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© Crown copyright 2005
Safeguarding public health
Risk based approach to the management of clinical trials
Oct 2011Dr Martyn Ward, MHRA CTU
© 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
© Crown copyright 2005
Risk Adaption – what is it?
• Europe· ESF · EFGCP· ECRIN
• FDA/Duke Univ· CTTI
• Series of workshops on IIT • Key recommendations to COMM• Risk proportionate regulation
but
• little detail or clarity on what it would look like
• Focus on monitoring approaches and proportionality
• Quality by design (Aug 2011)
© Crown copyright 2005
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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Non-Interventional
Type A Type B Type C
Adaptions possible?
1. Reduced MHRA role for approval2. Content of application 3. Labelling 4. Safety Surveillance5. IMP management 6. Documentation7. GCP Inspections
*******
YesYesYesYesYesYesYes
No(Yes)(Yes)(Yes)(Yes)(Yes)(Yes)
NoNo
(Yes)No
(Yes)No
(Yes)
Increasing potential risk of IMP
Adaptations related to risk within CTD
© Crown copyright 2005
Risk Adaptations Areas impacted1. Reduced MHRA role in approvals
2. Content of application
3. Labelling of trial drugs
4. Safety Surveillance
5. IMP management
6. Documentation
7. GCP Inspections
Notification v Approval
a) IMP dossier b) Investigator’s Brochure c) GMP Compliance a) Need for trial labelling b) Content of labelling
a) Adverse Drug Event recording/reporting b) Safety Monitoring
a) Tracking and Accountability b) Storage
a) TMF Content b) Essential Documents retention times
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
© Crown copyright 2005
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
© Crown copyright 2005
Safety Monitoring Plan
Study Title: Risks associated with Therapeutic Interventions
o LOW ≡ Comparable to the risk of standard medical care o MODERATE ≡ Higher than the risk of standard medical care o HIGH ≡ Markedly higher than the risk of standard medical care
Protocol No. EudraCT No.
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?
How will these risks be minimised?
Body system/Hazard IMP Activity Frequency Comments GIT – raised transaminases
ABC 123 LFTs 2-weekly Transient & reversible
CVS – prolonged QT interval
ABC 123 Digital ECG, Holter monitoring
X hours X hours
Arrhythmia
Risk Mitigation to ensure Safety of Participants
Table 2:
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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
© Crown copyright 2005
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
© Crown copyright 2005
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)
EligibilityDoes the trial require very precise assessment of eligibility for results to be applicable to the target population?
Randomisation methodIs 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?
InterventionIs 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
© Crown copyright 2005
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 Yes
Risk associated with the intervention /IMP
Type A Low intensityCentral 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 intensityCentral 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 intensityMore 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.
© Crown copyright 2005
Pilot with NIHR HTA
• Preliminary evaluation of tools and guidance• Coordinated through NETSCC, Southampton• Three levels of input:
· Project: HTA – Oxford, Liverpool, Hull, BristolEME – 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)