Managing the risks of clinical trials: the MRC/MHRA approach Sarah Meredith MRC Clinical Trials Unit at UCL UCL Institute for Clinical Trials and Methodology FCRIN Workshop, Hôpital Saint Louis, Paris 23 September 2012
Outline MRC/DH/MHRA ad-hoc review of issues for UK non-commercial clinical trials and working group on risk-adapted approaches to trial management Risk assessment guidance Practical application at the MRC Clinical Trials Unit Further research
Background MRC/DH Joint Project 2003 Assist in interpretation of CTD in UK Best practise guidance ct-toolkit MRC/DH/MHRA Ad hoc Review 2009-2011 Chaired by Profs Janet Darbyshire & Kent Woods Review issues for non-commercial trials since 2003, identify gaps Four work-streams 1. Risk-adapted approaches for managing clinical trials 2. Communications 3. Co-ordinated response to EC consultation on the CTD 4. Education and Training
Working Group for Risk-Adaptions Work-stream Martyn Ward, MHRA Clinical Trials Unit Sarah Meredith, MRC Clinical Trials Unit Co-leads Gillian Booth, Clinical Trials Research Unit, Leeds Carrol Gamble, MCRN Clinical Trials Unit, Liverpool Heather House, Oxford University & John Radcliffe Hospital Martin Landray, Clinical Trial Service Unit, Oxford Wilma van Riel, Birmingham Clinical Trials Unit Louise Mawer/Andrew Fisher, MHRA GCP Inspectorate
Safeguarding MRC/DH/MHRA public health Ad-hoc review of issues for UK clinical trials Risk-adapted approaches to trial management Objectives: Develop a process to facilitate the agreement of key stakeholderson the level of risk associated with a clinical trial. Identify how risk adapted approaches for clinical trials can be achieved within the current regulatory framework Develop a risk assessment tool with guidance principles on how to manage and conduct clinical trials of IMPs in a risk proportionate way.
Output of work-stream MRC/DH/MHRA Joint Project Risk-adapted approaches to management of clinical trials of investigational medicinal products Publication October 2011 Risk assessment framework Appendix 1 Guidance on risk-adapted approaches within the scope of the Clinical Trials Directive Appendix 2 Guidance on risk-proportionate approaches to the management and monitoring of clinical trials Availability: MHRA, NETSCC and MRC CTU London Hub Websites
Risk-based approach? Perception of clinical trial risks may depend on role and responsibilities in the trial Funder Sponsor Investigator Host Trust Ethics Committee Regulatory Assessor Regulatory Inspector Insurer Objective: to facilitate the agreement of stakeholders on risks associated with a clinical trial Focus: Risks inherent in the protocol
Project Scope Focus on risks inherent in the protocolfor Participant safety - 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 Identify, and if possible, integrate/align with other relevant initiatives in this area (UK & EU) Not addressed: site facilities, staff training/experience See NIHR Support Services Framework
Risk Assessment Framework Principles Risks for for participants should be be judged relative to to risks of of standard care IMP licensing status has implications for: --Risk Risk adaptations possible within the the EUCTD -Patient safety monitoring and and the the importance of of safety data -- Trial conduct and monitoring ( but but does not not determine them) - 1. IMP risk categorisation Other trial risks more complex and not easily less amenable to Other simple trial categorisation risks multi-faceted at the trial and level not easily less amenable to simple - To categorisation be assessed individually at the trial and level mitigation plan developed - To be assessed individually and mitigation plan developed 1. IMP risk category 2. Customised 2. Customised risk assessment assessment of other risks
1. Assessment of IMP risks Assess potential risk associated with trial interventions (IMP) Assess risk in relation to normal standard care Simple 3-level categorisation based on licensing status and standard practice To be agreed with the regulatory authority at submission of CTA Type A: Comparable to standard care Type B: Somewhat higher than standard care Type C: Markedly higher than standard care
Classification of risks associated with the IMP Type A = Risk no higher than standard medical care; e.g. Trials involving IMPs licensed in any EU Member State where the use: relates to the licensed range of indications, dosage and form, or off-label use if this is established practice and supported by sufficient published evidence and/or guidelines (e.g. paediatrics and oncology) Type B = Risk somewhat higher than standard care; e.g. Trials involving IMPs licensed in any EU Member State where the IMP: is used for a new indication (different patient population/disease group), or involves substantial dosage modifications, or is used in combinations for which interactions are suspected Trials involving IMPs not licensed in any EU Member State if the active substance is part of a medicinal product licensed in the EU Type C = Risk markedly higher than standard care; e.g. Trials involving a medicinal product not licensed in any EU Member State Lower grading may be justified based on pre-clinical or clinical evidence or clinical experience
Risk Adaptions possible within the CTD Increasing potential risk of IMP Non- Interventional Type A Type B Type C Risk Adaptations 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)
Safety Monitoring Plan Safeguarding public health Table 2: 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 Risk Mitigation to ensure Safety of Participants Protocol No. o HIGH Markedly higher than the risk of standard medical care 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
2. Customised approach to other risks Risks related to the design and methods of the trial participant safety and rights reliability of results Not amenable to simple categorisation at the trial level. To be assessed independently and mitigation plan developed Suggested process: Identify specific areas of vulnerability Consider specific mitigation and management strategies Determine whether monitoring detect/reduce potential for error Objectives of Risk Assessment: Inform protocol development Targeted management and monitoring plans
Assessment Safeguarding public health of non-intervention risks: 1. Participant safety and rights from study procedures a) Clinical procedures Risk to participants compared to standard care Additional procedures/additional risks? b) Consent Risk of inadequate consent compared to a fully competent adult with a chronic condition Consider population and circumstances c) Protection of personal data Are any particularly sensitive data being collected? With whom will they be shared? Personal identifiers?
Assessment Safeguarding public health of non-intervention risks: 2. Reliability of results Reliability of results is strongly related to robust trial design Identify specific areas of vulnerability Consider specific mitigation and management strategies Determine whether monitoring detect/reduce potential for error Some aspects to consider (list not comprehensive) 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?
Reliability of trial results cont d 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? Endpoints Objectivity Complexity of assessment/standardisation/valid methods Potential for external verification Follow-up Is the follow-up schedule difficult? (e.g. long and different from standard care)
Reliability of trial results cont d Statistical issues Sample size -Is there sufficient power to detect the anticipated effect of the intervention? Barriers to full recruitment? Clear/appropriate analysis plan Data collection Volume and complexity Design and piloting of CRF Database design/validation and testing Data transfer methods NB List is not comprehensive..
Risk-adapted monitoring strategy Potential risk of the intervention /IMP Type A Concerns identified in the assessment of risk associated with the design and methods of the trial (other than the intervention) No A 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 Yes A+ As outlined in A, plus appropriate monitoring to address the specific vulnerabilities associated with the design and methods identified in the risk assessment. Type B B 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 SAE reports (for studies where between-site comparisons are possible). Type C C More intense monitoring than above to have confidence in the completeness and reliability of safety data B+ As outlined in B, plus appropriate monitoring to address the specific vulnerabilities associated with the design and methods identified in the risk assessment. C+ As outlined in C, plus appropriate monitoring to address the specific vulnerabilities associated with the design and methods identified in the risk assessment.
Safeguarding Application public health of risk-based approach at the MRC Clinical Trials Unit Risk assessment undertaken by Trial Management Team High-level prior to funding application Full prior submission for regulatory/ethics approval Regular review throughout the life-time of the trial Formal review if risks have changed, and at least annually Risk assessments reviewed by Research Governance Committee Does the Committee agree with the assessment? Are the risks being adequately managed? Do the trial management documents address all the issues identified? Have there been any problems?`
Risk Assessment Any hazards or uncertainties integral to, or relevant to, a project which may put at risk either the successful achievement of the project objectives or the reputation or resources of MRC CTU should be identified. For each hazard identified, the probability and impact of adverse consequences are estimated and mitigation proposed Hazards specified on the RA form only if their mitigation requires quality management procedures that are in addition to the normal controls described in MRC CTU SOPs and Policies
Risk Assessment Categories Safety and Rights of Participants Nature of the intervention (for CTIMPs IMP type) Invasiveness of clinical procedures relative to standard care Participant vulnerability/rights Project Design and Reliability of Results Project Management and Governance Complexity of the collaboration Sponsorship arrangements Country level governance issues Sites Other Considerations Additional risks relevant to particular projects which should be assessed and documented
MRC CTU Research Governance Committee Review and approval of all trial Risk Assessment and Quality Management Plans Initial, as there are changes, annual review Oversight of implementation of MRC CTU quality management policy Oversight of SOP Committee Commissioning of audits if required Coordination of inspections and audits conducted by external groups and corrective action plan management Advisory board for governance and quality issues for staff
MRC CTU on-going research: TEMPER Study Prospective evaluation of triggered monitoring Monitoring visits to triggered and matched un-triggered site in the same trial Sites matched on time since opening and number of participants Comparison of number of critical/major findings