Site Monitoring in Clinical Trials:
the evidence, new approaches
and trial manager perspectives
Athene Lane
Overview: presentation/discussion
• Rationale for site monitoring
• Systematic review of on-site monitoring systems
• New approaches to site monitoring
• Peer review site monitoring system (PRIME)
• Evaluation of PRIME in the ProtecT trial
• Trial managers experiences and practices
Monitoring rationale: ICH- GCP
• The rights of participants are protected
• Data is accurate, complete & verifiable (SDV)
• Conduct adheres to the protocol and GCP
• ‘Generally there is a need for on-site monitoring,
before, during and after the trial’
• European Clinical Trials Directive based on ICHGCP for all IMP trials became UK law in 2004
Trial monitoring systems
MHRA
Ethics
TSC
DMC
CI & TMG
Regulators &
Sponsors
CTU
Protocol & SOPs
Site monitoring
Training
Data checks
Trial conduct & data collection
Trial sites
Systematic review of onsite monitoring systems
Rhiannon Macefield, Andrew Beswick, Jane Blazeby
PRISMA flow diagram
Records from other sources
n= 28
(Hand search of CT/CCT/CCT, referenced in other
papers , personal knowledge)
Records from database search
(Embase: 529, Medline: 536)
Removed duplicates n = 678
Records screened
n = 678
Records excluded
n = 526
Full-text articles
assessed
n =152
Excluded (n = 123)
Safety monitoring or
central monitoring
e.g. radiotherapy QA, no
details/methods, not full paper,
unavailable (2)
Included
n = 29
Articles included
n = 57
Publication characteristics (n)

1 RCT of site monitoring intervention – stopped early

Individual trial reports (30, 26 trials)


Heart disease (33%), cancer (23%)
Group or organisation descriptions (21)

16 groups: e.g. USA NCI cooperative groups, EORTC and
pharmaceutical industry

Cost simulations (2) and surveys (3)
Published monitoring structures
•
Frequency: multiple visits to all sites (where stated)
•
•
Range from 2 months to 3 years
Monitors varied:
•
sponsors, ‘independent evaluators’, DSMB/TSC, coordinating
centre staff, trial coordinators, data managers, clinical
investigators, CRA
•
1 to 8 monitors, typically up to 3
Site monitoring activities
•
Review trial documents
•
View site facilities/clinic tours
•
Walk through/discuss procedures with site staff
•
Interview site staff
•
Observe trial procedures
•
Often inadequately described: “A full onsite review”
Site monitoring assessments
•
Consent verification
•
SDV and data management
•
Protocol adherence
•
Drug accountability
•
Safety monitoring and ethical approvals
•
Site operation including accrual and retention
•
Staff training
Feedback and reports
•
Some exit interviews to outline findings and problems (NCI
cooperative groups)
•
Report templates (NIDA CTN, NHBLI, VA)
•
Written report distributed to:
•
Local investigator/site director
•
Sponsors/funders
•
CI and trial coordinator
•
TSC and performance review committees
Benefits of site monitoring (5)
•
Identified problems: procedural errors/data inconsistencies
•
Issues resolved quicker, e.g. increased recruitment (2)
•
Improved protocol adherence and GCP compliance (3)
•
Interactions of staff between sites and central staff
•
Shared best practice between sites
•
Opportunities for training
Site monitoring disadvantages
•
Costs: typically for one day but up to four days
•
EORTC = £600 direct costs in 1991
•
NIDA £1000 direct costs in 2009
•
Staff time regarded as a major cost but not measured
•
50% of site staff in a survey found visits annoying
Summary and ongoing research
•
Most publications from non-commercial trials & groups
•
No consistency in systems
•
Little evaluation of costs and benefits to trials
•
Abstract in Clinical Trials2010;7:428 (paper under review)
•
New trials of site monitoring:
•
Pharma standard v risk-adapted monitoring trials:
• France: OPTIMON (V Journot) CC Trials 2011 32: 16.
• Germany: ADAMON (O Brostaneau) C Trials 2009 6:585.
New approaches
• Monitoring workshop of best practice in 2012
• N West HTMR, C Tudur-Smith & other hubs
• Effective and efficient monitoring research
• CTTI & FDA in USA, M Landray, CTSU, Oxford
• FDA draft guidance on risk adapted monitoring
• ECRIN: QA working party on monitoring
• V Journot, Bordeaux
• [MHRA risk-adapted processes M Ward]
Peer Review Intervention
for Monitoring and
Evaluating Sites
Athene Lane, Rhiannon Macefield, Julia Wade, Liz Down, Sue
Bonnington, Pete Holding, Teresa Lennon, Amanda Jones, Liz
Salter, David Neal, Freddie Hamdy & Jenny Donovan
PRIME structure
Peer reviewers
TM & 2 site nurses (from 5)
Annual PRIME visits to all sites
(1-2 d)
SOP & report template
Exit meeting & problem solving
Report to CIs & local PI
PRIME Intervention & Evaluation
Component
Objective
PRIME activity
Hours
Orientation
Training
Orientation & trial progress meeting
Site performance
Performance
Site recruitment and attrition rates
0.5
Protocol adherence
GCP
Observation, feedback & meetings
6
Data collection
GCP
Observation of CRF completion
1
Safety monitoring
GCP
Review process & documentation
0.5
Documentation
GCP
Site file review
1
Training
Training
Site staff training discussion
0.5
Site organisation
Performance
Coordinating centre communication
0.5
Trial conduct observation
• Recruitment & follow-up appointments
• Individual feedback given to site staff
• Errors difficult to identify otherwise:
• Local exclusion criteria
• Weight taken with shoes on
Evaluation of PRIME
•
•
•
•
•
ProtecT: prostate cancer treatment trial
ISRCTN20141297, HTA funded trial
Three years of PRIME site reports analysed
Resource use
[Survey of site nurses]
Findings by component and year
Training
Performance
GCP adherence
PRIME benefits and costs
• Benefits: site performance gains, e.g.
• Increased radiotherapy CRF return (65%)
• Study cohesion & communication
• Identifies individual and study training needs
• “Useful for ensuring everything is in order!
Good for sharing good practice” (staff survey)
• Annual costs: staff time (32-56 d) & £5,600
Summary
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•
•
•
•
PRIME visits annually to all trial sites
Standardises trial conduct & good practice
Site staff focus including as peer reviewers
Improves GCP compliance
Performance gains
PRIME recent research
• Used in two other studies:
• SFP Cymru (SEWTU)
• DUTY (BRTC & SEWTU)
•
•
•
•
PRIME SOP adapted for these studies
Benefits from site visits and training
Currently seeking additional trials?
Evaluate in other trials, including costs
• Any questions?
• Group work and discussion
• Athene.lane@bristol.ac.uk
Group work and discussion
• 1. Survey on site monitoring practice
• 2. Small groups for 15 minutes to discuss:
•
•
•
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Your experiences of on-site monitoring
List benefits and disadvantages
Other ways to monitoring trial conduct at sites?
What sort of trials could benefit from PRIME?
• 3. Feedback main points to the whole group