After reviewing the FDA regulations on Risk Based Monitoring, review the details on how to put the principles into action! We include two reference documents to help you get started... and to make it a success.

1. Presented By
William Gluck, Ph.D.
VP, DATATRAK Clinical Knowledge
DATATRAK International, Inc.
Risk-Based Monitoring in Practice
5/29/2014
1www.datatrak.com

2. Confidential –
Dr. Bill Gluck
► Dr. Gluck has over 30 years of leadership experience in the
Life Sciences industry, and brings his expertise in the field of
Risk Based Monitoring to DATATRAK.
► Dr. Gluck has held management roles in sponsor companies,
including Amgen, BASF Corporation, Gilead Sciences, and
Triangle Pharmaceuticals. Dr. Gluck also has expertise with
CRO organizations, having served in senior management roles
for seven years.
► Dr. Gluck began his career in academia at the university level,
and now serves as the Program Director for the Clinical Trials
Research and Medical Product Safety/Pharmacoviligance
programs at Durham Technical Community College.
► Dr. Gluck has a Bachelor of Science degree from the University
of Scranton and Master and Ph.D. degrees from North Dakota
State University.
2

3. 3
Review of the Risk-Based
Guidance Document
How the Guidance is Re-
Defining How Studies are
Conducted
Insights to
Implementation

4. 4
http://www.fda.gov/Drugs/GuidanceComplianc
eRegulatoryInformation/Guidances/default.htm
History of Guidance Document
• Replaced 1988 Guidance on Monitoring
• New RBM Draft Guidance August 2011
• Final RBM Guidance August 2013

5. 5
Guidance
Document
General
Points:
Guidance focuses on monitoring – only one aspect of the
clinical trial process
Monitoring is a quality control tool
FDA defines monitoring as the methods used for the conduct
of and reporting of data from clinical investigations
Stronger support of risk-based monitoring approaches are
clearly stated
FDA recommends a quality risk management approach to
clinical trials
The risk-based approach is dynamic and can facilitate
continual improvement in trial conduct and oversight
Expect risk-based monitoring to enhance data quality

6. 6
Approaches to
Monitoring
On-Site Monitoring – an in-person evaluation
Centralized Monitoring – a remote evaluation

7. 7
On-Site
Monitoring
Assurance that
subjects and
study documents
exist
Sense of Quality
of overall conduct
at a site
Early in the study
Complete
administrative and
regulatory tasks
Centralized
Monitoring
Remote activities
Targeted on-site
monitoring
Review of data in
real-time
Verify source
data remotely
Conduct
aggregate
statistical analysis
of study data
Conduct analysis
of sites,
performance, and
data
Complete
administrative and
regulatory tasks
Types of Monitoring

8. 8
Centralized
Monitoring:
Alternative
Monitoring
Techniques
Monitor through routine review of entered data
Conduct statistical analyses to identify data trends
Analyze site characteristics, performance measures, and clinical
data to identify potential characteristics associated with
noncompliance and poor performance
Verify critical source data remotely, when source data are
available
Complete administrative and regulatory tasks

9. 9
Alternative
Monitoring
Techniques:
Other
Areas of
Focus
Communication with Study Site Staff
Review of Site Processes and Procedures
a. Informed Consent
b. Site Records
Source DataVerification and Corroboration

10. 10
How the Guidance is Re-Defining
How Studies are Conducted

11. 11
The
Guidance:
Focus on
Monitoring
No single approach works
Tailor monitoring plans to study – focused on
specific subject protection and data quality
Assess critical data and processes – informed
consent and eligibility criteria
Assess critical data and processes – documentation
of accountability and administration of
investigational products
Assess critical data and processes – focus on trial
integrity…processes such as maintaining the study
blind

12. 12
• Overall support and guidance
• Protocol developmentClinical R&D
• Sponsor Team Members
• Sites and Site Team Members
Clinical Study
Team
• Sponsor CRA’s or designated CRO representatives
• Site key personnelCRA/Site
• Clinical Data Management
• Biostatistics
• Regulatory, Quality, Compliance
Support
Services
Key Roles and Responsibilities

13. 13
Insights to
Implementation

14. 14
Risk
Assessment
Identify the risks
Analyze the risk
Implement controls

15. 15
Assessing
Risk for
Monitoring
Guidance
Discusses risk assessment in the context of
clinical monitoring
As noted: identifies analyses, and implements
controls to manage risk
Does NOT provide comprehensive detail on
how to perform risk assessment
Risk
Assessment
Methodologies
Guidance for Industry, Q9 Quality Risk
Management, June 2006.
ISO 31010:2009 Risk Management – Risk
Assessments Techniques
Risk
Identification
for Monitoring
“…consider the types of data to be collected,
the specific activities required to collect these
data, and the range of potential safety and other
human subject protection concerns…”
Assess and prioritize risk:
a. likelihood of occurrence
b. impact on safety and trial integrity
c. extent to which errors would be detectable

16. 16
Factors to
Consider in
Developing
Monitoring
Plans
Complexity of the Study Design
Types of Study Endpoints and Quantity of Data
Clinical Complexity of the Study Population and Geography
Relative Safety of the Investigational Product
Stage of the Study
Experience of the Sites and the Sponsor
Ability of LeverageTechnology

17. 17
Key
Components
of a
Monitoring
Plan
Description of Monitoring
Approaches
Communication of Monitoring
Results
Management of Noncompliance
Ensuring Quality Monitoring
Plan Amendments/History of Plan
Changes or Modifications

18. Confidential – 18
Monitoring Plan Template
Study Protocol:
Stage/Phase of Study:
Introduction:
Brief description of the study landscape – geography of the sites, anticipated reach of the population, potential
challenges in terms of enrollment and compliance by both study participants and sites.
Description of Monitoring Approaches:
Include in this section a description of the monitoring methods to be employed especially noting how the critical
elements/data points/end points will be collected. Note too and risks involved and how these risks might be mitigated
(at a high level). Also include the timing and frequency of the various approaches you are planning and how changes
will be made and communicated through the study team.
In this section also include what the threshold are for action or those specific trigger points that might require a site to
be monitoring on a more frequent basis.
Also include definitions for deviations and how they should be reported and recorded.
Communication Plan:
Describe how reports and monitoring results will be communicated throughout the team. Identify/Define specific
standard reports and how and when they will be generated and then communicated.
Also include an escalation process of communication should the need arise or unforeseen challenges emerge during the
course of the study.

19. Confidential – 19
Management of Noncompliance:
Describe the process for addressing challenges of noncompliance or the resolution of significant issues that have not
yet been resolved. Again build upon the communication escalation process to make sure that there is an escalation
process in place should it be necessary.
As part of the process, in this section you should also describe a procedure to conduct a root cause analysis and how
the issue will not resurface later in the study.
Quality Monitoring Process/Plan:
In this section describe the specific training and qualifications needed of all study team participants from the
sponsor’s perspective through to each site perspective.
Planned audits of monitoring across several levels should be defined as well as a description of the process in case
there is a need for an unplanned or for cause audit.
Also included in this section should be the plan for co-monitoring trips or oversight to ensure consistency of
monitoring and compliance to documented monitoring processes and procedures.
Amendments

20. 20
Additional
Strategies
to Help to
Ensure
Study
Quality
Protocol and CRF Design
Training and
Communication
Delegation of
Responsibilities
Site Selection and
Interaction

21. Confidential –
Sample Risk Assessment Worksheet
21
Risk Assessment
Worksheet
Risk Area/Category Potential Risk Assessed
Risk Examples (list study specific
issues)
Include in
Monitoring Plan
(Yes/No) Tolerance Threshhold

22. Confidential – 22
Risk Area/Category Potential Risk Assessed
Risk Examples (list study specific
issues)
Include in
Monitoring Plan
(Yes/No) Tolerance Threshold
Study Planning
Study protocol development and
related essential documentation
How complex is the protocol,
are there anticipated amendment
points, process of unintended
amendments, process for the
collection, review, and
management of FDA/ICH GCP
related essential documents, etc.
Is there a clear understanding of
roles and responsbilities,
transparancy in communication
and expectations?

23. Confidential – 23
Budgetary constraints
Does the budget allow for
adequate time and resources to
conduct the study, monitoring,
other study activities? Are the
contracts associated with all
supportive facets of a clinical
study available and/or in place?
Is there legal support if
applicable?
Site identification/Feasibility
Based on the study protocol
can sites be easily identified, is
the needed study population
obtainable, are the site reliable
in terms of attracting and
qualifying potential study
participants,etc.
Site Qualifications
Qualifications of the principal
investigator/clinical investigator,
qualificiation of the site overall -
are the proper site processes
and procedures in place, are the
site personnel trained,
experience and qualified, etc.
Vendor Qualifications
Qualifications of the vendor (is
this a core support service),
qualification of the vendor
overall - are the proper
processes and procedures in
place, are the personnel trained,
experience and qualified, etc.

24. Confidential – 24
Study Conduct Quality Management System-Sponsor Level
Is there a sponsor level QMS in place, at the
CRO/support company level, at the site level?
Required Regulatory Reporting
Does the sponsor have the infrastructure to
support the required regulatory reporting
needed? Does the supporting organization
have the infrastructure? Does the site have a
QMS or the essential quality controls in place?
Specific Study Activities
Informed consent process, enforcement of
INC/EXC, handling protocol
deviations/violations, stopping rules, SAE
handling, dose modifications, etc.

25. Confidential – 25
Investigational Product
Is there investigational product in place to conduct the study, is
there a re-supply process, is the supply chain establsied, are there
regulatory risks for international studies/transport/storage of the
investigational product?
Safety Concerns
Study participant protection and well-being
processes/procedures in place, safety monitoring, know adverse
evetns/reactions, process for documetnation and reporting of
unexpected events and SAE's
Study specific tasks
Endpoints, complexity of the study, stage of the study, number of
potential study participants and geographic availability

26. Confidential – 26
Performance Metrics
Time of entry after study participant visit, time of query
resolution/response, etc.
Quality Metrics Number of queries needed, number of re-queries needed, etc.
Biostatistics and CDM concerns
Technology availability and evaluation, quantity of data, clear
identification of endpoints and collection of needed study data,
identification and generation of reports, data transfer, internal
filtering etc., availability and use of standards such as CDISC
(STDM).

27. Confidential –
List of Selected References
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM269919.pdf
http://www.mhra.gov.uk/home/groups/l-
ctu/documents/websiteresources/con111784.pdf
http://www.transceleratebiopharmainc.com/wp-content/uploads/2013/09/Risk-
Based-Monitoring-Methodology-Position-Paper.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline
/2011/08/WC500110059.pdf
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effica
cy/E6_R1/Step4/E6_R1__Guideline.pdf
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Qual
ity/Q9/Step4/Q9_Guideline.pdf
27

28. 28
Summary
1. Risk-Based Monitoring is focused on monitoring
2. Regulatory bodies want to promote flexibility and the ability to
explore new methods for monitoring and to leverage advances
in technology where applicable
3. It is anticipated that there will be continued use of on-site
monitoring but also anticipate the evolving use of technology
and monitoring methodologies to achieve heighted levels of
study participant safety and increased levels of data quality

29. 29
William Gluck, Ph.D.
VP, DATATRAK Clinical Knowledge
DATATRAK
E-Mail: Bill.Gluck@datatrak.com