@ Murdoch Children’s Research Institute, 2017

Updates to Safety Monitoring & Reporting - Supplementary guidanceDr Kate Scarff

Clinical Research Development Office

06 March 2018

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Outline

NHMRC Safety monitoring and reporting in clinical trials involving

therapeutic goods

Reporting serious breaches

Risk-based management & monitoring

Data Safety Monitoring Boards

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What safety monitoring & reporting guidelines do we follow in Australia?

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Integrated Addendum to ICH E6 (R1): Guideline for GCP (TGA annotated version) Sections 4.11 and 5.17

ICH Note for Guidance on Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95) (E2A), annotated with TGA comments

NHMRC Guidance: Safety monitoring and reporting in clinical trials involving therapeutic goods (EH59), November 2016 NEW

NHMRC Guidance: Reporting of Serious Breaches of Good Clinical Practice (GCP) or the Protocol for Trials Involving Therapeutic Goods (EH59A), 2018 NEW

NHMRC Guidance: Risk-based Management and Monitoring of Clinical Trials Involving Therapeutic Goods (EH59B), 2018 NEW

NHMRC Guidance: Data Safety Monitoring Boards (DSMBs) (EH59C), 2018 NEW

ISO 14155: 2011 Clinical investigation of medical devices for human subjects – Good clinical practice

TGA Guidance: Pharmacovigilance responsibilities of medicine sponsors, Australian recommendations and requirements, September 2017

Guidelines

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Integrated Addendum to ICH E6 (R1): Guideline for GCP (TGA annotated version) Sections 4.11 and 5.17

ICH Note for Guidance on Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95) (E2A), annotated with TGA comments

NHMRC Guidance: Safety monitoring and reporting in clinical trials involving therapeutic goods (EH59), November 2016 NEW

NHMRC Guidance: Reporting of Serious Breaches of Good Clinical Practice (GCP) or the Protocol for Trials Involving Therapeutic Goods (EH59A), 2018 NEW

NHMRC Guidance: Risk-based Management and Monitoring of Clinical Trials Involving Therapeutic Goods (EH59B), 2018 NEW

NHMRC Guidance: Data Safety Monitoring Boards (DSMBs) (EH59C), 2018 NEW

ISO 14155: 2011 Clinical investigation of medical devices for human subjects – Good clinical practice

TGA Guidance: Pharmacovigilance responsibilities of medicine sponsors, Australian recommendations and requirements, September 2017

Guidelines

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NHMRC Guideline: Safety monitoring and reporting in clinical trials involving therapeutic goods (EH59, November 2016)

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NHMRC Guideline: Safety monitoring and reporting in clinical trials involving therapeutic goods (EH59)

This guidance addresses the collection, verification and reporting of adverse

events and adverse reactions that occur in clinical trials involving

investigational medicinal products (IMPs) and investigational medical

devices (IMDs) for trials conducted under the Clinical Trial Exemption (CTX)

or Clinical Trial Notification (CTN) schemes

To learn more, book into our new CRDO workshop: Safety oversight,

monitoring & reporting

Dates: 12 June or 24 October

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Safety Monitoring and Reporting in Clinical Trials of Therapeutic GoodsSupplementary Guidance: Reporting of Serious Breaches of Good Clinical Practice (GCP) or the Protocol for Trials Involving Therapeutic Goods

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What is the purpose of this guidance?

This guideline sets out a framework for the management and reporting of serious breaches. Its purpose is to:

Rationalise the reporting of protocol deviations to review bodies by only requiring the reporting of the small sub‐set of deviations that significantly impact on the safety or rights of participants or the reliability of the clinical trial data

Adopt a standard term (serious breach) to describe this sub‐set

Clarify the roles of key stakeholders

Define standard reporting timelines

Provide standard forms for serious breach reporting to HRECs to replace the forms currently used within jurisdictions to report protocol deviations

The guidance applies to both commercial and non-commercial clinical trials involving therapeutic goods

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Terminology

Deviation

Any (minor or major) breach, divergence or departure from the requirements of Good Clinical Practice or the clinical trial protocol

Serious Breach (NEW)

A breach of Good Clinical Practice or the protocol that is likely to affect to a significant degree:

The safety or rights of a trial participant, or

The reliability and robustness of the data generated in the clinical trial.

Suspected Breach (NEW)

A report that is judged by the reporter as a possible serious breach but has yet to be formally confirmed as a serious breach by the Sponsor.

Violation (SUPERSEDED)

The term ‘violation’ has been widely used in place of ‘deviation’ or to represent a subset of deviations but is not recommended.

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What is the role of the Investigator?

Ensure that the trial team is aware of the process for reporting serious breaches.

Report any suspected breaches to the sponsor within 72 hours of becoming aware of the suspected breach. Note: Exceptionally, the investigator, in liaison with their institution, may report the suspected breach directly to the HREC.

Report all serious breaches that have been confirmed by the sponsor as occurring at the site to their institution (research governance office) within 72 hours of being notified of the serious breach.

Provide any follow‐up information as required.

Work with the institution or sponsor, as appropriate, to implement any corrective and preventative actions that may be indicated.

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What is the role of the Sponsor?

Determine whether a suspected breach meets the definition of a serious breach

Assessment of impact on safety and rights of participants – may request advice of

HREC

Assessment of impact on validity of trial data considering:

trial design

type and extent of the data affected by the breach

overall contribution of the data to key analysis parameters

impact of excluding the data from the analysis

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What is the role of the Sponsor? (cont)

Develop SOPs, forms etc for managing serious breaches

Perform a route cause analysis and ensure that appropriate corrective and preventative actions are taken.

Keep written records of all suspected and confirmed serious breaches, including the justification for determining that a suspected breach does not meet the definition of a serious breach4.

Notify, in writing, the reviewing HREC without delay and no later than 7 calendar days of confirming a serious breach has occurred and provide follow‐up reports when required.

Review third party reports received directly by HREC and report back to HREC within 7 calendar days

For serious breaches occurring at a trial site, inform the site’s principal investigator within 7 calendar days of confirming a breach has occurred.

Inform the TGA and the reviewing HREC if the serious breach leads to the closure of the site.

Notify TGA of any serious breach that involves a defective product that may have wider implications for the supply chain for that marketed product

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What is the role of the HREC?

Evaluate reports of serious breaches from the Sponsor

Determine the impact of the serious breach on the continued ethical acceptability of the study

Is there a change required to the protocol that increases the burden on participants?

Is re-consenting of participants required due to inadequacies in the original consent process?

Satisfy itself that the the serious breach is managed appropriately

Are the corrective and/or preventative actions implemented/planned appropriate?

Upon receipt of reports of suspected serious breaches from third parties

Notify the Sponsor and establish why the serious breach was not reported

Request a written justification or explanation from the Sponsor if rationale for not reporting is unclear or contested by HREC

Inform the TGA and the sponsor if the notification of a serious breach leads to the suspension or withdrawal of the ethics approval for the trial (trials conducted under CTN/CTX)

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What is the role of the institution?

Develop clear guidance for investigators detailing the reporting and management of serious breaches that is consistent with the new guidance.

Assess each serious breach to determine its impact, e.g. any impact on other trials conducted by the institution/investigator.

Facilitate the implementation of any corrective and preventive actions if required by the Sponsor.

Take advice from the reviewing HREC regarding its assessment of the breach.

Inform the HREC if a serious breach leads to withdrawal of the governance authorisation.

Consider whether the conduct determined to be a serious breach requires the application of the Australian Code for the Responsible Conduct of Research.

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Safety Monitoring and Reporting in Clinical Trials of Therapeutic GoodsSupplementary Guidance: Risk-based

management and monitoring of clinical trials

involving therapeutic goods

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What is the purpose of this guidance? Who is it for?

Provides advice on how to comply with risk-based approach to quality management and monitoring introduced with updates to ICH E6 R2

Relevant for Sponsors of commercial and non-commercial trials involving IMPs through all phases of clinical research but may also be applied to all clinical trials

BUT written primarily for non-commercial sponsors, with focus on how to apply the revised GCP requirements related to risk-based management in the non-commercial setting

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GCP: Risk-based management approach

NEW 5.0 QUALITY MANAGEMENT: The sponsor should implement a quality management system to manage quality throughout all stages of the trial with a focus on subject protection and data integrity.

Methods to assure and control quality should be proportionate to the risksinherent in the trial and the importance of the information collected.

The quality management system should use a risk-based approach that includes:

Identify critical

processes &

data

Identify risksEvaluate the

riskRisk control

Risk

communicationRisk Review Risk Reporting

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Quality Risk Management Recommendations

Address the following questions early in the protocol design stage:

What are the critical processes?

What are the critical data?

How can any risks/vulnerabilities be mitigated to avoid errors that matter?

Conduct early and ongoing risk assessment with focus on critical processes and critical data

Use risk indicators and thresholds – trigger an action (e.g. increased data scrutiny, site follow-up)

Adjust monitoring activities based on the issues and risks identified throughout the trial

Ensure grant applications include requirements for quality management and monitoring

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What is a risk assessment?

“Risk assessment is the process of identifying potential hazards associated with a clinical trial and assessing the likelihood of those hazards occurring and resulting in harm to participants or to the validity of trial data”.

Two broad categories of risk:

1.Risk of the Investigational Medicinal Product

2.Risks associated with trial conduct, design and methods

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Risks related to the Investigational Medicinal Product

For each trial, risk category (A, B, C) should be assigned based on how much is known about the IMP being investigated.

The risk category would be used by:

Sponsors – to inform trial management plans, e.g. need for DSMB

HRECs/Regulatory Authorities/Funding bodies – aid in review, approval and authorisation process

For each clinical trial, risks related to the IMP should be categorised relative to:

Standard of care for the relevant medical condition

Level of clinical experience with the intervention

Rather than the participant’s underlying illness or the recognised adverse effects of the

intervention or by trial phase alone.

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Risk Categories Benchmarked Against Standard of Care

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Risks related to trial conduct, design and methods

Trial-specific risk assessment required (in addition to IMP risk-assessment)

Trial-specific risks include (but not limited to):

1. Safety monitoring and reporting

2. Manufacture and distribution of the IMP

3. Obtaining informed consent

4. Collection of indirectly identifying or sensitive characteristics

5. Participant well-being

6. Site feasibility assessment

7. Blinding of randomisation procedures

8. Objective assessment of primary and secondary outcomes

9. Complexity of trial procedures and measurements.

10. Education, training, experiences and resources of all site staff in GCP and study procedures

11. IMP accountability

12. Data collection and entry – contemporaneous, secure, accurate

13. Roles and responsibilities

14. Facilities

Areas where risk-based approaches can be applied

Methodology

Selective safety data collection

Non-expedited reporting of certain SAEs

Trial Monitoring

Accountability & Traceability

of IMP

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GCP: Risk-based monitoring

MOD 5.18.3 The Sponsor should develop a systematic, prioritised, risk-based approach to monitoring

Varied approaches that improve effectiveness and efficiency of monitoring

Combination of on-site and centralised monitoring may be appropriate

NEW 5.18.7 Develop a Monitoring Plan tailored to the human participant protection and data integrity risks of the trial

Describe the monitoring strategy (critical data and processes), monitoring responsibilities, methods and rationale for use.

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How will we comply with requirement for risk-based management and monitoring of clinical trials?

WHAT IS CRDO DOING?

Developing SOPs, templates and risk-assessment forms for RB management and monitoring of CTs

Training – workshops planned for late 2018 and in 2019

WHAT MUST THE SPONSOR (LEAD PI for non-commercial study) DO?

Conduct the risk assessment

Led by a member of the research team

Begin once funding confirmed and develop at same time as protocol

Finalise before any trial initiation activities commence

Obtain approval of any supporting departments involved in risk assessment, e.g. CT Pharmacy

Signed copy filed in TMF and circulated to research team

Update the risk assessment form if change to the risk or requirements for additional mitigating actions during the trial

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Safety Monitoring and Reporting in Clinical Trials of Therapeutic GoodsSupplementary Guidance: Data Safety Monitoring

Boards (DSMBs)

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What is in the guidance? Who is it for?

New guidance for Sponsors of commercial and non-commercial trials involving IMPs through all phases of clinical research but may also be applied to all clinical trials

Clarifies the following about Data Safety Monitoring Boards (DSMBs):

What is a DSMB?

Role in monitoring safety

When are they needed?

How do they operate?

Documentation

Discusses alternative mechanisms for monitoring safety when a DSMB is not required.

Identify critical

processes & dataIdentify risks Evaluate the risk Risk control

Risk

communicationRisk Review Risk Reporting

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What is a DSMB?

Data Safety Monitoring Board (DSMB) / Data Monitoring Committee (DMC)

An independent and multidisciplinary group established by the trial sponsor to review, at intervals, accumulating trial data, in order to monitor the progress of a trial and make recommendations on whether to continue, modify or stop the trial for safety or ethical reasons.

Guidance recognises two types of DSMB structures. Type used depends on whether the trial is commercial or non-commerical

Commercially sponsored trials - DSMBs where members are fully independent of the product manufacturer/sponsor and all trial investigators (and their institutions)

Non-commercial/investigator-initiated trials - DSMBs where members may be from (or affiliated with) the same institution as the sponsor or investigator but are not part of the trial team

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What is the role of the DSMB?

Risk DSMB Role How risk is mitigated

Participant

Interests

Identify serious emerging safety

concerns as rapidly as possible,

through regular monitoring, so as to

minimise the time that participants

may be placed at excess risk of harm

Interim monitoring of unblinded, comparative data,

(available only to the DSMB) allows DSMB to develop

a clear picture of the emerging balance of risks and

benefits.

Data validity Minimise bias in a trial

Periodically reviewing accumulating

trial data to inform trial conduct

decisions

Sponsors and trial investigators blinded to emerging

trends that may impact on their ongoing decision

making

Review trial conduct (e.g. recruitment rates,

protocol compliance, the accuracy and completeness

of data capture including missing data and rates of

loss to follow-up) to identify problems and

recommend action

Trial

credibility

Enhance trial credibility By involving experts that are widely recognised for

their expertise in the area being studied, the

uptake/acceptance of trial results by the medical

community may be enhanced

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What types of trials need a DSMB?

No single rule

When there is a significant potential risk of harm, or unknown or uncertain risks

FDA guidance recommends a DSMB when:

the study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility might ethically require termination of the study before its planned completion

there are a priori reasons for a particular safety concern, e.g. the procedure for administering the treatment is particularly invasive

the study is being performed in a potentially vulnerable population such as children, pregnant women or the very elderly, or those who are terminally ill or of diminished mental capacity

the study is being performed in a population at elevated risk of death or other serious outcomes

the study is large, of long duration, and multi‐centre

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When is a DSMB not needed?

Not all clinical trials require independent monitoring. DSMBs add administrative complexity to a

clinical trial and require resources to set-up the committee, coordinate meetings and prepare

reports for meetings.

DSMBs are not usually required in the following scenarios:

Single-centre open-label Phase I and II clinical trials, since the PI will have access to all relevant

safety data

A multicentre, Phase I clinical trial where there are very clear rules for stopping the trial. For

example, a classic open-label dose escalation trial with clear and objective criteria for halting the

dose escalation when unacceptable side effects are observed.

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Alternatives to DSMBs – some examples

Safety Review/Dose-Escalation Committee

Trial Management Group

Trial Steering Committee

Medical Monitor

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How does a DSMB operate?

DSMBs usually include a statistician and members with scientific expertise in the clinical aspects of the disease/patient population being studied, and members with practical experience and expertise in current clinical trial conduct and methodology

Appointed by the Sponsor and/or Trial Steering Committee

FDA suggest that it is optimal for a statistician independent of the sponsor to perform the unblinded interim analysis despite the fact that this is not common practice, particularly in non‐ commercial trials.

Membership to include combination of training and experience. Training should include:

Review of the fundamentals of the DSMB (via books, courses at professional meetings, and/or

on‐line content)

Review of published case studies.

Sponsor to establish a Charter for the DSMB that describes the DSMB’s operational procedures including: membership, the roles and remit of the DSMB, what recommendations are permissible, the minimum number of attendees before the DSMB is quorate for decision making, how often the DSMB meets, to whom they report and how decisions are made.

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What resources are available to staff for DSMBs?

MCTC SOP: Data and Safety Monitoring Boards

Assists researchers to determine if their research requires a DSMB

Provides procedures for establishing and operating a DSMB

MCTC Data and Safety Monitoring Board (DSMB) charter TEMPLATE

Facilitates the generation of a charter that:

Defines the responsibilities of the DSMB, its membership, and the purpose and

timing of its meetings.

Provides the procedures for ensuring confidentiality and proper communication, the

statistical monitoring procedures to be implemented by the DSMB, and an outline of

the content of the reports that will be provided to the DSMB.

Note: CRDO/MCTC will review our guidance and charter against the NHMRC’s newly-

released guidance.

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Need further help understanding the requirements?

Attend our new workshops or email CRDO at crdo.info@mcri.edu.au

Safety Oversight, Monitoring and Reporting

12 June 2018

24 October 2018

Monitoring Clinical Trials

21 November 2018

Register at https://www.mcri.edu.au/research/facilities-resources-and-training/clinical-research-development-office-crdo/crdo-workshop-1

@ Murdoch Children’s Research Institute, 2017

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