CBI CONFERENCE:RISK-BASED MONITORING FOR SMALL TO MID-SIZE

COMPANIES

Impact of Risk-Based Monitoring and eSource Methodologies on Clinical Sites, Patients,

Regulators and Sponsors

March 2015

For information contact:

Jules T. Mitchel, MBA, PhD

212-681-2100

JulesMitchel@targethealth.com

© Copyright Target Health 2015

A Touch of Philosophy

“Life is really simple, but we insist on

making it complicated” Confucius

“Simplicity is the ultimate sophistication”Leonardo da Vinci

“The art of being wise is the art of

knowing what to overlook” William James

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More Philosophy

Every truth passes through three stages before it is recognized:

In the first it is ridiculed

In the second it is opposed

In the third it is regarded as self-evident

(Arthur Schopenhauer)

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There is No Substitute for Doing

What a person hears he/she may doubt

What he/she sees, he/she may possibly doubt

But what he/she does, cannot be doubted

(Adapted from Seaman Knapp: American Agriculturist and Educator)

Target Health Inc.

1. Industry leader in software supporting the paperless

clinical trial

2. Private, New York City-based, full-service eCRO

3. Total Drug and Device Development, including:

• Regulatory Affairs

• Strategic Planning

• Clinical Research

• Data Management

• Biostatistics

• Medical Writing

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CTTI

Briggs W Morrison, Pfizer; Chrissy J Cochran, Division of

Bioresearch Monitoring, FDA; Jennifer Giangrande White,

Roche; Joan Harley, Training Extension/Pastor Consulting;

Cynthia F Kleppinger; Division of Scientific Investigation,

FDA; An Liu, Alquest; Jules T Mitchel, Target Health; David F

Nickerson, Pfizer; Cynthia R Zacharias, BMS; Judith M Kramer

Duke Translational Medicine Institute; and James D Neaton,

University of Minnesota6

Problem

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Solution

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The Opportunity

Quality by Design (QbD) allows for an intelligent approach

for assuring that the clinical sites and study subjects

understand and are following the protocol.

Electronic source documents greatly reduce the need to

generate paper records, dramatically reducing the follow-

on need for onsite monitoring and SDV.

We can no longer justify spending a lot of time and money

requiring that sites first capture clinical trial data on paper,

only to subsequently transcribe those data into an

electronic EDC system, and then check the accuracy of

the transcription. 9

Business Benefits

Beyond cost savings, when performing risk-based monitoring and DDE, benefits include…

1. Improved site/sponsor relationships

2. Savings accrued to sites

3. Value of making faster, mid-course corrections

4. Improved quality of data (w/associated cost savings)

5. Focus on things that matter more effective allocation of resources

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Key Messages

1. Full business benefit realized only through

use of processes developed to exploit its

potential

2. Direct cost savings are significant and

obvious – additional business benefits may in

fact deliver even greater value

3. Regulators can worry less about data quality

do to transcription errors

4. Clinical sites are happy as they can double

the number of office visits a day and get rid of

most of the paper!!! 11

Starting a Study

1. Write a meaningful and feasible protocol

2. During the kickoff meeting, assess the risks to the study and focus on the risk-based monitoring plan

3. Assure that the sites can really deliver subjects

4. Set up a lean hierarchy

5. Get feedback from the study sites

6. At the investigator focus on study implementation and the “10 things that can go wrong” and the risk mitigation strategies to minimize the occurrence of risky events.

7. Make sure the sites and monitors understand the importance of DDE and RBM

8. Train, train, train………………… 12

During the Study

1. Visit the sites early to do a “sniff test” and make sure the protocol is understood and being followed

2. Review the data and generate queries in real time

3. No tolerance for delays in CRF review and query aging

4. Meet weekly during the QbD meetings with all interested parties

5. Agree on review of RBM reports especially an analysis of the edit checks that are firing and queries being generated

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During the Study

6. Assess edit check that fire and do not be afraid to make changes when it is clear there is relevance or new ones are needed

7. Review queries to ensure that they focus on things that matter

8. Have study specific online reports that focus on the “things that matter”

9. Take immediate action10. Share results among all study staff who need to

know

11. Keep meeting minutes

12. Train, train, train the sites and monitors14

Table of Contents of Clinical Data

Monitoring Plan (CDMoP)

1. Purpose2. References3. Study Roles and Responsibilities4. Tools and Processes

4.1 Study Data4.2 EDC Monitoring Module

5. Risk Mitigation Strategy6. Source Documents7. Monitoring

7.1 Onsite Monitoring7.2 Central Monitoring7.3 Qualification Visit7.4 Site Initiation Visit7.5 Interim Monitoring Visits7.6 Closeout Visit 15

Detection Scales

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Severity and Probability

Scale

Detection Scale

3= high

2= medium

1= low

1= Least difficult

2= Intermediate

3 =Most difficult

Risk Mitigation Matrix

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Category Risk Severity Probability Detect RPN Risk Mitigation

Trial

Outcome

Patient dosing

compliance

3 2 2 12 1. Instructions for use dispensed

to subjects and each

application at clinical site

performed under medical staff

supervision

2. Scale calibration daily prior to

subject(s) visit(s)

3. Site training prior to study

4. Weighing of IMP

5. Edit checks and online reports.

6. IMP returned on Days 14, 35,

47, 56, 70, 84 and 90 and not

re-dispensed

Trial

Outcome

Contamination of

the blood samples

by exogenous

testosterone at all

PK visits (e.g. at

the phlebotomy

site)

3 3 1 9 1. Sites trained to have 3 swabs

available for every blood draw;

2. Re-training and monitoring of

testosterone levels,

3. Online reports,

4. On site monitoring visit at the

time of the first PK visit on Day

14.

5. Encourage sites to use

indwelling catheters.

6. Lab alert of any value above

2500.

Real-Time, On-Line EDC Reports

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Sample Reports

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Enrollment Status by Site

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Source Data Verification (SDV) Report

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Queries Issued

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Queries by Form

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Drill Down

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PID Description Modification

Reason

Start Stop Data Source Data Source

1 Kidney Stone Original Data u u DDE

Additional

Information

2007 2007 DDE

Entry Error 2007 2007 Paper

Mild erectile

dysfunction

Original Data u DDE

Additional

Information

2009 DDE

Entry Error 2009 Paper

eSource: eClinical Trial Record

Target e*CTR is an electronic clinical trial patient record system, access to which is controlled by the clinical investigator

Within the eCTR, the original patient record is created at the time data are initially entered into the electronic data base, and before the data are transmitted to the sponsor’s or EDC database

Therefore, the original record created within the eCTR can serve as the source

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Target e*CTR (eClinical Trial Record)

1. Direct data capture of manually entered clinical trial data as

specified within the protocol. Other source data such as

ECG files, MRI reading etc. are captured independently of

Target e*CTR.

2. Allows for source data to be accurate, legible,

contemporaneous, original, attributable, complete and

consistent.

3. Provides an audit for the original creation and subsequent

modification of the source data.

4. Real-time retrieval of the source data.

5. Investigator maintains independent access to the original

source data.

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Target e*CTR (eClinical Trial Record)

6. Source documents and data are protected from destruction.

7. Allows for accurate copies to be made.

8. Source documents are protected against unauthorized

access.

9. Sponsor does not have control of the source data.

10.Assure that the location of source documents and the

associated source data shall be clearly identified at all

points within the capture process.

11.Assure that when source data are copied, the process used

ensures that the copy is an exact copy preserving all of the

data and metadata of the original.

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Target e*CTR Workflow

eClinical Trial Record – Audit Trail

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eClinical Trial Record - PDF

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eClinical Trial Record - PDF

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Benefits of DDE Integrated with RBM

1. Screening errors picked up early

2. Improved data quality due to immediate feedback

3. Enables Real-time monitoring

4. Major reduction in onsite monitoring

5. EDC edit checks refined early in the study

6. Compliance issues identified in real time

7. Transparency of safety issues

8. Productivity gains for sites -> High site acceptance

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METRICS

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Time to Data Entry From Visit Date

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Pivotal Trial (eSource) – Time to Data Entry From Visit Date

DayCumulative Pages

EnteredDelta

Cumulative Data Entry

(%)

0 22,517 22,517 91.7%

1-5 23,359 842 95.2

6-10 23,609 250 96.2

11-20 23,766 157 96.8

21-188 24,547 781 100.0%

Time to Data Entry From Visit Date

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86.0%

88.0%

90.0%

92.0%

94.0%

96.0%

98.0%

100.0%

102.0%

0

5000

10000

15000

20000

25000

0 1 5 10 20 30 50 200 More

Fre

qu

en

cy

Days to Data Entry

Days-to-Data-Entry

Frequency

Cumulative %

Query Rate and Database Changes

Query Efficiency (QE) = Changes Post Query

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Subjects Sites Forms Pages With

Queries

(%)

Page Changes Post

Query

(%)

938 40 45,723 1,063 (2.3%) 550 (1.2%)

QE = 51.7%

Of 550 post-query changes…

• 17.5% of queries raised by monitoring CRO

• 82.5% of queries raised by CDM function

Just 4 forms represented 63% of all modified forms:

• Medications----------------30% (QE = 74%)

• Date of Visit----------------14% (QE = 24%)

• Other Medical History --11% (QE = 42%)

• Sitting Vital Signs ---------8% (QE = 42%)

ROI - Assumptions

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ASSUMPTIONS N

Sites 25

Subjects 500

Study duration (months) 12

CRF pages/subject 100

Monitoring rate/day $1,500

Average transportation cost/visit $750

Average travel time/visit $750

ROI - Assumptions

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Traditional

Monitoring

eSource

Monitoring

Monitoring visits/site 12 6

Monitoring visits 300 150

Duration of visit (days) 1.5 1

Days at the site 450 150

In-house activities (days) 300 150

eClinical Trial Record/site 0 $5,000

ROI = 2.6

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COST SUMMARIESTRADITIONAL

MONITORING

eSOURCE

MONITORINGDELTA

Monitoring Visits$675,000 $225,000 -$450,000

In-house eCRF Data Review$125,000 $125,000

In-House Activities$450,000 $225,000 -$225,000

eClinical Trial Record/Site/year $125,000 $125,000

Subtotal$1,125,000 $700,000 -$425,000

Pass-through Estimates

Direct Travel Costs$225,000 $112,500 -$112,500

Travel Time$225,000 $112,500 -$112,500

Subtotal$450,000 $225,000 -$225,000

GRAND TOTAL $1,575,000 $925,000 -$650,000

Thank You

Jules T. Mitchel, MBA, Ph.D., President

Target Health Inc.

261 Madison Avenue, 24th Floor, New York, NY 10016

jmitchel@targethealth.com

www.targethealth.com

TARGET HEALTH INC., founded in 1993, is a private, New

York City-based, full-service eCRO, engaged in all aspects of

Drug and Device Development, including Regulatory Affairs

Strategic Planning, Clinical Research, Data Management,

Biostatistics, Medical Writing and the paperless clinical trial.

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