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Standard Operating Procedure for the
Preparation and Submission of Development
Safety Update Reports
SOP ID Number: JRO/SPON/S31/02
Effective Date: 12/12/13
Version Number & Date of Authorisation: V02, 07/11/13
Review Date: 12/12/16
eDocument kept: S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor
SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc
SOP for DSUR
JRO/SPON/S31/02
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Revision Chronology:
SOP ID Number:
Effective
Date:
Reason for Change:
Author:
JBRU/SPON/S31/01 19/07/11
New SOP
Farhat
Gilani
JRO/SPON/S31/02
Deletion of Safety Committee Research
Fellow from the review process and
DSUR template. Update to DSUR
workflow, inclusion of RSI process and
for process to be used when trial has
not opened to recruitment.
12/12/13
Farhat
Gilani
ACRONYMS:
ASR
CI
DIBD
DSUR
GCP
IMP
ISF
JRO
MHRA
MREC
PI
QA
RM
RSI
SRA
SOP
TMF
Annual Safety Report
Chief Investigator
Development International Birth Date
Development Safety Update Report
Good Clinical Practice
Investigational Medicinal Product
Investigator Site File
Joint Research Office
http://www.ucl.ac.uk/joint-rd-unit
Medicines and Healthcare Products Regulatory Agency
Main Research Ethics Committee
Principal Investigator
Quality Assurance
Regulatory Manager Advanced Therapy Trials
Reference Safety Information
Sponsor Regulatory Advisor
Standard Operating Procedure
Trial Master File
SOP for DSUR
JRO/SPON/S31/02
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Standard Operating Procedure for the Preparation and
Submission of Development Safety Update Reports
1. PURPOSE
This Standard Operating Procedure (SOP) has been written to describe the procedure
for the production and submission of the Development Safety Update Report (DSUR)
to the MHRA and Ethics Committee. For international trials, reference on DSUR
production and submission will be detailed in contractual agreements and/or specific
protocol documents.
2. JOINT RESEARCH OFFICE POLICY
All SOPs produced from the JRO must be used in conjunction with local NHS Trust
and UCL policies and procedures.
The JRO acts as the representative of the sponsor and will be the official name used
on all SOPs.
3. BACKGROUND
All SOPs are written in accordance with applicable GCP requirements as outlined in
Directives 2001/20/EC and 2005/28/EC (in the UK, these Directives were transposed
into UK law by SI 2004/1031, SI 2006/1928) and subsequent amendments and where
applicable incorporates elements of ICH GCP tripartite guidelines (E6).
‘The Medicines for Human Use (Clinical Trials) Regulations 2004’ and subsequent
amendments regulate Clinical Trials in the UK and set out the legal requirements for
the production of “Annual Safety Reports” (ASR). To comply with the UK regulations,
sponsors need to provide procedures and systems to support the production and
submission of this safety document.
The Development Safety Update Report (DSUR) Guidance (ICH E2F) was published in
the European Union in September 2010 and implemented in September 2011. The
DSUR replaces the regulatory requirement for the Annual Safety Report (ASR) format
and content (Regulation 35 of SI 2004/1031, p34) but does not affect reporting
timelines.
Sponsors are required to submit a DSUR report to the MHRA and the Ethics
committee, once a year, throughout the life of a clinical trial or on request from the
MHRA. This DSUR should take into account all new safety information received during
the reporting period for the IMP, which may be used in other UCL sponsored trials, not
just for a specific trial.
4. SCOPE OF THIS SOP
This SOP relates to the process to facilitate the production and submission of the
DSUR. It will outline the key responsibilities of all personnel involved and detail the
interactions required to ensure the report is produced adequately and submitted to
meet regulatory timelines.
SOP for DSUR
JRO/SPON/S31/02
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5. RESPONSIBLE PERSONNEL




CI (CTIMPs) or trial team members with delegated duties regarding the production
of the DSUR
IMP specific trial team members for mechanistic studies
Pharmacovigilance Manager or SRA, Sponsor
RMG Senior Research Coordinators, Sponsor
6. PROCEDURE
Please ensure that you are using the most recent SOP version by looking up
www.ucl.ac.uk/jro
6.1 Periodicity and DSUR data lock Point
6.1.1
The Development International Birth Date (DIBD) is used to determine the
start of the annual period for the DSUR. This date is the sponsor’s first
authorisation to conduct a clinical trial in any country worldwide. The start of the
annual period for the DSUR is the month and date of the DIBD. The data lock
point of the DSUR should be the last day of the one-year reporting period. The
DSUR should be submitted to all concerned regulatory agencies no later than
60 calendar days after the DSUR data lock point.
6.1.2
If a trial has received a CTA approval and has not yet opened to recruitment at
DIBD then a cover letter may replace the DSUR detailing any safety updates
that have occurred. The cover letter should also include the EudraCT number
and trial title.
6.1.3
DSURs should continue to be submitted until the End of Trial notification has
been submitted for UK trials. For International trials this will be dependant on
their applicable laws and regulations. When submission of an annual report is
no longer required, the sponsor should state that the final DSUR serves as the
last annual report of the IMP (if this is known at the time of preparation of the
report). The Sponsor should also indicate whether or not clinical trials are
continuing elsewhere.
6.1.4
The sponsor will endeavour to inform the trial team of the DIBD date if it is
different from the CTA approval date either at trial initiation or at the DIBD data
lock point.
6.2 DSURs for combinations therapies
6.2.1
DSURs are IMP specific therefore for trials involving multi-drug therapy, i.e.,
combinations of drugs that are not fixed, the Sponsor, in conjunction with the CI
will decide to prepare either:
(1) A DSUR for the multi-drug therapy, or
(2) DSUR(s) for one or more of the individual components; in this case information on
the multi-drug therapy trials can be included in the DSURs of one or all of the
components.
The following table provides examples of strategies for preparation of DSURs for multidrug therapies.
SOP for DSUR
JRO/SPON/S31/02
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Multi-drug therapy used in clinical trial(s)
DSUR
Investigational drug (A) + marketed Either a single DSUR focusing on
drug(s) (X, Y, Z)
(A+X+Y+Z)
or
A single DSUR focusing on (A)
including data on the multi-drug therapy
Two investigational drugs (A) + (B)
Either a single DSUR focusing on (A +
B)
or
Two separate DSURs (A) and (B), each
including data on the multi-drug therapy
Two (or more) marketed drugs as an A single DSUR focusing on the multiinvestigational drug combination (X, Y, drug therapy
Z)
In general, a single DSUR should be prepared for clinical trials involving a fixed
combination product (i.e., a product consisting of at least two active ingredients in a
fixed dose that is administered in a single dosage form). If the sponsor is also
conducting clinical trials with individual component(s) of the fixed combination product,
separate DSUR(s) should be submitted for each component. Relevant findings from
each DSUR should be summarized in Section 8.5 of the other DSUR(s).
6.2.2
The sponsor in conjunction with the CI will select the most appropriate, option
based on judgment, taking into account patient population, indication,
formulation, etc., as well as the circumstances in which the clinical trials are
being conducted and national or regional laws or regulations. The rationale for
this decision should be provided in the report.
6.2.3
The Sponsor will endeavor to inform the trial team of the DSUR format at trial
initiation or at the DIBD data lock point.
6.3 Responsibilities for the Preparation and submission of a DSUR
6.3.1
All DSURs must meet the standard that adheres to the EUCTD (2001/20/EC)
and the UK trials regulations SI 2004/1031. The Sponsor has prepared a
template (Appendix 1) which meets these requirements and all sponsored trials
must use this document (unless stated otherwise in contractual agreements).
6.3.2
The Sponsor is considered responsible for the preparation, content and
submission of the report. Preparation of various sections of the DSUR is
delegated to individuals as listed below. However, the collation, final sign off
and submission is performed by members of the JRO (unless stated
otherwise in individual contractual agreements).
6.3.3
The Sponsor will coordinate the preparation of the document by emailing
requests for various sections of information to all relevant individuals (see
Appendix 1 for workflow diagram). On receipt, the information will be
amalgamated into the DSUR template by the Sponsor
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Individuals
SRA, PVG Manager (Sponsor)
Trial Chief Investigator(s) / Trial Team
Tasks
 Coordination and collation of document
 Final sign off
 Contents
 Submission of Report
 Executive Summary
 Trial specific safety information
 Literature searches
 Risk-Assessment
RMG SRA (Sponsor)
Mechanistic Trial Chief Investigator

Conclusion


Mechanistic Trial Information
Trial specific Safety Information
6.4 Reference Safety Information (RSI)
The RSI for a CTIMP is either detailed in the IB or SPC and is submitted as part of the
CTA application. The RSI for any IMPs involved in a clinical trial must stay consistent
during each DSUR reporting period. The RSI at the time of the beginning of reporting
period will be used.
6.4.1 When the IMP and therefore IB are produced by UCL it is recommended
submitting an IB with a RSI update in conjunction with a DSUR submission, as the
information within the DSUR will act as a justification for the changes.
6.4.2 When the IMP is provided directly from a commercial sponsor, UCL should
negotiate transfer of trial information thereby allowing a single DSUR being produced
for that product by the commercial sponsor. If this is not possible the following table
should be used to ensure the correct IB information is incorporated into the DSUR.
Process for IB updates from commercial and UCL manufacturers
Approval/amendments IB Comments
DSUR submission comments
DSUR 1
If not updated within the reporting period
for the first DSUR
Initial IB
Substantial amendment Updated
IB
of IB
approved by
MHRA prior to
being
implemented
The DSUR for that year will use the
previous version of the IB with regards to
the RSI (approved at the beginning of the
DIBD date) and will detail the new IB in the
DSUR. The newly approved IB will be used
for the following year DSUR production.
Non-Substantial
amendment of IB
The DSUR for that year will use the
previous version of the IB (approved at the
beginning of the DIBD date) and will detail
the new IB in the DSUR. The newly
approved IB will be used for the following
year DSUR production.
The updated
IB can be
implemented
immediately
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6.4.3
Process for SmPC updates
If the RSI is within the SmPC, the list of expected adverse reactions is contained in
section 4.8 Undesirable Effects. For trials where a SPC is used as the RSI the updates
are managed by the IMP manufacturer. When the JRO are made aware of an SmPC
update it will be reviewed:
6.4.3.1 To see if the safety profile of the IMP has been altered and impacts on trial
process and patient safety (new contraindicated drugs, dosing levels altered etc.)
6.4.3.2
To see if the RSI (expectedness) has been changed.
CT3 states SUSARs must be assessed against the RSI at time of occurrence of
the adverse event. Within a DSUR reporting period, the RSI may be updated and
an unexpected event becomes expected.
At the time of DSUR production the expectedness of events that have occurred in the
reporting period will be reassessed against the RSI at the beginning of the reporting
period. The RSI used to assess expectedness and any subsequent updates will
be attached as appendices and clearly detailed in the DSUR.
6.5 Submission Procedures
6.5.1 The DSUR will be submitted to both the MHRA and REC by the Sponsor. For
international trials and trials where this responsibility is delegated to another
organisation or to the trial team, a final signed copy must be sent to the Sponsor.
6.5.2 The DSUR should be signed by the person submitting the report and
should be submitted in pdf to the MHRA and on paper to the REC. All enclosures
should be listed and referenced on the report.
6.5.3 For the REC submission a standard cover sheet must also be submitted which
is available from the NRES website: http://www.nres.npsa.nhs.uk/
6.5.4 If a DSUR is being submitted late to the regulatory agencies, a cover letter must
also be sent from the sponsor detailing the reason for the late submission.
6.5.5
A copy of the DSUR will be forwarded to the CTIMP CI(s) to be filed in the TMF.
6.5.6
If an unblinded DSUR is prepared by the sponsor, a separate final blinded copy
will be forwarded to the CTIMP CI(s) if the blind has not been broken.
7. REFERENCES
http://www.ucl.ac.uk/joint-rd-unit
http://ec.europa.eu/health/documents/eudralex/vol-10/
ICH Harmonised Tripartite Guideline for Development Safety Update Report E2F
ICH Harmonised Tripartite Guideline for Good Clinical Practice (1996) E6
The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 1031)
The Clinical Trials Directive 2001/20/EC
8. TEMPLATES/LOGS ASSOCIATED TO THIS SOP
1
2
DSUR workflow
DSUR template
SOP for DSUR
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1. DSUR work flow
Estimated Timelines and workflow, for the Preparation and Submission of DSURs by the Sponsor’s office, for trials
managed by CIs (not for CTU managed trials).
-30 Days to Day 0
Collate information from:





Mechanistic Information
Trial Specific Information
(e.g. Urgent Safety
Measures in Sponsor TMF)
IMP Specific Information
Review IB/SmPC changes
0 Days
DIBD Date
+30Days
Email sent to CI approximately
within 2 week +/- of Day 0



With any new documents
from searches.
Requesting literature search
and results.
Update of trial relevant trial
status
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Incorporate ALL
information into
the DSUR
+45 Days
+60 Days
Final QC check
by Sponsor
Submitted to



MHRA
REC
CI(s)
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9. SOP DISSEMINATION AND TRAINING
SOPs will be distributed to the concerned staff, by the named author on the front page
of the SOP. Staff concerned by the SOP will sign the SOP training log (12. SOP
TRAINING LOG) which is part of each SOP.
In some instances, the SOP or the changes to the SOP will be basic. The training will
constitute of the person reading the SOP and being provided with the opportunity to
ask specific questions to the author of the SOP. In some instances, the staff member
being trained will carry out the procedure under supervision of the author of the SOP or
under supervision of a staff member who has been trained and is using the SOP. Both
trainee and trainer (should the SOP require training) will need to sign and date the
‘SOP training log’ in section 12 of each SOP.
10. SIGNATURE PAGE
Author and Job Title:
Farhat Gilani, Pharmacovigilance Manager
Signature:
Date: 07/11/13
Authorised by:
Name and Job Title:
Helen Cadiou, Quality Assurance Manager
Signature:
Date: 07/11/13
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12. SOP TRAINING LOG
Job Title:
Name of Staff (Capital letters)
Department:
Training
Date
I confirm that I
understand & agree
to work to this SOP
SIGNATURE
1
2
3
4
5
6
7
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Name of Trainer (if training
required)
Signature
Date
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Job Title:
Name of Staff (Capital letters)
Department:
Training
Date
I confirm that I
understand & agree
to work to this SOP
SIGNATURE
8
9
10
11
12
13
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Name of Trainer (if training
required)
Signature
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Date
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14
15
16
17
18
19
20
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