RBM – A PRIMERINITIATION OF RISK-BASED MONITORING (RBM) FOR THE BEGINNERSSep 2015

Gopal Pai

DISCLAIMER• This presentation is “my creation” from “others creations” with my interpretations of the

limited knowledge I have gained in Sep. 2015

• My sincere thanks for making these available freely on the web, but that does not stop me from saying “THANK YOU” again to the original authors who made these available to me as “food for my thoughts” to crystalize

• My thoughts are presented here with an aim to simplify the concept and as a training aid to whosoever uses this presentation

• I admit these are not my ideas but an adaptation of “other Author’s ideas”

• The intent is to just spread the knowledge of this topic around with my industry colleagues

RESOURCES - 1• US Food and Drug Administration

• Guidance on Monitoring of Clinical Investigations, 1988 • Guidance on Providing Clinical Evidence of Effectiveness for Drug and Biological Product,

acceptance on difference levels of documentation of data quality, 1998 • Human Subject Protection/Bioresearch Monitoring (HSP/BIMO) Concept Paper, 2007 • Guidance for Industry Oversight of Clinical Investigations – A Risk- Based Approach to Monitoring,

Procedural 8/2013 http://www.fda.gov/downloads/Drugs/.../Guidances/UCM269919.pdf

• International Conference on Harmonisation (ICH): • ICH E6 addresses flexibility in how trials are monitored which includes reduced or no onsite

monitoring, 1996 • ICH Q8, Q9 & Q10 addresses the risk assessment methodology to be used in improvement of

manufacturing and other process oriented industry practices, 2005

• European Medical Agency (EMA): • Reflection Paper, 2013

RESOURCES - 2• Medicines and Healthcare Products Regulatory Agency (MHRA) UK:

• Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products, 2011

• The Clinical Trials Transformation Initiative (CTTI) • Public-private partnership (2007) identifying practices to increase quality and efficiencies

• TransCelerate BioPharma Inc • Risk-Based Monitoring Methodology, Position Paper (2013)

• Metrics Champions Consortium (MCC) – (2014)

AGENDA• Knowing that RBM is a new name to old ways of monitoring

• Myths of RBM busted

• History of PDCA, QbD & IQRMP

• What is RBM methodology looking like

• How is eRBM used

• New role of the CRA/PM in the RBM/e-RBM world

IS RBM DIFFERENT FROM WHAT WE DO NOW?

100% SDV Reduced SDV

Focused SDV Quality by Design

Performance Metrics Performance & Risk metrics

Risk-based monitoring

Evolving “Art” to the “Science” of Monitoring

No, Not really!

2005 : ICH Q8,Q9,Q10

4 COMMON E-TOOLS IN THE RECENT PAST USED FOR REMOTE MONITORING…

CTMS Safety database EDC E-TMFOperational Data -collection

Safety data-collection Case Record Data-collection

Regulatory Document Collection

Performance metrics- Site metrics- Project metrics- Ops metrics…

- Site metrics- Regulatory metrics- Ops metrics…

- Site metrics- Project metrics- DM metrics…

- Site metrics- Project metrics- Timeline

metrics…Risk metrics

- Issue tracking- Issue escalation- Issue resolution- Findings (A & I)- CAPA …

… WE DO HAVE A CHOICE,

DON’T WE?

STOP OR PROCEED !?• If you have to keep with regulatory trends and thoughts

• If you relate with Harry and decide to go on……do not read the rest of the

slides!

CRA THEN…. VS …. CRA NOW!

PM THEN…. VS …. PM NOW!

PM

DM Bios

COps

QACTSM

Vendors

MYTHS AROUND RBM• Reduces the monitoring visit(s) frequency and revenue

• NOT REALLY – IT HELPS FOCUS THE MONITORING EFFORTS WHERE IT IS NEEDED MOST• FOR SOME STUDIES IT WILL BE TRUE BUT FOR OTHERS NOT SO

• All the terminologies are different & new• NOT REALLY – FUNCTIONALY AND PRINCIPALY THEY ARE SIMILAR & STILL BEING USED• NEW TERMINOLOGIES, TO MATCH THE HOLISTIC/INTEGRATED APPROACH

• We are concentrating only on quantitative measures• NOT REALLY – IT HAS MOVED TO BE MORE OBJECTIVE AND HOLISTIC - BASED ON DATA

FROM DIFFERENT AREAS, FROM SUBJECTIVE AND ISOLATED DATA• QUALITATIVE DATA STILL MATTERS TO CHANGE QUANTITATIVE PARAMETERS

RBM EVOLUTIONARY PATH

QBD : FEEDBACK MECHANISMS FOR

IMPROVEMENTS

PDCA – THE QBD PRINCIPLE

IQRMP CONCEPT

…OLD WINE IN A NEW BOTTLE!

SIMPLY PUT, RBM REQUIRES…

STEP-1 : ASSESS YOUR RISK

STEP-2: DETERMINE KEY RISK INDICATORS

STEP-3: DEFINE PERFORMANCE THRESHOLDS

STEP-4: DETERMINE RESPONSE PLAN

STEP-5: DEFINE A DM PLAN

STEP-6 & 7: DEFINE A COMMUNICATION PLAN

STEP-8: ADJUST THE PLAN

STEPS, QBD & RBM CONNECTED

E-RBM : WHAT DOES IT DO ?!

Dashboards

WHAT’S BEHIND THAT

DASHBOARD?!

HOW AN RBM E-TOOL WILL WORK!

Data Filters

Metrics Thresholds

Flags

Dashboards

VIEW & ACT BASED ON MEANINGFUL FOCUSED MONITORING

EXAMPLES OF DASHBOARDS

ONE EXAMPLE

METRIC

SO WHAT WILL CHANGE FOR ME ?!• Adaptive approach vs Fixed approach• Focused monitoring vs Random sample monitoring• Integrated approach vs Isolated/silo’d approach• Centralized/Remote monitoring vs Classical monitoring• Proactive approach vs Reactive approach• Predictive capability vs Discover / Uncover• Prevention mode vs Patch-up mode• Holistic data reviews vs Patient/Visit wise data

reviews

WHAT’S IN IT FOR THE CRA?• NO MORE “THE LONE SCAPEGOAT” AT AN AUDIT OR INSPECTION • Does not put you on the test mode at every visit• Monitoring will be “fit for purpose”• Work plan focused on “things that matter”• Reduce frequency of travel and related voes• Improves transparency and objectivity as the monitoring agenda is tailored by

data-driven observations• Gives the monitor more time for qualitative aspects to be checked• Most of the monitoring agenda preparations can happen in-house• Easy to convince the sites as there is a standardized way for all sites to resolve

and assess quality and HENCE performance of monitoring visits

IS ON-SITE MONITORING GOING AWAY?

SKILLS REQUIRED FOR CENTRAL MONITOR

• Clinical development expertise: comprehension of the protocol and the output from risk identification and assessment

• Critical thinking: define and analyze data from complex, overlapping domains to make well-supported decisions; see the bigger picture and target specific issues of importance for focused debate

• Data management and clinical operations knowledge: this allows for the ability to identify and provide insight into trends or outliers in data

• Communication skills (written and verbal)• Ability to use the available technologies

DIFFERENCE BETWEEN TRADITIONAL MONITORING & RBM

Gopal Pai

For PMs only

TRANSCELERATE RBM METHODOLOGY

NEWER TYPES OF MONITORING

WHAT ARE REGULATORS LOOKING FOR

WITH RBM?

METRICS & INDICATORS• Generic or protocol specific• Multiple therapeutic areas or specific to protocol / therapeutic

area• Quantitative + Qualitative or quantitative• Leading or lagging

Types of Metrics• Productivity / Timeliness• Quality• Efficiency

INDUSTRY WANTS POTENTIAL COST SAVINGS

HOW IS RISK ASSESSMENT

DONE?

Step 1: Prepare• 1a. Obtain Buy-In from Program Manager • 1b. Identify and Notify Stakeholders • 1c. Identify and Distribute Objectives and Requirements • 1d. Identify Risk/Hazard Taxonomies

Step 2: Identify Risks and Hazards• 2a. Assemble Stakeholders for Risk Assessment • 2b. Review Objectives, Taxonomies, and Process • 2c. Conduct Risk Identification • 2d. Group-Related Risks • 2e. Consolidate Related Risks and Write

Step 3: Assess and Prioritize Risks• 3a. Identify and Get Consensus on Impact/Severity • 3b. Identify and Get Consensus on Probability • 3c. Identify Time Window when Risk Could Occur • 3d. Reassess Any Existing Risks in Database • 3e. Prioritize Risks by Impact, Probability, and Time • 3f. Identify Handling Bands Step 4: Decide on Control Options• 4a. Identify Handling Options Within Each Risk Band • 4b. Identify Risks to be Assumed or Watched • 4c. Identify Risks to be Avoided, Transferred, or Mitigated • 4d. Assign Plan OPRs for Avoided, Transferred, or Mitigated • 4e. Establish or Update Risk Database

Step 5: Establish Handling Plans• 5a. Develop Draft Handling Plans and Resources • 5b. Manager Review and Approval of Handling Plans • 5c. Handling Plan Funded, Directed, and Integrated

Step 6: Implement Handling Plans

• 6a. Finalize Risk Management Plan and Management Infrastructure • 6b. Mechanism to Monitor Triggers, Cues, and Handling • 6c. Implement Handling as Authorized, Funded, and Scheduled • 6d. Provide Reporting on Handling Results and Progress

Step 7: Monitor Handling Plans

• 7a. Periodically Review Handling Plan Results • 7b. Stop or Modify Handling Plans and Resources • 7c. Retire Risks When Handling Plans Completed • 7d. Update Risk Database for Handling Process and Retirement

Step 8: Decisions

• New Phase or Stakeholder? • Key Milestone Approaching? • "N" Months Since Last Assessment? • Is the Risk Process Working?

CM MODELS- 1

CM MODELS- 2