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.

1. October 22, 2014
How to Optimize Your EDC Solution for Risk Based Monitoring

2. 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.
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3. 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
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4. Confidential –
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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
History of Guidance Document
• Replaced 1988 Guidance on Monitoring
• New RBM Draft Guidance August 2011
• Final RBM Guidance August 2013

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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

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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

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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

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Common Metrics
Completeness
Page Report
Time to Entry
Time to SDV
Time to Sign
Time to Resolve Queries
Quality
Query Counts

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Implementing A Risk-Based Approach That Optimizes the Benefits of EDC by Focusing on Education

10. 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
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11. 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
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12. 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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13. Confidential –
Key Components to Risk Based Monitoring Implementation
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People
with New Skills
EDC/ESource/ eDiary/
eConsent
ESF/eTMF
Clinical Data Warehouse/ Reporting Tools
Operational Reports
Metrics Reports
Safety Reports
LABS
IVR/IWR
CTMS
Technology:
New Data from Technology/ New Technologies
Processes: New Processes

14. 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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15. 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).
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No SDV? Now what do we do?
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17. Confidential –
SDV: your job was to compare size and color between two images instead of words.
Source Data Verification
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18. Confidential –
Now your job is to explore the big picture
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19. Confidential –
Critical Data
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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

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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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21. 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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22. 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
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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.
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25. Confidential –
Monitor Competency Results
•https://www.surveymonkey.com/s/MonitorCompetencyA
Respondents:
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Yes
No
Have you ever worked as a monitor
109
9
Have you ever worked as a Data Manager
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101
0-2 years
>2-5 years
>5-10 years
>10 years
How many years did you monitor trials?
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36
21
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26. 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.
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27. 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.
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28. Confidential –
Site Management with Risk Based Monitoring
Site Performance Across Sites
Site Performance Across Subjects
Subject SDR
Subject SDR
Subject SDR
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29. 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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30. Confidential –
Source Data Review—Don’t forget:
Complete Subject Assessment
Subject Disposition
Documentation (Informed Consent, Certified Electronic Source
IP Administration
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Paper  Electronic Documents Remote Review
Any paper document can be converted to a certified electronic copy.
Informed Consent
Informed Consent
Informed Consent
Informed Consent
Informed Consent
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
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32. 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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33. 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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34. 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?
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35. Confidential –
Risk Based Monitoring
High Risk: Dosing
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36. 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?
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37. 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

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Cross Site Performance-Screen Failures
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-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
Zscore (Screen Fail)
Site Number
Month 3 Zscore
Month 6 Zscore
Month 9 Zscore

39. Confidential –
Risk Based Monitoring- High Risk/Critical Data—Rater Performance
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40. 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
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41. 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
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42. 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
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43. 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.
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44. Confidential –
Questions
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45. 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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46. from Concept to Cure
with DATATRAK ONE
DATATRAK International
Cleveland, Ohio
Bryan, Texas
Cary, North Carolina London, UK
888.677.DATA (3282) Toll Free
www.datatrak.com
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