Sandra Maddock, RN, BSN, CCRA and President of IMARC Research, Inc. presents on Applying FDA’s Risk-Based Approach in an audio conference on September 11, 2012.
4. Overview of Monitoring
Definition
• FDA Regulations
• ICH Guidelines
• ISO 14155:2011 (E)
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5. 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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6. 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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7. 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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8. 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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9. 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 5.18.1
ISO 8.2.4
FDA’s draft guidance
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10. Overview of Monitoring
Day in the Life
• Review regulatory • Address action items from
documents previous visits
• Verify source data • Meet with PI, Co-I, or CRC to
• Issue queries on the CRFs discuss findings
(EDC or paper) • Train staff on protocol
• Address and resolve requirements
queries with site staff • Assess continued acceptability
• Perform device of site to perform protocol
accountability requirements… and so much
more!
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11. Overview of Monitoring
Who Monitors?
• Physicians
• Nurses
• Biomedical Engineers
• Public Health workers
• Biology majors
• Pharmacists
• And more….
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12. Monitoring Regulations/Standards
Regulations: FDA
Standards: FDA Guidelines
Standards: ICH Guidelines
Standards: ISO 14155:2011 (E)
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13. Monitoring Regulations/Standards
Regulations: FDA
• 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 “
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14. Monitoring Regulations/Standards
Regulations: FDA
• 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
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15. Monitoring Regulations/Standards
Standards: FDA Guidelines
• 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
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16. Monitoring Regulations/Standards
Standards: ICH Guidelines
• 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…”
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17. Monitoring Regulations/Standards
Standards: ISO Guidelines
• 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…”
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19. 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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20. Current Practice
General Industry 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
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21. Current Practice
Our Report Card
• 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
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22. Current Practice
Our Report Card
• 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
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23. Current Practice
Our Report Card
• 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
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24. Current Practice
Our Report Card
• 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
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25. Current Practice
Our Report Card
• 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
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26. Current Practice
Our Report Card
–Inadequate monitoring
–Failure to bring investigators into
compliance
–Inadequate accountability
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27. FDA’s Guidance on Risk-Based
Monitoring
Introduction
Rationale
General Recommendations
Monitoring Plan
Documentation
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28. 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
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29. FDA’s Guidance on Risk-Based
Monitoring
Rationale
• 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
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30. FDA’s Guidance on Risk-Based
Monitoring
Rationale
• Tasks that historically could only be done on-site,
may now be done remotely due to technology
– EDC systems
– Webcasts
– Email
– Online Training Modules
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31. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• 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
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32. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• 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
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33. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• 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)
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34. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• Centralized monitoring can assess:
– Analyze site characteristics (high screen failure rates,
eligibility violations, delays in submitting data)
– Collect – Review – and archive regulatory documents
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35. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• Use of both types of monitoring is encouraged
• Greater emphasis of on-site monitoring may be
required earlier in the study
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36. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• Higher frequency monitoring may be needed to
assess:
– Critical study endpoints
– Safety assessments
– Documentation surrounding serious adverse
events/unanticipated adverse device effects
– Eligibility criteria
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37. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• Higher frequency monitoring may be needed to
assess:
– That study blind is maintained
– Product accountability
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38. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• Monitoring plan considerations
– Complexity of the study design
– Types of study endpoints
– Clinical complexity of the study population
– Geography
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39. FDA’s Guidance on Risk-Based
Monitoring
General Recommendations
• Monitoring plan considerations
– Experience of the clinical investigation site
– EDC considerations
– Relative safety of the investigational product
– Stage of the study
– Quantity of data
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40. FDA’s Guidance on Risk-Based
Monitoring
Monitoring Plan
• 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
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41. FDA’s Guidance on Risk-Based
Monitoring
Monitoring Plan
• 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.
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42. FDA’s Guidance on Risk-Based
Monitoring
Monitoring Plan
• Communication of monitoring results is critical to
effective implementation
Management
Internal Study Team On-site Monitor
Data Management
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43. FDA’s Guidance on Risk-Based
Monitoring
Monitoring Plan
• Managing Non-compliances
Internal
Study
Monitor Team
Data
Mgmt
What action is indicated?
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44. FDA’s Guidance on Risk-Based
Monitoring
Monitoring Plan
• Special Training Requirements?
– For on-site monitors?
– For centralized “monitors”?
• Planned Quality Checks?
• Reference to SOPs
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45. FDA’s Guidance on Risk-Based
Monitoring
Monitoring Plan
• Amendments to the monitoring plan
– What “triggers” would require review and revision
– Consider writing the monitoring plan broadly enough to
include built-in flexibility
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46. FDA’s Guidance on Risk-Based
Monitoring
Documentation
• 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
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47. 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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48. Application
Case Study
• 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
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49. Application
Case Study
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
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50. Application
Case Study
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
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51. Application
Case Study
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
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52. Application
Case Study
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
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53. Application
Case Study
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
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54. Application
Case Study
Centralized “monitors”:
• Assess overall site performance
– Is data timely?
– Are they responsive to query requests?
– Are they available?
– Can they readily retrieve needed documentation?
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55. Application
Case Study
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
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56. Application
Case Study
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
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57. 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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59. 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
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