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 ICH-
GCP for all IMP trials became UK law in 2004
Trial monitoring systems
TSC DMC
CI & TMG
Trial conduct & data collection
Regulators & Sponsors
CTU
Trial sites
Site monitoring Training Data checks
Protocol & SOPs
EthicsMHRA
Systematic review of on-site monitoring systems
Rhiannon Macefield, Andrew Beswick, Jane Blazeby
PRISMA flow diagramRecords from database search
(Embase: 529, Medline: 536)
Removed duplicates n = 678Records from other sources
n= 28(Hand search of CT/CCT/CCT, referenced in other
papers , personal knowledge)Records screened
n = 678Records excluded
n = 526
Full-text articles assessedn =152
Excluded (n = 123)
Safety monitoring or central monitoring e.g. radiotherapy QA, no details/methods, not full paper, unavailable (2)
Articles included n = 57
Includedn = 29
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
Report to CIs & local PI
Annual PRIME visits to all sites (1-2 d)
PRIME structure
Exit meeting & problem solvingSOP & report template
Peer reviewersTM & 2 site nurses (from 5)
PRIME Intervention & Evaluation
Component Objective PRIME activity Hours
Orientation Training Orientation & trial progress meeting 0.5
Site performance Performance Site recruitment and attrition rates
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
GCP adherencePerformanceTraining
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
Summary
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
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