MRC/DH/MHRA Joint Project Risk Assessment Guidance · MRC/DH/MHRA Joint Project Risk Assessment Guidance Sarah Meredith HTMR Workshop, Liverpool ... MRC/DH/MHRA Ad-hoc review of issues

© Crown copyright 2005

Safeguarding public health

MRC/DH/MHRA Joint Project Risk Assessment Guidance

Sarah Meredith

HTMR Workshop, Liverpool

10 May 2012


Safeguarding public health Outline

• MRC/DH/MHRA ad-hoc review of issues for UK non-commercial clinical trials

• Working group on risk adapted approaches to trial management

• Risk assessment guidance

• International initiatives

• Introduction to Workshop



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


Safeguarding public health Working Group for Risk-Adaptions Work-stream

• Martyn Ward, MHRA Clinical Trials Unit

• Sarah Meredith, MRC Clinical Trials Unit

• 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



MRC/DH/MHRA 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 stakeholders on 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.


Safeguarding public health Output of work-stream

• MRC/DH/MHRA Joint Project Risk-adapted approaches to management of clinical trials of investigational medicinal products

• Initial publication April 2011

• Risk assessment framework

• Appendix 1 – Guidance on risk-adapted approaches within the scope of the Clinical Trials Directive

• Final version published October 2011 following piloting by NETSCC

• 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 depends 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 protocol for

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


Safeguarding public health Risk Assessment Framework Principles

• Risks for participants should be judged relative to risks of standard care

• IMP licensing status has implications for:

- Risk adaptations possible within the EUCTD

- Patient safety monitoring and the importance of safety data

- Trial conduct and monitoring ( but does not determine them)

- 1. IMP risk categorisation

• Other trial risks multi-faceted and not easily less amenable to simple categorisation at the trial level

- To be assessed individually and mitigation plan developed

2. Customised risk assessment

• Risks for participants should be judged relative to risks of standard care

• IMP licensing status has implications for:

- Risk adaptations possible within the EUCTD

- Patient safety monitoring and the importance of safety data

- Trial conduct and monitoring ( but does not determine them)

• Other trial risks more complex and not easily less amenable to simple categorisation at the trial level

- To be assessed individually and mitigation plan developed

1. IMP risk category

2. Customised assessment of other risks


Safeguarding public health 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 MHRA at submission of CTA

Type A: Comparable to standard care

Type B: Somewhat higher than standard care

Type C: Markedly higher than standard care



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

Classification of risks associated with the 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)

Increasing potential risk of IMP

Risk Adaptions within CTD


Safeguarding public health 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:


Safeguarding public health 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


Safeguarding public health Assessment 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?


Safeguarding public health Assessment 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?


Safeguarding public health 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)


Safeguarding public health 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…..


Safeguarding public health Risk-adapted monitoring strategy

Concerns identified in the assessment of risk associated with the

design and methods of the trial (other than the intervention)

No Yes

Potential risk

of the

intervention

/IMP

Type A L 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

L+ As outlined in L, plus appropriate

monitoring to address the specific

vulnerabilities associated with the

design and methods identified in

the risk assessment.

Type B M 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).

M + As outlined in M, plus appropriate

monitoring appropriate monitoring

to address the specific




Type C H More intense monitoring than above

to have confidence in the

completeness and reliability of safety

data

H+ As outlined in H, plus appropriate

monitoring to address the specific





Safeguarding public health International context

• EMA

• Reflection paper on risk-based quality management in clinical trials

• EU Commission

• Concept paper on revision of the CTD

• OECD Global Science Forum

• Working group to facilitate international cooperation in non-commercial clinical trials - Workstream on risk-based approaches

• CTTI (FDA/Duke University)

• Recommendations for monitoring

• FDA draft guidance on monitoring


Safeguarding public health What next?

• MHRA is taking the lead on facilitating the sharing of examples

• Risk Adaptation Consultative Group (Andrew Fisher for further information)

• Collecting examples of trials that have a risk adaptive approach

• Methods for managing specific vulnerabilities

• Metrics that could act as triggers to escalate monitoring

• Development of FAQs

• Prepared to review monitoring plans

• Current guidance based on experience not evidence

• Role for MRC Hubs for Trial Methodology Research

– evaluation of methods and development of evidence-based tools, eg

• For central monitoring

• Management and monitoring strategies for specific vulnerabilities

• Framework for intensity of monitoring &/or thresholds for site visiting

• To judge data quality for decision-making


Safeguarding public health Introduction to Workshop

• Draft template developed with guidance in packs

• NB not included in final version because used as tick-box in NETSCC pilot rather than framework for thinking

• Tables asked to discuss specific vulnerabilities in their trials in the various categories

• Identify specific vulnerabilities

• Discuss mitigations/monitoring implications

• Each table asked to record good examples (for collection)

• Groups to focus initially:

1. IMP risk assessment and safety monitoring plan

2. Non-intervention risks to participant safety/rights

3. Risks to reliability of results – start at beginning of template

4. Risks to reliability of results – start at end of template

Documents

MRC/DH/MHRA Joint Project Risk Assessment Guidance · MRC/DH/MHRA Joint Project Risk Assessment Guidance Sarah Meredith HTMR Workshop, Liverpool ... MRC/DH/MHRA Ad-hoc review of issues