Risk-Based
Monitoring
Methodology
These materials were revised September 2014
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Legal Disclaimer
These materials are intended to facilitate and reduce the
burden on clinical trial sponsors and others in training
personnel with regarding to risk-based monitoring
methodologies. Each clinical trial sponsor or other company
engaging in such training activities bears full responsibility for
its own training and accompanying materials to ensure both
the accuracy of the training and materials and compliance
with all applicable local, state, and national laws and
regulations. This training is not intended to replace any indepth training that clinical trial sponsors or others may wish or
need to provide to their personnel or investigator sites to
educate them on required or desirable clinical trial
monitoring methodologies. By using these training materials,
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Material in the training materials may include technical
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Copyright ©2014 TransCelerate BioPharma Inc.,
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Module Content
1
INTRODUCTION TO RISK-BASED
MONITORING (RBM) METHODOLOGY
2
RISK ASSESSMENT
3
RISK MANAGEMENT
4
RBM AND CHANGE MANAGEMENT
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Module 1 Objectives
AT THE CONCLUSION OF THIS
SECTION, ATTENDEES WILL BE
ABLE TO:
1. Explain the rationale for Risk-Based
Monitoring (RBM)
2. Describe TransCelerate’s founding
principles and key assumptions
3. Describe the Risk-Based Monitoring
(RBM) Methodology as compared
to traditional monitoring methods
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Rationale
for RBM
Module 1: Section 1
What do you think?
Take a couple of minutes and see if you
can name at least three reasons why the
industry’s traditional monitoring approach
may need to be changed.
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Why should the traditional monitoring approach
be changed?
Various Reasons for Change
NEW
TECHNOLOGY
REGULATORY
SHIFT
ADAPT TO
NEEDS
RISK
MITIGATION
SMARTER
RESOURCE
ALLOCATION
COMPLEX
PROTOCOLS
COSTBENEFIT
RATIO
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Regulatory Agencies - Leading the Movement
EMA Draft Reflection
Paper & FDA Draft
Guidance on RBM
(issued August 2011)
FDA Guidance –
Monitoring of
Clinical
Investigations
(retired 2010)
FDA Guidance
provides standards
for minimal on-site
monitoring
CTTI focuses on
clinical trial
monitoring
efficiency and
effectiveness
FDA and
EMA Final
Guidance
on RBM
(issued August
2013)
Formation of
TransCelerate
1988
1996
1998
ICH E6 provides
flexibility in how
trials are monitored
2007
2009
Janet
Woodcock,
FDA, introduces
risk-based
approach
concepts in
clinical research
2010
2011
2009-10
6 FDA sponsor
warning letters
citing “inadequate
monitoring”
2013
2014
FDA supports
TransCelerate with
review of pilot RBM
plans
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RBM Industry Movement
CTTI
FDA Guidance
EMA Reflections Paper
Quality by Design
Quality Clinical Trial Data
– Change approach
– Assess Risk
Risk Based Quality
Management
– No single approach is
appropriate
– Combination of monitoring
activities
– Tailor monitoring approach
– Tailor Monitoring Plan
– Protocol quality impacts
monitoring quality
– Plan
– Adapt
– Build on experience and
advances
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FDA Perspective
“Quality in clinical trials
may be defined by the absence
of errors that matter.”2
1Meeker-O‘Connell
2Clinical
A., Ball L., Current Trends in FDA Inspections March/April 2011
Trial Transformation Initiative (CTTI)
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EMA Perspective
“Application of risk based quality
management approaches to clinical
trials can facilitate better and more
informed decision making [and] better
utilisation of the available resources.”
EMA “Reflection paper on risk based quality management in clinical trials,” November 2013
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Challenge Yourself
The rationale for focusing on RBM includes
which of the following:
A. To increase efficiency
B. To refocus monitoring efforts on areas of greatest
need
C. To update industry practices to make use of
advanced technology
D. All of the above
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Challenge Yourself
Answer Key
The rationale for focusing on RBM includes
which of the following:
A. To increase efficiency
B. To refocus monitoring efforts on areas of greatest
need
C. To update industry practices to make use of
advanced technology
D. All of the above
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Transcelerate’s
Founding Principles
& Key Assumptions
Module 1: Section 2
TransCelerate BioPharma Inc.
Our vision
Our core values
To improve the health of people
around the world by accelerating and
simplifying the research and
development of innovative new
therapies.
Quality, Transparency & Openness, Trust
& Integrity, Collaboration, Courage
Our mission
To collaborate across the global
biopharmaceutical R&D community to
identify, prioritize, design and facilitate
implementation of solutions designed
to drive the efficient, effective and high
quality delivery of new medicines.
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Engages With The Wider Clinical
Ecosystem Globally
INDUSTRY
INITIATIVES
INVESTIGATIVE
SITES
REGULATORY
BODIES
RESEARCH & CRO
COMMUNITY
Strategically focusing
engagement efforts with
selected key stakeholder
groups – the intent is not
to recreate, but partner
whenever feasible.
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TransCelerate Position Paper:
Risk-Based Monitoring Methodology
Promoting risk mitigation and early issue
detection
Leveraging risk-based approaches and
advances in technology
Taking a holistic, proactive approach
through Off-site and Central Monitoring
Implementing targeted On-site Monitoring
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TransCelerate Monitoring Methodology:
Assumptions
1. Central and off-site monitoring
are the foundation
6. RBM expectations can be
formalized in SOPs
2. Monitoring activities are
responsive to issues/risks
7. Methodology applies to all types
and phases of trials
3. Tailor methodology to available
technology
8. Communication plans should be
tailored for efficiency
4. Timely data entry and query
resolution are critical
9. Risk assessments should take
place prior to protocol/CRF
finalization
5. Functional oversight and
documents should respond to
changes/risks
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Quality by Design (QbD) Concepts
PROGRAM &
PROTOCOL DEVELOPMENT
STUDY EXECUTION
QbD
RBM
Build Quality into the scientific and operational
design and conduct of clinical trials to:
Effectively & efficiently answer intended questions about
benefits/risks
Identify fit for purpose data
Focus on key risks to Patient safety & data integrity
Design efficient MP to rapidly detect/correct issues
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TransCelerate RBM Methodology
MONITORING
PLANS
RISK ASSESSMENT
CATEGORIZATION
TOOL
Building QbD
into design &
planning of
trial
Conducting
early and
ongoing risk
assessments
CRITICAL
VARIABLES
Focusing on
Critical
Processes and
Data
Using Risk
Indicators,
Thresholds &
Action Plans
Adjusting
monitoring
activities
based on risks
CROSS FUNCTIONAL
TEAM WORK IS KEY!
Employ best
mechanisms to monitor
the remaining risks
Focus on what
matters
Identify the risks;
mitigate as possible
Target interventions
based on identified
quality issues
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Challenge Yourself
True or False:
RBM is a fixed approach to clinical trial monitoring that
assumes all trials and all data points represent the
same level of risk to product development.
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Challenge Yourself
Answer Key
RBM is a fixed approach to clinical trial monitoring that
assumes all trials and all data points represent the
same level of risk to product development.
This is False.
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RBM Methodology
as compared to
traditional
monitoring methods
Module 1: Section 3
Discussion Point
What does “traditional” monitoring
mean to you?
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Traditional Approach:
On-Site Monitoring
In person evaluation carried
out by sponsor/CRO personnel
at the investigative site location
to:
Identify missing data in source records
and data entry errors in case report
forms
Assess compliance with protocol and
investigational product accountability
Evaluate Investigator supervision
Review essential documents
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Types of Monitoring
Term “Monitoring” is used in different ways
in the clinical trial context
Site Monitoring
Safety Monitoring
Medical Monitoring
Quality Control monitoring by Sponsor and CRO
internal processes and systems
Quality Control mechanisms at site
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How Does RBM Differ from “Traditional”
Monitoring?
Monitoring is customized to sites/trials needs
Schedule is flexible to comply with sites’ needs
Identifies risks proactively
Leverages technology for centralized surveillance
Shares monitoring responsibilities across many
functional areas
Relies more heavily on central and off-site monitoring
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Key Ideas
Monitoring in the RBM Methodology
Monitoring defined by risks
Ongoing Central and/or
Off-site monitoring
activities
Triggered On-site
monitoring
Monitoring is crossfunctional
CENTRAL MONITORING
Remote analysis of aggregated
study data to identify trends/outliers
OFF-SITE MONITORING
Remote assessment of site issues,
data, site performance
ON-SITE
MONITORING
Assessment of site quality
GCP assessment
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Challenge Yourself
Which of the following statements are true when
discussing the concept of centralized monitoring?
(select all that apply)
A. Defined as a remote evaluation carried out by
sponsor personnel or representatives at a location
other than the investigative site.
B. Used to identify unusual distribution of data.
C. Used to identify higher risk sites to target additional
monitoring.
D. Used to ensure routine review of data in near real
time.
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Challenge Yourself
Answer Key
ALL OF THE FOLLOWING statements are true when
discussing the concept of centralized monitoring.
A. Defined as a remote evaluation carried out by
sponsor personnel or representatives at a location
other than the investigative site.
B. Used to identify unusual distribution of data.
C. Used to identify higher risk sites to target additional
monitoring.
D. Used to ensure routine review of data in near real
time.
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Module 1 Summary
Rationale for RBM is driven by industry,
regulatory, risk and technology changes.
TransCelerate’s founding principles and
key assumptions include a proactive
quality by design approach to assess,
mitigate, and manage risks.
RBM is intended to improve upon the
“traditional” monitoring model.
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Module Content
1
INTRODUCTION TO RISK-BASED
MONITORING (RBM) METHODOLOGY
2
RISK ASSESSMENT
3
RISK MANAGEMENT
4
RBM AND CHANGE MANAGEMENT
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Module 2 Objectives
AT THE CONCLUSION OF THIS
SECTION, ATTENDEES WILL BE
ABLE TO:
1. Identify protocol risks
2. Identify Critical Data/Processes for
Risk-Based Monitoring (RBM)
application
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Identifying Risk
for Planning
Purposes
Module 2: Section 1
Background
Risk is defined as the combination of the
probability of occurrence of harm, the
severity of that harm and how easy that
harm can be detected.
For risks there are four major questions:
1. What might go wrong?
2. What is the likelihood it will go wrong?
3. What are the consequences?
4. How easy is it to detect?
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Risk Management Components of the
RBM Methodology - RACT
Early identification of risks is the best way
to manage the situation if a risk “materializes”
IDENTIFYING AND EVALUATING RISKS = RISK ASSESSMENT
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Risk Assessment and Management Components
of the RBM Methodology
WHAT ARE
OUR RISKS?
RACT
WHAT HELPS US
DETECT RISK?
Risk Indicators
WHEN WILL WE
KNOW TO TAKE
ACTION?
Thresholds
HOW WILL WE
RESPOND?
Planned Actions
Critical Data
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Identifying Critical
Data/Processes for
RBM application
Module 2: Section 2
Critical Data and Processes - Definitions
Critical Data …
Critical Processes…
Support primary and key secondary
objectives
Underpin data quality
Critical to subject safety
Underpin subject safety
Support ethical and GCP compliance
Support decision-making about
efficacy of the IP
What are some examples of Critical Data and Critical
Processes in the studies you’ve worked on?
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Activity #1 – Critical Data/Processes (1)
Study Design:
Phase 3, prospective, randomized, double-blind study
Use of G-1517 in Preventing Flares in Patients Initiating
Allopurinol Treatment for Gout
Duration: 16 weeks
Dosing schedule: 1 daily dose based on BMI
Placebo controlled
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Activity #1 – Critical Data/Processes (2)
Primary Objective:
Secondary Objectives:
To evaluate the safety and efficacy of the
addition of G-1517 during the initiation of
allopurinol treatment in order to reduce the
gout flares in patients with previously
diagnosed gout (>1 year) measured over 16
weeks of treatment as assessed by the
Physician.
The secondary objectives are to evaluate
the following in subjects taking G-1517
added on to allopurinol treatment vs.
placebo added on to allopurinol treatment.
The number of gout flares based on subject
assessment.
The percentage of patients with serum uric
acid (sUA) < 6 mg/dl at 16 weeks of
treatment.
The percent change of the sUA from baseline
to 16 weeks of treatment.
Time from baseline to first flare in the
allopurinol + placebo vs the allopurinol + G1517 groups.
Safety assessment of renal function.
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Activity #1 – Identifying Critical Data/Processes
Based on the Sample Protocol
(slides 40 & 41) Determine the Critical
Data and Critical Processes for this
protocol.
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Activity #1
Answer Key
NP-213-100 Critical Data
NP-213-100 Critical Processes
• Physician assessment of gout flare
• Informed Consent
• Subject assessment of gout flare
• Randomization
• Serum uric acid
• Maintaining the blind
• Study medication administration,
compliance and dose modification
• Study medication storage and
management
• Study medication reconciliation
KEY ELIGIBILITY CRITERIA:
• Height/Weight
• Age
• History of gout
• Creatinine clearance
• Study medication dose calculation of
Allopurinol
• AE collection and reporting
• Lab collection, processing and
shipment
• Performance Gout Flare Assessment
• Calculation of BMI
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Identifying Risks:
Program
Are there:
New/unique tools or procedures associated with
the program?
Specific safety requirements or adverse events of
special interest?
Any issues that are unique for the product such as
storage requirements that are potentially difficult?
Risks inherent to the indication and/or therapeutic
area?
Risks from a regulatory perspective?
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Identifying Risks:
Trial-Level
Do the new/unique tools and procedures being used
on this trial differ from standard of care?
Are there unique safety considerations as a result of
comparator drugs or the indication?
Do you have competitive studies that need to be
considered for the study population?
Are there some inclusion/exclusion criteria open to
interpretation or unclear for study staff?
Does the complexity of the study increase risks for
execution?
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Evaluating Risks
Risk ranking is often relative
For example, a risk with a high impact, low likelihood
and high detectability may or may not be prioritized
above a risk with a moderate impact, higher likelihood
and low detectability.
Risk Level may be defined as high,
medium, or low
HIGH
RISK
MEDIUM
RISK
LOW
RISK
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Preventing or Planning For Risks
Elimination of risks is preferable
Not always possible
• Protocol requirements
• Case Report Form (CRF) design
Plan for risks that are not preventable
Risk management: accept or mitigate
• Detection, measurement, and action
Monitoring strategy
WHAT ARE SOME
EXAMPLES OF SITE
RISKS THAT NEED TO
BE MANAGED?
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Risk Assessment and Categorization Tool (RACT)
Documentation
of Critical Data
& Processes
Consistent
Approach to
Assessment
Team alignment on
“what matters”
Each category has a
series of questions
Focused Risk Assessment
Provides examples of high,
medium, and low risks
Output
Determines the Overall
Risk Level for monitoring
activities
Provides direction for
focused monitoring and
mitigation
Assess for impact,
probability and
detectability
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Risk Assessment and Categorization Tool (RACT)
PROGRAM LEVEL
PROTOCOL LEVEL
RACT
RACT
**categories**
Safety
Technology
Study Phase
Medication
Endpoints
Organizational
Experience
Subject Pop.
Blinding
Endpoints
Clinical Supply
Chain
Investigational
Product (IP)/Study
Medication
Technology
Data Collection &
CRF Source
IP/Study
Operational
Complexity
Geography
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Which DATA and processes are critical?
Your car is monitoring itself – how do you avoid being overwhelmed?
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RACT - Discussion Point
When?
During study planning, before functional risk mitigation
plans (Monitoring Plan, Data Plan, Safety Plan, etc.)
are finalized
Who?
A cross-functional group involving various roles and
team members (e.g. Data Managers, Monitors,
Clinical Scientists)
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Activity #2 Identify the Risks for Sample Protocol
1.
Identify 2 or 3 risks that your team
determines to be high
2.
Why do you consider it to be a risk?
3.
Explain the impact if the risk were to turn
into an issues.
4.
Determine the probability of the risk turning
into an issue.
5.
Determine the ability to detect the risk.
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Activity #2 Identified Risks
Dosing of allopurinol
Endpoint Assessment
Multiple factors to determine dosing
There is subjectivity in the evaluation of
endpoints that could lead to variability
in the assessment of the endpoint
Moderate impact on dosing if not
correct
Likely possibility that there will be errors
High possibility of detecting any errors
Variability will have a high impact
It is likely there will be some variability
Variability may be difficult to detect
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Activity #2 Identified Risks
Patient Population
The ability to provide documentation of the
requirement for the diagnosis of gout for more than 1
year. Although the subject may have recall of the
diagnosis, it is doubtful that they would recall the
specific requirements.
The impact could be that the wrong subjects are
enrolled which could affect the efficacy analysis.
It is likely some ineligible subjects may be enrolled.
Enrollment of ineligible subjects may be difficult to
detect.
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Module 2 Summary
Early and proactive identification and
assessment of risks is a core activity of the
RBM methodology.
Risk assessment should focus on the Critical
Data and Processes which have been
identified at the program and protocol
levels.
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Module Content
1
INTRODUCTION TO RISK-BASED
MONITORING (RBM) METHODOLOGY
2
RISK ASSESSMENT
3
RISK MANAGEMENT
4
RBM AND CHANGE MANAGEMENT
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Module 3 Objectives
AT THE CONCLUSION OF THIS
SECTION, ATTENDEES WILL BE
ABLE TO:
1. Define and utilize Risk
Indicators and Thresholds in
decision-making
2. Discuss implementation of
risk mitigation plans
3. Identify site-level risks
4. Describe how to conduct
monitoring activities in the
RBM model – including
central, off-site and on-site
monitoring
5. Describe appropriate
responses to potential issues
and risks throughout the study
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Risk Indicators
and Thresholds in
Decision-making
Module 3: Section 1
Risk Management
Definition
DEFINED BY ICH AS:
The systematic application of quality
management policies, procedures, and
practices to the tasks of assessing, controlling,
communicating, and reviewing risks.
Topic Q9: Quality Risk Management,
International Conference on
Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH)
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Risk Management Components of the
RBM Methodology – Risk Indicators
WHAT ARE
OUR RISKS?
WHAT HELPS US
DETECT RISK?
WHEN WILL WE
KNOW TO TAKE
ACTION?
RACT
Risk Indicators
Thresholds
HOW WILL WE
RESPOND?
Planned Actions
Critical Data
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Risk Indicator - Terminology Review
TransCelerate Definition
Critical Data and other study variables to be assessed
(in many cases by comparing across program /
protocol / country / site)
Working Definition
Variables which are considered to have underlying
influence on the quality of a study or impact on a
subject's safety and are assessed by comparison
across a program, study, country, and/or site
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Risk Indicator Categories and Examples
SAFETY
IP
•Outliers/trends in number of adverse events per subject
visit/site
•Incidence of temperature excursions
RECRUITMENT/DISCONTINUATION
•Number of screen failures compared to average across
sites
ISSUE MANAGEMENT
•Number of deviations per subject visit/site compared to
average across sites
DATA QUALITY
ON-SITE CRA WORKLOAD
ESSENTIAL DOCUMENTS
STAFFING, FACILITIES, SUPPLIES
•Abnormal trend or lack of variability in data
•Amount of data outstanding for verification or review
•Number of overdue or missing documents
•Amount of staff turn-over
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Steps to Identify Risk Indicators
1.
Review the Critical Data/Processes and RACT
2.
Identify the monitoring approach(es) to detect
potential problems
3.
Identify which data will be the signal for the Risk
Indicator
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Risk Management Components of the
RBM Methodology – Thresholds
WHAT ARE
OUR RISKS?
WHAT HELPS US
DETECT RISK?
WHEN WILL WE
KNOW TO TAKE
ACTION?
HOW WILL WE
RESPOND?
RACT
Risk Indicators
Thresholds
Planned Actions
Critical Data
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Threshold - Terminology Review
TransCelerate Definition
The level, point, or value associated with a Risk
Indicator that will trigger an action
Working Definition
A pre-determined number, value, % or range
associated with a Risk Indicator that indicates the
need for a follow-up action
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Threshold Levels
Risk Indicators may have several different
thresholds set
Tools/Systems can be used to display and track
Risk Indicators to compare data:
Within a site
Across all sites
Within countries or regions
Across protocols
Tools/Systems should enable the detection of
issues that require further investigation
THRESHOLD LEVELS
HIGH – Warning range
MEDIUM – Awareness range
LOW – Acceptable range
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Risk Management Components of the
RBM Methodology – Mitigation Actions
WHAT ARE
OUR RISKS?
WHAT HELPS US
DETECT RISK?
WHEN WILL WE
KNOW TO TAKE
ACTION?
HOW WILL WE
RESPOND?
RACT
Risk Indicators
Thresholds
Planned Actions
Critical Data
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RBM Toolkit:
Companion Guide to Risk Indicators
LOW
MEDIUM
HIGH
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Actions: Responses to Thresholds
LOW
MEDIUM
HIGH
ACCEPTABLE/LOW
AWARENESS/MEDIUM
WARNING/HIGH
No action needed
beyond ongoing
monitoring
Expanded central and /
or off-site monitoring to
assess other data
remotely
Contact site to get
additional information
Contact site to get
additional information
Visit site to review
documentation not
available remotely for root
cause analysis
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Sample Decision Tree for Responding to Thresholds
Contact
site to get
additional
info
Assess
other data
remotely
Resolved?
YES
NO
Resolved?
YES
NO
Arrange to
address at
on-site visit
STOP
STOP
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Implementation
of risk mitigation
plans
Module 3: Section 2
What is a Risk Mitigation Plan?
Documented plan
Assigns responsibility
Actions taken to prevent or
decrease the probability of a risk
becoming an issue
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IQRMP: Core of Quality Risk Management
DATA PLANS
OTHER
FUNCTIONAL
PLANS
TRAINING PLAN
IQRMP
QUALITY PLAN
RACT
CRITICAL
DATA
MONITORING
PLAN
RISK
INDICATORS /
THRESHOLDS
MEDICAL
MONITORING
PLAN
STATISTICAL
ANALYSIS PLAN
SAFETY PLAN
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Discussion Point:
Data Management Plan and Risk Mitigation
Describes procedures for:
Data collection
Data review
Data query and resolution
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Discussion Point:
Monitoring Plan (MP) and Risk Mitigation
Defines the baseline monitoring approach.
Details Central, Off-site, and On-site
monitoring activities.
Describes changes to monitoring based on:
Stage of study
Response to risk
Response to issues
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Discussion Point:
Safety Plan and Risk Mitigation
Ongoing review of safety data
Expediting communications for certain events
Evaluating incidence and severity against
existing product information
Thresholds for stopping the study
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Activity #3 Risk Mitigation and Monitoring
Based on one of the risks you previously
identified can you think of a way to
mitigate or monitor the risk?
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Activity #3 Answer Key
Allopurinol Dosing
Mitigation/Monitoring
Provide an example of dose modification .
Training of sites at investigator meeting and Site
Initiation Visit.
Create validations that check the allopurinol dose to
ensure it is within acceptable range.
SDR source to ensure:
• Allopurinol dose modification verification
• BMI was documented to determine the dose administered
• Uric acid level was recorded to measure efficacy
Risk Indicator to identify protocol deviations related to
dosing.
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Activity #3 Answer Key
Assessment of Gout Flare
Mitigation/Monitoring
Primary endpoint based on assessment by licensed
Professional.
Requirement for specific licensure for those performing
assessment.
Use of a scale to provide consistency in assessment.
Training provided on how to perform assessment.
Subject diary to allow timely documentation of
symptoms.
Risk Indicator
Number of missing scales per site.
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Activity #3 Answer Key
Patient Population
Mitigation/Monitoring
Provide details on criteria for definition of Gout.
SDR of medical history to determine subject eligibility
including source for medical history. Prioritize the
criteria most likely to be missed.
Flagging of lab exclusion criteria on lab reports.
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Site-level risk
assessment
Module 3: Section 3
When is Site-Level Risk Assessed?
PRE-STUDY
EVALUATION
SITE FEASIBILITY
ON-SITE
MONITORING
VISITS
ISSUES
MANAGEMENT
TOOL
OFF-SITE
MONITORING
VISITS
SITE
INITIATION
VISIT
ON-GOING SITE
MANAGEMENT
CENTRAL
MONITORING
ASSESSMENTS
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Identifying Risks: Site Level
Will you be using new/unique tools or procedures
required by the protocol?
Are there specific safety requirements or adverse
events of special interest that you need to follow or
collect?
What unique issues do you need to plan for in
managing the product, such as storage requirements
or reconstitution?
Is your staff familiar with the risks inherent to the
indication and/or therapeutic area, is special training
needed?
What are the risks from a regulatory perspective, such
as country level requirements related to
pharmacogenomics sample retention?
WHAT OTHER
RISKS DO YOU
THINK SITES FACE
OR EXPERIENCE?
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Site-Level Risks: Factors to Consider
Principal Investigator
Site Staff
Previous experience / time
available for new trial?
Qualified to perform required
tasks?
Patient population /
competing studies for trial?
Experience / training needs /
time available for new trial?
Support from sub-investigators
/ institution?
Frequency of staff turn-over?
Site Infrastructure
and Organization
Adequate facilities /
calibrated and well
maintained equipment?
Site / institution SOPs and
process documentation?
Site staff reporting structure?
GENERAL RISK ASSESSMENT:
UNIQUE TO SITE-LEVEL RISKS:
1. What might go wrong?
1. What about this specific site might create additional risk?
2. What is the likelihood it will go wrong?
2. What does prior exprience with this site tell us?
3. What are the consequences if it goes wrong?
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Documentation of Site Risk
Expectations of
sites described in:
• Site source documents
Communication
of mitigation and
resolution of risks
documented in:
• Site Contracts
• Site Trial Master Files
• Site Trial Master Files
• Operational Manual,
Pharmacy Manual, Lab
Manual
• Pharmacy Logs
• Responses to Follow-up
letters
• 1572 or equivalent
regulatory agreement
• Previous site performance
metrics
• Protocol and related
training
Specific risks and
related mitigations
found in:
• AE listings
• Communication records:
emails, correspondence,
etc.
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Risk Mitigation
Not all risks require mitigation
When risks require mitigation:
When you do decide to mitigate a risk, what other
site-level risk mitigation factors should you consider?
• Do your SOPs specify actions?
• Is there guidance for the specific risk you are trying to
address?
• Who should be involved at your site?
Propose the best strategy to suit the risk. For example:
• Train for your staff
• Teleconference with study team – especially before you
enroll your first subject if study procedures or inclusion /
exclusion criteria are complicated or new to your staff
• If risk levels are high and mitigation strategies have been
unsuccessful, consider if this study is right for your site
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Monitoring Activities in
the RBM Model Including:
CENTRAL, OFF-SITE, AND ON-SITE
MONITORING
Module 3: Section 4
Key Ideas
Monitoring in the RBM Methodology
Monitoring defined by risks
Ongoing Central and/or
Off-site monitoring
activities
Triggered On-site
monitoring
Monitoring is crossfunctional
CENTRAL MONITORING
Remote assessment of study
& site Risk Indicators
OFF-SITE MONITORING
Remote assessment of site issues,
data, site performance
ON-SITE
MONITORING
Assessment of site quality
GCP assessment
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RBM: Central Monitoring
CENTRAL
MONITORING
Remote evaluation carried out by
sponsor/CRO personnel at a location
other than the investigative site to:
Use analytics to target on-site/off-site monitoring
activities on areas of most need.
Identify unusual distribution of data earlier: trends &
outliers.
Identify higher risk sites to target additional monitoring.
Ensure routine review of data in near real time.
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RBM: Off-Site Monitoring
OFF-SITE
MONITORING
Confirm timeliness and quality of data entry
Review query resolution
Review CRF to check protocol compliance
Confirm site’s completion of previously identified actions
Assess site’s recruitment and enrollment
Monitor for changes in site staff
Monitor delegation of responsibilities
Conduct training
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What RBM Off-Site Monitoring Is NOT
Faxing source documents from sites to
monitors office
Conducting prolonged telephone calls
with sites (e.g. 3+ hours)
Accessing site source data remotely
Calling sites at any time during day
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RBM: On-Site Monitoring
ON-SITE
MONITORING
Informed Consent Review
Eligibility verification
Investigational Product Accountability
Safety Review (AEs / SAEs )
Essential Documents Review (if appropriate)
Protocol compliance-deviations/issue management
F2F Training & Discussions
Source Data Review (SDR)
Source Data Verification (SDV)
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Source Data Verification (SDV)
Transcription Check
Two-way check
(Source to CRF and CRF to Source)
Done on Critical Data only
Amount varies by risk
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Source Data Review (SDR)
Reviewing source documents for important
areas where there is no associated CRF
data field.
Monitoring the site’s Critical Processes.
Not a two-way review of Source to CRF.
Amount of review varies by risk.
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SDV/SDR – What is the Difference?
SDV Transcription Checking
SDR Compliance Checking
Two-way check
Done on Critical Data only
Reviewing source documents for
important areas where there is no
associated CRF data field
Amount varies by risk
Monitoring the site’s Critical Processes
(Source to CRF and CRF to Source)
Not a two-way review of Source to CRF
Amount of review varies by risk
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The value of SDV: Retrospective Analysis
1168 phase I - IV biopharmaceutical
studies across 53 sponsors
1. Only 1% of the total eCRF data corrections were
attributable to SDV
2. AEs / SAEs not initially recorded in the eCRF
(temporal relationship to SDV):
AEs: Overall industry median values: 7.5% (<=1 day) and
11.8% (<=7 days).
SAEs: Overall industry median values: 1.7% (<=1 day) and
3.6% (<=7 days).
SDV can be safely reduced / eliminated; to be set at a level
to ensure that minimum transcription expectations for data
accuracy have been met (visit data)
Evidence supports using SDR to detect missing events (event
data)
Literature review,
retrospective analysis
and audit data review
by TransCelerate
overwhelmingly
supports shifting
monitoring resources
to focus on SDR (to
monitor the protocol,
not just the data) and
to employ central
monitoring (to trigger
the need for SDV / SDR
to assess low event
reporting at sites)
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Retrospective Analysis – Additional Insight
4%
100%
32% of data
corrections
from SDV
3%
80%
2%
60%
1%
40%
96.3% of data is
never corrected after
entry to database
20%
0%
Corrected
data
SDV
Other corrections DM Queries etc.
System checks (auto query) System Queries
0%
N=1168
Changed data
Never corrected
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Challenge Yourself
True or False:
The TransCelerate RBM methodology improves
efficiency by changing the focus to Central or Off-site
monitoring activities that have the potential to identify
issues earlier than a monitoring strategy that relies
primarily on a fixed on-site monitoring schedule.
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Challenge Yourself
Answer Key
True
The TransCelerate RBM methodology improves
efficiency by changing the focus to Central or Off-site
monitoring activities that have the potential to identify
issues earlier than a monitoring strategy that relies
primarily on a fixed on-site monitoring schedule.
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RBM Monitoring is Cross-Functional
Data
Management
Central
Monitoring
Off/On-site
Monitoring
Aggregated topical
review to ensure data
is analyzable
Surveillance
Process Compliance
(GCP, ICH, Protocol)
Holistic data review
(clinical & operational)
to identify protocol
compliance issues,
outliers, and trends
SDV, SDR
COMPREHENSIVE MONITORING (RBM)
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How Does RBM Affect My Role?
STUDY TEAM:
Project Manager, Stats, Data
Managers, Medical Monitors,
Pharmacovigilance/Safety
• Defines essential data and
study priorities
• Evaluates and mitigates risks
• Provides in-stream data and
reports
SITE FACING ROLES:
Monitor/CRA, Site Managers
• Assess site for quality of
performance - use sound
judgment to adjust type &
frequency of engagements
• Merges RBM principles with
site interactions
• Training
SITE STAFF
• Takes accountability for site
quality
• Embraces RBM to enhance
compliance and accuracy
of data
• Enters data into eCRF in
near real time
• Identifies trends
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Responses to Potential
Issues and Risks
Throughout the Study
Module 3: Section 5
Steps in Issue/Risk Response
IDENTIFY
ISSUE
DETERMINE
CAUSE
IMPLEMENT
SOLUTION(S)
EVALUATE
EFFECTIVENESS
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RBM: Central Monitoring
Performed by Central Monitors
Identified issues tracked (e.g. issue management tool, tracker)
Variable frequency determined by study needs
Documentation management per study file
requirements (best practice)
1. Generate
reports to
assess/Visualize
Risk Indicators
2. Investigate the
data further to
assess trends and
outliers
3. Determine if
trends, outliers
are issues
4. Report issues to
the appropriate
study role (Site,
Country, Study)
5. Escalate as
needed, Resolve
and Document
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Group Challenge: #1
Reminder:
An investigational product (IP) is known to be
associated with elevated liver enzymes (ALT and AST)
in some subjects. Therefore, all protocols for this IP
require investigators to perform re-tests whenever the
ALT or AST values from the central lab are > 2 times the
upper limit of normal (ULN).
RISK INDICATOR =
COMPARISON ACROSS
SITES FOR NUMBER OF
MISSING REQUIRED
RE-TESTS
(i.e., when ALT/AST > 2 x ULN)
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Group Challenge
Potential Issue/Risk
Central lab data is analyzed and shows:
The average number of missing required retests/active site = 6.7
The average incidence of elevated ALT/AST values
requiring re-test/active site = 10.3
At six of the twenty active sites, the average number
of missing required re-tests is at least 15% higher than
the overall average of 6.7
WHAT ARE THE
POTENTIAL ISSUES /
RISKS WE CAN
IDENTIFY FROM
THIS DATA?
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Group Challenge
Issues/Risks Answer Key
IDENTIFY
ISSUE/RISK
High overall average rate of missing
required re-tests.
6.7 missed out of 10.3 incidence
6 sites have higher than average number
of missing required re-tests.
WHAT ARE THE
POSSIBLE CAUSES
OF THESE POTENTIAL
ISSUES/RISKS?
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Group Challenge
Root Causes Answer Key
DETERMINE
CAUSE
Unclear expectations
Reporting issues
Subject compliance
Training gap
WHAT ARE THE
POSSIBLE SOLUTIONS
TO ADDRESS THE
ISSUES/RISKS?
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Group Challenge
Solutions Answer Key
IMPLEMENT
SOLUTION(S)
Decision tree tool for re-testing
Lab reports to include “re-test flag”
Subject travel stipend for re-test visits
Training materials
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Group Challenge
Evaluate Effectiveness
EVALUATE
EFFECTIVENESS
Continue monitoring the Risk Indicator
Reduction in average number of missing required
re-tests/active site.
Reduction in average number of missing required
re-tests for the 6 “outlier” sites.
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Off-Site Monitoring Activities
Site-level assessment conducted by Site Monitors.
Interpretation of information to determine if a site
intervention is needed.
Call, email or on-site visit
Variable frequency determined by study/site needs.
Documentation per company reporting requirements.
Gather available
information
(e.g. issues identified
by central monitor, site
enrollment etc.)
Confirm whether
potential issues
are actual issues
(Not every outlying
variable = a problem)
Document the
assessment and
any intervention
Communicate/
Escalate as
needed
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Group Challenge - #2
You are the monitor for NP-2013-100, for Dr.
Smith (Site #012).
You completed the first two on-site visits as
required by the monitoring plan (MP) and did
not identify any substantial issues.
The site has treated 10 subjects and the staff are
very experienced.
Subsequent on-site visits will only be triggered
by central review and off-site monitoring
assessments.
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Group Challenge
Issues/Risks Answer Key
IDENTIFY
ISSUE/RISK
You receive an alert from the central
review that Site #012 (Dr. Smith) has a
higher rate of SAEs than other sites in
the study.
WHAT ARE THE
POSSIBLE CAUSES
OF THESE POTENTIAL
ISSUES?
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Group Challenge
Root Causes Answer Key
DETERMINE
CAUSE
Safety Issue
Training gap
WHAT MIGHT YOU
DO FIND OUT MORE
ABOUT POTENTIAL
ROOT CAUSE?
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Group Challenge
Further Investigation
You obtain an “AE Supplemental Data Report”
and generate the following data Site #012:
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Group Challenge
Further Investigation
In your telephone discussion with the
coordinator (Jane) you learn that she is a
new study coordinator who has recently
joined the site. She was not aware that AE
symptoms should be grouped and reported
as a single AE (syndrome) and you
provided this clarification.
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Group Challenge
Root Causes Answer Key
DETERMINE
CAUSE
Safety Issue
Training gap
WHAT ARE THE
POSSIBLE SOLUTIONS
TO ADDRESS THE
ISSUES/RISKS? WHAT
ACTIONS WILL YOU
TAKE?
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Group Challenge
Solutions Answer Key
IMPLEMENT
SOLUTION(S)
Provide training and/or training materials
to site
During a call you provide training relative to the
definitions of AEs and SAEs.
While you are defining SAEs, Jane states, “Wow, we
might have had a couple of those, but I can’t
remember now which subject it might have been.”
WHAT ADDITIONAL
ACTION WOULD
YOU TAKE?
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On-Site Monitoring Activities
Conducted by Site Monitors/CRAs
SDR of selected subjects to identify
unreported events
Documentation per company reporting
requirements
Determined by
monitoring plan;
targeted visits by
off-site/central
monitoring
Investigate to
confirm if actual
issues and identify
root cause
Perform
appropriate
intervention (e.g
training, process
revisions)
Communicate/
Escalate and
document as
required
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Group Challenge
Solutions Answer Key
IMPLEMENT
SOLUTION(S)
You determine that a
targeted on-site visit is
needed to perform additional
SDR to address the potential
for unreported SAEs and
reinforce the training.
You also schedule time to
speak with Dr. Smith to discuss
investigator involvement with
assessment of AES, the issue of
unreported SAEs and staff
training.
You document a protocol
deviation for the events that
are identified that were not
reported in a timely manner
You escalate to the study
manager, medical monitor
and line manager to
determine additional action
to be taken.
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Group Challenge
Evaluate Effectiveness
EVALUATE
EFFECTIVENESS
What are your next steps?
Continue monitoring the Risk Indicator.
Increased SDR? How will you go about selecting the
additional charts to review for unreported SAEs?
For how long?
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Make The Decision: Which Decision?
The bottom line is:
The decision to go to the site should be either required
by the monitoring plan (MP) or supported by a need
that cannot be adequately managed off-site.
TO GO OR NOT TO
GO… THAT’S THE
QUESTION.
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Issues/Risks Identified During the Study
Communication Plan
Risk Management Log
Describes the pathway for
communicating and escalating issues
A tool used by the cross-functional
team to track and monitor risk
management, including the progress
and actions relating to identified risks
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Module 3 Summary
Risk Indicators and Thresholds
Risk mitigation plans
Site-level Risk Assessment
Monitoring activities in the RBM model
including: central, off-site and on-site
monitoring.
Responding to issues and risks
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Module Content
1
INTRODUCTION TO RISK-BASED
MONITORING (RBM) METHODOLOGY
2
RISK ASSESSMENT
3
RISK MANAGEMENT
4
RBM AND CHANGE MANAGEMENT
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Module 4 Objectives
AT THE CONCLUSION OF THIS
SECTION, ATTENDEES WILL BE
ABLE TO:
1. Discuss considerations with
implementation within an
organization and at sites
2. Describe metrics used to measure
the impact of the proposed
methodology
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RBM Implementation:
ORGANIZATIONAL CHANGE
MANAGEMENT
Module 4: Section 1
Areas of Implementation
GLOBAL/REGIONAL
COMPANY
INVESTIGATOR
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Challenges with Change
Cultural
We’ve always done it this way
Systems
The systems we have require
that we do it this way
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Global/Regional Considerations
Regulatory authority perspective
Acceptance by ethics committees
Language and Cultures
Availability and use of technology
Research infrastructure
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Company Considerations
SOPs may be complex or not easily
changed
Resourcing
Change management support
Technology and systems
Strategic partnerships
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Investigator Considerations
Institutional SOPs
Resourcing
Technology
Contract/budgeting
CAN YOU THINK OF
ANY ADDITIONAL
CHALLENGES THAT
MAY BE
ENCOUNTERED WITH
SPECIFIC SITES OR
INVESTIGATORS?
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RBM Impact on Sites
EARLY
IDENTIFICATION
OF ISSUES, TRENDS
& OUTLIERS
Queries in real time
PATIENT SAFETY &
DATA INTEGRITY
MAINTAINED
Prevent recurrence
of errors
SITE OWNERSHIP
OF DATA
QUALITY
A VARIETY OF
MONITORING
TECHNIQUES
Timely CRF data
entry
On-site and Off-site
monitoring
Site inspection
readiness
Centralized
monitoring
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RBM Site Advocacy Group Feedback
RBM Methodology
Because sponsors have not shared with you how they will be
implementing RBM, plus experience to date with “remote” monitoring
approaches, you feel uninformed and vulnerable.
Perception or assumption that sponsors are shifting the burden of
monitoring / work from themselves to the sites, e.g. fax documentation
to both sponsors and CROs.
This “extra work” was not foreseen and not budgeted.
Some sites are currently using their own risk assessment methodology, it
is unclear as to how the site’s methodology will integrate with the RBM
approach.
Sites are eager to understand and learn the RBM process and want to
be trained.
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RBM Site Advocacy Group Feedback
Communication
With RBM and reduced on site time / checking, quality will
decrease.
There is a need for sites and sponsors to more proactively
share risk assessment and management strategies.
Questions to study staff are not always answered in a timely
fashion by a knowledgeable source. Prefer single/dual
point of contact with the CRO/sponsor.
Technology and number of vendors can create additional
complexity, e.g. – study portals.
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Benefits for Investigative Sites
Subject safety is maintained
Problems are solved before they recur
Personnel can focus on core job functions
Investigative sites are inspection-ready
Site quality is enhanced
Timely decision-making and
communications
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Challenge Yourself
Which of the following statements reflects a
potential impact to investigative sites from the
adoption of Risk-Based Monitoring (RBM)?
(select all that apply)
A. Sites will no longer be required to accommodate on-site
monitoring.
B.
Sites may be expected to audit or perform quality checks
on their own data.
C. Sites will be required to attend daily teleconferences with
sponsors to discuss central monitoring findings.
D. Sites can expect a greater use of technology and
electronic systems in clinical trials.
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Challenge Yourself
Answer Key
Which of the following statements reflects a
potential impact to investigative sites from the
adoption of Risk-Based Monitoring (RBM)?
(select all that apply)
A. Sites will no longer be required to accommodate on-site
monitoring.
B. Sites may be expected to audit or perform quality
checks on their own data.
C. Sites will be required to attend daily teleconferences with
sponsors to discuss central monitoring findings.
D. Sites can expect a greater use of technology and
electronic systems in clinical trials.
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Time For Reflection
What are the challenges with RBM
implementation facing your specific
role?
Can you identify any tools, systems,
or strategies to help manage these
challenges?
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Summary of Organizational Change
Management Considerations
Apply Risk Indicators/Thresholds on new or
existing tools
Enhance existing reporting systems
Develop RBM-specific training for sites
Develop Advanced EDC training
Provide scenario-based training for monitoring
personnel in regards to evaluating Thresholds
and responding to issues
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Metrics to Measure
Impact of the RBM
Methodology
Module 4: Section 2
Defining Metrics
Standards of measurement by which
efficiency, performance, progress, or
quality of a plan, process, or product
can be assessed.1
• Measurement
• Applied to quantifiable aspect of performance
• Used for decision-making
1Source:
BusinessDictionary.com
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Evaluating RBM
Dimensions to Assess
QUALITY
TIMELINESS /
CYCLE TIME
EFFICIENCY
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Evaluating RBM
Possible Quality Metrics:
Number and classification of
major/critical audit/inspections findings
per audited site
Number of significant protocol
deviations per site
Number of unreported, confirmed SAEs
as discovered through any method
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Evaluating RBM
Possible Timeliness /
Cycle Time Metrics:
Average number of days from data
entry to initial monitoring
Median number of days from visit to
CRF data entry
Median number of days from query
open to close
Median number of days from issue
open to close
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Evaluating RBM
Possible Efficiency Metrics:
Average monitoring (all types) cost
per site
Average interval between On-site
Monitoring visits per site
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Module 4 Summary
Successful transitioning to the RBM
methodology requires
Understanding and preparing for potential
challenges
Strategies to measure the impact of RBM
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RBM Methodology
Key Concepts
Focus on Central and/or Off-site
monitoring activities
Identify and resolve issues more quickly
Focus on errors that matter
Related to subject safety, data integrity, and/or
regulatory compliance
Reinforce Investigators’ responsibility
for data quality
Partners with the Sponsor to address, resolve, and
prevent issues
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Summary
RBM will refocus monitoring
Source to CRF checking does not effectively find or
resolve issues
Prioritizes monitoring focus on protocol compliance,
safety and data integrity at the site and patient level
Focus only on the data and processes that matter
Identifies when sites need more attention
RBM ENABLES A
BETTER WAY!
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THANK YOU!
Q&A
Key Takeaways
What are your key
takeaways from the
workshop?
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Links
TransCelerate Home Page
http://www.transceleratebiopharmainc.org
FDA Guidance for Industry Oversight of Clinical Investigations
- A Risk-Based Approach to Monitoring [Final].
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM269919.pdf.
EMA Reflection Paper on Risk Based Quality Management in
Clinical Trials (EMA/INS/GCP/394194/2011).
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/
11/WC500155491.pdf
Clinical Trials Transformation Initiative. Effective and efficient
monitoring as a component of quality.
http://www.ctti-clinicaltrials.org/files/documents/MonitoringWS2FinalReport.pdf
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