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Controlling the Killer KRINew Solutions to Address Protocol Deviations

Kenneth Wu, MS, MBAClinical ConsultantKenneth Wu and Associates, LLC

@kennwu

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• The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated.

• These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners.

Disclaimer

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I am a subject matter expert consultant to Comprehend Systems, a technology company with a class of cloud software to help Clinical Operations.

Financial Disclosure

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Persistent Key Risk Indicators (KRI) Over Time

Top 3 Critical Findings# 2000-2006 2007-2009 2010-2012

1 IMP Compliance

Patient Selection* Monitoring**

2 Clinical Study Report

Source Documentation

Patient Selection*

3 Safety Reporting* Monitoring** Efficacy

Assessment*

(Source: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/12/WC500178525.pdf)

*Protocol Compliance by Investigator**Trial Management by Sponsor

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Consistent KRIs by Inspectors

Top 3 483 Issued# 2010-2011 2012-2013 2014-2015

1 Protocol Compliance*

Protocol Compliance*

Protocol Compliance*

2 Source Documents*

Source Documents*

Source Documents*

3 IRB Meeting Minutes

Accountability Records

IRB Meeting Minutes

(Source: www:fda.gov/ICECI/Inspections/ucm250720.htm)

*Protocol Compliance and Source Documents by Investigator

Confidential and Proprietary: Not for Distribution

Investigators

Monitors

Safety Reps

Data Managers

Multiple CROs

Slow Investigation

Limited Visibility

Don’t Know Where to Focus

No Audit Trail

Act Slowly

Uninformed Decisions

Distributed ClinOps Teams

Biostaticians

Focus on Sites

SILOED OPAQUE DISTRACTED

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Issue management

Identify

Triage

Validate

CAPA

Implement Four-step Process

Analyze

Continuous Improvement

Clinical Intelligence

Regulatory Risk Operational Risk

Protocol Compliance Enrollment Site Management

Subject Visit FunnelProtocol Deviations

Adverse EventsPrimary Endpoint Data

Site ActivationEnrollment Funnel, based on

patient status:ConsentedScreened

RandomizedEnrolled

WithdrawnEvaluable

Monitoring VisitsData Entry

Query ResolutionIssue ResolutionDrug Inventory

Step 1: Identify KRIs

Step 2: Triage

Risk Type High Risk Low Risk

Operational Risk

Enrollment high screen failure high withdrawal

slow enrollment unknown barriers

Site Productivity non-performing sites high number of queries

low site performance aged queries

Regulatory Risk

Protocol Compliance protocol deviations unexpected events

low data quality missing data

Missed Milestones Milestone Achievement

FDA Action FDA Approval

Step 3: Analyze

Confidential and Proprietary: Not for Distribution

ClinOpsTeams

Fully Defend

See Everything

Focus on What Matters

ActivelyInvestigate

Act Faster

SitesInvestigators

Monitors

Safety RepsData Managers

Biostaticians

multipleCROs

Make Smarter Decisions

operational/clinical data

Step 4: Validation with Clinical Intelligence

Study Coordinators

Clinical Intelligence

Confidential and Proprietary: Not for Distribution

Use Case: Issue Management

1 Identify Real-time alert when deviations breach configured threshold

2 Triage Composite risk score provides a real-time comparison

3 Analyze One-click analysis: study, issue, and site levels

4 Validate Task management and follow up with audit trail

Protocol Compliance KRI

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Protocol Deviation: Alert and Triage

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3

4

2

Process Steps1. Protocol

Deviation

1. Risk Score 18

1. Medtrack Mount Center

1. CRA North America assigned

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Analyses: Study, Category, Trend

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1

3

Process Steps1. Beta 21

Study

1. Prohibited Concomitant Medication

1. June 2015 10 prohibited Concomitant Medications were reported

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Analyses: Outlier and Benchmark

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2

Process Steps1. Single outlier

on Prohibited Concomitant Medications

1. Canadian site was 1300% prohib. con. meds (1000x)

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Analyses: Granular Site Trend

Process Steps1. Prohibited

Con. Meds violations high %

1. Appears to be seasonal trend

1. Implement corrective actions

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2

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Validation: Audit trail, Continuous Monitoring

Process Steps1. Audit trail of

corrective action

1. Continuous monitoring

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© Comprehend 2015, Confidential & Proprietary | Page 18

Operational Risk

Regulatory Risk

High Low

High

Low

Value: Reduce operational and regulatory risks

ClinicalUncertainty

Reactive with high risk exposure

Clinical IntelligenceProactive with risk mitigation

Multiple benefits of this approach

Reduce cost of clinical operations

Minimize trial cycle time

Increase productivity

Mitigate Operational and

RegulatoryRisk

Proactively manage and resolve issues to keep trials on time

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Kenneth Wu, MS, MBAClinical ConsultantKenneth Wu and Associates, LLC@kennwuken@kenwullc.com

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