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Centralized vs. Onsite MonitoringApplying FDA’s Risk-Based
Approach
Sandra Maddock, RN, BSN, CCRAPresident, IMARC Research, Inc.
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Agenda
Overview of Monitoring
Monitoring Regulations/Standards
Current status
FDA’s DRAFT Guidance on Risk-based Monitoring
Application
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Overview of MonitoringDefinition
Qualifications
Purpose of monitoring
Day in the Life
Who monitors?
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Overview of Monitoring
• FDA Regulations• ICH Guidelines• ISO 14155:2011 (E)
Definition
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Overview of Monitoring
Definition
• FDA: 21 CFR 812.3 (j) – “When used as a noun, means an individual designated by a sponsor or contract research organization to oversee the progress of an investigation.”“When used as a verb, means to oversee an investigation.”
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Overview of Monitoring
Definition
• ICH GCP: 1.39 – “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs) GCP, and the applicable regulatory requirement(s).”
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Overview of Monitoring
Definition
• ISO 14155 3.29 –“act of overseeing the progress of a clinical investigation and to ensure that it is conducted, recorded, and reported in accordance with the CIP, written procedures, this International Standard, and the applicable regulatory requirements.”
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Overview of Monitoring
Qualifications
• Qualified by training and experience• Have scientific and/or clinical knowledge needed for
specific trial• Should be familiar with investigational products,
protocol, informed consent, pertinent aspects of the trial, GCP, and regulatory requirements
• Qualifications should be documented
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Overview of Monitoring
Purpose
• Verify:– Rights and well-being of human subjects are protected– Reported trial data are accurate, complete, and
verifiable– The conduct of the trial is in compliance with protocol,
GCP and applicable regulatory requirements
ICH 5.18.1ISO 8.2.4
FDA’s draft guidance
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Overview of Monitoring
Day in the Life• Review regulatory
documents• Verify source data• Issue queries on the CRFs
(EDC or paper)• Address and resolve
queries with site staff• Perform device
accountability
• Address action items from previous visits
• Meet with PI, Co-I, or CRC to discuss findings
• Train staff on protocol requirements
• Assess continued acceptability of site to perform protocol requirements… and so much more!
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Overview of Monitoring
Who Monitors?• Physicians• Nurses• Biomedical Engineers• Public Health workers• Biology majors• Pharmacists• And more….
Monitoring Regulations/Standards
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Regulations: FDA
Standards: FDA Guidelines
Standards: ICH Guidelines
Standards: ISO 14155:2011 (E)
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Monitoring Regulations/Standards
• Sponsor requirements noted in various places throughout 21 CFR 812 & 312:– 21 CFR 812.25: Investigational plan shall include the monitoring
procedures and the name/address of the monitor(s)– 21 CFR 812.40: “… ensure proper monitoring of the investigation,
ensuring that IRB review and approval are obtained, …..”– 21 CFR 312.50: “…ensuring proper monitoring of the investigation(s),
ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols “
Regulations: FDA
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Monitoring Regulations/Standards
• Sponsor requirements noted in various places: – 21 CFR 312.50- General Responsibilities of Sponsors– 21 CFR 812.46 (a) Sponsors shall secure compliance with
• Investigational Plan• Regulations• Conditions imposed by IRB or FDA
– If non-compliance continues• Discontinue shipment of investigational product• Terminate participation in investigation
Regulations: FDA
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Monitoring Regulations/Standards
• Guideline for Monitoring Clinical Investigations, January 1988– Vague in its requirements– Effective monitoring requires personal contact between
the monitor and the investigator throughout the trial
Standards: FDA Guidelines
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Monitoring Regulations/Standards
• April 1996• Pharmaceutical-focused• Began laying the groundwork for a risk-based
approach: extent and nature of monitoring should depend on “the objective, purpose, design, complexity, blinding, size, and endpoints of the trial…”
Standards: ICH Guidelines
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Monitoring Regulations/Standards
• 2011• Device focused• Monitoring plan shall take into account “..objective,
design, complexity, size, critical data points and endpoints…”
• However, it also indicates that monitors shall conduct “routine on-site monitoring visits…”
Standards: ISO Guidelines
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Current Status
General Industry Practice
Our Report Card
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Current Practice
General Industry Practice“Many sponsors have understood these guidances as contributing to the notion that FDA expects sponsors to conduct frequent on-site monitoring and 100% verification for all trials, regardless of their design and complexity.”
-FDA’s DRAFT Risk-Based Monitoring Guidance
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Current Practice
• Monitoring of 100% source data• Monitoring conducted at pre-determined time
intervals, for example…– Every 4-6 weeks– Every 5th patient– At least once a quarter
General Industry Practice
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Current Practice
• Most common sponsor-monitor deficiencies noted during FDA inspections:– 2007: • 46% of sponsors inspected had voluntary or official action
indicated• Most common citings:
– Inadequate monitoring– Failure to bring investigators into compliance– Inadequate accountability
Our Report Card
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Current Practice
• Most common sponsor-monitor deficiencies noted during FDA inspections:– 2008: • 39% of sponsors inspected had voluntary or official action
indicated• Most common citings:
– Inadequate monitoring– Failure to bring investigators into compliance– Inadequate accountability
Our Report Card
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Current Practice
• Most common sponsor-monitor deficiencies noted during FDA inspections:– 2009: • 36% of sponsors inspected had voluntary or official action
indicated• Most common citings:
– Inadequate monitoring– Failure to bring investigators into compliance– Inadequate accountability
Our Report Card
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Current Practice
• Most common sponsor-monitor deficiencies noted during FDA inspections:– 2010: • 50% of sponsors inspected had voluntary or official action
indicated• Most common citings:
– Inadequate monitoring– Failure to bring investigators into compliance– Inadequate accountability
Our Report Card
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Current Practice
• Most common sponsor-monitor deficiencies noted during FDA inspections:– 2011: • 45% of sponsors inspected had voluntary or official action
indicated• Most common citings:
– Inadequate monitoring– Failure to bring investigators into compliance– Inadequate accountability
Our Report Card
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Current Practice
–Inadequate monitoring–Failure to bring investigators into compliance–Inadequate accountability
Our Report Card
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FDA’s Guidance on Risk-Based Monitoring
DRAFT
Introduction
Rationale
General Recommendations
Monitoring Plan
Documentation
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FDA’s Guidance on Risk-Based Monitoring
Introduction
• Assist sponsors in developing monitoring strategies• Enhance human subject protection• Enhance the quality of clinical trial data
Variety of approaches
DRAFT
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FDA’s Guidance on Risk-Based Monitoring
• Provide increased ability to protect patients– Not caught up in the minute details, but rather focused
on key data points• Improve overall study quality• Monitor more effectively
DRAFT
Rationale
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FDA’s Guidance on Risk-Based Monitoring
• Tasks that historically could only be done on-site, may now be done remotely due to technology– EDC systems– Webcasts– Email– Online Training Modules
DRAFT
Rationale
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FDA’s Guidance on Risk-Based Monitoring
• No single approach can work for every clinical study
• Modify based on risks of the trial• Include mix of centralized and on-site• Document intended approach in a monitoring plan
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• On-site monitoring activities:– Source data verification– Verification that study documentation exists– Assessment of site’s familiarity and compliance with
protocol– Investigational product accountability– Get a general sense of how things are going at a site
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• Centralized monitoring activities:– Standard checks (ranges, blanks, unusual data,
outliers)– Identify sites with more errors, dropouts, protocol
violations– Data trends– Verify source data remotely (when applicable)
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• Centralized monitoring can assess:– Analyze site characteristics (high screen failure rates,
eligibility violations, delays in submitting data)– Collect – Review – and archive regulatory documents
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• Use of both types of monitoring is encouraged• Greater emphasis of on-site monitoring may be
required earlier in the study
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• Higher frequency monitoring may be needed to assess:– Critical study endpoints– Safety assessments– Documentation surrounding serious adverse
events/unanticipated adverse device effects– Eligibility criteria
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• Higher frequency monitoring may be needed to assess:– That study blind is maintained– Product accountability
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• Monitoring plan considerations– Complexity of the study design– Types of study endpoints– Clinical complexity of the study population– Geography
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• Monitoring plan considerations– Experience of the clinical investigation site– EDC considerations– Relative safety of the investigational product– Stage of the study– Quantity of data
DRAFT
General Recommendations
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FDA’s Guidance on Risk-Based Monitoring
• What should be included?– Description of monitoring methods to be employed– Criteria for determining timing, frequency, and intensity of
monitoring– Reference to any tools that will be used (i.e., checklists)– Identification of events that may trigger changes– Identification of deviations or failures that would be critical to
study integrity
DRAFT
Monitoring Plan
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FDA’s Guidance on Risk-Based Monitoring
• What should be included?– When writing your monitoring plan, define the activities you
will be doing centrally and those that you will be doing on-site• i.e., centralized monitoring will consist of remote review of regulatory
documentation including CVs, licenses, IRB correspondence, etc.• i.e., onsite monitoring will consist of review of informed consent
documents, source data, product accountability, etc.
DRAFT
Monitoring Plan
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FDA’s Guidance on Risk-Based Monitoring
• Communication of monitoring results is critical to effective implementation
DRAFT
Monitoring Plan
Management
On-site Monitor
Data Management
Internal Study Team
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FDA’s Guidance on Risk-Based Monitoring
• Managing Non-compliances
DRAFT
What action is indicated?
Data Mgmt
Monitor
Internal Study Team
Monitoring Plan
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FDA’s Guidance on Risk-Based Monitoring
• Special Training Requirements?– For on-site monitors?– For centralized “monitors”?
• Planned Quality Checks?• Reference to SOPs
DRAFT
Monitoring Plan
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FDA’s Guidance on Risk-Based Monitoring
• Amendments to the monitoring plan– What “triggers” would require review and revision– Consider writing the monitoring plan broadly enough to
include built-in flexibility
DRAFT
Monitoring Plan
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FDA’s Guidance on Risk-Based Monitoring
• For on-site traditional monitoring reports• For centralized use what works within your
system– Cover sheets, cumulative electronic log of deficiencies,
centralized “work space” to list study-related issues, etc.
• Incorporate into quality system; note in monitoring plan
DRAFT
Documentation
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Application
Case Study• Significant risk implantable device study• Device is relatively complicated to deploy• Study conducted at 20 US-based sites• Both experienced and research-naïve sites
involved in the trial• EDC being utilized
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Application
• Sites are asked to email PDFs of regulatory documents
• Screening logs gets faxed every week• Once every 3 months, the sites are asked to fax
product accountability logs
Case Study
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Application
Administrative:• Write monitoring plan to include strategy for
centralized and on-site monitoring• Train staff on expectations, including relevant
procedures, checklists, etc.• Determine mechanism for communicating
Case Study
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Application
On-site Monitors:• Conduct site initiation visits• Monitor each site’s first 3 patients• Monitor research-naïve sites on regular basis until
competency determined (define threshold)• Monitor other sites as needed based on central
monitoring activity
Case Study
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Application
On-site Monitors:• Conduct periodic product accountability• Assess site’s continued adequacy for conducting study• Conduct focused assessment of regulatory documents• Review adverse events• Secure compliance (regardless of origin of finding)• Report to study team
Case Study
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Application
Centralized “monitors”:• Review EDC for:– Standard range checks– Consistency of data– Completeness of data– Unusual distribution (i.e., too little variance)– Adverse event assessment– Eligibility criteria
Case Study
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Application
Centralized “monitors”:• Review regulatory documents – Think beyond just logging them in and filing them. Read and
understand them within each site’s context.• CV that hasn’t been updated in 10 years• IRB approval letter that lists the wrong study or approves a
consent form that you do not have on file
Case Study
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Application
Centralized “monitors”:• Assess overall site performance– Is data timely?– Are they responsive to query requests?– Are they available?– Can they readily retrieve needed documentation?
Case Study
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Application
Communicate• Issues get discussed in a team meeting• Deficiencies noted in central electronic “workspace” • Monitoring effort re-evaluated regularly• Project manager determines that increased or decreased
frequency for a particular site is appropriate
Case Study
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Application
Result?• Could be more efficient use of on-site monitors’ time– Time spent on critical areas as opposed to administrative areas
• Cost savings due to decreased number of trips and/or decreased amount of time needed at sites for each visit
• Sites may appreciate having less on-site monitoring
Case Study
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4 Main Points• We’re all “monitors” in some capacity• Determining the nature and frequency of monitoring
requires a risk-based assessment• Documenting all monitoring activity and
communicating findings is essential to successful implementation
• Utilizing central monitors to help direct on-site monitoring efforts can increase efficiency and decrease cost
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Thank You!
QUESTIONS?
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References
• FDA Guidance: Risk-Based Approach to Monitoring (2011). Retrieved from http://1.usa.gov/rjmVrh
• FDA Guidance: Monitoring of Clinical Investigations (1988).• Code of Federal Regulations: 21 CFR 812• Guidance for Industry, E6 Good Clinical Practice• International Standards ISO 14155:2011 (E)• FDA’s Annual BIMO Inspection Metrics (2007-2011). Retrieved from
http://1.usa.gov/HLS1Lt