Risk based approach to the management of clinical trials

1. Risk based approach to the management of clinical trials Dr Martyn Ward, MHRA CTU Oct 2011

2. 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. 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) Risk Adaption – what is it?

4. 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. 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. 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. 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. 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. Adaptations related to risk within CTD Increasing potential risk of IMP

11. 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

12. Safety Monitoring Plan

13. 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. 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. 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. 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. Assessment tool for other risks

18. 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. Risk-adapted monitoring strategy

20. 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. 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)