October 22, 2014

How to Optimize Your EDC Solution

for Risk Based Monitoring

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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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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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• New RBM Draft Guidance August 2011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

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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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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

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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).

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Confidential –

No SDV? Now what do we do?

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Confidential –

SDV: your job was to compare size and color

between two images instead of words.

Source Data Verification

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Confidential –

Now your job is to explore the big picture

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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

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

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Confidential – 23

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.

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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

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.

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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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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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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

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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

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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?

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Confidential –

Risk Based Monitoring

High Risk: Dosing

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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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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

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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

Zsc

ore

(S

cre

en

Fail

)

Site Number

Month 3 Zscore

Month 6 Zscore

Month 9 Zscore

Confidential –

Risk Based Monitoring- High Risk/Critical Data—Rater Performance

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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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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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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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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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Confidential –

Questions

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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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from Concept to Cure

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DATATRAK International Cleveland, Ohio

Bryan, Texas

Cary, North Carolina

London, UK

888.677.DATA (3282) Toll Free

www.datatrak.com

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