Managing Risks in Outsourced Clinical Trials 2014

1 ©Copyright 2014 QD-Quality and Training Solutions, Inc. All Rights Reserved©Copyright 2014 QD-Quality and Training Solutions, Inc. All Rights Reserved
Managing Risks in Outsourced Clinical Trials
Liz Wool, CCRA, CMT
President and CEO QD-Quality and Training Solutions, Inc.
©Copyright 2014 QD-Quality and Training Solutions, Inc. All Rights Reserved

2 ©Copyright 2014 QD-Quality and Training Solutions, Inc. All Rights Reserved2 ©Copyright 2014 QD-Quality and Training Solutions, Inc. All Rights Reserved
Disclosure
I have no relevant financial relationship in
relation to this educational activity

3 ©Copyright 2014 QD-Quality and Training Solutions, Inc. All Rights Reserved
Learning Objectives
• Analyze prospectively the risk attributes of the
protocol/investigational plan.
• Identify the industry think tanks that provide
protocol risk assessment tools.
• Describe the areas of risk analysis when
partnering with a Clinical Vendor.

4 ©Copyright 2014 QD-Quality and Training Solutions, Inc. All Rights Reserved4
INSPECTIONS TODAY…
HOW DID YOU MANAGE THE TRIAL FOR QUALITY

DEMONSTRATE PROVIDING
EFFECTIVE TRIAL OVERSIGHT

FDA: Sponsor Oversight of CROs
• Delegation of Monitoring Responsibilities to a CRO:
Sponsor Oversight of CRO (think also CRO
management of their ‘subcontractors ’)
– Compliance with regulatory requirements,
ongoing manner (aka: GCP, HSP, investigational
plan, etc.)
– Compliance with contractual obligations,
ongoing manner (aka: study plans -quality
standards, SOPs, procedures etc.)
FDA Guidance for Industry – Oversight of Clinical Investigations-A Risk Based Approach to Monitoring,
August 2013

• Delegation of Monitoring Responsibilities to a CRO:
Sponsor Oversight of CRO (think also CRO
management of ‘subcontractor ’)
– Methods (a few examples by FDA)
• Sponsor periodic review of monitoring visit reports
• Vendor performance assessment
• Vendor quality metrics
• Documented communication regarding monitoring
progress and findings
• Sponsor share risk assessment information with CRO
• *Refer to Guidance for additional details
FDA Guidance for Industry – Oversight of Clinical Investigations-A Risk Based Approach to Monitoring,
August 2013
FDA: Sponsor Oversight of CROs

Oversight of CROs and Vendors
• What is Your ‘quality management system and
quality monitoring program’ for the trial? Sponsors:
Your Vendor?
• Do you assess risks with your vendors– even your
preferred vendors?
• What is your Vendors QMS and Quality Monitoring
program? Do they have a risk management
framework? Their business? Their programs? Their
sub-contractors?
– Apply to applicable vendors, contractors,
consultants
– Example: CRA Assessment visits (CRA
Supervisor,
» Performed, documented, additional support
to CRA (re-training), or???
Ohiodentures
http://www.riskmanagementmonitor.com

Foundational Principles
Quality Framework
Risk Management Framework

©2014 Metrics Champion Consortium, All rights reserved
Oversight Strategy and Methods

Quality Definition
• ISO 9000
– The quality of something can be
determined by comparing a set of
inherent characteristics with a set
of requirements.
– The work that is performed and
delivered
– To the requisite reference standard (s)
– If those inherent characteristics
meet all requirements, high or
excellent quality is achieved.
– If those characteristics do not meet
all requirements, a low or poor
level of quality is achieved.
Adapted from http://www.praxiom.com/iso-definition.htm#Quality and
https://www.iso.org/obp/ui/#iso:std:iso:9000:ed-3:v1:en

GCP Quality Management System
“Building Quality Into the Clinical Program”
GCP
Process Performance –Systems, Processes, Documentation to “Quality Standards”
Quality-Performance Monitoring System (QC/QA)
Corrective & Preventive Action (CAPA) System
Change Management System, CQI, Document Control
Management Review: On-Going Acceptability of the QMS
Management Responsibilities
Quality Culture, Policy , Objectives
Resources
Quality Commitment: All Staff
Knowledge Management
Risk Management
Study
Start Up
Data Analysis,
CSR
Study
Conduct
Study
Close-Out
Protocol Design &
Operational Design
Study
Planning
POST
Marketing
Enabler
Investigational Product-Device
Enabler
QMS
Elements
QMS
Elements
Marketing
Application

Protocol
(Plan)
- assess key risks
(likelihood, impact)
- plan mitigation
- plan evaluation
Operations
(Do)
- organization, training,
systems and procedures
tailored to the protocol
Monitoring
(Check)
- measure and evaluate
performance
Make improvements
(Act)
- re-assess risks
- make appropriate changes
to protocol, operations or
monitoring
Dr. Christina Reith
CTSU, University of Oxford
CTTI 2013
Quality by Design- Translated!

Risk Definitions
*
Effect of uncertainty on objectives ISO 31000
Objectives (protocol, business, organization) are influenced by
internal and external factors which create uncertainty in
achieving those objectives. The effect of this uncertainty is “risk”
to the organization’s objectives.
An uncertain event or condition that, if it occurs,
has a positive or
negative effect on one or more project objectives
such as scope, schedule, cost, or quality.
PMBOK
Probability-Impact-Detectability

ISO 31000 OverviewISOPRINCIPLE
Provide
foundation and
describe the
qualities of
effective risk
management
in the
organization
FRAMEWORK
Manages the
overall process
and its full
integration
into the
organization
PROCESS
Process for
managing risk
focuses on
individual or
groups of risks,
their
identification,
analysis,
evaluation and
treatment
MONITORING AND REVIEW, CONTINUAL
IMPROVEMENT AND COMMUNICATION OCCUR
THROUGHOUT THE PROJECT

Principles
Clause 3
Mandate &
Commitment
Design of the framework:
manage risks
Framework
Clause 4
RM Process
Clause 5
Implementing
risk
management
Monitoring and
review of the
framework
Continual
improvement of
the framework
Establish the
context
Communicateandconsult
Monitorandreview
Risk identification
Risk analysis
Risk treatment
Risk evaluation
Risk assessment
• Creates value
• Integral part of
organizational
processes
• Part of decision
making
• Explicitly
addresses
uncertainty
• Systematic,
structured and
timely
• Based on best
available
information
• Tailored
• Takes human and
cultural factors
into account
• Transparent and
inclusive
• Dynamic, iterative
and responsive to
change
• Facilitates
continual
improvement and
enhancement of
the organization
P
D
C
A
ISO 31000:2009 Risk Management Principles

ISO 31000 Context for Risk:
Structured Approach
External
Legal
Regulatory (regulatory agencies/HA)
Financial ($$ for the entire program,
currency exchange rates)
International, national, regional or local
(local requirements)
Relationships with perceptions and
values of external stakeholders (‘wall
street’, private investors, patients,
Internal
Organizational
objectives
Project, process, or activity objectives
(e.g., protocol design, operational
design)
Policy, standards, guidelines, quality
plans, etc.
Contractual relationships
RM Process
Objectives, scope,
responsibilities,
methods
Defining risk
criteria –
measures,
tolerance levels,
views of
stakeholders

People &
Site
Resources
Operations,
Standards,
Processes
Technology

Positive Risk
• Occurrence may have a
positive impact on the
project.
– Managing budget risks:
• Purchase of study materials
in bulk- save $$
• Is there a negative risk at all?
– Rapid enrollment
• Positive risk –we hit
enrollment early!
• Negative risk- do you
evaluate these at all?
Negative Risks: Failures
• Occurrence may have a
negative impact on the
delivery of the project.
– Protocol design
– Operational design
– Investigational Product
– Trial Execution
• Randomization
• Blinding Study Procedures
• GCP non-adherence
• HSP non-adherence
Risks

Analyze Prospectively Risk in the
Protocol – Investigational Plan

Investigational Plan- Protocol
• Methodologies are embedded in risk based monitoring
regulatory agency communications (FDA, EMA, MHRA),
industry publication and presentations, industry think tanks
– Strengths: Reference starting point for industry, per
clinical trials
– Weaknesses:
• Some do not present materials with a systematic
approach to managing risk as a ‘framework,
discipline’, with the goal of continuous improvement
over time, varied terminology and approaches, ‘in
it’s infancy’, EU regulatory agencies communicate
gaps with current published methods, companies do
not focus on saying ‘what else do we need to
assess’?
• Low budgets, limited resources – how do I do this?

Investigational Plan- Protocol
• Methodologies are embedded in risk based monitoring
regulatory agency communications (FDA, EMA, MHRA),
industry publication and presentations, industry think tanks
• Solutions: Reference and learn risk management first!
– ISO 31000 Risk Management Principles
– ISO 31010 Risk Assessment Techniques
– Normalize terminology from risk management methods to
what clinical research is using to implement risk
management
• Solutions: Implement a Quality Management Approach
– Quality Management Plans
– Protocol Quality Plans
– Vendor Oversight Plans
– Mapping out the trial
» Processes: solely owned, shared processes

Industry Think Tanks Risk Assessment Tools
CTTI QUALITY BY DESIGN WORKSHOPS PROJECT
CRITICAL TO QUALITY (CTQ) FACTORS
CTTI REMINDER:
This document is intended to
be a discussion tool, not to
serve as a checklist.
http://www.ctti-clinicaltrials.org/files/documents/QRMworkshop-PrinciplesDoc.pdf

http://www.ctti-clinicaltrials.org/files/documents/QRMworkshop-PrinciplesDoc.pdf
CTTI REMINDER:
This document is intended to
be a discussion tool, not to
serve as a checklist.
CTTI QUALITY BY DESIGN WORKSHOPS PROJECT
CRITICAL TO QUALITY (CTQ) FACTORS

http://www.transceleratebiopharmainc.com/rbm-resources/

http://www.transceleratebiopharmainc.com/rbm-resources/
Training Available on Website

Consolidated Recommendations

• Study risk assessment should
occur in parallel to protocol
development
• Focus on Critical to Quality
• Focus on Critical to Participant
Safety
• Focus on Critical to Human
Subject’s Protection
• Don’t forget: Focus on Critical to
Success for your Organization
• “Focus on ‘errors that matter’ to
the above

• What question is the protocol
looking to answer? (e.g. null
hypothesis?)
• What can wrong?
• What must go right?
• What is the probability?
• What is the impact –
consequence?
• How will the error be
detected?
• “What is really important”?

• Stage of the Study
• Study Planning
– Organizational experience
– Personnel expertise, experience
– Feasibility: Study, Site
– CI-Site experience
– Population: complexity
– Accrual
– Budget
– Regulatory authorities
– Geography: standards of care,
ethical approvals, experience
– Tap into ‘historical data,
evidence’
Analysis
Def: The study of
separate parts of a
problem or
compound to learn
more or decide on
action

• Study Planning
– Feasibility: Study, Site
– Therapeutic Area
– Study Population
– Accrual
– Budget
– Protocol design & complexity:
eligibility criteria, data quality,
endpoints, complexity of
procedures supporting the
endpoints and data integrity,
type of controls,
randomization, blinding
Analysis
Def: The study of
separate parts of a
problem or
compound to learn
more or decide on
action

• Study Planning
– Patient safety:
informed consent,
withdrawal criteria and
subject retention
– Novel product, label
extension
– IP: dosing,
administration,
stopping rules, de-
escalation rules,
logistics and supply
chain
Analysis
Def: The study of
separate parts of a
problem or
compound to learn
more or decide on
action

• Study Conduct
– Technology (EDC, e-PRO,
IWRX etc.)
– Training: all stakeholders
– Data collection, CRF
source, recording and
reporting
– Data monitoring and
management
– Statistical analysis
• Post - Study Reporting
– Clinical Study Reports
– Protocol/Trial Registry
requirements
Analysis
Def: The study of
separate parts of a
problem or
compound to learn
more or decide on
action

Risk Analysis with Vendors
In addition to the protocol/investigational plan…

Vendor Risk Analysis
• Trial’s operational complexity?
• Does your vendor selection program include a risk
assessment ?
• Are you performing a risk assessment of your vendors for
your trial?
– New ?
– Preferred Providers?
– Used before?
• If not, why not?
• What variables change from study to study – that
necessitate a risk assessment?
• How do you collect, retrieve and analyze performance
information of your vendors if you use them a lot or they
are a PP?
– Prior to the next contract!

CTTI Recommendations..

QD-QTS Tool: Clinical Trial Schema

Trial Processes and Procedures
• Solely owned
• Shared
• New and distinct process for the trial
– Adjudication Committee – blinding the data
• Training
• *Test Cases* - validate methods
– Perform QC, Sponsor Oversight QC
http://visualmapper.blogspot.com

Trial Processes and Procedures
• Map out for each trial:
– What are the controls/plan for
quality and managing risk?
• SOPs, procedural
documents, forms, tools
• Study Plans
• Data handling and controls
• Communications
• Documentation
• Periodic QC
• Sponsor Oversight
• Training
http://www.modernanalyst.com

Summary
• Internal assessments:
– Quality Management System
– Risk Management Approach and
Framework
– Sponsor and vendors:
organizational and professional
experience and capabilities
– Educating, equipping and
mentoring staff
• Implement/augment your QMS, RMF
• Utilize regulatory agency documents
and industry think tank tools as ‘a
starting point’ and augment for your
organization’s needs
www.Dreamtimes.com

HOW DID YOU MANAGE THE TRIAL FOR QUALITY

DEMONSTRATE PROVIDING
EFFECTIVE TRIAL OVERSIGHT

Questions & Discussion
44

Learning Objectives
• Analyze prospectively the risk attributes of the
protocol/investigational plan.
• Identify the industry think tanks that provide
protocol risk assessment tools.
• Describe the areas of risk analysis when
partnering with a Clinical Vendor.

References
• Kleppinger, C., Ball., L., Building Quality in Clinical Trials
with Use of a Quality Systems Approach, Clinical
Infectious Diseases, 2010:51 (S1): S-111-S116
• Meeker-O’Connell, A., Ball, L., Current Trends in FDA
Inspections Assessing Clinical Trial Quality: An Analysis of
CDERs Experience, FDLI, March/April 2011
• Ball, L., Defining Quality in Clinical Trials: An FDA
Perspective, DIA Annual Meeting, 2012
• Wool, L., Intertwining Quality Management Systems with
Metrics to Improve Trial Quality, The Monitor, August,
2012

• Assuring Data Quality and Validity in Clinical
Trials for Regulatory Decision Making: Workshop
Report, IOM 1999 at http://www.iom.edu/CMS/3740/5583.aspx
• ICH Q9 Quality Risk Management
• EMA Reflection Paper on Risk Based Quality
Management in Clinical Trials, 2013
• FDA Guidance for Industry – Oversight of
Clinical Investigations-A Risk Based Approach to
Monitoring, August, 2013
References

• MRC/DH/MHRA Joint Project, Risk – adapted
approaches to the Management of Clinical Trials
of Investigational Medicinal Products, 10Oct2011
• MHRA: GCP Risk Based Inspections
• A structured approach to Enterprise Risk
Management (ERM) and the requirements of ISO
31000, airmic, alarm & IRM
• Huckvale, T. and Ould, M, Process Modeling –
Who, What and How: Role Activity Diagramming,
in Business process change : concepts, methods,
and technologies, Grover, V. and W. J. Kettinger,
(Eds), Harrisburg, Pa. Idea Group Pub. 1995.
References

Back Up Slides

Additional Free Resources: Vimeo; YouTube
http://vimeo.com/79997443

• Quality design and
deployment to meet work
product requirements
• Quality Standards to meet
expectations of customers
• Production, Calibration
• Personnel accountability
• Quality Control
• Quality Assurance
• Continuous
Improvement
• (Plan, Do, Check, Act)
• Personnel jobs and their
talents aligned with job
function and requirements
• Training targeted and current
for the job description
• Communication
• Facilities & Equipment
provided to do the job
• All employees engaged in
quality culture
• Quality Policy
• Quality Objectives
• Quality Planning/Plans
• Decision Making
• Issue Escalation
• Resources
• Commitment
Management
Responsibility
Resource
Management
Quality by
Design and
Work Product
Measurement,
Analysis,
Improvement

Managing Risks in Outsourced Clinical Trials 2014

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