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

• 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:• 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