The document discusses the FDA's risk-based approach to monitoring clinical trials, outlining definitions, regulations, qualifications, and purposes of monitoring. It highlights the need for a combination of centralized and on-site monitoring to enhance patient protection and data quality while addressing common deficiencies noted during FDA inspections. Additionally, it emphasizes the importance of a well-documented monitoring plan that considers various factors to ensure effective implementation.

1. Centralized vs. Onsite Monitoring
Applying FDA’s Risk-Based
Approach
Sandra Maddock, RN, BSN, CCRA
President, IMARC Research, Inc.
1

2. Agenda
Overview of Monitoring
Monitoring Regulations/Standards
Current status
FDA’s DRAFT Guidance on Risk-based Monitoring
Application
2

3. Overview of Monitoring
Definition
Qualifications
Purpose of monitoring
Day in the Life
Who monitors?
3

4. Overview of Monitoring
Definition
• FDA Regulations
• ICH Guidelines
• ISO 14155:2011 (E)
4

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.”
5

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).”
6

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.”
7

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
8

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FDA’s draft guidance
9

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!
10

11. Overview of Monitoring
Who Monitors?
• Physicians
• Nurses
• Biomedical Engineers
• Public Health workers
• Biology majors
• Pharmacists
• And more….
11

12. Monitoring Regulations/Standards
Regulations: FDA
Standards: FDA Guidelines
Standards: ICH Guidelines
Standards: ISO 14155:2011 (E)
12

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 “
13

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
14

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
15

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…”
16

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…”
17

18. Current Status
General Industry Practice
Our Report Card
18

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
19

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
20

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
21

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
22

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
23

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
24

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
25

26. Current Practice
Our Report Card
–Inadequate monitoring
–Failure to bring investigators into
compliance
–Inadequate accountability
26

27. FDA’s Guidance on Risk-Based
Monitoring
Introduction
Rationale
General Recommendations
Monitoring Plan
Documentation
27

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
28

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
29

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
30

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
31

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
32

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)
33

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
34

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
35

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
36

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
37

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
38

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
39

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
40

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.
41

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
42

43. FDA’s Guidance on Risk-Based
Monitoring
Monitoring Plan
• Managing Non-compliances
Internal
Study
Monitor Team
Data
Mgmt
What action is indicated?
43

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
44

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
45

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
46

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
47

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
48

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
49

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
51

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
52

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?
54

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
55

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
56

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
57

58. Thank You!
QUESTIONS?
58

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
59

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