Site Monitoring in Clinical Trials

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
Regulators &
Protocol & SOPs
Site monitoring
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
n =152
Excluded (n = 123)
Safety monitoring or
central monitoring
e.g. radiotherapy QA, no
details/methods, not full paper,
unavailable (2)
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
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
PRIME activity
Orientation & trial progress meeting
Site performance
Site recruitment and attrition rates
Protocol adherence
Observation, feedback & meetings
Data collection
Observation of CRF completion
Safety monitoring
Review process & documentation
Site file review
Site staff training discussion
Site organisation
Coordinating centre communication
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
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
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)
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
• [email protected]
Group work and discussion
• 1. Survey on site monitoring practice
• 2. Small groups for 15 minutes to discuss:
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

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