Site Monitoring in Clinical Trials: the evidence, new approaches and trial manager perspectives

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Site Monitoring in Clinical Trialsthe evidence,
new approaches and trial manager perspectives

• Athene Lane

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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

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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

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Trial monitoring systems
Regulators Sponsors
TSC
DMC
Ethics
MHRA
CI TMG
CTU
Protocol SOPs
Site monitoring
Training
Data checks
Trial conduct data collection
Trial sites
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Systematic review of on-site monitoring systems

• Rhiannon Macefield, Andrew Beswick, Jane Blazeby

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• PRISMA flow diagram

Records from database search(Embase 529,
Medline 536) Removed duplicates n 678
Records from other sourcesn 28 (Hand search of
CT/CCT/CCT, referenced in other papers , personal
knowledge)
Records screenedn 678
Records excluded n 526
Excluded (n 123) Safety monitoring or central
monitoring e.g. radiotherapy QA, no
details/methods, not full paper, unavailable (2)
Full-text articles assessedn 152
Includedn 29
Articles included n 57
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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)

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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

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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

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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

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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

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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

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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

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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 Trials20107428 (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
  6585.

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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

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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
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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
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PRIME Intervention Evaluation
Component Objective PRIME activity Hours
Orientation Training Orientation trial progress meeting 0.5
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
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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

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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

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Findings by component and year
GCP adherence
Performance
Training
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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

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Summary

• PRIME visits annually to all trial sites
• Standardises trial conduct good practice
• Site staff focus including as peer reviewers
• Improves GCP compliance
• Performance gains

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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

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• Any questions?
• Group work and discussion
• Athene.lane_at_bristol.ac.uk

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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