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This presentation presents best training practices to leverage EDC technology and risk-based monitoring to effectively and efficiently monitor clinical research. Our focus is on the practical process of preparing your team to optimize the tools made available through an EDC solution. This presentation is applicable to CRA’s, clinical project managers, clinical data managers, regulatory compliance professionals, and those involved in the design and implementation of risked-based monitoring plans.
Citation preview
Confidential –
Your Speakers ► Penelope Manasco, MD
• Dr. Manasco‘s clinical research experience spans 25 years at the National Institutes of Health, Burroughs Wellcome, GlaxoWellcome, and GlaxoSmithKline (GSK). Dr. Manasco has also worked as an Investigator, Medical Monitor, Clinical Program Leader, and Pharmaceutical Executive (Vice-President). For the past 12 years, she has focused on enhancing the efficiency of the Clinical Research process through the use of technology and new research methods. She founded MANA Consulting (MANA) in 2012. MANA pioneered remote trial management and Risk Based Monitoring through the use of its Paperless Trials. In 2013, Dr. Manasco worked with a group of clinical researchers to develop Monitor Competencies for Risk Based Monitoring and has released a self assessment of monitor competencies that is offered free to the industry.
► Bill Gluck, Ph.D. • Dr. Gluck has over 30 years of expertise in clinical research, with
experience in sponsors, CROs, and with DATATRAK in a variety of roles. Dr. Gluck is also the Program Director for the Clinical Trials Research and Medical Product Safety/Pharmacovigilance programs at Durham Technical Community College. Dr. Gluck earned his Bachelor of Science Degree at the University of Scranton and Master and Ph.D. degrees from North Dakota State University.
2
Confidential –
Agenda
► The Connection: EDC + RBM
• Guidance Document Review
• Evolving Roles and Skill-Sets
► Leveraging EDC Tools
► Preparing for Risk-Based Monitoring
• Why
• Key Components to Implementing the RBM Approach
• To SDV or Not To SDV……
• New Competencies New Roles
• Remote Review and Assessments
• Optimization through Education
3
Confidential – 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• New RBM Draft Guidance August 2011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
Confidential – 5
Guidance Document Key Points:
Flexibility to choose optimal combination of monitoring strategies
Appropriate use of centralized monitoring and technological advances
Patient safety and rights are critical
Stronger support of risk-based monitoring approaches are clearly stated
See technology as an enabler of risk-based monitoring
Data quality is critical
Expect risk-based monitoring to enhance data quality
Confidential – 6
Approaches to Monitoring
Traditional Clinical/Efficacy Trials – On-Site Monitoring with typically 100% SDV
Government/Academic Studies – Minimal On-Site Monitoring Visits (usually 2-3 per year)
NIH and Outcomes Research Studies - Critical Outcomes Trials: No On-Site Monitoring
Confidential – 7
The EDC Toolbox
Clinical Operations working together with CDM
Focus on critical data
Identify Systemic Issues
Align with the Site Monitoring Plan
Enabler: EDC Tools Targeted Configuration and Functionality to Match Study Designs
Identify and use the tools that are part of the EDC application
Evolving Skill-Sets Learn to Leverage the Tools and technology in the EDC Toolbox
Enhance teaching and communication skills
Confidential – 8
Common Metrics
Completeness
Page Report
Time to Entry
Time to SDV
Time to Sign
Time to Resolve Queries
Quality
Query Counts
Confidential – 9
Implementing A Risk-Based Approach That Optimizes the
Benefits of EDC by Focusing on Education
Confidential –
Quote
“I did then what I knew how to do. Now that I know
better, I do better.”
― Maya Angelou
“The technology itself is not transformative. It’s the
school, the pedagogy, that is transformative.”
– Tanya Byron
10
Confidential –
FDA Guidance For Industry (Aug 2013):
Oversight of Clinical Investigations -
A Risk-Based Approach to Monitoring
The overarching goal of the guidance is “to enhance human subject
protection and the quality of clinical trial data by focusing sponsor oversight
on the most important aspects of study conduct and reporting.”
Despite 100% SDV,
1. Top 10 Pharma cited for inadequate oversight of Study Drug Dosing
2. Top 10 Pharma and CRO cited for not identifying suspected fraud in
study drug administration
FDA
483
11
Confidential –
FDA Guidance For Industry (Aug 2013):
Oversight of Clinical Investigations -
A Risk-Based Approach to Monitoring
► Multiple approaches are acceptable
► FDA Encourages greater use of centralized monitoring
methods (remote data review) where appropriate.
► Focus on the most critical data elements and processes
to achieve study objectives.
• More likely to ensure subject protection and overall study and
data quality than routine visits to all clinical sites and 100% SDV.
► Electronic systems enable remote near real-time review
of data and documents
• Statistical and data visualizations are now possible
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Confidential –
Key Components to Risk Based
Monitoring Implementation
13
People
with New Skills EDC/ESource/
eDiary/
eConsent
ESF/e
TMF
Clinical Data
Warehouse/
Reporting Tools
Operational Reports
Metrics Reports
Safety Reports
LABS IVR/I
WR CTMS
Technology:
New Data from Technology/
New Technologies
Processes: New Processes
Confidential –
TranCelerate View of SDV and SDR
► “SDV, commonly known as ‘transcription checking’
• “as a quality control measure it was the opinion of the
RBM working group that SDV as purely a transcription
checking exercise was not valuable.”1
► Source Data Review (SDR), which puts the focus on
review of source documentation in the context of a
comprehensive review of the quality of the data.
“SDR is not a comparison of source data against CRF
data.”1
1Transcelerate Biopharma Inc, (2014) Risk-Based Monitoring Update-Volume 1. Pages 2-3. http://www.transceleratebiopharmainc.com/wp-
content/uploads/2014/01/TransCelerate-RBM-Update-Volume-I-FINAL-27JAN2014.pdf
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Confidential –
Why Not Source Data Verification?
► Tedious
► Doesn’t require any special skills
► Extremely costly
► SDV doesn’t add value:
• 90-95% of on-site monitoring findings can be identified
using central monitoring strategies
• 95% of transcription errors detected during SDV have no
impact on study outcome
• Monitoring costs are the highest single item (excluding
investigator payments).
15
Confidential –
SDV: your job was to compare size and color
between two images instead of words.
Source Data Verification
17
Confidential –
Critical Data
19
Low error rate on
Baseline characteristics No significant effect on
Study Outcome
Smaller error rate on
key efficacy endpoint,
study procedure, dosing BIG effect on study
outcomes
Confidential –
What Are Critical Data? Affect outcome, Integrity, or Human Subject
Protection
Verification that informed consent was obtained
appropriately
Adherence to protocol eligibility criteria and conduct
Key efficacy and safety data
Investigational Product Management
Informed
Consent
Protocol
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Confidential –
RBM: What Is Different?
► Review Timing - Immediate
► SDV - Little - Only key data items not collected electronically
► Type of review - Integrated/Three Tier
• Data Management
• Risk Based Monitor
• Trend Analysis
► Type of data reviewed - More comprehensive
• Operational Metrics
• Audit Trail Data
• Query Trail
• Integrated views of data across data sets
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Confidential –
RBM: What Is Different?
► Technology
• EDC to collect source questions
• Clinical data warehouse/Reports
– Standardization
• eTMF/eISF to enable remote review of informed consent;
management of site documents remotely
► Interaction with existing processes
• RBM review with issue identification provided “behind the
scenes” with issue logs provided to monitors
22
Confidential –
New Competencies
► Evaluate clinical data from an individual subject to
assure subject is appropriate—Source Data Review
► Perform centralized review and interpret data on site
performance in comparison with other sites
► Understand Clinical Trial Technology
► Develop consistent strategies for assessing and
resolving problems. This includes root cause
identification, remediation, and evaluation.
24
Confidential –
Monitor Competency Results
• https://www.surveymonkey.com/s/MonitorCompetencyA
Respondents:
25
Yes No
Have you ever
worked as a
monitor
109 9
Have you ever
worked as a
Data Manager
15 101
0-2 years >2-5 years >5-10 years >10 years
How many
years did you
monitor trials?
15 36 21 39
Confidential –
Survey Summary
► The competencies specific to the new skills required
for Risk Based Monitoring were most often missed.
► More questions about clinical trials technology may
be needed to assess knowledge of this competency.
► Many monitors enjoyed the challenge of taking the
survey and appear eager to learn the new aspects of
the monitor’s role.
26
Confidential –
The New Monitor’s Role
► The additional competencies and responsibilities for
monitors result in a more significant role in
interpreting analytic data to identify
• quality issues,
• determining root cause,
• developing, and evaluating intervention strategies.
27
Confidential –
Site Management with Risk Based
Monitoring
Site Performance Across Sites
Site Performance Across Subjects
Subject SDR
Subject SDR
Subject SDR
28
Confidential –
Demographics
IP Administration—easy to see AE relationship
to IP start
Start/Stop of AE’s—easy to identify if no stop
date
Timing of Start and Stop of
Prior and Con Meds easily visible
As well as relationship to AE’s
Study Timeline allows orientation of
subjects based on relative day
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Confidential –
Source Data Review—Don’t forget:
Complete Subject Assessment
Subject Disposition
Documentation (Informed Consent, Certified Electronic
Source
IP Administration
30
Confidential –
Paper Electronic Documents Remote Review
Any paper document can be converted to a certified electronic copy.
Inform
ed
Conse
nt
Inform
ed
Conse
nt
Inform
ed
Conse
nt
Inform
ed
Conse
nt
Inform
ed
Conse
nt
Informed
Consent Scan to convert
To electronic
version
(PDF) Confirm paper and
electronic versions
are the same
Electronically Sign
Confirming they
are the same
Date/Time of
signature and
attestation
wording attached
to document
31
Confidential –
Remote Verification of Consent
and other Study Documents ► Informed Consent:
► Systems • The sponsor can set up an internet portal where site staff can
upload the signed consent forms, which can then be accessed by the Monitor.
• Electronic informed consent may also be considered.
► Processes • Complete review of Informed Consent (IC) can be done within
day(s) of subject visit.
• Complete review and any verification of Source can be done remotely. All source in electronic format remains part of the ISF.
• Metrics on site document issues feeds into overall site performance.
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Confidential –
Reviewing Site Performance
Across Subjects and Across Sites
► Data presented in tables or graphs
• No one right way to look at data:
– Some people can “see differences” in tables
– Others can “see differences in graphs
► Need to understand what you are looking at (Titles,
Axes, Scale of Axes, Timeframe)
► Triggers vs. Outliers
► Normalizing Data
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Confidential –
Site Performance Across Subjects ► Done in combination with Data Management
► Are Data too Organized/Regular (e.g. end number of VS
always 2,6)?
► Are assessment times reasonable for study staffing?
• Can 3 subjects all have their VS taken at 9:00 a.m. on 7/14/14 by the
same person
• Can multiple subjects all have infusions administered at the same time
by the same person
► Is the dosing correct for all subjects?
► Is there a pattern of missed assessments?
► Are there issues with the informed consent process?
34
Confidential –
Study Start-Up
Training
Site Mgmt
Resourcing
Investigational Product
Safety Assessments
Deviations
Study
Disposition
Operations Protocol
Documentation
Data Processing
Technology
Therapeutic/Trial
Design Specific Risks
Data/Documents
RBM Domains
How is the site performing compared to
other sites across these domains?
36
Confidential –
Risk Based Monitoring Domains to Review
• High Risk Areas
– Primary Efficacy Endpoint(s)
– Safety reporting from Subjects
– Dosing by Subject
• Enrollment • Data Entry (only for EDC, not eSource) • Safety • Data Quality (including Query responses) • Informed Consent/Human Subject’s protection • Document Issues • Deviations • Investigational Product Management* • Premature Discontinuation • Site Staff Turnover
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Common to
all studies
Study Specific
Confidential –
Cross Site Performance-Screen Failures
38
-1.5
-1
-0.5
0
0.5
1
1.5
2
2.5
1 2 3 4 5 6 7 8 9 10 11 12
Zsc
ore
(S
cre
en
Fail
)
Site Number
Month 3 Zscore
Month 6 Zscore
Month 9 Zscore
Confidential –
Determining Root Cause Site
Number
Issues Potential Root
Causes
Intervention
005 Inconsistent Ratings that
don’t conform to natural
history of disease
• Different person
doing ratings on
different days
• Person did not
rate subject
correctly.
• Is the PI doing
the ratings or
someone else
using ID?
• Two lesions rated
together
• Emphasize
importance of
transition rating
on day before
• Additional
training issue
• Significant site
performance
issue—for cause
visit.
• Nothing more
needed
40 40
Confidential –
Follow Up is Critical
Site # Issue Root Cause Intervention Follow Up
005 Inconsistent
Ratings
Ratings on
different days by
different raters
Review
transition
process
Review ratings
at site where
there is a
transition
between raters
and check for
better
consistency
41 41
Confidential –
Clinical Data
Warehouse
J Review
QlickView
Site Enters Data into EDC
Monitor Reviews data in EDC
and performs SDV at Site
Laboratory Data Sets Third Party Vendor Sponsor Project Managers
Risk Based Monitoring
Evaluation/Interpretation/Trend Analysis
Issue Log Development/ Potential Root Cause
Analysis
Confirmation of Intervention Success/Issue
resolution
Data Manager Review
Monitor works with Site to
Confirm Root Cause, Perform
Interventions
Additional issues identified with
RBM now followed to conclusion
by Monitor
EDC data PRO Data Sets
Sponsor Standard Process
New Inputs into Sponsor Process
IVR Data
RBM Process
Data Mapping for Standardization
42
Confidential –
Summary ► Risk Based Monitoring requires:
• Expanded Skill sets for Monitors doing remote monitoring
• New Collaborative Working Relationships
• New uses of technology and data
• New processes.
► Adoption can be accomplished within current
organizational structures with a separate workflow
for review
► Training programs are in development for monitors-
to be launched in Q1 2015.
43
Confidential –
Contact Information ► Penelope Manasco, MD
• pmanasco@manaconsulting.co
► Bill Gluck, Ph.D.
• Bill.Gluck@DATATRAK.com
► General Questions about DATATRAK
• Dorothy.Radke@DATATRAK.com
► Find Us Online
• www.DATATRAK.com / www.manaconsulting.com
• http://www.slideshare.net/DATATRAK
• @DATATRAKinc on Twitter
• https://www.linkedin.com/company/datatrak-international
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