How to Efficiently and Effectively Balance Central

Monitoring with On-Site Monitoring

Experience from Phase 3 Study Using Risk-Based Monitoring and eSource

Methodologies

December 2013

For information contact: Jules T. Mitchel, MBA, PhD

212-681-2100 JulesMitchel@targethealth.com ©Copyright Target Health 2013

A Touch of 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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A Touch of Philosophy

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)

The Problem

© Copyright 2011 by Target Health Inc. 4

Problem Solution

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Quality Redefined

Quality in clinical trials = the absence

of errors that matter

Are the data fit for use/purpose

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What are “Errors that Matter”?

Errors that have a meaningful impact on

Patient safety or Interpretation of trial results

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Ongoing RBM and eSource Programs

Met with FDA at Type C meeting under a US IND 16 studies under 10 INDs and 1 IDE 1. 3 INDs with big pharma (US, Argentina, Singapore) 2. 4 INDs with mid-size pharma (US, Demark) 3. 3 INDs with small pharma (US) 4. 1 IDE with small pharma (US, Sweden) NDA planned Q3 2014

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eSource Data Flow

IT IS ALL ABOUT THE DATA

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Analysis of Results Pre and Post Source Document Verification With 100% SDV

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Data were collected using paper records (40,000) of 492 randomized subjects with a urological disease. Queries were generated based on edit checks that fired at the time of data entry and on online edit checks run in a batch mode within the EDC system. Each data element change was subject to an electronic audit trail and for each modification, a reason for change was required. In order to evaluate the impact of data changes on the data analysis, an assessment was made of 331 data changes of 5 numeric variables contained within 1,287 endpoint forms.

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EDC IS JUST A BRIDGE

With EDC and paper source records, SDV is required to verify how well the clinical site can transcribe from one medium to another

Total Pages

Entered

Total Number of Forms That

Changed

Changes Due to Data Entry Errors

Changes Due to Additional Information

Changes Due to Other

Reasons

41,568 2,584 (6.2%)

1,836 (4.4%)

486 (1.2%)

262 (0.63%)

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Just a Few Forms Drove Most Changes

Of the 2,584 changes to the database: 20.8% occurred in the Diary Log 13.9% in the Medication form 12.6% in the Illness (medical history) form

Query Rate and Database Changes Post Query – Paper Source

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Examples of Changes

Screening No.

Variable 1

Variable 2

Variable 3

Variable 4

Variable 5

0101S001 7.6 4.1 39 4 161

0101S001 7.6 4.1 42 43 161

0101S003 15 8 25 29 203

0101S003 15.3 8 25 29 203

4201S010 12 5,9 22,7 10,3 178,5 4201S010 12 5,9 82.7 70.3 178.5 4201S012 12 6 45 7 283 4201S012 12 5,7 44,9 6,7 282,6

Mean and SD Values Do Not Change Pre and Post SDV

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Initial Final Variable 1

Mean 10.81 10.77 SD 4.71 4.55

Range (0-56.0) Variable 2

Mean 5.56 5.54 SD 2.21 2.16

Range (0-20.6)

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Definition of Monitoring Observe and check the progress or quality of (something) over a period of time; keep under systematic review Related Words: surveil, eye, behold, espy, look, note, notice, observe, regard, see, sight, spy, view, witness, gape, gawk, gaze, glare, goggle, peer, rubberneck, stare; glance, glimpse, peek, peep

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Proposed Onsite Monitoring Activities Be there when a subject has an appointment Chart Reviews Drug supply accountability Personnel delegation and signature log Staff knowledge of the protocol Training Change in study personnel Change in physical status of the clinical site Interviews on how the study is progressing “Sniff test” that all is well at the site

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Current Onsite Monitoring Activities That May be Able to be Performed Centrally

Study conduct and protocol adherence Review of Informed Consent forms Subject Eligibility Evaluation of medications associated with adverse events Drug supply accountability Protocol deviations and violations

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Central Monitoring Activities

Evaluate, by site and across sites:

Enrollment and dropout status Number of forms entered and reviewed Edit checks and queries by form and variable Numbers and reasons for database changes Adverse events and medications Protocol deviations and violations

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Tips on Centralized Monitoring

1.Make sure the data are available rapidly from the time of the clinic visit

2.Review data at least once-a-day 3.Review online quality checks every day 4.Meet periodically to review findings of central

monitoring 5.Communicate findings to the monitors, sites and

other interested parties 6.Maintain meeting minutes with findings and

corrective actions

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METRICS

Phase 3 Study 18 Sites

180 Completed Subjects

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Monitoring

There were:

18 monitoring visits and reports 211 central monitoring reports Savings of about $270,000

Time to Data Entry From Visit Date

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

Day Cumulative Pages Entered Delta Cumulative Data Entry

(%)

0 12,111 12,111 90.5%

1-5 12,745 634 95.3%

6-10 13,088 343 97.8%

11-20 13,182 94 98.5%

21-30 13,243 61 99.2%

Time to CRF Review When Doing Centralized Monitoring

1 5 10

25

50

75

90 95 99 100

0

20

40

60

80

100

120

0.02 0.07 0.13 0.6 2.4 7.7 32.3 91.5 243.8 446.5

Cum

ulat

ive

%

Time to Initial Review (hours)

Query Rate and Database Changes Post Query – eSource

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Summary of Changes Made to the Database Post SDV

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Form # Forms # of Changes Medications 530 13 (27%) Hormone Result 1,326 11 (23%) Medical History 1196 10 (21% Informed Consent 328 4 (8%) PK Samples 742 3 (6%) Eligibility 215 2 (4%) Titration 355 2 (4%) Body Measurements 26 1 (2%) Demographics 238 1 (2%) Drug Admin 15 1 (2%)

Total 4,971 48 (100%)

Business Benefits of Risked-based Monitoring

Beyond cost savings, 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 28

Key Messages

1. Risk-based monitoring and eSource tools are enablers – full business benefit realized only through use of processes developed to exploit its potential

2. Savings identified represent direct cost savings only – additional business benefits may in fact deliver even greater value

3. Sites are *not* the problem

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

Target Health Inc. 261 Madison Avenue, 24th Floor, New York, NY 10016

JulesMitchel@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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