Risk Based Monitoring in Clinical Trials - Impact on Sites

©Copyright QD-Quality and Training Solutions, Inc. All Rights Reserved©Copyright QD-Quality and Training Solutions, Inc. All Rights Reserved
Hidden Risks with Risk Based Monitoring-
Site Perspective
Liz Wool, RN, BSN, CCRA, CMT
President and CEO
QD-Quality and Training Solutions, Inc.
www.qd-qts.com
lizwool@qd-qts.com
Franklin, TN
Member, Standards Committee, Society of Clinical Research Sites
Member Board of Trustees
Association of Clinical Research Professionals (ACRP)
ACRP Raleigh-Durham Chapter Annual Conference 2013

©Copyright QD-Quality and Training Solutions, Inc. All Rights Reserved
Learning Objectives
• Identify two (2) areas for
site’s to assess regarding the
impact of Risk - Based
Monitoring to site practices in
clinical trials.
• Describe two (2) questions to
ask the Sponsor/CRO for a
Risk-Based Monitoring model
in order to assist in
determining the resourcing
plan and trial budget.

Quality
Quality is characterized by the ability to :
1. Effectively and efficiently answer the
intended questions about the benefits
and risks of a medical product
(therapeutic or diagnostic) or
procedure, while,
2. Ensuring protection of human
subjects
Clinical Trials Transformation Initiative FDA- CTTI

GCP Quality Management System
“Building Quality Into the Clinical Program”
GCP
Process Performance –Systems, Processes, Documentation to “Quality Standards”
Quality-Performance Monitoring System (QC/QA)
Corrective & Preventive Action (CAPA) System
Change Management System, CQI, Document Control
Management Review: On-Going Acceptability of the QMS
Management Responsibilities
Quality Culture, Policy , Objectives
Resources
Quality Commitment: All Staff
Knowledge Management
Risk Management
Study
Start Up
Data
Analysis, CSR
Study
Conduct
Study
Close-Out
Protocol Design &
Operational Design
Study
Planning
Marketing
Application
Enabler
Investigational Product-Device
Enabler
QMS
Elements

Let’s Normalize the Terminology

Centralized RBM
TargetedRBM
Adaptive RBM

The THREE PILLARS OF RBM™
Centralized (Statistical)
Monitoring
Remote Site
Management
On-Site
Site Management
www. Wordpress.com 8

Focuses on
“Performance Monitoring of the Trial”
9
Reliance on electronica data sources
Examples include...

E-Data Sources
EDC
EPRO
CTMS
EHR -
EMR
IWRS
10

E-Data Sources

Centralized
Monitoring
Plan
Data Analytics
(performance reporting through various
edata sources)
Metrics and Tolerance Limits for ‘error rate’
Adhere to Monitoring Plan requirements
Determine outlier ranges for analysis and
further investigation
*Review EDC and query rates, various
reports/metrics on an ongoing basis per e-data
sources for trial*
Documentation *refer to FDA Guidance
Remote Site
Management
Plan
Site Relationship:
Webex video /webcam– not just email,
personal touch still needed!
Early communication, evaluation and
re-training for performance
issues/gaps; tracking regulatory
requirements and site adherence to
GCP/HSP/EDC/protocol requirements
Adhere to Monitoring Plan
requirements
* Site Specific Plan: customization for
site performance issues
On-Site - Site
Management
Plan
Site Management: HSP, GCP
Performance gaps and issues
requirements
Site Specific Monitoring Plan:
customization for site performance
issues
12

Centralized
Monitoring
Plan
Data Analytics
(performance reporting through
various edata sources)
Metrics and Tolerance Limits for ‘error
rate’
sources for trial*
Documentation *refer to FDA
Guidance
Remote Site
Management
Plan
Site Relationship:
Webex video /webcam– not just
email, personal touch still needed!
Early communication, evaluation and re-
training for performance issues/gaps;
tracking regulatory requirements and site
adherence to GCP/HSP/EDC/protocol
requirements
* Site Specific Plan: customization for site
performance issues
Guidance
On-Site - Site
Management
Plan
customization for site performance issues
Guidance
13

Centralized
Monitoring
Plan
Data Analytics
(performance reporting through various
edata sources)
Metrics and Tolerance Limits for ‘error rate’
sources for trial*
Remote Site
Management
Plan
Site Relationship:
Webex video /webcam– not just email,
personal touch still needed!
Early communication, evaluation and
re-training for performance
issues/gaps; tracking regulatory
requirements and site adherence to
GCP/HSP/EDC/protocol requirements
requirements
* Site Specific Plan: customization for
site performance issues
Documentation*refer to FDA Guidance
On-Site - Site
Management
Plan
requirements
customization for site performance
issues
IMPLEMENTED DIFFERENTLY IN ORGANIZATIONS
NEED TO KNOW HOW AN ORGANIZATION IS
EXECUTING
*All of these areas per job title?
*One area per job title?
*Other?
*Example: CRA reviews e-TMF/EDC site information
14

A Risk Based Approach can only
occur if there is a solid foundation
Cynthia Kleppinger, MD
Senior Medical Officer
FDA, Office of Scientific Investigations, CDER
DIA Annual Meeting 2012
15

IT’S ABOUT RISK MANAGEMENT!
16
Combination of the probability of occurrence
of harm and the severity of that harm. And,
detectability ...

How does RBM Impact Sites?

Where to start?

Site
Impact
Trial
Execution
Resourcing
Financial
Working
With
Sponsor
and CRO
Quality
Program

Areas to Assess
• How does the organization define RBM ?
• What is their model?
– Some are saying ‘RBM’ – in reality it is reduced
SDV only
– Monitoring Plan for your site and other sites
• When and how is the site informed and trained?
Feasibility Questionnaire? Qualification Assessment?
Investigator Meeting? Site Initiation?
• What does the Monitoring Plan entail? What is the plan
for communicating site performance to you via
centralized statistical monitoring and data analytics
review? Remote site management communications?

Areas to Assess
– Monitoring Plan for your site and other sites
• Type and frequency of ‘on site’ visits
–Static plan for ‘all sites’
–Variable approach and plan for site
monitoring based on risk variables (history
with your site, therapeutic area, phase of
trial, IP requirements etc)
»Do they perform ‘risk scoring of sites’
and take this into account for the
Monitoring Plan?
* This is not an all inclusive list of questions to ask*

Areas to Assess
• Resources and execution of the RBM
– Who is your ‘one point of contact’
• What is their title?
• What is their role and responsibilities?
– Who will your site be engaging with – multiple
communication modalities – for the study?
• Job title
• Role
• Responsibility
• Internal communications
Will one person be calling your site?
Or Multiple people be calling your site?
* This is not an all inclusive list of questions to ask*

Usage of and frequency of site surveys
'how are we as the Sponsor/CRO
doing? 'areas for improvement?'

Allows for understanding of the model
for sites to:
• Develop study budget and contract terms
• Resource Allocations
– Personnel attributes
– Resource modeling
– Scheduling personnel for the study
• Quality Management Plan for the Trial
• Identify potential risks in trial execution
• Determine communication plans

What about your Site Practices?

Ask questions for each
‘monitoring model’
• Historically – what has been performed during a site visit?
• What will or will not be done at a site visit?
• What elements of GCP or the protocol/investigational plan
can ONLY be verified by visiting the site?
• ‘’5” Risk Assessment Questions
• AND MORE!

People &
Site
Resources
Operations,
Standards,
Processes
Technology

Risk Assessment
1. What might go wrong?
2. What needs to go right?
3. What is the likelihood
(probability) it will go wrong?
4. What are the consequences –
impact (severity)?
5. How will these be detected?

Site Practices
Business
Impact
Cost modeling
for RBM – ‘all the
work’ previously
performed with
‘site visits’
Resource Models
Personnel
Assignments
Team meetings
Meetings with PI
Quality
Management
System
*Protocol Quality
Plan*
* This is not an all inclusive list *

Site Practices
Business
Impact
Good Documentation
Practices (phone
contacts, retain
emails, responses to
requests etc
*CRITICAL*)
Monitoring ‘trial
performance’
Sponsors/CRO
adherence to their
monitoring plan
On –site visits –
costing this out as well
Monitoring site staff
performance and
adherence to study
and monitoring plan
commitments (e.g.,
respond to calls,
queries)
Access EDC reports of
your site performance

Site Practices
Business Impact
REVENUE:
Charge for
Time and
Materials
REVENUE:
Unit Base
Pricing
REVENUE:
Overhead
Percentage
FINANCIAL:
Utilization
FINANCIAL:
Realization
FINANCIAL:
Variable
Costs

Internal Communication Plans
Escalating Issues to Management
Training and Re-training of Staff

What About HIPAA
and
Informed Consents?

If the CRA is visiting your site less
frequently, what does your site need
to ‘fill in’ or ‘do’....

• What is your current program?
• Is your Quality Management Model
defined with standards, methods and
documentation for communicating to
staff?
• Resources to meet the needs for the size of
your business/research enterprise?
• Have you trained staff to the model? Their
Roles? Their responsibilities for quality?
• What are the required qualifications and
training for staff with a ‘quality’ role?
• How is this program deployed, managed
and evaluation performed? (e.g., protocol,
TA, staff, business enterprise etc.)
• Continuous Quality Improvement during
the trial?
• QC for protocol, staff, programs
• QA program: Internal Audits
• HAVE YOU IDENTIFIED THE HIGH RISK
AREAS: your business, and with each
protocol?

Goal is:
HSP
Data Quality
Data Integrity
DATA
RELIABILITY

Protocol “Life – Cycle” Approach
Site
Contacted –
Interest in
Study
Feasibility
and
Protocol
Assessment
Study
Planning
Study
Initiation
Study
Conduct
Study Close-
Out
Post – Study
Activities
Focus on Your Organization
“How you do your business”
Sub-processes for each ..map out..
“ safety risks, risk to clinical trial quality; risk to
subjects; risk to data quality/integrity”

“An investment in knowledge
pays the best interest”
Benjamin Franklin

FARBMAES

References

References
• Ball, L., Defining Quality in Clinical Trials: An FDA
Perspective, DIA Annual Meeting, 2012
• Copeland, D., Is Your Site Ready for Risk – Based
Monitoring, ACRP Global Conference, 2013
• CTTI: Developing Effective Quality Systems in Clinical
Trials: An Enlightened Approach , Summary of an
Expert Meeting held October 13–14, 2010
• Kleppinger, C., Ball., L., Building Quality in Clinical
Trials with Use of a Quality Systems Approach,
Clinical Infectious Diseases, 2010:51 (S1): S-111-
S116

References
• Sweeney, F., Defining Quality in Clinical Trials: EMA
Perspective, DIA Annual Meeting, 2011
• Wool, L., Intertwining Quality Management
Systems with Metrics to Improve Trial Quality, The
Monitor, August, 2012
• Assuring Data Quality and Validity in Clinical Trials
for Regulatory Decision Making: Workshop
Report,IOM 1999 at http://www.iom.edu/CMS/3740/5583.aspx

Balancing Risk-Based Monitoring
http://www.grc-lounge.com/en/ARIS-GRC/173329.html
49

Risk Based Monitoring in Clinical Trials - Impact on Sites

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