Safeguarding public health
Risk based approach – Implications
for GCP Inspections
Paula Walker, GCP Inspector
October 2011
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GCP Inspections & Risk Adaptation
• The allocated trial category may impact on selection for
inspection….unlikely that Type A trials will be inspected
(unless trigger) due to low risk nature.
• May be differences in documentation required and/or
reviewed on inspection in the following main areas of trial
conduct:
IMP Implications
Safety Reporting Implications
Monitoring implications
TMF review
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IMP Implications
• Adaptations to level of documentation required to verify
IMP Administration.
• Type A trial examples:
 IMP supplied via NHS prescription.
Subject may be asked to keep a diary, or return used drug containers.
This may eliminate need for detailed drug accountability log.
 Inpatient or vaccine trials commonly have IMP administered at the
trial site by staff. Subjects then supervised. For Type A, sponsor
could consider reduction in level of records required.
That is, is it necessary to maintain :
• A Pharmacy drug accountability log,
• Plus another set of accountability worksheets for the product
prepared in an aseptic unit by pharmacy.
• Plus administration on an inpatient drug chart and an infusion chart (if
applicable).
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Safety Reporting Implications
•
•
•
•
Type A may have reduction in SAEs requiring reporting.
Protocol may define certain events as not needing immediate reporting
(despite meeting SAE definition) e.g. trial endpoints or disease
defining events. Must be approved!
Could be covered in Safety Monitoring Plan submitted with CTA.
Case:
Trial investigating IMP safety in pregnant women.
During trial, all women would be hospitalised at labour. Standard SAE
definitions would result in all participants having an SAE.
Protocol could define admission for normal labour as not requiring an
SAE report.
Same could apply to standard expected side-effects of chemo in
oncology trials, which may not require SAE reports (unless frequency
or severity is unusual).
•
Such SARs would still need reporting in annual DSURs.
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Monitoring Implications
•
Risk-adaptive approach enables sponsor to conduct risk assessment
prior to trial start to determine level/ type of monitoring.
•
Monitoring can take many forms:
 traditional on-site monitoring;
 central and statistical monitoring;
 peer review;
 trial steering committees and data monitoring committees,
 other remote activities (such as telephone calls, selfassessment/status or progress reports etc.)
•
Once optimal monitoring strategy has been decided, should be
documented plan with clear documentation of:
 Type & frequency of monitoring
 Responsibilities
 Escalation process (e.g. if central monitoring, what triggers will be
utilised for escalation to on-site visits)
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For Reference…
Central Monitoring
Pro’s
Con’s
On-Site Monitoring
Pro’s
Con’s
Automatic data checks Can only see data that’s Early detection of
can identify issues with
captured on CRFs, may protocol deviations and
plausibility or consistency not identify other protocol violations
deviations/violations
Early identification of
Won’t identify unreported Ongoing training
sites not
AE/SAEs/SUSARs
completing/submitting
CRFs/data
Statistical monitoring can Lose the personal touch Verifying existence of
identify site outliers, and of face to face contact
patients
conspicuous data patterns with sites
and trends
Early safety signal
More motivational
detection (i.e. increase of
values close to defined
limits etc.)
More contactable by
sites, as not “out on the
road”
More personal service
with face to face
interaction
More cost effective
Assess information not
captured on CRFs (SDV)
Time consuming
Visiting sites means
more travel, therefore
unable to be contacted
when “out on the road”
May not identify trends
and outliers across the
study (as too close to the
data)
•Expensive
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TMF Implications
Type A or B trials are likely to have TMF documentation
adaptations, essentially less documentation may be
needed. For example:
 IMP Accountability documentation.
Temperature (T) records are usually needed for IMP
storage, however:
• Unlicensed product used in Type C trial may be unstable outside
particular T. range +/or have limited stability data +/or short shelf
life.
• T records may be irrelevant in Type A trials where IMP is
marketed, used as per normal clinical practice, as storage
arrangements are deemed appropriate standard practice (no
additional requirements for trial purposes).
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TMF Continued
 Evidence of Laboratory Quality Standards
• Type C trial: a CRO lab may be used for drug sample
analysis. Accreditation certificates would be appropriate.
• Type A trial: if hospital lab used for haematology/
biochemistry analysis (as per normal clinical practice)
supply of CPA certificates in TMF adds no value in terms of
risk to patient safety or data quality.
Plus, as labs require evidence of standards for normal
clinical practice, such documentation could be made
available upon request if necessary.
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TMF Summary
• GCP inspectors will take a pragmatic approach to the
TMF content for Type A/ B trials.
• Recommended approach for sponsors and PIs regarding
TMF checklists:
Is the document needed based on trial process to be used
i.e. don’t include if it doesn’t apply!
Is the information already available elsewhere in TMF?
Does the document add value in showing quality of the
trial conduct?
Does having this document in the TMF matter for meeting
trial objectives ?
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Development of guidance
•Risk adaptation will impact on the way that the GCP
principles are complied with. Inspectorate guidance to be
produced (likely in Q&A format).
•Aim is to develop guidance with commercial/ non-commercial
researchers conducting risk adaptive trials, to include real
examples that may be published and used.
•Priority topic will be trial monitoring. Volunteer
organisations requested to assist with guidance development.
Aim is to have ~10 clinical trials as potential source of
approaches/ documents. Volunteers requested!
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Volunteer Criteria
 Sponsoring/managing UK trial with risk based monitoring approach
(documented risk assessment +/or monitoring plan).
 Should not follow the ‘regular on-site monitoring visit' model i.e. should
use central monitoring techniques.
 Willing for trial documentation to be potentially published as examples
e.g. protocol summary, risk assessment, monitoring plan (can be
anonymised).
 Organisations formally comparing monitoring approaches of
particular interest.
 Small consultative group planned of stake holders conducting
suitable trials, including individuals with direct experience of
managing/monitoring trials outlined above.
If you wish to help with the guidance, please contact at:
GCP.Inspectors@mhra.gsi.gov.uk
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Summary
The aim of risk adaption is to reduce duplicated or
costly processes that are surplus to requirement.
The GCP Inspectorate is keen to work with both
industry and non-commercial organisations to
implement this proportionate approach, and
reduce the burden while maintaining the quality of
the trial conduct.
© Crown copyright 2011