Safeguarding public health
Risk based approach to the
management of clinical trials
Dr Martyn Ward, MHRA CTU
Oct 2011
© Crown copyright 2005
Risk Adaption – what is it?
• Commission:
· Recognised some trials could be treated differently
· Commercial, Non-commercial sponsors
· Specific Modalities (2006)
· Risk proportionality
· EMA/Comm conference (Sept 2007)
· CTD impact assessment consultation (2010)
· CTD concept paper consultation (2011)
· Recognised need for change but so far little detail and only applies
to application process
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Risk Adaption – what is it?
• Europe
· ESF
· EFGCP
· ECRIN
• Series of workshops on IIT
• Key recommendations to COMM
• Risk proportionate regulation
but
• little detail or clarity on what it
would look like
• FDA/Duke Univ
· CTTI
• Focus on monitoring approaches
and proportionality
• Quality by design (Aug 2011)
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Risk Adaption – what is it?
• OECD – Global Science Forum
· Risk based approaches
· Stratified
· Customised
• EMA
· Reflection paper
· Risk based Quality management in clinical trials
• UK
· AMS report
· Growth Agenda
· DH/MRC/MHRA project
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Problem?
• Risk averse research community
• Driven by a QA culture
• Regulatory requirements are:
- Generally poorly understood
- Frequently over-interpreted
• Little published guidance
• Fear of Inspectors
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UK Project Scope
• Focus on risks inherent in the protocol for
 Participant safety to the trial intervention
- due to the trial intervention
- due to clinical procedures
 Participant rights
- due to inadequacy of the consent process
- due to failure to protect participant data
 Reliability of results
• Site facilities, staff training/experience, Finance etc not
addressed
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UK Approach
• Work within current legislation/guidance;
• Identify what can be done differently/less of for
certain types of trial?
· Application process
· Conduct of the trial
• Develop documented tools & guidance
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1. Intervention Safety Risk
• Assess risk associated with trial interventions (IMP)
• Assess risk in relation to normal standard care
• Comparable to standard care (Type A)
• Somewhat higher than standard care (Type B)
• Markedly higher than standard care (Type C)
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Adaptations related to risk within CTD
Increasing potential risk of IMP
NonType A
Interventional
Type B Type C
Adaptions possible?
1. Reduced MHRA role for
approval
2. Content of application
3. Labelling
4. Safety Surveillance
5. IMP management
6. Documentation
7. GCP Inspections
*
*
*
*
*
*
*
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
(Yes)
(Yes)
(Yes)
(Yes)
(Yes)
(Yes)
No
No
(Yes)
No
(Yes)
No
(Yes)
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Risk Adaptations
Areas impacted
1. Reduced MHRA role in approvals
Notification v Approval
2. Content of application
a) IMP dossier
b) Investigator’s Brochure
c) GMP Compliance
3. Labelling of trial drugs
a) Need for trial labelling
b) Content of labelling
4. Safety Surveillance
a) Adverse Drug Event recording/reporting
b) Safety Monitoring
5. IMP management
a) Tracking and Accountability
b) Storage
6. Documentation
a) TMF Content
b) Essential Documents retention times
7. GCP Inspections
a) Organisation and selection processes for
routine GCP systems inspection
b) Increase in routine GCP inspection
reviews at the study level
c) Frequency and duration of inspections
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Risk based approach for assessment
• Type A trials - CTA notification only to MHRA
· Default approval after 14 days
· Limited triage/assessment internally
· Potential to object to Notification – full assessment
· Amendments
· Not substantial if within SmPC (Type A) – no
submission needed
· Submission for substantial – beyond SmPC
• Live from 1st April 2011
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Safety Monitoring Plan
Risk Mitigation to ensure Safety of Participants
Table 2:
Study Title:
Risks associated with Therapeutic Interventions
Protocol No.
o
o
o
LOW ≡ Comparable to the risk of standard medical care
MODERATE ≡ Higher than the risk of standard medical care
EudraCT No.
HIGH ≡ Markedly higher than the risk of standard medical care
Justification: Please briefly justify your conclusions below (where the table is completed in detail the detail need not be repeated, however a summary
should be given):
What are the key risks related to therapeutic
interventions you plan to monitor in this trial?
Body system/Hazard
GIT – raised transaminases
IMP
ABC 123
CVS – prolonged QT interval
ABC 123
How will these risks be minimised?
LFTs
Activity
Frequency
2-weekly
Comments
Transient & reversible
Digital ECG,
Holter monitoring
X hours
X hours
Arrhythmia
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2. Non IMP risks
•
Risks related to the design and methods of the trial
·
·
•
•
participant safety and rights
reliability of results
Multi-factorial and less amenable to simple categorisation
at the trial level.
Must be assessed independently and mitigation plan
developed
 Identify areas of vulnerability
 Specify mitigation and management plan
 Can trial monitoring detect/reduce potential for error?
Targeted management and monitoring plan
Informed protocol development
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Risks to participant safety and rights
from study procedures
Clinical procedures
- Risk to participants compared to standard care
· Additional procedures/additional risks?
Consent
- Risk of inadequate consent compared to a fully competent adult with a
chronic condition
Protection of personal data
- Are any particularly sensitive data being collected?
- With whom will they be shared?
- Personal identifiers?
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Risks to reliability of results
- related to robust design and methods
Eligibility criteria
- Complexity/special assessments required
- Precision required for trial validity
- Potential for external verification
Randomisation method
- Is there any possibility that the randomisation schedule would
differ from that described in the protocol or that treatment
allocation might be predicted prior to randomisation?
Intervention
- Is it a complex intervention/treatment regimen in which might be
applied incorrectly?
- Demanding IMP management/dispensing requirements
Masking/blinding
- Who needs to be masked?
- If it is required is it effective?
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Risks to reliability of results
- related to robust design and methods
Endpoints
- Objectivity
- Complexity of assessment
- Potential for external verification
Follow-up
- Is the follow-up schedule difficult? (e.g. long and different from
standard care)
Power
- Is there any concern that the study may have insufficient power
to detect the anticipated effect of the intervention?
Data collection
-
Volume and complexity
Design and piloting of CRF
Database design/validation and testing
Data transfer methods
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Assessment tool for other risks
Category
Particular
risk
identified
(Yes/No)
If yes, list specific concerns
If yes, how will risks be
minimised?
If yes, could monitoring
methods help to address
concerns (specify)
Eligibility
Does the trial require
very precise assessment
of eligibility for results to
be applicable to the
target population?
Randomisation method
Is there any possibility
that the randomisation
schedule would differ
from that described in
the protocol or that
treatment allocation
might be predicted prior
to randomisation?
Intervention
Is it a complex
intervention/treatment
regimen in which might
be applied incorrectly?
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Common monitoring approaches
• Trial oversight committees
- e.g. TMG, TSC, IDMC,
• Remote routine monitoring
- e.g. telephone contact, training teleconferences,
recruitment monitoring, data returns, investigator meetings
• Central monitoring
- e.g. eligibility checks, missing/invalid data, adherence to
study protocol, unusual data patterns, external verification
• On-site monitoring
- e.g. review of site training/resources, adherence to study
protocol, review of clinical records, source data verification
• Evidence needed on efficacy and cost-effectiveness
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Risk-adapted monitoring strategy
Concerns identified in the assessment of risk associated with the design, methods or conduct of the
trial (other than the intervention) which remain after mitigations are in place
No
Risk associated with
the
intervention /IMP
Yes
Type A
Low intensity
Central monitoring of protocol adherence and
data quality. No requirement for site visiting
unless there are concerns identified from central
monitoring that cannot be addressed by other
means
Low+
As outlined in A, plus appropriate monitoring to
address the specific vulnerabilities associated with
trial design, methods or conduct identified in the
risk assessment.
Type B
Moderate intensity
Central monitoring of safety data quality and
timeliness as well as protocol adherence and
quality of other trial data.
Triggered visits for poor data return or protocol
adherence concerns as well as unusually low or
high frequency of Serious Adverse Events (SAE)
reports (for studies where between-site
comparisons are possible).
Moderate+
As outlined in B, plus appropriate monitoring
appropriate monitoring to address the specific
vulnerabilities associated with trial design, methods
or conduct identified in the risk assessment.
Type C
Higher intensity
More intense monitoring than above to have
confidence in the completeness and reliability of
safety data
Higher+
As outlined in C, plus appropriate monitoring to
address the specific vulnerabilities associated with
trial design, methods or conduct identified in the
risk assessment.
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Pilot with NIHR HTA
• Preliminary evaluation of tools and guidance
• Coordinated through NETSCC, Southampton
• Three levels of input:
· Project:
HTA – Oxford, Liverpool, Hull, Bristol
EME – Newcastle, Nottingham, Christy
· CTU:
Imperial, Sheffield, Birmingham, Warwick, Norfolk
· NHS Trust R&D offices:
Liverpool, Southampton, Birmingham, Bristol
• Timeline: March – May 2011
• Report: July 2011
• Pilot Report on the NETSCC website
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Next Steps
• Continue UK development work
•
•
•
•
Consultation (commercial and non-commercial)
Develop worked examples
Evaluate (qualitative, quantitative)
Publication (web based, Journals)
• ? MRC methodology work on monitoring
• Share progress with EU partners (CTFG, EMA, COMM)
• Share progress with global partners (OECD GSF, CTTI)
© Crown copyright 2005