Presented By

William Gluck, Ph.D.

VP, DATATRAK Clinical Knowledge

DATATRAK International, Inc.

Risk-Based Monitoring in Practice

5/29/2014 1 www.datatrak.com

Confidential –

Dr. Bill Gluck ► Dr. Gluck has over 30 years of leadership experience in the

Life Sciences industry, and brings his expertise in the field of

Risk Based Monitoring to DATATRAK.

► Dr. Gluck has held management roles in sponsor companies,

including Amgen, BASF Corporation, Gilead Sciences, and

Triangle Pharmaceuticals. Dr. Gluck also has expertise with

CRO organizations, having served in senior management roles

for seven years.

► Dr. Gluck began his career in academia at the university level,

and now serves as the Program Director for the Clinical Trials

Research and Medical Product Safety/Pharmacoviligance

programs at Durham Technical Community College.

► Dr. Gluck has a Bachelor of Science degree from the University

of Scranton and Master and Ph.D. degrees from North Dakota

State University.

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Review of the Risk-Based Guidance Document

How the Guidance is Re-Defining How Studies are

Conducted

Insights to Implementation

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http://www.fda.gov/Drugs/GuidanceComplianc

eRegulatoryInformation/Guidances/default.htm

History of Guidance Document

• Replaced 1988 Guidance on Monitoring

• New RBM Draft Guidance August 2011

• Final RBM Guidance August 2013

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Guidance Document General Points:

Guidance focuses on monitoring – only one aspect of the clinical trial process

Monitoring is a quality control tool

FDA defines monitoring as the methods used for the conduct of and reporting of data from clinical investigations

Stronger support of risk-based monitoring approaches are clearly stated

FDA recommends a quality risk management approach to clinical trials

The risk-based approach is dynamic and can facilitate continual improvement in trial conduct and oversight

Expect risk-based monitoring to enhance data quality

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Approaches to Monitoring

On-Site Monitoring – an in-person evaluation

Centralized Monitoring – a remote evaluation

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On-Site Monitoring

Assurance that subjects and

study documents exist

Sense of Quality of overall conduct

at a site

Early in the study

Complete administrative and regulatory tasks

Centralized Monitoring

Remote activities

Targeted on-site monitoring

Review of data in real-time

Verify source data remotely

Conduct aggregate

statistical analysis of study data

Conduct analysis of sites,

performance, and data

Complete administrative and regulatory tasks

Types of Monitoring

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Centralized Monitoring: Alternative Monitoring Techniques

Monitor through routine review of entered data

Conduct statistical analyses to identify data trends

Analyze site characteristics, performance measures, and clinical data to identify potential characteristics associated with noncompliance and poor performance

Verify critical source data remotely, when source data are available

Complete administrative and regulatory tasks

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Alternative Monitoring Techniques: Other Areas of Focus

Communication with Study Site Staff

Review of Site Processes and Procedures

a. Informed Consent

b. Site Records

Source Data Verification and Corroboration

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How the Guidance is Re-Defining How Studies are Conducted

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The Guidance: Focus on Monitoring

No single approach works

Tailor monitoring plans to study – focused on specific subject protection and data quality

Assess critical data and processes – informed consent and eligibility criteria

Assess critical data and processes – documentation of accountability and administration of investigational products

Assess critical data and processes – focus on trial integrity…processes such as maintaining the study blind

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• Overall support and guidance

• Protocol development Clinical R&D

• Sponsor Team Members

• Sites and Site Team Members

Clinical Study Team

• Sponsor CRA’s or designated CRO representatives

• Site key personnel CRA/Site

• Clinical Data Management

• Biostatistics

• Regulatory, Quality, Compliance

Support Services

Key Roles and Responsibilities

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Insights to Implementation

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Risk Assessment

Identify the risks

Analyze the risk

Implement controls

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Assessing Risk for Monitoring

Guidance Discusses risk assessment in the context of clinical monitoring

As noted: identifies analyses, and implements controls to manage risk

Does NOT provide comprehensive detail on how to perform risk assessment

Risk Assessment Methodologies

Guidance for Industry, Q9 Quality Risk Management, June 2006.

ISO 31010:2009 Risk Management – Risk Assessments Techniques

Risk Identification for Monitoring

“…consider the types of data to be collected, the specific activities required to collect these data, and the range of potential safety and other human subject protection concerns…”

Assess and prioritize risk:

a. likelihood of occurrence

b. impact on safety and trial integrity

c. extent to which errors would be detectable

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Factors to Consider in Developing Monitoring Plans

Complexity of the Study Design

Types of Study Endpoints and Quantity of Data

Clinical Complexity of the Study Population and Geography

Relative Safety of the Investigational Product

Stage of the Study

Experience of the Sites and the Sponsor

Ability of Leverage Technology

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Key Components of a Monitoring Plan

Description of Monitoring Approaches

Communication of Monitoring Results

Management of Noncompliance

Ensuring Quality Monitoring

Plan Amendments/History of Plan Changes or Modifications

Confidential – 18

Monitoring Plan Template

Study Protocol:

Stage/Phase of Study:

Introduction:

Brief description of the study landscape – geography of the sites, anticipated reach of the population, potential

challenges in terms of enrollment and compliance by both study participants and sites.

Description of Monitoring Approaches:

Include in this section a description of the monitoring methods to be employed especially noting how the critical

elements/data points/end points will be collected. Note too and risks involved and how these risks might be mitigated

(at a high level). Also include the timing and frequency of the various approaches you are planning and how changes

will be made and communicated through the study team.

In this section also include what the threshold are for action or those specific trigger points that might require a site to

be monitoring on a more frequent basis.

Also include definitions for deviations and how they should be reported and recorded.

Communication Plan:

Describe how reports and monitoring results will be communicated throughout the team. Identify/Define specific

standard reports and how and when they will be generated and then communicated.

Also include an escalation process of communication should the need arise or unforeseen challenges emerge during the

course of the study.

Confidential – 19

Management of Noncompliance:

Describe the process for addressing challenges of noncompliance or the resolution of significant issues that have not

yet been resolved. Again build upon the communication escalation process to make sure that there is an escalation

process in place should it be necessary.

As part of the process, in this section you should also describe a procedure to conduct a root cause analysis and how

the issue will not resurface later in the study.

Quality Monitoring Process/Plan:

In this section describe the specific training and qualifications needed of all study team participants from the

sponsor’s perspective through to each site perspective.

Planned audits of monitoring across several levels should be defined as well as a description of the process in case

there is a need for an unplanned or for cause audit.

Also included in this section should be the plan for co-monitoring trips or oversight to ensure consistency of

monitoring and compliance to documented monitoring processes and procedures.

Amendments

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Additional Strategies to Help to Ensure Study Quality

Protocol and CRF Design

Training and Communication

Delegation of Responsibilities

Site Selection and Interaction

Confidential –

Sample Risk Assessment Worksheet

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Risk Assessment

Worksheet

Risk Area/Category Potential Risk Assessed Risk Examples (list study specific

issues)

Include in

Monitoring Plan

(Yes/No) Tolerance Threshhold

Confidential – 22

Risk Area/Category Potential Risk Assessed Risk Examples (list study specific

issues)

Include in

Monitoring Plan

(Yes/No) Tolerance Threshold

Study Planning Study protocol development and

related essential documentation

How complex is the protocol,

are there anticipated amendment

points, process of unintended

amendments, process for the

collection, review, and

management of FDA/ICH GCP

related essential documents, etc.

Is there a clear understanding of

roles and responsbilities,

transparancy in communication

and expectations?

Confidential – 23

Budgetary constraints

Does the budget allow for

adequate time and resources to

conduct the study, monitoring,

other study activities? Are the

contracts associated with all

supportive facets of a clinical

study available and/or in place?

Is there legal support if

applicable?

Site identification/Feasibility

Based on the study protocol

can sites be easily identified, is

the needed study population

obtainable, are the site reliable

in terms of attracting and

qualifying potential study

participants,etc.

Site Qualifications

Qualifications of the principal

investigator/clinical investigator,

qualificiation of the site overall -

are the proper site processes

and procedures in place, are the

site personnel trained,

experience and qualified, etc.

Vendor Qualifications

Qualifications of the vendor (is

this a core support service),

qualification of the vendor

overall - are the proper

processes and procedures in

place, are the personnel trained,

experience and qualified, etc.

Confidential – 24

Study Conduct Quality Management System-Sponsor Level Is there a sponsor level QMS in place, at the

CRO/support company level, at the site level?

Required Regulatory Reporting

Does the sponsor have the infrastructure to

support the required regulatory reporting

needed? Does the supporting organization

have the infrastructure? Does the site have a

QMS or the essential quality controls in place?

Specific Study Activities

Informed consent process, enforcement of

INC/EXC, handling protocol

deviations/violations, stopping rules, SAE

handling, dose modifications, etc.

Confidential – 25

Investigational Product

Is there investigational product in place to conduct the study, is

there a re-supply process, is the supply chain establsied, are there

regulatory risks for international studies/transport/storage of the

investigational product?

Safety Concerns

Study participant protection and well-being

processes/procedures in place, safety monitoring, know adverse

evetns/reactions, process for documetnation and reporting of

unexpected events and SAE's

Study specific tasks Endpoints, complexity of the study, stage of the study, number of

potential study participants and geographic availability

Confidential – 26

Performance Metrics Time of entry after study participant visit, time of query

resolution/response, etc.

Quality Metrics Number of queries needed, number of re-queries needed, etc.

Biostatistics and CDM concerns

Technology availability and evaluation, quantity of data, clear

identification of endpoints and collection of needed study data,

identification and generation of reports, data transfer, internal

filtering etc., availability and use of standards such as CDISC

(STDM).

Confidential –

List of Selected References

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

http://www.mhra.gov.uk/home/groups/l-ctu/documents/websiteresources/con111784.pdf

http://www.transceleratebiopharmainc.com/wp-content/uploads/2013/09/Risk-Based-Monitoring-Methodology-Position-Paper.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500110059.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf

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Summary

1. Risk-Based Monitoring is focused on monitoring

2. Regulatory bodies want to promote flexibility and the ability to

explore new methods for monitoring and to leverage advances

in technology where applicable

3. It is anticipated that there will be continued use of on-site

monitoring but also anticipate the evolving use of technology

and monitoring methodologies to achieve heighted levels of

study participant safety and increased levels of data quality

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William Gluck, Ph.D.

VP, DATATRAK Clinical Knowledge

DATATRAK

E-Mail: Bill.Gluck@datatrak.com