Risk Based Monitoring Overview at BMS

Patricia Clerton – Central Monitor

« Clinical Data, Real Data, Open & Big Data »

7 Novembre 2016 Cité Universitaire

1

• What is RBM at BMS ?

• Focus on CMN role

• Questions

Agenda

2

• What is RBM at BMS ?

• Focus on CMN role

• Questions

Agenda

3

TransCelerate was founded in 2012

by 10 Biopharmaceutical

organizations.

What or Who is TransCelerate?Vision:

To improve the health of people around the world by accelerating and simplifying the research and development of innovative new therapies.

Mission Statement:

To collaborate across the global biopharmaceutical R&D community to identify, prioritize, design and facilitate implementation of solutions designed to drive the efficient, effective and high quality delivery of new medicines.

Strategic Priorities:

TransCelerate assesses industry challenges and selects initiatives aligned with five strategic priorities:

Enable Harmonization of Clinical Trial

Processes

Improve the Site Investigator Experience

Facilitate Information Sharing

Enhance Sponsor Efficiencies

Improve the Patient Experience

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RBM - 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.

“The validity of a clinical trial is as dependent on monitoring GCP and adherence to the protocol as it is to the identification of errors and inconsistencies in the data” [Applied Clinical Trials 2011]

Agencies

• 2011: FDA, EMA, and MHRA guidances encourage risk-based monitoring, including adoption of alternative monitoring methods todecrease the reliance on on-site monitoring and utilize available technologies; CITI endorses QbD approach to study monitoring

• 2015: ICH E6

BMS

• RSDV program is difficult to implement and focuses on efficiency not quality;

• Audit and inspection findings cite deficits related to protocol compliance and unrelated to SDV. How can we identify that data is invalid even if it matches the source?

Consensus

• Focusing all roles on the most critical data elements is more likely to ensure overall study quality than 100% SDV with frequent monitoring visits

• BMS joins TransCelerate in 2012 to share solution ideas

Dri

vers

for

cha

nge:

Why is Risk-Based Monitoring necessary?

5

newnew

SeptemberTransCelerate

BioPharma Incorporated

1st North American BMS RBM Pilot

July•BMS Adapted RBM Process

guidance

November•1st BMS Global

Pilot Study

2015

Embed RBM

CMN Function officially created

ImplementationPhased

CMN support initiated

Pilot Phase

Full Implementation

RBM Key Events

February•Studies in full RBM

process

201420132012 2016

HeadCMN

Centralized Statistical Analysis

(CSA) OC studies

August•RBM Audit

January•Medidata & BMS partner

CMN Team

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Identification of Critical Data/Risk

Assessments

PROGRAM

Identification of Critical Data/Risk

Assessments

PROTOCOL

Risk Plans Monitoring Execution

Program Level RACT*

Risk-Based Monitoring

Protocol Level RACT*

Monitoring Plan

Data Review Plan

Quality Risk Indicators

Acronyms:*RACT = Risk Assessment Categorization Tool

RBM => Planning for and Managing Risks and Issues

The BMS RBM Methodology

On & Off-Site Monitoring

Central Monitoring

Ongoing Site Management

Focus on the most meaningful data

Customize monitoring to

the needs of the trial;

Adjust activities based on

findings/issues

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Program Level RACT

Risk Assessment and Categorization Tool (RACT)

Documentation of Critical Data & Processes

• Team alignment on “what matters” • Focused Risk Assessment

Consistent Approach to Assessment

• Each category** has a series of questions to identify risks

Impact , Probability & Detectability

• Determines the impact to the study if the risk becomes an issue• Determines the probability of the risk occurring• Determines the ability to detect if a risk is becoming an issue

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

**Categories**

Protocol Level RACT

Program Level RACT

• Safety• Endpoints• IP• Technology• Operational

Experience

• Study Phase

• Pt. Population

• Endpoints

• Technology

• Data Collection & CRF Source

• Study Medication/IP

• Blinding

• Clinical Supply Chain

• Operational Complexity

• Geography

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1

Identify Critical Data and Critical Processes

Critical Data Critical Processes

Definition

• Support primary and key secondary objectives

• Are critical to subject safety & the ethical treatment of subjects

• Processes that are critical to the reliability of the study findings. This may include: Processes that support the collection of

critical data Processes related to ensuring subject

safety Compliance with ICH-GCP regulationsDocumentation of trial integrity

Process

• Critical Data will be Source Data Verified (SDV) (i.e. transcription checking)

• SDV will initially target a percentage of subjects based on RACT determined Overall Study Risk Score

• Critical Processes will be Source Data Reviewed (SDR)

• SDR will initially target a percentage of subjects based on RACT determined Overall Study Risk Score

Example(s)• AE/SAE data• Date of progression

• Laboratory tests (collection, shipment)• Disease progression determination (accuracy

of tumor assessment criteria)

Critical Data & Critical Processes

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Central Monitoring

Remote assessment of study-level Quality

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

Data ManagementReview

Safety Review

StatisticalReview

Comprehensive approach to monitoring

Fit for purpose

RBM Monitoring Execution

Medical Review

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Focus monitoring on the most critical data and processes Share responsibility for subject safety, data quality Customize monitoring approach to each trial/site based on risk assessment Monitoring as a cross-functional responsibility Use of technology to monitor study conduct Adapt monitoring approach in response to findings Rely more on Off-site and Central Monitoring

Recommended RBM Core Principles

As of September 2016, RBM has been implemented in ~58 of ongoing/planned studies(~46% total studies)

By the end of 2016, RBM is expected to be implemented in ~70% of studies

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GCOS: Clinical

Operations Risk Managers

**New Role**

RCO: Monitoring Excellence

Leads (SMN)

GDSS: Central Monitors (CMN)

RCO: SMP Writers & Global Site Monitors

RCO: Global Site Managers

(STM)

GCOS: Protocol

Managers (PTM)

RCO: Clinical Data Quality

Managers (CDQM)

GDSS: Data Leads and

Protocol Data Managers

Successful RBM

Cross-Functional RBM Team

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• What is RBM at BMS ?

• Focus on CMN role

• Questions

Agenda

13

USA-Based

• Protocol Manager

• Manager of Site Manager

• Protocol Data Manager

• R&D Learning & Development

• Statistical Programming

• Site Monitor

• Global Regulatory Safety and Biometrics

• Manager of Protocol Data Managers

UK-Based

Clinical Data Quality Manager

Japan-Based

Clinical Data Quality Manager

France-Based

Clinical Data Quality Manager

Argentina-Based

Clinical Data Quality Manager

Head of

Central Monitoring

Central Monitoring Team - Former roles

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Centralized monitoring is a remote evaluation of ongoing and/or cumulative data collected from trialsites, in a timely manner. Centralized monitoring processes provide additional monitoringcapabilities that can complement and reduce the extent and/or frequency of on-site monitoring bysuch methods as:

Routine review of submitted data. Identification of missing data, inconsistent data, data outliers or unexpected lack of variability

and protocol deviations that may be indicative of systematic or significant errors in datacollection and reporting at a site or across sites, or may be indicative of potential datamanipulation or data integrity problems.

Using statistical analyses to identify data trends such as the range and consistency of data withinand across sites.

Analyzing site characteristics and performance metrics. Selection of sites and/or processes for targeted on-site monitoring.

ICH Addendum 5.18.3 to ICH E6

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To provide a unique analysis of ongoing and/or cumulative data To assess risk across sites, countries and studies To allow for early issue detection and targeted intervention

Central Monitor Responsibilities

Remote assessment of Quality Risk Indicators (QRIs) Identify issues/emerging risks in study specific variables (trends/outliers/poor performing sites) Support risk mitigation and global monitoring of processes that align with BMS programs and

protocols

Purpose

Central Monitoring at BMS

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Process

Central Monitoring Process

Generate reports to assess QRIs and

study specific risks

Investigate clinical data and

operational metrics for outliers and trends

Assign/escalate issues

at site, country, or study level to the appropriate role

Assess resolution, follow-up, and

provide documentation

1 2 3 4

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Risk Indicator Summary Cards – Quality Risk Indicators

• Screen fail rate• Treatment discontinuation

rate• Significant protocol deviation

rate

• SAE rate• % PT W/SAE• AE rate• % PT W/AE• RELAE rate• % PT W/RELAE• % RELAE of all NSAE

• Number of incomplete pages• CRF completion timelines• Discrepancy rate• Discrepancy resolution timelines

• SAE reporting timelines

• Systolic BP• Diastolic BP• Heart Rate

• Counts of Issues by type at each site reported on Issues Management Tool

Site Quality Site Safety Site Performance

Rate of Repeats Site Issues

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• Variety of reports in multiple systems

• Manually run and analyzed

• System retrieved reports• System analysis for outliers /

trends / thresholds• Improved graphical interfaceFu

ture

Sta

te

Centralized Monitoring ToolsC

urre

ntSt

ate

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VV1

Study team input, as needed

Central Monitors align

on findings

Site Level IssuesclinSIGHT issues management: Site

Monitor (SMN)

The issue resolver works with the site

The CMN is not a site facing role

Study/Country Level Issues

Email, TC: PTM, PDM, hub designee

Study team devises a plan of action to

address with sites e.g. training, email,

newsletter

PMF toolkit issues & risks log

Team Updates

RBM Q&A Calls

Team Meetings (e.g., IPT)

Issue Escalation

Communication Flow

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R e g u l a t o r yS u p p o r t

A n a l y t i c s & V i s u a l i z a t i o n s

R i s k M i t i g a t i o n

Central Monitoring

I s s u e E s c a l a t i o n

Unique analysis of aggregate data and comparison of QRIs

Utilize analytics & visualizations for assessment of issues/risks at the study, program, country, and therapeutic level

Early identification of critical data issues

Document findings for tracking, targeted intervention and timely resolution

Support regulatory audits and Health Authority inspections

Assess for potential fraud and protocol compliance

Ensure data quality at the program, indication and/or TA level

Application of RACT, DRST and risk mitigation plans

Key Benefits of Central Monitoring

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Risk Based Monitoring is an Industry-Wide Change driven by Regulators

Risk Based Monitoring is a Cross-Functional Collaboration

Risk Based Monitoring is an adaptive process that involves the early identification and assessment of risks, implementation of risk mitigations,

and execution of holistic monitoring approaches

Risk Based Monitoring focuses on what is most importantin order to protect the rights and safety of human subjects and to ensure data

integrity and GCP compliance

RBM: Key Takeaways

ICH recent Addendum supports how RBM is being implemented acrossindustry

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Questions?

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