© Crown copyright 2005

Safeguarding public health

MRC/DH/MHRA Joint Project Risk Assessment Guidance

Sarah Meredith

HTMR Workshop, Liverpool

10 May 2012

© Crown copyright 2005

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

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Safeguarding public health

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

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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

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Safeguarding public health

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.

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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

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Safeguarding public health

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

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Safeguarding public health

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

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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

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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

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Safeguarding public health

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

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Safeguarding public health

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

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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:

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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

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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?

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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?

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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)

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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…..

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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

vulnerabilities associated with the

design and methods identified in

the risk assessment.

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

vulnerabilities associated with the

design and methods identified in

the risk assessment.

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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

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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

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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