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Identifying Clinical Non-compliance, Conducting the Root Cause Analysis,
and Responding with Appropriate Corrective and Preventive Actions
4th Clinical Quality Signals, RCA and CAPA
EXECUTIVE SUMMARY
CONTENTS
INTRODUCTION: THE 4TH CLINICAL QUALITY SIGNALS, RCA AND CAPA CONFERENCE 3
2014 SESSION SUMMARIES 4
RESOURCES FOR INFORMATION AND DISCUSSION 11
3www.exlevents.com/CAPA
INTRODUCTION: THE 4TH CLINICAL QUALITY SIGNALS, RCA AND CAPA CONFERENCE
If you weren’t able to join us this year, here is what you missed at the
4th Clinical Quality Signals, RCA and CAPA Conference …
With the theme of “Identifying Clinical Non-compliance, Conducting the Root Cause
Analysis, and Responding with Appropriate Corrective and Preventive Actions,” the
4th annual summit, held January 28-29 in Alexandria, Virginia, served as a gathering
for clinical quality and operations professionals from companies of all sizes and
types to discuss and share their experiences. This event continues to act as the
only industry forum dedicated to identifying non-compliance, understanding the
root cause and executing corrective and preventive actions in the GCP environment,
and provides a unique forum for candidly sharing experiences, best practices and
lessons learned.
This summit brought together professionals from pharmaceutical, biotechnology
and medical device companies as well as CROs and other clinical trial service
providers, who work in quality systems development, management and training,
clinical quality assurance and control, clinical operations and management, GCP
compliance, clinical auditing, monitoring, and more.
Through the use of an audience response system, speakers were able to poll
the audience, which provided valuable insight into the industry’s perceptions,
understanding and progress as they related to the topics discussed. These topics
included effective tools for identifying clinical non-compliance and assessing the
criticality, prioritizing and managing findings to determine the response, conducting
an effective root cause analysis, initiating a CAPA process and developing a system,
employing proactive approaches to prevent non-compliance and much more,
including the critical site perspective and the role of clinical monitoring.
Following are session summaries and highlights to give you an idea of the
information presented and topics discussed at the 4th Annual Clinical Quality
Signals, RCA and CAPA Conference.
2014 Audience Breakdown
- Pharmaceutical, Biotech, Medical Device Companies
- CROs
- Other Clinical Service and Technology Providers
- Sites
65%
10%20%
Company Type
5%- Quality/Compliance
- Clinical Operations/Management
- Audits/Inspections
- Other
60%
10%
20%10%
Department
4www.exlevents.com/CAPA
In the Chairperson’s opening remarks, Kevin Wilson,
the Manager of Global Medical Quality Systems for
Eli Lilly, talked about building a common language,
and behaviors for success, such as creating a culture
of accountability rather than a culture of blame.
He surveyed the audience on what signals they
are currently tracking and 70% indicated audit
observations, deviations and non-compliance.
With regards to root cause, 58% said they are
conducting root caused based on levels of
criticality with 43% indicating Quality teams have
responsibility for documenting the root cause.
In the opening session, Celeste Gonzalez, Senior
Clinical Quality Assurance Specialist at Boston
Scientific, discussed “Strategies for Identifying
Clinical Non-Compliance and Assessing the
Criticality at the Sponsor, CRO and Site Levels.”
After defining the importance of clinical quality
signals, she outlined different sources to use for
identification and shared examples of clinical QA
audit findings, providing guidance for uncovering,
categorizing and analyzing these signals, including
determination of the severity, scope and impact.
A panel discussion on management and
prioritization focused on “Practical Tools and
Methodologies for Prioritizing and Managing
Findings to Determine an Adequate Response.”
The panel was moderated by Lynn Van Dermark,
CEO of Medtrials, Inc. and the panelists included:
Suzanne Elliott, Associate Director, R&D Compliance
& Process, Continuous Quality Improvement at
Shire; Venessa Galate, Director Quality Process
Liaison, Janssen Pharmaceuticals; and Sunil
Kotecha, Corporate Audit for Pfizer. The group
discussed tools and methodologies for categorizing
and prioritizing non-compliances, the departments
responsible for managing non-compliance and the
levels of visibility.
During the panel, the audience was asked to
consider the following scenario: “Gaps were
identified in the timely distribution of SUSAR to
the investigator sites. Who should be involved in
determining appropriate actions?” The response
was split with about a third selecting Safety/PV
Group, another third selecting Study Management
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
What signals are you tracking?
1 2 3 4
15%
70%
9%7%
1. Audit Observations 2. Deviations 3. Non-compliance 4. All of the above
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Conduct root cause based on?
1 2 3 4
58%
9%9%
23%
1. Levels (Critical, Major, Other)
2. Risk analysis 3. All signals get a
CAPA 4. Management
review
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Who documents the root cause?
1 2 3 4 5 6
23%
43%
11%
0%
11%11%
1. Clinical Operations 2. Quality 3. Compliance 4. Audited area 5. General admin 6. Other
SESSION SUMMARIES
3 Boston Scientific Confidential -- For Internal Use Only. Do Not Copy, Display or Distribute Externally
Importance of Clinical Quality Signals ACHIEVE and MAINTAIN
• Data Integrity • Subject Protection • Subject Safety • Protocol Compliance • SOP Compliance • Compliance with national/regional/local
regulations and requirements • Compliance with various contractual
agreements Sponsor CRO Investigative sites IRB
Clinical Quality Signals, RCA & CAPA, January 28-29, 2014, Alexandria, VA
5www.exlevents.com/CAPA
Staff/CRA and 39% indicating Another Combination
of Staff.
And when polled about the following: “During a
routine audit, several protocol deviations were
identified at an investigator site. Who should be
involved in determining appropriate actions?” 57%
responded with Study Management Staff/CRA.
On the topic of Responding to Non-Compliance,
Jeanette Johnson, Manager of Consulting Services
at Pathwise, offered a presentation on “Developing
the Necessary and Appropriate Actions for
Different Types of Audit Findings.” She noted
the importance of characterizing findings and of
gathering specifics. Each problem statement should
answer: What is the problem? What requirement
was met? What evidence is there to show that the
requirement was not met? Jeanette provided
valuable insight on defining actions, based on the
criticality of the finding. In her polling, 76% of
companies were reported to have escalation criteria,
but only 16% had de-escalation criteria.
She went on to discuss effective risk evaluation
indicating it should include two separate actions,
assessing the impact and frequency, and deciding
where the event will be recorded in the quality
system. Then she addressed using that evaluation
for risk-based decision-making to implement
actions, noting that decisions within the CAPA
system should be based on risk commensurate
to complexity, risk-based decisions should occur
throughout the CAPA process to meet regulatory
expectations, and it’s necessary to document the
rationale for the actions throughout the CAPA
process. Concluding with, the most successfully
implemented CAPAs are managed by operational
teams, have management buy-in, and are shared
throughout the organization.
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Gaps were identified in the timely distribution of SUSAR to the investigator sites.
Who should be involved in determining appropriate actions?
1 2 3 4
31%
39%
31%
0%
1. Safety/PV Group 2. Study Clinician/ Legal 3. Study Management
Staff/ CRA 4. Another Combination
of Staff
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
During a routine audit, several protocol deviations were identified at an investigator site.
Who should be involved in determining appropriate actions?
1 2 3 4
5%
38%
57%
0%
1. Audit Department 2. Study Clinician/ Legal 3. Study Management
Staff/ CRA 4. Another Combination
of Staff
6www.exlevents.com/CAPA
A panel discussion on “The Role of Clinical
Monitoring: Developing and Training Clinical
Monitors to Identify Non-Compliances Early,
Quickly and Efficiently to Facilitate Necessary
Escalation” was moderated by Liz Wool, President
and CEO of QD-Quality and Training Solutions,
Inc. Panelists were: Dwayne Brazelton, Director of
Clinical Quality Assurance for Macrogenics, Inc.;
Celeste Gonzalez, Senior Clinical Quality Assurance
Specialist for Boston Scientific; Jennifer LaLonde,
Director of Research for the Cardiac and Vascular
Research Center of Northern Michigan; and Sue
Latham, Senior Manager of Quality Assurance for
Medtrials, Inc. The discussion included strategies
for CRA training, approaches to confirming
competency, identifying and overcoming common
challenges and what has been deemed “critical” for
CRA performance.
When polled, just over half of the audience said
their companies had a training program for issue
identification and management and half also
indicated they had a training program for root cause
analysis and CAPA methods.
When asked about the effectiveness of such
programs, no one in the group said that their
company’s training programs were extremely
effective and 39% indicated they were just average.
When asked if a process is established for the sites
to give feedback to the sponsor regarding the
clinical monitor, only 10% of the audience answered
yes, with 55% indicating no and 35% not knowing.
Day two led off with a panel discussion on
“Effective Root Cause Analysis” offering the
perspectives of experts who shared their company’s
processes, best practices and lessons learned when
conducting root cause analyses. The moderator
was Diane Carter, Clinical Quality Auditor for BTG,
and panelists were: Venessa Galate, Director Quality
Process Liaison, Janssen Pharmaceuticals; Helen
Labus, Compliance Director, Global R&D Quality,
Amgen; and Jamie Sweeney, Director of Quality
Management, Research Pharmaceutical Services.
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Question #1 Do you have a training program for
issue identification and management?
1 2
48%
53%1. Yes 2. No
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Question #2 Do you have a training program for
root cause analysis and CAPA methods?
1 2
50%50%
1. Yes 2. No
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Question #3 How effective is your training program?
1 2 3 4 5
0%
27%
0%
33%
39%1. Extremely effective 2. Very effective, but
there’s always some room for improvement
3. Average 4. Not very effective, needs
much improvement 5. Terrible, not effective at
all
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Question #4 Do you have a process established for sites to give
feedback to the Sponsor regarding the Clinical Monitor?
1 2 3
10%
35%
55%1. Yes 2. No 3. I don’t know
7www.exlevents.com/CAPA
Audience polling revealed that more than half
have an immature CAPA process, and that only
one-third of companies have a formal process for
communicating RCA results to the organization and
partners.
The panel offered a brief overview of the tools and
philosophies they use when conducting an RCA,
who leads the investigation at their companies,
tips for managing costs when conducting an RCA,
communication strategies and what to do when
the sponsor and CRO differ on their assignment of
cause.
“Utilizing the Results from the Root Cause Analysis
to Develop Effective and Corrective Preventive
Actions” was presented by Brett Preston and
Kristine Yahagi, both of the Quality Process Liaison
group at Janssen Pharmaceuticals. They shared the
key elements of an executed root cause analysis,
and discussed the importance of writing a SMART
(specific, measurable, achievable, relevant and time-
bound) CAPA.
Establishing the link between RCA and CAPA, they
noted since CAPA seeks to eliminate root causes,
corrective/preventative actions should directly
correlate to one or more of the identified root
causes and when working with multiple causes, it’s
important to prioritize based on risk. Validating
the CAPA includes expert weigh-in, roundtable
discussion and validity confirmation (or not) via
effectiveness checks. The presenters also provided
insight on how to document and record the CAPA
and what information should be captured.
Jennifer LaLonde, Director of Research at the
Cardiac and Vascular Research Center of Northern
Michigan provided the critical site perspective with
a presentation on “Understanding Compliance
Obstacles at the Site Level and How Sponsors
Can Best Support sites to Optimize Quality.” She
discussed the common obstacles to compliance
at the sites that included comprehension/
interpretation of protocol, complex and/or
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
How mature is your company/organization’s CAPA process
1 2 3
51%
20%
29%
1. Immature/newly developed
2. Fairly established with moderate experience
3. Mature process with multiple iterations of development
4th Clinical Quality Signals, RCA and CAPA – January 28-29, 2014 www.exlpharma.com/clinicalCAPA
Does your company/organization have a formal process for communicating the RCA results to the organization
and partners?
1 2 3
33%
7%
60%1. Yes 2. No 3. Don’t Know
Elements of an Executed Root Cause Analysis
Summary of event or nonconformance
Sequence of events (including dates and Jmes where applicable)
List of implicated products or processes
Summary of immediate correcJons that have been completed
Summary of root cause invesJgaJon
9 ExL Pharma 4th Clinical Quality Signals, RCA and CAPAs Conference January 29, 2014
30
Documenting RCA and CAPAs: Depth of Information
• Summary of event or nonconformance • Sequence of events • List of implicated products or processes • Summary of immediate completed correcJons • Summary of root cause invesJgaJon
RCA • AcJon Type (CA vs PA) • AcJon DescripJon • Due Date • Owner • Department • GCP and/or PV and/or GLP • Pharma and/or Consumer and/or Medical Devices
CAPA
ExL Pharma 4th Clinical Quality Signals, RCA and CAPAs Conference January 29, 2014
8www.exlevents.com/CAPA
difficult to understand inclusion and exclusion
criteria, unclear or unknown communication plan
when the sites need to make contact with the
trail sponsor, and lack of expertise with study
provided equipment. To improve compliance, she
recommended sponsors differentiate their training
based on the experience level of the coordinators,
bringing the “new-bies” in early to learn
fundamentals and basics. She also accentuated the
importance of communication, and establishing an
open relationship where the sites want to call and
share their discovery at the first occurrence.
When asking the audience about their policy for
remote monitoring, 55% of the audience indicated
they do not have remote monitoring. Sharing the
impact of risk-based monitoring at the site level,
Jennifer indicated it as a loss of reassurance with a
sense that there are no more checks and balances.
She recommended query resolutions as the best
tool for determining if the site is on track when
executing risk-based monitoring. She concluded by
stating that research is a team effort and you must
lay down a strong foundation and give your sites
“longevity.”
“Deconstructing a Broken Clinical Trial; Rebuilding
with CAPA-Driven Processes to Successfully
Rescue the Trial” was a case study shared by
Nancy Showden, CEO of NCGS, Inc. She described
a critical path compound trial that was near
termination and how to determine when a rescue is
necessary. She then outlined how to deconstruct
and reconstruct the trial using RCA, CAPA and
quality by design. This included executing a
comprehensive assessment of failed processes,
rapid rescue implementation, understanding the
elements and related impact, identifying the root
cause(s), mapping the CAPA scope, understanding
the risk (current, future and enterprise), developing
a plan with stakeholder support, measuring the
success of interventions and reconstruction, and
sustainability.
Krista Kerr, Associate Director, Team Lead
Global R&D Quality & Compliance at Janssen
Pharmaceuticals offered a session on “Employing
Proactive Approaches for Determining Potential
Problem Areas to Prevent Non-compliance and
CAPA.” She noted challenges to quality and
compliance, including increasing complexity
and globalization, evolving regulations and
requirements, emerging regulators and regulations,
an even greater number of third parties, and rapid
evolution and adoption of new technologies.
She accentuated that proactive compliance
includes strategies to proactively manage the
risk to organizations and prevent or reduce the
likelihood of non-compliance; to that end, quality
should be integrated into day-to-day processes and
companies should continually monitor processes
and service providers and collect/analyze data to
identify trends, determine root causes and enact
process improvement. She reminded the audience
that the goal is to identify issues before they occur,
and that the benefits of proactive compliance
include increased likelihood of achieving objectives,
performance improvements, informed choices and
Question Do you have a policy for Remote Monitoring?
1 2 3 4
6%
55%
18%21%
1. Mandated by occurrence 2. Mandated by the
calendar 3. Mandated by Subject
Enrollment/Follow-‐up 4. Do not have remote
monitoring
9www.exlevents.com/CAPA
decisions, efficiency, consistent and reliable results,
and the facilitation of continual improvement.
Next was a case study presentation by Elizabeth
Luczak, Vice President, Medical Regulatory
Compliance at Pfizer detailing the “Development
and Implementation of a Global CAPA Process
to Optimize Reporting and Gain Insight into
Process Gaps and Potential Non-Compliance.”
When polling the audience, she found that 37% are
working with site and function based CAPA systems
that are NOT global, and that the biggest challenges
in implementing/maintaining the current CAPA
system were sponsorship from senior management
and engagement of critical team members.
She noted key factors to the success/failure of
sustained CAPA outcomes include ownership/
engagement, accountability/empowerment,
investigation, formality of implementation,
communication/training, outcomes demonstrated,
monitoring sustained effectiveness and changes
post-CAPA closure. She shared valuable
insight from her experiences on the key goals/
considerations for a global CAPA system, including
• Escalation/line of sight to significant
quality issues
• Global standards across medical
processes/interconnectedness
• Proactive identification of significant
quality issues
• Engagement/ownership
• Quality of the investigation to determine
scope of impact and scope
of CAPA required
• Preventing future/repeating quality issues
• Visibility/transparency of execution status
and risk
• Quality improvement
• Integration in quality management system
19
Proactive Compliance Consistent and considered approach to risk management
Qualita3ve, metric-‐based risk assessment process
Awareness of interdependent risks
Ongoing monitoring for awareness of changing risk profiles
Integra3on of quality into processes and opera3ons
Culture of con3nuous improvement
Proac3vely apply informa3on across the enterprise
Question How global is your current CAPA system?
3
1 2 3 4 5 6
37%
18%
3%
13%
21%
8%
1. Not global – site and function based
2. Global across GCP/Clinical Trial Execution
3. Global across GCP and Pharmacovigilance (PV)
4. Global across GCP/PV and Other Medical Areas
5. Enterprise Global 6. Other
Question What is your biggest challenge in implementing/maintaining your CAPA system?
9
1 2 3 4 5 6
30% 30%
3%
8%
20%
10%
1. Sponsorship from Sr. Management
2. Engagement of critical team members
3. Quality of investigation 4. Prioritizing CAPA
execution 5. Tools and systems 6. Other
10www.exlevents.com/CAPA
The concluding panel discussion on System
Implementation shared “Best Practices and Lessons
Learned for Defining and Implementing a System for
Tracking, Escalating and Correcting Non-Compliances
and Preventing Reoccurrence.” The panel moderator
was Kevin Wilson, Manager, Global Medical Quality
Systems, Eli Lilly; panelists were Pearl Boakye,
Head of Compliance Management, Bayer; Paula
Parsons, Compliance Senior Manager, Amgen; Jamie
Sweeney Director of Quality Management, Research
Pharmaceutical Services.
When determining what is meant by the word
“system,” ninety-six percent of audience members
defined a CAPA system as a process and practice for
recording and tracking CAPA, which may or may not
include an electronic tool, while only four percent
defined it as a computer system or electronic tool for
recording and tracking CAPA.
The panelists shared tips for designing a cost-effective
system that meets required needs, strategies for
obtaining corporate buy-in and resources to develop
and implement a clinical CAPA system, best practices
for informing, educating and training internal teams
on the importance of CAPA and the CAPA system,
determining clinical partners accessibility and visibility
of the CAPA system and common obstacles to
development and implementation and the steps that
were taken to overcome them.
11www.exlevents.com/CAPA
RESOURCES FOR INFORMATION AND DISCUSSION
5TH SIGNAL DETECTION, ROOT CAUSE ANALYSIS AND CAPA SUMMIT
The 5th Signal Detection, Root Cause Analysis and CAPA summit taking place
January 22-23, 2015, will address the main considerations for implementing a pre-
market CAPA system that ensures quality in clinical operations and addresses post-
market CAPAs that touch upon risk assessment and post-market surveillance in
order to support product safety and compliance. This unique event is designed to
help all life science organizations gain insights on how to develop corrective action
plans and tremendously improve proactive preventive plans.
Please visit www.exlevents.com/CAPA to learn more!
PROACTIVE GCP COMPLIANCE ONLINE DISCUSSION GROUP
Discuss the topics addressed during this conference as well as other GCP-related
subjects by becoming a member of the Proactive GCP Compliance LinkedIn®
Discussion Group. With close to 2000 members, this active group offers a valuable
forum for learning from and engaging with like-minded professionals all focused on
optimizing clinical quality management and improving clinical performance. Use
this forum to ask questions, share best practices, link to relevant articles and white
papers and learn from one another. Click here and request to join.