Were there any major GCP related issues?
Source: Hernandez and Reist (2011), CTTI Workshop Presentation

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28. CS 2: GLOBAL STUDY – BOEHRINGER
INGLEHEIM, DESIGN
 RCT, Double Blind, Outcome trial in
respiratory area
 Total17,000 patients
 At1,200 sites
 At 50 countries
 Over ~3 ½ years duration
1 yr recruitment
 2.5 yr follow-up
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Source: Andy Lawton (2011), CTTI Workshop Presentation

29. CS 2: GLOBAL STUDY – RBQM
 Early detection of risks or non-compliance
 Leads to earlier implementation of actions → Increase quality of trial
 Structured overview of trial risks on multiple levels
 Trial / Country / Site
 Optimised monitoring process
 Optimised audit strategy
 Weekly risk report Initially based on “Recruitment” phase
factors
 Now updated for “ongoing” (follow-up) phase
 Some items dropped / score reduced
 Essential to form quality feedback loops for issues
 Use the information that is already available or simple to
get
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 Utilize your Meta data!!
Source: Andy Lawton (2011), CTTI Workshop Presentation

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31. CONCLUDING REMARKS
1. If quality is defined as the absence of errors that matter,
the definition needs to be specified for a given trial.
2. However, general principles about what really matters in
clinical trials can and should be developed.
3. A shift to a QbD and RM-based approach across the
clinical research enterprise are being promoted.
4. Harmonization both within and across regulatory agencies
is highly desired.
5. Addition of processes on top of existing ones would be
regressive rather QbD should transform how things are
done in the first place.
6. Quality and regulations should act as enablers and not 31
obstacles to innovation.

32. Acknowledgement:
THANK YOU VERY
MUCH
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