keele clinical trials unit - keele.ac.uk · sop 21: non-compliance: ... service or other...

SOP 21: Non-Compliance: © Keele University Deviations and Serious Breaches of GCP and/or the Trial Protocol

Ref: KCTU/SOP21/v4.0/27-Oct-2017 of 13

Keele Clinical Trials Unit

Standard Operating Procedure (SOP) Summary Box

Title Non-Compliance: Deviations and Serious Breaches of GCP and/or the Trial Protocol

SOP Index Number SOP 21

Version 4.0

Approval Date 13-Oct-2017

Effective Date 27-Oct-2017

Review Date October 2019

Lead Author Steve Alcock

Reference KCTU/SOP21/v4.0/27-Oct-2017

DISCLAIMER

This SOP is the property of Keele Clinical Trials Unit (Keele CTU), Faculty of Health, Keele University and the content cannot be reproduced without specific permission from

the owner.

All SOPs and associated documents must be accessed through the dedicated SOP area of the Research Institute for Primary Care and Health Sciences (iPCHS) Intranet to

ensure the correct version is being used. If this document is being accessed through any other method, such as electronic copies saved onto a network drive or in printed form, it is only valid for use if the version number and effective date shown above is the same as

that shown on the iPCHS Intranet.

Any superseded versions of this document need to be promptly withdrawn from use.

All individuals undertaking functions outlined in this document are responsible for ensuring that they are trained in the procedures outlined in the correct version of this

document. SOP Template v6.0 date 18 Aug 2016

Signature Box

Print Name Signature Date

Research Integrity Manager

Emma Skinner Signed hard copy stored in

approved SOP file with Research Integrity office

13-Oct-2017

Senior Trial Manager

Susie Hennings Signed hard copy stored in

approved SOP file with Research Integrity office

13-Oct-2017

http://www.keele.ac.uk/pchs/intranet/sops/



Version History Log

Version Date Approved

Reason(s) for Change Implementation Plan

1.0 22-Oct-2015 Approval of version 1.0 All Research Institute staff will be notified of the SOP release. Staff are expected to read the SOP, as applicable to their role. Study Coordinators are to cover the procedures at the next operations and management group meetings for the trials.

2.0 11-Jul-2016 Update to trial deviation form, and addition of conditions of sponsorship withdrawal

All Research Institute staff will be notified of the SOP release. Staff are expected to read the SOP, as applicable to their role. Trial Managers are to cover the procedures at the next operations and management group meetings for the trials.

3.0 31-Jan-2017 Update following serious breach notification to clarify process.

All Keele Health and Social Care Research QMS users will be notified of the new SOP. Staff are expected to read the new version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date

4.0 13-Oct-2017 Update following changes made to the forms for reporting and investigation, and the management of the process.

All Keele Health and Social Care Research QMS users will be notified of the new SOP. Staff are expected to read the new version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date Training sessions to be led by Lead Author focusing on the completion of the new form.



Table of Contents 1. Purpose ........................................................................................................................ 4

2. Scope and Applicability ................................................................................................. 4

3. Background .................................................................................................................. 4

4. Procedures ................................................................................................................... 6

4.1 All Studies ............................................................................................................... 6

4.1.1 Summary Flow Diagram ................................................................................... 6

4.1.2 Identification of potential non-compliance ........................................................ 7

4.1.3 [FOR25.1 - Initial Report] ................................................................................. 8

4.1.4 [FOR25.2 - Research Integrity Office Assessment] .......................................... 9

4.1.5 Additional Information ...................................................................................... 9

[FOR25.3 - Local PI Assessment] .................................................................... 9

[FOR25.4 - Further Assessment] ................................................................... 10

[FOR25.5 - Independent Review] ................................................................... 10

[FOR25.6 - Serious Breach Submission]........................................................ 10

[FOR25.7 - Urgent Safety Measures] ............................................................. 10

[FOR26 - Corrective and Preventative Action (CAPA) Plan] .......................... 10

4.1.6 [FOR25.8 - Deviation closure] ........................................................................ 10

4.1.7 Reporting deviations ...................................................................................... 11

4.2 Serious Breaches ................................................................................................. 11

4.3 Non-compliance Data ........................................................................................... 12

5. Key Personnel to whom this SOP Applies .................................................................. 12



1. Purpose This Standard Operating Procedure (SOP) describes the process for management and escalation of non-compliance and serious breaches of Good Clinical Practice (GCP) and/or the approved trial/study protocol. 2. Scope and Applicability This SOP applies to all individuals undertaking functions outlined herein. This includes all core Keele CTU staff and all other academic, research, management or admin staff, or students working on Keele University sponsored/Keele CTU managed clinical research projects through site agreements, service or other contractual arrangements.

This SOP must be followed in line with the NHS Research Governance Framework, and the

University, Research Institute and CTU policies.

Where applicable to Clinical Trials of Investigational Medicinal Products (CTIMPs) this SOP

must be followed in line with the UK Medicines for Human Use (Clinical Trials) Regulations

2004 and subsequent amendments, and the EU Clinical Trials Directive. This SOP must

also be followed in line with any current MHRA requirements as detailed on their website.

Where applicable to non-CTIMP studies this SOP must be followed in line with the principles

of Good Clinical Practice. Whilst elements of this SOP relate only to CTIMPs, e.g. reporting

Serious Breaches to the MHRA, the principles of identifying and managing non-compliance

apply to non-CTIMP studies.

For Keele University Sponsored research studies, operational responsibility for

identification, classification and reporting of non-compliance is delegated to the Chief

Investigator (CI) with the support of the Sponsor.

3. Background Deviations from study protocols and Good Clinical Practice (GCP) occur commonly in health

and social care research. The majority of these instances are technical non-compliances

that do not result in harm to participants, do not compromise data integrity, or significantly

affect the scientific value of the reported results of the study. These technical deviations

must be still be documented, and appropriate corrective and preventative actions must be

taken.

It is the responsibility of the sponsor to assess the impact of any serious breaches on the

scientific value of the study. The sponsor can terminate or suspend a study if there are

concerns around patient safety or study conduct (see HSCRC-POL-01 Policy for Health

and Social Care Research for further information).

http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4108962

http://www.legislation.gov.uk/uksi/2004/1031/contents/made

http://www.legislation.gov.uk/uksi/2004/1031/contents/made

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF

https://www.gov.uk/guidance/good-clinical-practice-for-clinical-trials#report-a-serious-breach

http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice.html



Where Keele University is not the Sponsor but the function of reporting serious

breaches to the main REC and MHRA is delegated by the Sponsor to Keele University,

the arrangement does not affect the legal responsibility of the Sponsor. All reports

and correspondence relating to the issue must be collated and supplied to the

Sponsor.



4. Procedures 4.1 All Studies 4.1.1 Summary Flow Diagram

Identification of potential non-compliance (section 4.1.2)

Sponsor notified of non-compliance event via [FOR25.1 – Initial Report] submitted to

Research Integrity Office(section 4.1.4)

Sponsor records event on Edge workflow, assigns unique deviation code and completes

[FOR25.2 – Research Integrity Office Assessment] (section 4.1.4)

Local PI review [FOR25.3 – Local PI Assessment] (if required)

(section 4.1.5)

[FOR26 – Corrective and Preventative Action Plan] (if required) (section 4.1.5)

Further assessment carried out by CI or other relevant individual [FOR25.4 – Further

Assessment] (if required) (section 4.1.5)

Final sponsor review of non-compliance [FOR25.2 – Research Integrity Office

Assessment] (section 4.1.5)

Independent review of deviation if sponsor review does not agree with CI assessment

[FOR25.5 – Independent Review] (section 4.1.5)

Deviation closure and reporting [FOR25.8 - Closure]

(section 4.1.6)

Serious breach identified at any stage (section 4.2)

Serious Breach Notification Form completed by Sponsor and CI

(section 4.2)

Research Integrity Manager submits Serious Breach Notification Form to MHRA (CTIMPS) and NHS REC (section 4.2) and completes

[FOR25.6 – Serious Breach Submission]

CI completes [FOR25.1 – Initial Report] and e-mails to Research Integrity Office

(section 4.1.3)

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4.1.2 Identification of potential non-compliance

Potential non-compliance identified

For all research, non-compliance may be identified

through any study activity, but in particular through:

Central monitoring procedures such as consent form

review or data management (SOP 14: Monitoring)

Site visits

Self-reporting by a study site or participant

Potential non-compliance reported to the Chief Investigator

A potential non-compliance event affecting a study must

be reported to the Chief Investigator (CI) as soon as any

member of the study team becomes aware of an event.

This must be followed up in writing (e.g. via email or a

logged telephone call). The CI or delegated individual

must then follow up the event and is classed as the

‘investigator’ for the purposes of this SOP.

Confirm non-compliance

The investigator must collect information to assess

whether the event is a true non-compliance event or

could be a misunderstanding or otherwise not a non-

compliance event. For example, a protocol written

broadly to cover variation in activity at site may cause

activity to be misinterpreted as non-compliance by a

local study team.

Investigator completes Section A of [FOR25.1

– Initial Report]

If the CI wishes to initiate an urgent safety measure, (see SOP 20: Safety Reporting and Pharmacovigilance) to protect participants from any immediate hazard to their health and safety, this must be indicated in Section A of [FOR25.1 – Initial Report].



4.1.3 [FOR25.1 - Initial Report]

CI or delegate completes Section B of

[FOR25.1 – Initial Report] within 24

hours of being notified of event.

This section is used by the CI to assess the severity of

the non-compliance event, in accordance with the study

protocol.

Investigator completes Section C of [FOR25.1 – Initial Report] (if known at this time)

Completion of section C should NOT delay submission of

[FOR25.1 – Initial Report] to the Research Integrity

Office and should therefore only be completed at this

time if the information necessary to classify the deviation

and / or root cause is already available when Section B

is completed.

CI completes and signs Section D of [FOR25.1 – Initial Report], for

CTU managed studies a Senior Trials

Manager must also sign, and they (or the Investigator) send to

the Research Integrity Office.

Submit to the Research Integrity Office via e-mail to

[email protected] with a subject

heading of “[RG/sponsor code: study acronym/short

title] – Non-compliance notification”.

The judgement on whether an instance of non-compliance is likely to have a significant

impact on the scientific value of the study depends on a variety of factors e.g. the design of

the study, the type and extent of the data affected by the breach, the overall contribution of

the data to key analysis parameters, the impact of excluding the data from the analysis etc.

For examples of what is classed as a serious breach see guidance for the notification of

serious breaches of GCP or the study protocol on the MHRA website.

mailto:[email protected]




4.1.4 [FOR25.2 - Research Integrity Office Assessment]

Research Integrity Office logs event on Edge as a workflow

and assigns a deviation code.

The Research Integrity Office will log the event on Edge

as a workflow and assign a unique deviation code using

the code allocation spreadsheet. The Research Integrity

Office will acknowledge receipt of the form and notify the

Investigator of the deviation code.

Research Integrity Manager reviews [FOR25.1 – Initial

Report] and completes section A of [FOR25.2 – Research Integrity Office Assessment].

In [FOR25.2 – Research Integrity Office

Assessment] the Research Integrity Manager will

make an initial assessment regarding the non-

compliance event.

If further information is required to complete

the review the Research Integrity

Manager will initiate the applicable form.

Where further information is required, the Research

Integrity Manager will complete [FOR25.4 – Further

Assessment] and return this to the Investigator.

If the non-compliance has the potential to be a serious breach, the Research Integrity

Manager will notify the Head of Academic Legal Services and Head of Research Integrity at

the earliest opportunity.

If the CI has identified the non-compliance as a Serious Breach

the NHS REC and MHRA (in the case of CTIMPs) must be notified within 7 calendar

days. The process for reporting a serious breach is detailed in section 4.2.

4.1.5 Additional Information The following Forms will be initiated by the Research Integrity Manger if they are required:

[FOR25.3 - Local PI Assessment] The investigator, CI or Research Integrity Manager, will indicate in [FOR25.1 – Initial

Report] or [FOR25.2 – Research Integrity Office Assessment] (as applicable) whether

[FOR25.3 – Local PI Assessment] needs to be completed by the PI at the research site.

The Research Integrity Manager will initiate [FOR25.3 – Local PI Assessment]. This is only

required for deviations that have occurred at a specific research site. This process must be

facilitated by the CI / investigator.



[FOR25.4 - Further Assessment] If there is a need for further assessment this will be indicated by the CI on [FOR25.1 – Initial

Report] or the Research Integrity Manager on [FOR25.2 – Research Integrity Office

Assessment]. [FOR25.4 – Further Assessment] will be initiated by the Research Integrity

Manager and must be completed by the CI or their delegate.

[FOR25.5 - Independent Review] Where additional expertise is required to assess the severity of an event, the Research

Integrity Manager will initiate [FOR25.5 – Independent Review]. For CTIMPs; if the

Research Integrity Manager’s review of seriousness is different from the CI’s decision, an

independent reviewer must be asked to complete [FOR25.5 – Independent Review]. If the

outcome of the independent review is that a serious breach has occurred and this had not

been previously reported the processes in Section 4.2 of this SOP must be followed.

[FOR25.6 - Serious Breach Submission] (See section 4.2)

[FOR25.7 - Urgent Safety Measures] Where an USM is required in relation to the deviation, [FOR25.7 – Urgent safety Measures]

is completed by the Research Integrity Manager. USMs are managed in accordance with

SOP 20: Safety Reporting and Pharmacovigilance.

[FOR26 - Corrective and Preventative Action (CAPA) Plan] It may be sufficient for all CAPA to be detailed in [FOR25.1 – Initial Report] Section A.

Where a full CAPA is required, the Research Integrity Manager will initiate [FOR26 –

Corrective and Preventative Action Plan]. This must be completed by the investigator

through liaison with the CI and study team. The CAPA must describe what actions are

required to correct the deviation and how to prevent it happening again in the future. If the

separate [FOR26 - Corrective and Preventative Action Plan] has been used, the CAPA

code must be referenced in the respective box in [FOR25.2 – Research Integrity Office

Assessment]. The Research Integrity Manager will review the proposed CAPA and

associated timeframes to ensure that actions are completed in a reasonable period. The

Research Integrity Manager may escalate breaches of timeframes or other issues to the

Head of Research Integrity.

4.1.6 [FOR25.8 - Deviation closure] The Research Integrity Manager will review the information provided in all completed forms.

If unsure about any aspect of the information, the Research Integrity Manager may contact

the CI, Investigator, Lead Statistician or appropriate Trial Manager for further clarification

using [FOR25.4 – Further Assessment]. The Research Integrity Manager will complete

Section B of [FOR25.2 – Research Integrity Office Assessment]

Once the deviation has been resolved [FOR25.8 - Closure] must be completed by the

Research Integrity Manager. For CTIMPs, any serious breaches must be considered as

ongoing until confirmed closed by the MHRA Inspector. The original completed GCP and

Protocol Deviation Forms must be filed in the Study Master File and copies with the

Research Integrity Office.



4.1.7 Reporting deviations The Research Integrity Manager will notify the Head of Academic Legal Services and Head

of Research Integrity of potential and confirmed serious breaches.

All deviations must be reported to the Trial Management Group (TMG), Trial Steering

Committee (TSC) and Data safety Monitoring Committee (DMC). TSC and DMC reports

must include data regarding deviations in accordance with SOP 33: Trial Steering

Committees and Data Monitoring Committees.

In addition, deviations should be included and considered when producing the final

CONSORT diagram, which describes how such deviations have been handled during

analysis, and their impact on patient safety and the conduct of the analysis reported in the

applicable Study Report (SOP 16: Analysis).

4.2 Serious Breaches

A “serious breach” is defined as a breach of the protocol or of the conditions or principles of

Good Clinical Practice (or equivalent standards for conduct of non-CTIMPs) which is likely

to affect to a significant degree the safety or physical or mental integrity of the trial subjects,

or the scientific value of the research.

For CTIMPs, Where it is confirmed that a Serious Breach of the trial protocol or GCP has

occurred, or there is uncertainty, the CI must complete the MHRA’s Notification of Serious

Breaches of GCP or the Trial Protocol Form, the current version of which is available on the

MHRA’s Website and send it to the Research Integrity Office (via

[email protected]).

The MHRA and NHS REC must be notified of a confirmed serious breach within 7

calendar days of becoming aware of the breach.

The Research Integrity Manager will notify the MHRA GCP Inspectorate of the serious

breach via the email provided on the MHRA website using the notification form which the CI

has completed. If there are any queries the Research Integrity Manager, as sponsor

representative, will telephone the MHRA Inspectorate to discuss the serious breach. The CI

must also notify the Research Ethics Committee of the serious breach via e-mail.

The Research Integrity Office will continue to be the contact for the allocated MHRA

Inspector. [FOR25.6 – Serious Breach Submission] will be used by the Research Integrity

Manager to record serious breach submission information. The Research Integrity Manager

will notify the Head of Academic Legal Services and Head of Research Integrity.

Consideration will be made regarding notifying the University’s insurance broker.

For serious breaches in non-CTIMPs the CI must notify the NHS REC. Time lines for reporting of serious breaches in non-CTIMPs are the same as those for CTIMPs.






The CI must respond with urgency to any actions or queries relating to a serious breach.

4.3 Non-compliance Data

The data collated by the Research Integrity Office regarding non-compliance events for all

health and social care research studies, whether CTIMP or not, will be reviewed for trends

and to identify any critical activity that may require further training or an audit to be

performed.

5. Key Personnel to whom this SOP Applies

Responsibility of

Undertaken by Activity

1 All staff to which SOP applies

Users of SOP

Identification of non-compliance with trial protocol

and /or GCP and highlighting to the Trial

Manager/Study Coordinator and CI

2 Chief Investigator

Chief Investigator (with support of Research Integrity Manager)

Assessment

Assessment of impact of non-compliance on

participant safety and scientific integrity of the trial

Escalation of any non-compliance that is

potentially a serious breach of the trial protocol or

GCP

Completion of MHRA’s Notification of Serious

Breaches of GCP or the Trial Protocol Form as

required

Reporting of confirmed Serious Breaches to the

NHS REC

Oversight of agreed Corrective and Preventative

Action Plans [FOR26 - Corrective and

Preventative Action Plan]





Responsibility of

Undertaken by Activity

Trial Manager/Study Coordinator (with support of, CI and Research Integrity Manager)

Maintenance of record of all non-compliance

occurring within the trial

Investigation into instances of non-compliance

Reporting

Reporting confirmed and potential serious

breaches to the CI and Research Integrity Office

for assessment

Supporting the CI in completion of serious breach

report for submission to MHRA and REC

Development and implementation of Corrective

and Preventative Action plan [FOR26 -

Corrective and Preventative Action Plan] as

agreed with all parties

3 Sponsor Research Integrity Office

Support CIs and trial teams in investigations into

non-compliance

Maintenance of a central University record of all

non-compliance across all trials

Support CIs and trial teams to develop

appropriate corrective and preventative action

plans [FOR26 - Corrective and Preventative

Action Plan] as necessary

Report confirmed serious breaches to MHRA on

behalf of the University within regulatory

timeframes

Point of contact for MHRA for correspondence

relating to serious breach reports

Report all non-compliances assessed as potential

serious breaches to the Head of Academic Legal

Services and the Head of Research Integrity.

Report all non-compliances and CAPA plans (if

appropriate) to the appropriate University

Committee(s)

keele clinical trials unit - keele.ac.uk · sop 21: non-compliance: ... service or other...

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