1. © Crown copyright 2005 Safeguarding public health Risk based approach to the management of clinical trials Oct 2011 Dr Martyn Ward, MHRA CTU

2. © 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

3. © 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)

4. © 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

5. © Crown copyright 2005 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

6. © Crown copyright 2005 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

7. © Crown copyright 2005 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

8. © Crown copyright 2005 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)

9. © Crown copyright 2005 Non- Interventional Type AType BType 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 No (Yes) No (Yes) No (Yes) No (Yes) Increasing potential risk of IMP Adaptations related to risk within CTD

10. © Crown copyright 2005 Risk AdaptationsAreas impacted 1. 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

11. © 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 1 st April 2011

12. © Crown copyright 2005 Safety Monitoring Plan

13. © Crown copyright 2005 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

14. © 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?

15. © Crown copyright 2005 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?

16. © Crown copyright 2005 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

17. © Crown copyright 2005 Assessment tool for other risks CategoryParticular risk identified (Yes/No) If yes, list specific concernsIf 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?

18. © Crown copyright 2005 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

19. © 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 NoYes Risk associated with the intervention /IMP Type ALow 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 BModerate 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 CHigher 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.

20. © 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, 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

21. © Crown copyright 2005 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)