TransCelerate Risk-Based Monitoring – The Approach

Topics

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• Risk-Based Monitoring - The Case for Change

• Risk-Based Monitoring – The Approach

– Alignment with other key concepts

– Components of the methodology

• Cross-functional risk assessment

• Critical data and processes

• Integrated Quality Risk Management Plan

• Risk Indicators and thresholds

• Monitoring execution (Central, Off-site and On-site)

• Key Lessons and Updates

19 Pharmaceutical Companies* providing their best talent to collaborate and develop solutions to overcome industry Inefficiencies

* 10 Pharmaceutical Companies chartered TransCelerate and 9 additional companies joined in 2013

Trial Oversight & Monitoring

• The Approach is Changing

• The Goal of Fit for Purpose Quality Has Not

Quality by Design (QbD) Concepts

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Build Quality into the scientific and operational design and conduct of clinical trials

QbD RBM

Program and Protocol Development Study Execution

Identify risks at the program, study, and site level to apply the appropriate level of monitoring / risk mitigation

TransCelerate Approach – Overview

Build QbD into trials

Risk identification & assessment

Critical Processes and Data in Study Plans

Risk Indicators, Thresholds & Action Plans

Adjustment of monitoring activities

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Data Plans

Training Plan

Monitoring Plan

Statistical Analysis Plan

Safety Plan

Medical Monitoring

Plan

Quality Plan

Other Functional

Plans

IQRMP

RACTCritical

DataRisk

Indicators / Thresholds

RACT

Critical

Process & Data

IQRMP

Risk Indicators

and Thresholds

An adaptive approach to clinical trial monitoring that directs monitoring focus and activities to the evolving areas of greatest need which have the most potential to impact patient safety and data quality.

Risk Assessment and Categorization Tool (RACT)

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**Categories**

Protocol Level RACT

Program Level RACT

• Safety• Endpoints• IP• Technology• Operational

Experience

• Study Phase

• Subject Population

• Endpoints

• Technology

• Data Collection & CRF Source

• Study Medication /IP

• Blinding

• Clinical Supply Chain

• Protocol Complexity

• Operational Complexity

• Geography

Documentation of Critical Data & Processes

• Team alignment on “what matters”

• Focused Risk Assessment

Consistent Approach to Assessment

• Each category** has a series of questions

• Provides examples of high, medium, and low risks

Impact & Probability

• Determines the impact to the study if the risk becomes an issue

• Determines the probability of the risk occurring

Output

• Provides direction on where the most attention is needed for monitoring and mitigation

• Determines the Overall Risk Level (high, medium, or low) for monitoring activities

Critical Data …

• Support primary and key secondary objectives

• Critical to subject safety

• Support decision-making about efficacy of the IP

Critical Processes…

• Underpin data quality

• Underpin subject safety

• Support ethical and GCP compliance

Critical Data and Processes - Definitions

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Risk Indicator - Terminology Review

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TransCelerate Definition

Risk Indicator: Critical Data and other study variables to be assessed (in many cases by comparing across program / protocol / country / site)

Working Definition

Risk Indicator: Variables which are considered to have underlying influence on the quality of a study and are assessed by comparison across a program, study, country, and/or site

Risk Indicator Categories and Examples

• Number of adverse events per subject visit/siteSafety

• Incidence of temperature excursionsIP

• Number of screen failures compared to average across sites

Recruitment/Discontinuation

• Number of deviations per subject visit/site compared to average across sites

Issue Management

• Abnormal trend or lack of variability in dataData Quality

• Number of overdue or missing documentsEssential Documents

• Staff turn-overStaffing, Facilities, Supplies

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Threshold (Tolerance Limits) - Terminology Review

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TransCelerate Definition

Threshold: The level, point, or value associated with a Risk Indicator that will trigger an action

Working Definition

Threshold: A pre-determined number, value, % or range associated with a Risk Indicator that indicates the need for a follow-up action

RBM Toolkit: Companion Guide to Risk Indicators

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BMS RBM Monitoring Execution Central Monitoring

Remote assessment of study-level Risk

Indicators

Off-Site Monitoring

Remote assessment of site-level Issues,

data, site performance

On-Site Monitoring

Assessment of site quality via SDV, SDR, GCP assessment at the investigational

site

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IQRMP: Core of Quality Risk Management

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Data Plans

Training Plan

Monitoring Plan

Statistical Analysis

Plan

Safety Plan

Medical Monitoring

Plan

Quality Plan

Other Functional

Plans

IQRMP

RACT Critical Data

Risk Indicators / Thresholds

Click to edit Master title style

KEY LESSONS LEARNED AND UPDATES

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Publications and Related Tools

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Published Timeframe Destination

Position Paper May 2013 TransCelerate website

RBM Update Volume I January 2014 TransCelerate website

RBM Training Materials January 2014 TransCelerate website

Risk Assessment and Categorization Tool (RACT) v2.0

April 2014 TransCelerate website

RBM Update Volume II July 2014 TransCelerate website

Defining a Central Monitoring Capability: Sharing the Experience of TransCelerate BioPharma’s Approach, Part I

September 2014 Therapeutic Innovation and Regulatory Science

Technology Considerations to Enable the Risk-Based Monitoring Methodology

September 2014 Therapeutic Innovation and Regulatory Science

Evaluating Source Data Verification as a Quality Control Measure in Clinical Trials

Anticipated November 2014

Therapeutic Innovation and Regulatory Science

RBM Update Volume III Anticipated November 2014

TransCelerate website

Risk Assessment – Updated RACT Tool

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Cross-functional discussion

Facilitator

Timing: impact on protocol finalization

Incorporating feedback

Lessons Learned

Updated RACT

Posted in April 2014

FDA RBM Pilot review communication material

Risk Assessment

• Ensuring cross functional participation

• Rationale for overall risk determination of study

• Also ensure focus on

o Discontinuation/Retention/Follow-up

o Study drug compliance with dosing regimen

o Adjudication process/identification of events

Monitoring Plan

• Clarity of monitoring responsibilities

• Clarity on activities that must be done on-site, off-site (remote) and central

• Supportive of SDV sampling plans – two comments that SDV may be too much

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Risk Mitigation

• Threshold values, actions, predefined contingency plan (when possible)

• Ensure risk indicators are measurable and informative

• Escalation of site/country/study/program issues by central monitoring function

• Defined Issue Communication Flow

General Considerations

• Impact on other program and study-related oversight processes

• Site training regarding the application of RBM

For more information

http://www.transceleratebiopharmainc.com/rbm-resources/

Includes access to:

TransCelerate Position Paper: Risk-Based Monitoring Methodology

RBM Learning modules (5)

• Train-the trainer manuals

• Participant workbook

• Pre-course / post-coursework

RBM Updates #1 & #2

eLinks to current publications:

• Defining a Central Monitoring Capability: Sharing the Experience of TransCelerate BioPharma’s Approach, Part 1

• Technology Considerations to Enable the Risk-Based Monitoring Methodology

• Evaluating Source Data Verification as a Quality Control Measure in Clinical Trials 19