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Standard Operating Procedure
for the Recording and Reporting of
Deviations, Violations, Potential Serious
breaches, Serious breaches and
Urgent Safety Measures
SOP ID Number: JBRU/SPON/S15/03
(was generated by merging JBRU/SPON/S15/02: “SOP for the
sponsor’s Management of Protocol Violations and Deviations”
and JBRU/INV/S06/02: “SOP for the recording and reporting of
protocol deviations and violations for investigators”)
Effective Date: 10-01-2010
Version Number & Date of Authorisation: V03, 05/01/2010
Review Date: 10-01-2012
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Revision Chronology:
SOP ID Number:
Effective
Date:
Reason for Change:
Author:
JBRU/07/S06/00
18/06/2007
N/A
Adeeba
Ashgar
JBRU/INV/S06/01
02/07/2008
To make SOP specific to Investigator
Responsibilities.
Yvanne
Enever
JBRU/INV/S06/02
15/10/2008
JBRU/SPON/S15/03
10/01/2010
To implement a new JBRU formatting and
Ira
numbering system as reflected in SOP on SOPs
Jakupovic
(JBRU/SPON/S01/02).
To merge 2 SOPs:
1. “SOP for the sponsor’s Management of
Protocol Violations and Deviations”
(JBRU/SPON/S15/02) and
2. “SOP for the recording and reporting of
protocol deviations and violations for
investigators” (JBRU/INV/S06/02).
To incorporate:
1. the requirement for the PI/CI/Labs to notify the
Sponsor of any “serious breaches”, in line with
Regulation 29A:SI 2006/1928
2. the requirement for the PI/CI/Labs to record
and report “urgent safety measures”. Regulation
30 (SI 2004/1031) and the amendment to that
Regulation:SI2009/1164
3. the use of the template from the MHRA
“Serious Breaches Guidance Version 2” (Final,
15-10-09)
4. the use of the following logs in the recording
process:
Ann
Cochrane
1. PI’s Log of (Protocol &or GCP)
Deviations/Violations/ “Potential Serious
breaches/Serious breaches & Urgent Safety
measures”.
2. JBRU Log of “Potential Serious breaches/ Serious
breaches”
3. JBRU Log of “Urgent Safety Measures”.
Format amended in line with revised SOP on SOPs to
incorporate a UCL logo only, as UCLH no longer
provides sponsorship for CTIMPs, an Acronyms table,
eDocument file path, associated templates/log table,
SOP dissemination and training and a signature page.
ACRONYMS:
JBRU
GCP
SOP
ISF
PI
CI
CRF
Joint Biomedical Research Unit
http://www.ucl.ac.uk/joint-rd-unit
Good Clinical Practice
Standard Operating Procedure
Investigator Site File
Principal Investigator
Chief Investigator
Case Report Form
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Standard Operating Procedure
for the Recording and Reporting of
(protocol &/or GCP)
Deviations,
Violations,
Potential Serious breaches,
Serious breaches and
Urgent Safety Measures
1. PURPOSE
This Standard Operating Procedure (SOP) specifies the overall process and procedure
for the Investigators and the JBRU to follow for a UCL sponsored clinical trial in the
event of a protocol and/or GCP deviation. Criteria to follow are outlined in order to
assess the impact of the deviation in light of the definition of a potential serious
breach and /or an urgent safety measure.
This SOP describes the procedure for the Investigator to record the event and notify the
JBRU and/or the MHRA/REC and for the JBRU to report to the MHRA and/or REC as
and when necessary.
2. JOINT UCLH/UCL BIOMEDICAL RESEARCH UNIT (JBRU) POLICY
All JBRU SOPs will be produced, reviewed and approved in accordance with the JBRU
SOP on SOPs.
3. BACKGROUND
Regulation 29 “Conduct of trial in accordance with clinical trial authorisation etc.” of the
UK regulations (SI 2004/1031) ‘The Medicines for Human Use (Clinical Trials)
Regulations 2004’ stipulates that all CTIMPs must be conducted in accordance with a
Protocol that has been approved by a Research Ethics Committee (REC) and the
Competent Authority (MHRA in the UK).
It is the Sponsor’s responsibility to oversee the conduct of all CTIMPs and to ensure
compliance with the approved protocol and prevailing UK regulations.
The JBRU does NOT allow the use of “protocol waivers” or departures
from the approved inclusion/exclusion criteria of the protocol. Occurences of
this nature will be considered as a serious breach reportable to the MHRA.
The Investigator/Institution should only conduct the trial in accordance with the
approved protocol unless an urgent safety measure must be taken, according to SI
2004/1031 under Regulation 30 and in section 3.1.3 below.
The Investigator, or person designated by the Investigator (in the trial delegation log),
should document and explain any deviation from the approved protocol (ICH GCP
section 4.5.3).
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3.1 Definitions used throughout this document
3.1.1 Protocol Deviation: A deviation is usually an un-intended departure from the
expected conduct of the trial and is often classified as non-serious or minor in nature
e.g. a protocol visit date deviation (a common deviation in clinical trials) which does not
need to be reported to the sponsor. These events will be identified by the trial team
during trial conduct and must be continually monitored by the CI/PI or as delegated and
the CI/PI made aware. It is the responsibility of the CI/PI to train their trial staff on the
trial protocol requirements and this training must be documented and filed in the ISF.
The regular completion of the JBRU’s self-monitoring report form will help the CI identify
and quality check compliance not only with the trial protocol but also with GCP and the
UK Regulations.
It is recognised that minor deviations from approved clinical trial protocols and GCP
occur commonly in CTIMPs. Not every deviation from the protocol will result in a serious
breach. The majority of these instances are technical deviations that do not result in
harm to the trial subjects or significantly affect the scientific value of the reported results
of the trial (see MHRA “Guidance for the notification of serious breaches of GCP or the
trial protocol”, document version 2.0). These cases should be documented in the CRF
or in a file note and appropriate corrective and preventative action taken in order to
ensure they do not recur. They do not need to be reported to the JBRU. Please use the
CRF and the PI’s Log of (Protocol and/or GCP) Deviations/ Violations/ “Potential
Serious breaches”/”Serious breaches”/“Urgent Safety Measures” provided by the
JBRU to the PIs to record each case during trial conduct.
3.1.2 Violations to the Protocol &/or GCP: You are required to report to the sponsor
any violations that may impact on the subjects’ safety or affects the integrity of the study
data (this may also constitute a potential Serious Breach of GCP &/ or protocol and will
require further reporting in accordance with this SOP). Examples of this include but are
not limited to;
o Failure to obtain informed consent (i.e. no documentation in source data or an Informed
Consent form)
o Enrolment of subjects that do not meet the inclusion/exclusion criteria
o Undertaking a trial procedure not approved by the REC and/or the MHRA (unless for
immediate safety reasons)
o Failure to report an SAE/R/SUSAR to the JBRU
o IMP dispensing/dosing error
Please also refer to Appendix 2 for examples of notifications to the MHRA.
Minor Violation - a violation that does not impact on subjects’ safety or compromise the
integrity of study data. Examples of this maybe;
Missing original signed consent form (only photocopy present)
3.1.3 Serious Breaches of the protocol and/or GCP
Please consider whether the violation that has occurred on site meets the following
definitions. These cases must be reported to the JBRU as soon as the PI has become
aware of the event.
Under Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations
2004 [SI 2004/1031], as amended by SI 2006/1928, there is a requirement for the
notification of “serious breaches” of GCP and/or the trial protocol:
“29A. (1) The sponsor of a clinical trial shall notify the licensing authority in writing of
any serious breach of (a) the conditions and principles of GCP in connection with that trial; or
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(b) the protocol relating to that trial, as amended from time to time in
accordance with regulations 22 to 25, within 7 days of becoming aware
of that breach.
(2) For the purposes of this regulation, a “serious breach” is a breach which is likely to
effect to a significant degree –
(a) the safety or physical or mental integrity of the subjects of the trial; or
(b) the scientific value of the trial”.
This requirement was implemented in UK legislation in order to:
• Enhance the safety of trial subjects by seeking to ensure that the licensing authority is
promptly informed of such serious breaches, in order to take appropriate action in
response to the breach and/or,
• To take the information regarding serious breaches into account when assessing
future applications for clinical trial authorisation, and applications for marketing
authorisation, which include data from trials affected by serious breaches.
See section 6.13 below for the REPORTING procedures.
3.1.4 Urgent Safety Measures (Implementing a Protocol Deviation under an
emergency)
The Investigator may implement a deviation from, or a change of the protocol to
eliminate an immediate hazard(s) to trial subjects without prior approval from the
REC/MHRA. This is defined as an Urgent Safety Measure under UK Regulation 30:
“The sponsor and investigator may take appropriate urgent safety measure to protect
clinical trial subjects from any immediate hazard to their health and safety The
measures should be taken immediately”. However, in order to meet the legal timelines
the investigator must inform the MHRA and the JBRU (in parallel) in writing
immediately and within 3 days.
See section 6.13 below for the REPORTING procedures.
3.1.5 A Trust Reportable Incident
Each investigator is reminded to report any Incident to the Trust as per their local Trust
Incident reporting policy under the Research Governance Framework 2005.
For UCLH employed staff please refer to:
http://www.ucl.ac.uk/joint-rd-unit/researchincidents
These incidents should also be notified to your local R&D office in line with their local
reporting requirements. Please ensure you are aware of how to report such incidents
before your trial commences.
4. SCOPE OF THIS SOP
This SOP details the process (for Investigators and for the JBRU regarding UCL
sponsored clinical trials) to follow for the recording and reporting of CTIMP protocol
deviations and violations. It describes what consideration must be taken into account to
assess whether the deviations and violations also meet the definition of a potential
serious breach or urgent safety measure. It describes the reporting process to the
JBRU, MHRA and MREC so that the legal 7/3 days reporting requirement may be met.
Where this has been delegated to a partner organisation (e.g. CTC, ICH etc) via a MoU
or through Service Level Agreement (SLA) it will be the responsibility of that partner
organisation to report the “serious breaches” and “urgent safety measures” to the
Competent Authority & REC. For the completion of the UCL MHRA GCP compliance
report, the partner organisations will submit the “potential serious breaches”, “serious
breaches” and urgent safety measures logs to the JBRU.
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International Trials
For UCL international sponsored trials, UCL delegates the responsibility for
reporting “serious breaches” and “urgent safety measures” to regulatory
authorities (RAs) and ethics committees (ECs) outside the UK, to country coordinating centres and/or country lead sites participating in the trial.
5. RESPONSIBLE PERSONNEL
5.1 The Investigator has the responsibility to record and report any violations to the
JBRU within the agreed timeframes and in accordance with this SOP if these are
deemed a potential serious breach/urgent safety measure under the definitions
above. Deviations need only be documented on site, in the CRF, in a file note and on
the PI’s Log of (Protocol and/ or GCP) Deviations/Violations/“Potential Serious
breaches”/”Serious breaches”/“Urgent Safety Measures”. Any corrective and
preventative action should also be documented and retained in the site file. It is
recommended by the MHRA that the investigator should also have a process in place to
identify and notify the JBRU of serious breaches. This SOP should therefore be followed
or detailed in the protocol.
Consideration should be given to what actions to take if the JBRU does not report the
breach to the MHRA (due diligence is required e.g. should you continue with the trial,
should you report to the authorities, etc.).
5.2 The JBRU has a legal duty to report serious breaches to the MHRA within the
timelines laid down under SI 2004/1031 and as amended under SI 2006/1928. There
should be a formal process in place to cover the legislative requirements of serious
breach notifications including:
Receipt and Assessment (i.e. assessment of deviations/violations by JBRU/delegate,
isolated/systematic incident, patient(s) harmed or put at risk/data credibility etc.)
 Investigation
 Corrective and Preventative Action (CAPA)
 Reporting to MHRA
 Compliance with 7-day reporting timescale.
Lack of systems and failure to report serious breaches may result in findings at GCP
Inspections (the grading will be dependent on the impact).
If the Investigator is unsure whether a deviation or violation is a potential serious
breach then please notify the JBRU as soon as possible and provide as much
information as possible.
It is the responsibility of the JBRU to assess the impact of the breach on the scientific
value of the trial, this can be carried out in conjunction with the PI/CI. If a potential
serious breach is identified by a member of the JBRU, either via review of a selfmonitoring report, audit, a phone call or other means, the JBRU QA manager should
also be alerted as soon as possible with a further discussion with the CI in order to
clarify the situation and take appropriate corrective and preventative action.
If the JBRU retains the notification function as part of an agreement with another party,
then it is recommended that agreements between the sponsor and other parties
involved in the trial e.g. CROs, contractors, investigators, etc should state that the other
party will promptly notify the JBRU of a serious breach (as defined in regulation 29A that
they become aware of in order for the sponsor to meet their legal obligation). In this
case, the clock starts when the JBRU becomes aware of an event.
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6. PROCEDURE
6.1 Identification of a potential serious breach
The judgment on whether a breach is likely to have a significant impact on the scientific
value of the trial depends on a variety of factors e.g. the design of the trial, 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.
In addition, it is important that site notifies the JBRU of what corrective and preventative
action has been taken (CAPA) in order to devise a formal plan of corrective and
preventative action.
If a deviation is deemed minor in nature then these cases should be documented in the
CRF and in the deviations and violations log and a file note written where necessary
in the ISF. In addition, these deviations should be included and considered (where
applicable) when the clinical study report is produced, as they may have an impact on
the analysis of the data.
If the deviation/violation is identified at JBRU the case must be discussed with the QA
manager as soon as possible and senior management notified if that person is not
available. As much information as possible should be obtained from site and discussed
with the PI/CI, documented in email or via a documented telephone log.
6.2 Procedure for notifying the JBRU of a POTENTIAL serious breach
The person having identified the breach must complete the Notification of Serious
Breaches of GCP or Trial Protocol form (see Appendix 1), add the mention
« POTENTIAL serious breach » and email this to the JBRU via both the Lead Trial
Coordinator and Trial Monitor for any event deemed potentially a serious breach. Full
available details of the deviation must be given including: date identified at site, any
immediate corrective or preventative action taken and the assessment of the event in
relation the definition of a serious breach.
The initial report to the sponsor should include the following information:
-Name/Chief Investigator/PI at the site where the breach occurred
-Full title of the trial and sponsor ID Number
-An explanation of how the breach was identified
-Details of the breach
-Details of any initial corrective actions
-Assessment of the impact the breach will have on the trial/subjects/and/or -scientific
integrity of the trial.
All potential serious breaches must be emailed to the JBRU immediately after being
identified so that the JBRU may inform the MHRA within 7 calendar days should the
event be confirmed a “serious breach”. The person having notified the JBRU must
request the Lead Trial Coordinator/Trial Monitor to reply to his email to acknowledge
receipt of the notification of “Potential serious breach”. The PI must save the email
from the JBRU acknowledging receipt of the notification, print it out and file it in his ISF.
If acknowledgement of receipt has not been received with a working day, the PI should
phone the JBRU to request acknowledgment of receipt.
In addition the PI must log the “Potential serious breach” in the PI’s Log of
(Protocol
and/
or
GCP)
Deviations/Violations/“Potential
Serious
breaches”/”Serious breaches”/“Urgent Safety Measures”.
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For Protocol Violations the Investigator must also complete PI’s Log of (Protocol and/
or
GCP)
Deviations/Violations/“Potential
Serious
breaches”/”Serious
breaches”/“Urgent Safety Measures” and email it to the JBRU via both the Lead Trial
Coordinator and trial monitor. All major violations must be reported to the JBRU within 3
calendar days of the Investigator being made aware of the violation. A copy of the
completed form must be filed in the ISF. The PI must request acknowledgement from
the JBRU and file it in the ISF.
A violation may constitute the JBRU to undertake an urgent monitoring visit. All major
violations must be resolved to conclusion Depending on the nature of the violation it
may constitute a Serious Breach of GCP and further follow up and reporting maybe
required by the JBRU in line with current regulations.
Should a deviation or violation occur that relates to more than one site only one report
should be made and filed in the applicable section of the ISF.
6.3 Assessment by the JBRU
The JBRU will work with the CI/PI to identify the extent and nature of the breach, and to
decide on a CAPA plan in order to implement the necessary corrective and preventative
actions. The assessment process must be clearly documented to include any meetings
and discussions within the team where possible. Minutes of meetings may also be used
(e.g. CTOG or the Safety Committee if a case was discussed there).
Some degree of investigation and assessment may be required by the sponsor prior to
the notification in order to clarify if a serious breach has actually occurred. It may be
necessary to place the trial on hold, alert other sites taking part, notify pharmacy and
consider a substantial amendment to the revised protocol.
If the sponsor obtains clear and unequivocal evidence that a serious breach has
occurred the default position should be for the JBRU to notify the MHRA first, within 7
days, investigate and take action simultaneously or after notification. In this case, the
JBRU should not wait to obtain all of the details of the breach prior to notification.
If the sponsor is unclear then the case may also be reported to the MHRA in the first
instance to discuss the issue.
Inspectors will review the process for notification during MHRA GCP Inspections and
delays in notification may be classed as non-compliance. If in doubt about whether of
not to notify, contact the MHRA GCP Inspectorate.
6.4 Corrective and Preventative Actions (CAPA):
The JBRU and the CI/PI must agree on the appropriate corrective and preventative
action to be taken and this should be documented and detailed within the body of the
notification report.
6.5 Notification to the MHRA:
The JBRU member alerted to the serious breach will work with the JBRU QA Manager
to collate all information and complete the Notification of Serious Breaches of GCP
or Trial Protocol form (Appendix 1).
It is recommended that the most recent form is used to ensure all appropriate
information is submitted to the GCP Inspectorate. An example of how to complete the
form is given in the MHRA “Serious Breaches Guidance Version 2” (Final, 15-10-09). An
initial telephone call to the Inspectorate may also be necessary.
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The completed form should be sent to the GCP Inspectorate within 7 days of the JBRU
becoming aware of the breach. It is not necessary to wait until all the information is
obtained, updates to the report are acceptable. In such cases, plans should be indicated
with projected timelines for completion on follow up reports.
The completed form (Appendix 1) should be emailed to:
GCP.SeriousBreaches@mhra.gsi.gov.uk
Alternatively, if this is not possible, notifications may also be sent by fax or post to any of
the three MHRA Inspectorate offices as per the MHRA website.
All “Potential serious breaches” and “Serious breaches” must be recorded in the “JBRU
Log of “Potential Serious breaches”/”Serious breaches” reported by the
PI/CI/Lab/CTC/ICH to the JBRU on UCL sponsored CTIMPs by the QA or by a monitor.
6.6 Follow up reports:
Follow up reports should be made in writing (the serious breaches form can also be
used for this) and should ideally:
Be clearly identified as a follow up report
Identify the unique GCP ID allocated when the initial report was acknowledged by the
MHRA
Be forwarded to the initial inspector dealing with the case
6.7 Notifications to other MHRA Units and/or the REC
Organisations should also consider if there are any relevant MHRA units that require to
be notified to comply with other legislation e.g. notification to the Clinical Trials Unit
(CTU) if the breach constitutes an Urgent Safety Measure or if a substantial amendment
is required due to a temporary halt in the study or the Defective medicines Report
Centre if the breach involves defective medicines or IMP recall etc. and/or if the REC
needs to be notified.
6.8 MHRA Actions:
Wherever possible, MHRA will provide an acknowledgement of receipt of notification.
The MHRA will triage the notification and a variety of actions may be taken, depending
on the nature of the breach and its potential impact. In general the following will occur
as per the Guidance document version 2.0:
1. An administrator for the GCP Inspectorate checks the GCP/PV mailbox
for any referrals (including serious breaches).
2. The administrator will acknowledge receipt of the notification and
assign it a unique identifier. The administrator then forwards the
notifications to a GCP inspector for triage.
3. The referral/breach is logged on a spreadsheet and the inspector
determines if the breach/referral is considered to be a serious breach
by the Inspectorate.
4. The inspector is responsible for reviewing the serious breach and any
additional information provided or action required.
5. The inspector will decide if:
• the referral only requires to be logged with no further action (the
case may be examined during future MHRA inspections),
• further information/investigation is required from the notifier. If
insufficient information is provided in the initial notification to assess
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the impact of the breach, follow-up information will be requested.
• if any other bodies require to be notified (e.g. other competent
authorities/EMEA, Licensing Division, Clinical Trials Unit (CTU),
NRES/ethics committees, other GxP areas, etc.),
• further actions are required (e.g. refer to the MHRA Inspection
Action Group if critical, trigger an inspection to investigate further,
etc.),
• referral to CTU for consideration of suspension or termination of a
clinical trial authorisation,
• referral to the MHRA Enforcement Unit for consideration of
enforcement action e.g. infringement notices, criminal investigation,
• referral to professional bodies e.g. the General Medical Council.
6. Once any/all required actions have been satisfactorily completed, the
inspector will close the referral.
6.9 Examples of Serious Breaches:
Please refer to the table in Appendix 2 and the MHRA Guidance Document version 2.0
at the website in the references section of the SOP. Please keep a copy of this
document in your ISF.
6.10 Retention:
As a minimum, copy or copies of the initial and any follow up reports should be retained
in the ISF, TMF under Section 4 (MHRA documentation) and centrally in the “Potential
serious breaches, serious breaches” folder hold by the JBRU QA manager. The PI
should retain the email ackowledging receipt of the notification from the monitor/trial coordinator in his ISF. Equally, the monitor/QA manager must file the MHRA
acknowledgement of receipt of the notification in the “Potential serious breaches,
serious breaches” folder hold by the JBRU QA manager.
The QA manager/monitor must update the “JBRU Log of “Potential Serious
breaches”/”Serious breaches” reported by the PI/CI/Lab to the JBRU on UCL sponsored
CTIMPs on the S:drive for all notifications received after this SOP becomes effective. If
a “potential serious breach” is investigated but does not become a serious breach, it
should be logged as a “Potential serious breach” (after this SOP becomes effective).
The log must be reviewed periodically to help identify any trends, in particular those
relating to recurrent findings that may require additional training or monitoring visits to
site.
The “JBRU Log of Potential serious breach and serious breach” will be used to
complete the MHRA “GCP compliance report”.
6.11 Escalation and dissemination process:
Internally:
The line manager(s) (both Trust and University) of the Investigator from the site where
the breach took place must be notified of the “notification of serious breach” having
been sent to the MHRA and be informed of what CAPA is in place. The line manager(s)
of these organisations will have to inform their QA and senior management if necessary
and according to their own SOPs.
The serious breach might be notified to the Safety Committee, CTOG, the Clinical Trial
Strategic Committee, and the Research Governance Committee as deemed
appropriate.
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The R&D Department of the site where the serious breach took place must be informed
of what CAPA is in place.
Externally:
This will be dependent on the nature of the breach and may include other sites and
pharmacies affected, other MHRA departments, Ethics Committees etc.
The breach should be circulated to relevant staff for inclusion of relevant information in
to the study report or publication. Serious breaches relating to investigator
sites/Laboratories etc. should also be made available to those selecting sites for studies
.i.e. careful assessment should be made before using a non-compliant site in future
studies.
The UCL GCP training teams should be informed on a regular basis of the serious
breaches having been reported by the JBRU to the MHRA.
All CTIMPs’ CIs’ teams sponsored by UCL should be notified of the serious breach in an
anonymised manner, to try and ensure that no similar breach recur.
6.12 Further actions:
Until the serious breach has been fully resolved and given the amount of resources
diverted from the JBRU to process/address serious breaches, the JBRU will not be
carrying out any activities on trials that the CI might have in set up.
UCL reserves the right to withdraw sponsorship for the trial as and when necessary.
6.13. Notification of an Urgent Safety Measure by a site
The CI/PI should phone the Clinical Trial Unit at the MHRA and discuss the issue with a
medical assessor immediately once an urgent safety measure was taken at a site. The
CI/PI must then notify the MHRA, the MREC and JBRU (a monitor and a Trial coordinator should be emailed) in writing, of the measure taken and the reason for the
measure within 3 days by submitting a substantial amendment form (Annex 2).
The substantial amendment form
(http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/11_an2_14-2005.pdf)
should include a covering letter detailing the measures taken, the reason for them and
the medical assessor contacted; a Notification of Amendment form and supporting
documentation.
The substantial amendment should be:
1. Faxed to the Clinical Trials Unit on 020 7084 2443 or sent by e-mail to
clintrialhelpline@mhra.gsi.gov.uk) marked ‘Urgent Safety Measure’ and
2. Sent as PDF documents on disk to: Information Processing Unit, Area 6,
Medicines and Healthcare products Regulatory Agency, Market Towers, 1 Nine Elms
Lane, London. SW8 5NQ
The PI should copy this notification and file it in his ISF. The PI should be logging this
event into the PI’s Log of (Protocol and/ or GCP) Deviations/Violations/“Potential
Serious breaches”/”Serious breaches”/“Urgent Safety Measures”. The PI should
be filing all the acknowledgements received from the JBRU, MHRA, REC in his
ISF. If no acknowledgement was received by the PI within a working day from
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these organisations, the PI should phone and ensure that the notification has
been received.
See also the Sponsor SOP on Amendments.
N.B. The recently amended regulation (SI2009/1164) to the Medicines for Human Use
(Clinical Trials) Regulations 2004 to allow for notice of urgent safety measures (taken in
order to protect the subjects of a clinical trial against any immediate hazard to their
health or safety and the circumstances giving rise to those measures) to be given as
soon as possible to the licensing authority and an ethics committee established under
Part 2 of those Regulations during a period in which a disease is pandemic and is a
serious risk to human health or potentially a serious risk to human health. See
http://www.opsi.gov.uk/si/si2009/uksi_20091164_en_
Once the JBRU has received the substantial amendment notifying of an “urgent safety
measure”, the monitor/QA manager should be logging it into the “JBRU Log of Urgent
safety measures” reported by the PI/CI/Lab to the JBRU on UCL sponsored CTIMPs.
The notification of “urgent safety measures” should be filed in the “urgent safety
measures” folder hold by the QA manager. Acknowledgement from the MHRA and REC
should also been filed in this folder.
7. REFERENCES
http://www.ucl.ac.uk/joint-rd-unit
MHRA Serious Breaches Guidance Version 2.0 dated 15/10/09
The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031)
The Medicines for Human Use (Clinical Trials) Amended Regulations 2006 (SI
2006/1928)
The Medicines for Human Use (Clinical Trials) Amended Regulations 2009 (SI
2009/1164)
http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodClinica
lPractice/CON009678
King’s College London, Joint Clinical Trials Office, SOP on Serious Breaches of Good
Clinical Practice or Trial Protocol, final version 1.0 dated 4th July 2008.
8. APPENDICES
Appendix 1 Notification of a Serious Breach form, version 2.0
Appendix 2 Notification Examples
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Appendix 1: Notification of a Serious Breach form, version 2.0
Notification of Serious Breach of Good Clinical Practice or Trial Protocol
(Ref: UK Statutory Instrument 2004/1031 Regulation 29A, as amended by 2006/1928)
Please forward this notification to GCP.SeriousBreaches@mhra.gsi.gov.uk OR
GCP Inspectorate, MHRA, 2a Hunter house, 57 Goodramgate, York, YO1 7FX.
Your Name:
Your Organisation:
Your Contact Details:
Date Breach Identified by Sponsor:
Date Breach Notified to MHRA:
Details of Individual or Organisation
committing breach:
Details of related study (if applicable):
(e.g. EudraCT No, CTA number, study title)
Report:
Tick appropriately
Follow-up
Report
Initial
Report
Please give details of the breach
Potential impact to patient safety and/or data credibility:
Patient safety
Scientific value / data credibility
Patient confidentiality
NA/None
Approval Issues
Other Non-compliances (specify)
IMP
Background:
(continue on additional sheets if required)
Other relevant information:
(i.e. study status, site(s), ethics, trust, CRO /sponsor details etc.)
(continue on additional sheets if required)
Please give details of the action taken:
This should include: Any investigations by your organisation, details of investigations by other
organisations (e.g. CRO/ethics/trust), the results and outcomes of the investigations (if known or
details of when they will be available/submitted), how it will be reported in the final
report/publication, the corrective & preventative action implemented to ensure the breach does
not occur again.
(continue on additional sheets if required)
Actual impact to patient safety and/or data credibility:
Patient safety
Scientific value / data credibility
Patient confidentiality
NA/None
Approval Issues
Other Non-compliances (specify)
IMP
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Appendix 2: Notification Examples from MHRA Guidance document version 2.0
Notifier
Sponsor
Sponsor
Breach
Is it considered a Serious
Breach?
Dosing error. Ethics Committee & MHRA
informed. Subjects withdrawn. The sponsor
stated that there were no serious
consequences to subjects or data.
No
As no significant impact on the
integrity of trial
subjects or on scientific validity of the
trial.
Possibly not. If this was not a
systematic or
persistent problem and if no harm to
trial subjects
resulted from the delay.
Yes, if there was a significant impact
on the integrity of trial subjects (e.g.
there was key safety information not
relayed to subjects in a timely manner
etc.).
No
Minor protocol deviation, which does
not meet the criteria for notification.
No, if it did not result in this or other
trial subjects
being put at risk, and if it was not a
systematic or persistent problem.
In some circumstances, failure to
report a SUSAR could have a
significant impact on trial subjects.
Sufficient information and context
should be
provided for the impact to be
assessed adequately.
Yes
Patient Information Leaflet and Informed
Consent updated. At one trial site this was
not relayed to the patients until approximately
2-3 months after approval. More information
on the potential consequences of the delay
should have been provided.
Sponsor
Visit date deviation.
A common deviation in clinical trials.
Contractor
Investigator failed to report a single SAE as
defined in the protocol (re-training provided).
Sponsor
Investigator site failed to reduce or stop trial
medication, in response to certain laboratory
parameters, as required by the protocol. This
occurred with several patients over a one
year period, despite identification by the
monitor of the first two
occasions. Patients were put at increased
risk of thrombosis.
Became aware of fraud at an investigator site
in the UK, which did not affect the overall
scientific value of the Sponsor’s trial or the
integrity of trial subjects in the UK. However,
the
Sponsor is aware that the investigator site
was also involved in trials being sponsored
by other organisations.
IMP temperature excursions reported.
Sponsor
On two separate occasions sponsors
identified issues with the same organisation.
Identified
during an
Inspection
Sponsor
Although, in this situation, not a legal
requirement under 29A, MHRA
encourages voluntary reporting of all
fraud cases in the UK, because
MHRA will need to establish the
impact on the other trials in case
subject integrity or the scientific value
of those trials was compromised.
No, if the excursions had been
managed
appropriately (i.e. IMP moved to
alternative
location/quarantined as necessary
and it was
identified by qualified personnel that
there was no impact on stability of the
product and therefore no impact on
patient safety/data integrity).
Yes, if this went unmanaged and
subjects were dosed with IMP found
to have become unstable and this
resulted in harm or potential harm to
subjects.
Yes, this subsequently led to
enforcement action against the
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MHRA (CTU)
CRO
Sponsor
Identified
during an
Inspection
NRES
Sponsor
Sponsor
CRO
First with consenting issues and the second
with potential fraud in recruitment and
consenting.
However, there was not unequivocal
evidence of fraud at the time of reporting.
One of the studies involved children.
GCP Inspectorate notified that a substantial
amendment had been submitted regarding
changes to dosing on a first in human study,
as a result of an SAE after dosing the initial
subject. The sponsor had temporarily halted
the trial and only after further investigation
had assigned the SAE as unrelated.
The sponsor had not notified the CTU of the
“urgent safety
measure” implemented or reported the SAE
as a potential SUSAR.
A cohort had invalid blood samples as they
were processed
incorrectly. As a result one of the secondary
endpoints could not be met. Therefore, a
substantial amendment was required to
recruit more subjects to meet the endpoint.
Patients were dosed unnecessarily as a
result of this error.
A pharmacy dispensing error resulted in a
non-serious
adverse event. The incident was investigated
and the
notification from the Sponsor confirmed that
training had
occurred and more robust procedures were
being
implemented by the site.
A potential serious breach was identified, but
not reported (i.e. documentation in the
Sponsor’s TMF identified that there may have
been fraud at an investigator site, re-use of
previous time point data in later time points).
The Sponsor had investigated and the issue
was subsequently found to be a genuine
error not fraud.
Destruction of investigator site files early (i.e.
one study had only been completed a year
earlier and one study was still ongoing.)
Concerns raised during monitoring visits
about changes to
source data for a number of patients in a trial,
which
subsequently made patients eligible with no
explanation. An audit was carried out by the
Sponsor and other changes to source data
were noted without explanation, potentially
impacting on data integrity. Follow-up reports
sent to MHRA confirmed Sponsor concerns
over procedures for approvals, consenting
issues and data changes made to source
without adequate written explanation.
A study patient attended A&E, who attempted
to contact
pharmacy (using the phone number on the
patient’s
emergency card) in order to break the
unblinding code.
Unable to break code in a timely manner, and
the patient decided to withdraw from the
study feeling unhappy that the pharmacy was
not available for emergency situations.
Patient safety compromised as, protocol not
organisation in question.
Yes
Yes
No, information provided by the
Sponsor identified this as a single
episode and the Sponsor supplied
detailed corrective and preventative
action.
Yes, if it was persistent and
systematic, occurring after the CAPA
had been put in place by the Sponsor.
No, on this occasion.
However, had this been identified as
fraud
impacting on the integrity of the data,
then this
serious breach would not have been
notified within the regulatory
timeframe (i.e. 7 day window).
Yes
Yes
Note: not all information provided in
original
notification and Sponsor provided
follow-up
updates.
Yes, as this could have resulted in
significant
potential to harm to the subject if
unblinding would
have affected the course of treatment.
Yes
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followed and, therefore, repeat ECGs were
not conducted when required.
Also potential stopping criteria missed due to
inadequate QC of the interim clinical
summary report for dose escalation.
9. TEMPLATES/LOGS ASSOCIATED TO THIS SOP:
1
PI’s Log of (Protocol &/or GCP) Deviations/Violations/Potential serious
breaches/Serious breaches/ Urgent safety measures
2
JBRU Log of “Potential Serious breaches”/”Serious breaches” reported to the
JBRU on UCL sponsored CTIMPs
3
JBRU Log of “Urgent Safety Measures” reported to the JBRU, MHRA and MREC on
UCL sponsored CTIMPs
10. SOP DISSEMINATION & TRAINING
This SOP will be provided to the PIs prior to, or at initiation at the latest. All staff trial
team concerned by this SOP will sign the SOP training log (12. SOP TRAINING LOG)
part of this SOP. In addition each PI trial team member should have an “Individual staff
SOP and courses log” which will need to be updated once trained on this SOP. These
documents should be filed in the ISF.
Existing trials “in progress”: This SOP will be emailed to the PIs and their teams having
existing trials “in progress”. These investigators will be requested to read the new SOP
and email back to acknowledge receipt and understanding of this new SOP. These PIs
should ensure that relevant team members have read and understood this SOP. They
should ensure that section 12 has been signed. The email sent to the investigators and
their email acknowledging receipt and understanding of the SOP should be printed out
and filed in the JBRU SOP folder.
11. SIGNATURE PAGE
Author and Job Title:
Signature:
Ann Cochrane, JBRU Trial Monitor
Ann Cochrane
Date:
05/01/2010
Authorised by:
Name and Job Title
Helen Cadiou, QA Manager
Signature:
Helen Cadiou
Date:
05/01/2010
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12. SOP TRAINING LOG:
Name of Staff
(Capital letters):
Job Title:
Department:
Training
Date
I confirm that I
understand & agree
to work to this SOP
SIGNATURE
Name of Trainer
(if applicable)
Signature
1
2
3
4
5
6
7
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Date
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Name of Staff
(Capital letters):
Job Title:
Department:
Training
Date
I confirm that I
understand & agree
to work to this SOP
SIGNATURE
Name of Trainer
(if applicable)
Signature
8
9
10
11
12
13
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Date