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Development Safety Update Report Template
Purpose:
This document provides instructions for the preparation and submission of a Development Safety
Update Report (DSUR) for a Clinical Trial of an Investigational Medicinal Product (CTIMP). A template
for and detailed guidance on the contents of the DSUR is also included.
Scope:
This document may be used for all clinical trials for which a UoB staff member has been delegated the
Sponsor duty for annual safety reporting of Adverse Events (AEs) for a CTIMP and where no other
template is in effect. This document only applies to the production of a DSUR within the European
Union. However, a DSUR may also be prepared for use in the USA and other ICH Countries.
Implementation plan:
This process will be implemented directly after the implementation date.
Date of implementation:
12-Jun-2012
Property of the University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, United Kingdom.
Not to be printed, copied or distributed without authorisation.
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DSUR Template
Abbreviations and Definitions:
AE
Adverse Event
CTA
Clinical Trial Authorisation
CTIMP
Clinical Trial of an Investigational Medicinal Product
DSUR
Development Safety Update Report
ICH Countries
Counties using the guidelines set up by the International
Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
IB
Investigator Brochure
IMP
Investigational Medicinal Product
MHRA
Medicines and Healthcare product Regulatory Agency
Non-commercial clinical trial In accordance with Directive 2001/20/EC, a non-commercial
clinical trial is defined as a trial:
 Conducted by a non-commercial organisation, with no
industry sponsor, that is not part of the development program
for a marketing authorisation of a medicinal product; or,
 If potentially leading to a marketing application, where the
holder of the intellectual property/patent is a not-for profit
organisation
REC
Research Ethics Committee
RSI
Term used within EC Detailed Guidance (CT3) June 2011,
meaning the applicable product information which is used to
determine the expectedness of an Adverse Reaction. This
information is normally obtained from within the SPCs or IB; when
referring to the IB the relevant section must be defined. It may be
a separate document in its own right. It must be defined at the
start of a trial.
SAE
Serious Adverse Event
SAR
Serious Adverse Reaction
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
UoB
University of Birmingham
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Background:
Sponsors of CTIMPs must submit a DSUR to the competent authority of the member states in which
the trial has a Clinical Trial Authorisation (CTA). A summary of this information must also be submitted
to the ethics committee of the concerned member states.
The aim of the DSUR is to provide a review, and evaluation of, all new available safety information
received during the reporting period. It should also provide an ongoing assessment of the risk to trial
subjects; describing concisely the results of such analyses and summarising the evolving safety
profile of the IMP or combination of IMPs.
For trials conducted in the UK, the full DSUR should be submitted to the Medicines and Healthcare
product Regulatory Agency (MHRA) and the Research Ethics Committee (REC). For trials run in other
concerned countries; a full DSUR should be submitted to the competent authority but the
requirements for submission to the ethics committee may differ and should therefore be confirmed at
the time the DSUR is required to be submitted.
The DSUR:
 Replaces the requirement to submit an Annual Safety Report in the UK and other EU countries
(working under the EU Clinical Trials Directive) and the US IND Annual Report in the USA. It is
also effective in all other ICH Countries
 Came in to effect on 1st September 2011 for trials run within the EU. Annual Safety Reports will no
longer be accepted by the competent authority
 Is developed with pharmaceutical companies in mind, and aside from published DSUR examples
for non-commercial Sponsors (see references) there is no official guidance available for noncommercial trials. It is recognised however by official bodies such as MHRA (during the GCP noncommercial symposium in November 2011 and the European Medicines Agency information day
in July 2011) that the current guidelines cannot always be followed for non-commercial trials. The
following is therefore assumed –

In situations where the Sponsor does not have access to the information to be included in
specific sections (e.g. the Sponsor might not have information on manufacturing issues, nonclinical data, and marketing status), this should be clearly stated in the report

The DSUR should concentrate primarily on the IMP(s) within the trial; it is expected that there
will only be one DSUR per trial in the non-commercial setting
 The DSUR is submitted annually for the duration of the clinical trial until the ‘End of Trial’
notification has been submitted In the commercial setting, the “Development International
Birth Date” 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 Development
International Birth Date
 For non-commercial trials it is suggested to submit annually from the date that the first
CTA was received for the trial from a competent authority (i.e. MHRA for UK only trials). If
the trial is conducted in multiple countries this should be the date the first approval was
received in any of the participating countries
 When submission of an annual report is no longer required, it should be stated that the
final DSUR serves as the last annual report for the trial in question (if this is known at the
time of preparation of the report). It should be indicated whether or not clinical trials are
continuing elsewhere, if known
In the EU, the DSUR should contain the following information:
 The report: an analysis of the subjects’ safety in the context of the concerned clinical trial – as per
the DSUR Table of Contents (see Template)
 Appendices: the order and nomenclature of the appendices are as per the DSUR guideline. Some
appendices are contained in the body of the main report; the list below refers to mandatory
appendices supplied as separate documents
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DSUR Template
a. Appendix 1: Current and any revisions to the Reference Safety Information (RSI)*
b. Appendix 5: A line listing of all Serious Adverse Reactions (SARs) and all Suspected
Unexpected Serious Adverse Reactions (SUSARs) that were reported in the concerned trial
during the reporting period*
c. Appendix 6: A cumulative tabulation of all SAEs including SARs and SUSARs that have been
reported since the start of the trial*
d. Appendix 7: Scientific abstracts* (if relevant)
e. Appendix 8: A cumulative tabulation of all SARs and SUSARs that have been reported since
the start of the trial*
Responsibilities:
Chief Investigator:
 On a yearly basis report safety information to the relevant competent authority(ies) and ethics
committee(s)
 Ensure all relevant documentation including acknowledgment receipts from the competent
authority(ies) and ethics committee(s) are filed in the Trial Master File
 Inform the Sponsor of any potential significant safety issues that may have to be reported to any
other trials in the Sponsor’s portfolio using the same IMP
 Inform relevant third parties of any relevant safety data or significant safety issues as appropriate
 Provide UoB Research Support Group and/or any external Sponsor (as per agreements) with a
copy of the DSUR
 Maintain confidentiality of trial data
Note the CI may delegate the preparation of the DSUR to appropriate members of the trial
management team, but the CTI retains the responsibility for reviewing the DSUR prior to submission.
There may be circumstances (e.g. where safety is the primary end point for the trial) where it is not felt
appropriate for the Chief Investigator to review the aggregated summaries of the DSUR, in which case
another independent clinician should be appointed to assume this role.
Sponsor:
As per their local procedures:
 Ensure safety information is reported annually to the relevant competent authority(ies) and ethics
committee(s)
 When informed of any potential significant safety issues that may have to be reported to any other
trials in the Sponsor’s portfolio using the same IMP, ensure further reporting is undertaken
 Upon receipt of the DSUR, process accordingly
Procedure:
Reporting time frame
 Take a snapshot of data for analysis on the anniversary of the date the trial first received approval
from a competent authority

If the trial has yet to open to recruitment submit a letter explaining this to the competent
authority and the ethics committee in place of the DSUR
 Submit the DSUR to the competent authority(ies) and ethics committee(s) within 60 days of the
date of the snapshot
 End of reporting period:

For UK only trials, submit a DSUR annually until the trial is closed with the competent
authority
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
For international trials, the last report can be submitted at the end of the reporting period
during which the last patient completed treatment in the concerned member state
Preparing the report
Where the CI is delegated the duty of preparing the DSUR on behalf of the Sponsor:
 Generate a report based on this template; the information contained in the DSUR should:

Be written from a Sponsor perspective:
 Where the Sponsor does not have access to the information to be included in specific
sections (e.g. manufacturing issues, non-clinical data, and marketing status), this should
be clearly stated
 Where the University of Birmingham or other non-commercial Sponsor is not the
Manufacturing or Marketing Authorisation holder for the IMP(s), there will be sections of
the DSUR which cannot be completed; this information need not be actively sought unless
contractually agreed to be provided by a third party

Only capture the IMP(s) within the trial (as stated in the CTA application, including placebos),
i.e. do not include any non-IMPs used in the trial
 For non-commercial trials, it is expected that the DSUR will be produced on a trial-by-trial basis,
providing information on the IMP or combination of IMPs within the named trial
 Include an entry under every heading, even if this is to state that the requested information is not
available

Note the same information may be asked in different places in the form; do not re-enter the
information, but refer to the section where the information has been entered for the first time.
 Check for updates to the relevant Reference Safety Information (RSI): (i.e. (sections of) Summary
of Product Characteristics (SmPCs) or Investigator Brochure (if provided externally); where
necessary obtain updated versions from the manufacturer
 Collate information regarding the evolving safety profile of the IMP(s) and where necessary:

Perform relevant literature searches

Obtain relevant information, from a third party (e.g. pharmaceutical company) if contractually
agreed

Where possible, obtain from the Sponsor of this trial a summary of any other DSUR which
has been prepared for other trials sponsored by the same Sponsor that utilise the same
IMP(s). This includes both ongoing and completed trials.
Preparing the appendices
 Generate line listings, i.e. list all SARs and their details underneath each other; see appendix 5.
 Ensure that all SAEs (including SARs and SUSARs) are reported from countries for which the
Sponsor is responsible
 If the line listing or summary tabulations are produced electronically, perform checks to ensure
accuracy of data, for example cross check a minimum of 2 events for accuracy of all data fields
and ensure total number of listed events is as expected. If errors are indentified, amend report as
appropriate.
 Obtain signature(s)

Chief Investigator (or delegate); note there may be circumstances (e.g. where safety is the
primary end point for the trial) where it is not felt appropriate for the Chief Investigator to
review the aggregated summaries of the DSUR, in which case another independent clinician
should be appointed to assume this role

For externally sponsored trials, the Sponsor may also request to sign the report
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Reference Safety Information (RSI)
The RSI is the safety information that is used to assess expectedness of adverse reaction. This
information is embedded in an IB or SmPC.
 As part of the DSUR reporting check on the anniversary of the CTA if this safety information as
embedded in the IB or SmPC has changed over the last year in such a way that the
expectedness of adverse reaction has changed as well.

Where the RSI has changed:



Submit a substantial amendment to the competent authority at the same time as
submitting the DSUR. The amendment should reference and be supported by the DSUR
Note: the revised RSI can only be implemented once approval from the competent
authority has been received
Attach old and revised RSI as Appendix 1 of the DSUR
Where the RSI has not changed, attach the (unchanged) current RSI to the DSUR
Submitting the report in the UK
 Prepare/obtain the relevant documentation:

DSUR (signed)
 Scan signature page
 Create signed PDF version

Appendices
 Create PDF version

Supporting documentation (e.g. current and any revisions to the RSI)

Write a cover letter specifying that the DSUR has been prepared on a trial specific basis

Complete the National Research Ethics Service Clinical Trials of Investigational Medicinal
Products Safety Report Form available on the NRES website (at time of writing this is
http://www.nres.npsa.nhs.uk)
Submitting to the MHRA
 Documentation must be submitted electronically in PDF format on a data CD
 Recorded delivery is recommended
 Submit to Information Processing Unit, Area 6, Medicines & Healthcare products Regulatory
Agency, 151 Buckingham Palace Road, Victoria, London, SW1W 9SZ

The MHRA do not routinely acknowledge the receipt of DSURs, therefore consider including a
DSUR acknowledgment slip (or add acknowledgment receipt to the cover letter) and selfaddressed envelope with the CD and instructions for the MHRA to return in order to
acknowledge receipt

Alternatively send an E-mail to [email protected] detailing the EudraCT and
submission date and request acknowledgement of receipt

The details above are correct at the time of writing but should be checked prior to submission;
see MHRA website for current details:
http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyr
eporting-SUSARSandASRs/index.htm
 The MHRA should acknowledge receipt of the report when supplied with an acknowledgement
slip or a request is made via E-mail; if this is not received request for this again upon receipt
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DSUR Template
Submitting to the REC
 Send the National Research Ethics Service Clinical Trials of Investigational Medicinal Products
Safety Report Form available on the NRES website (at time of writing this is
http://www.nres.npsa.nhs.uk)
 Documentation must be submitted electronically in PDF format via E-mail (extensive documents
may be submitted via data CD; 3 copies should be provided)

Appendix 1: the RSI appendices need not be sent to the REC
 Submit to the relevant REC (refer to NRES website for REC E-mail addresses)
 The REC should acknowledge receipt of the report by signing and returning a copy of cover form
within 30 days; if this is not received it should be requested
Filing documentation
 File all documentation (i.e. original signed DSUR, signed copy of the cover letter to MHRA,
acknowledgment of receipt from the MHRA and signed (returned) REC covering form) in the Trial
Master File

It is recommended that all documents are filed together in the Trial Master File (e.g. in DSUR
section)
Informing third parties
 The DSUR is a confidential document potentially containing information split by treatment arm
hence it should only be sent to third parties where this is a contractual requirement. It should not
be forwarded to sites
 Forward copy of DSUR to third parties (e.g. Sponsor, DMC, international collaborators) as
required

For UoB trials, a copy should be sent to Brendan Laverty [email protected] (correct at
time of writing)

Highlight any significant safety issues as appropriate
 Where the UoB is Sponsor, the Research Governance Team will ensure that any other CI utilising
the same IMPs will be informed of any potential significant safety issues identified in the DSUR
Template
 Use this template as a basis for producing the DSUR
 Within the document instructions and notes are in red italic text
 Instructions from the DSUR guidance document (ICH E2F) is referenced in grey text
 Delete the introductory pages, notes and instructions before use
 In the report all sections in the Table of Contents are mandatory

Maintain all headers

If no relevant information is available, this must be stated
 All sections/questions must be kept in the order that they appear in this QCD
 All appendices marked * are mandatory

Maintain order and nomenclature
 For both the report and appendices:

Insert the relevant trial specific information where specified by <text>

Be concise and do not repeat information; cross reference where necessary

Throughout the template replace the text Investigational Medicinal Product (IMP) with the
specific drug name(s) as appropriate
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
Ensure naming of drugs is consistent in the use of generic or brand names and in keeping
with the protocol, CTA and other trial documentation
 The format of the report can be modified to make it consistent with other trial specific
documentation
 Obtain signed approval for the final report from the Chief Investigator (or delegate) and Sponsor if
applicable

Note that there may be circumstances (e.g. where safety is the primary end point for the trial)
where it is not felt appropriate for the Chief Investigator to review the aggregated summaries
of the DSUR and sign the DSUR, in which case another independent clinician should be
appointed to assume this role
References:
 (2011/C 172/01) Detailed guidance on the collection, verification and presentation of adverse
event/reaction reports arising from clinical trials on medicinal products for human use (CT-3).
Version 11.6.2011
 ICH Harmonised Tripartite Guideline: Development Safety Update Report E2F – current Step 4
version dated 17th August 2010
 DSUR Examples Non-commercial Sponsors: at time of writing
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2F/Examples_
DSUR/E2F_Example_non-commercial_DSUR.pdf
Acknowledgements:
The first version of this document has been based on the equivalent Cancer Research UK Clinical
Trials Unit document with feedback from the Birmingham Clinical Trials Unit, the Primary Care
Clinical Research and Trials Unit, and the UHB R&D department. We would like to thank all staff
members within the CTUs and UHB R&D who have been involved in developing these documents for
their time and efforts.
.
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Development summary:
Author:
Name:
Wilma van Riel
Signature:
Function:
Clinical Trials Quality Assurance Manager
Date:
See original copy
Reviewed by:
Clinical Trials Oversight Committee, Shahnaz Gill-Stokes
Issue date:
29-May-2012
Supersedes:
N/A
See original copy
Reason for update:
N/A
Review of final version:
Date:
Reviewed by:
Document code:
UoB-CLN-QCD-002
Version no:
1.0
Signature:
Outcome:
Print Date:
04-May-17
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Keep Title Page to 1 page
<Identifier e.g. Trial Name>
Development Safety Update Report (DSUR)
Report Number:
<insert number; sequential,
starting at 1>
For the first DSUR after an Annual Safety Report,
insert <This is the first DSUR for the use of <insert
IMP/combination> in the <insert name> trial.
Annual Safety Reports were previously submitted.>
If this is the last DSUR insert <This is the final
DSUR for the use of <insert IMP/combination> in
the <insert name> trial <in the UK>. For
international trials state <All patients have now
completed treatment and this will be the final report
submitted in <specify member state>.>
IMP(s):
<list trial IMPs (as per CTA)>
Reporting Period:
e.g. 19-May-2011 to 18-May-2012
Report Date:
<insert date of finalised report>
Sponsor:
<enter Sponsor name and address>
Sponsor Ref Number:
<insert number; for UoB sponsored trials, this is the RG number>
EudraCT Number:
<insert number>
REC Reference Number:
<insert number>
Name:
Trial Role <Chief Investigator or
Clinical Coordinator>:
Signature:
Date:
DD / MON / YYYY
This report was prepared by <add name> on behalf of the Sponsor and contains confidential
information. For blinded trials also include: <This report includes unblinded Adverse Event data>
Consider adding trial correspondence address
Page: 10 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Executive Summary
This section should provide a concise summary of the important information contained in the report.
Together with the title page, it can serve as a “stand-alone” document suitable for submission to
stakeholders.
This section should be written after all the sections of this report have been completed. Where
possible, keep to 1-2 sides of A4:
IMP(s):
<List trial IMPs (as per CTA)> Include details of mode of action and
therapeutic class e.g.
Pegfilgrastim 6 mg solution for injection
Mode of action: binds to the G-CSF receptor. As a G-CSF analogue, it
controls proliferation of committed progenitor cells and influences their
maturation into mature neutrophils. Also stimulates the release of
neutrophils from bone marrow storage pools and reduces their
maturation time. Acts to increase the phagocytic activity of mature
neutrophils. In patients receiving cytotoxic chemotherapy, can
accelerate neutrophil recovery, leading to a reduction in duration of the
neutropenic phase.
Therapeutic class: blood modifying drug
<Where an IMP is supplied by the Sponsor, include statement of who
is providing IMP e.g. <supplied by Novartis>>
Treatment Arms:
<insert different treatment arm(s). Include dose, route and
formulation.>
Indication and Population:
<insert indication and population e.g. relapsed refractory breast cancer
in post menopausal women aged over 60 years>
Estimated Cumulative
Exposure:
<insert details from section 6.1>
Marketing Approval
<insert details from section 2>
Summary and Conclusions:
Include the following.
•
A summary of the overall safety assessment (based on Section 18 of the DSUR);
• A summary of the important risks (based on Section 19 of the DSUR);
• Actions taken for safety reasons, including significant changes to RSI;
• Conclusions
<insert page break>
Page: 11 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Table of contents
All headers must remain as listed. Update page numbers only after completion of report.
1. Introduction .................................................................................................................................... 14
2. Worldwide Marketing Approval Status .......................................................................................... 14
3. Actions Taken in the Reporting Period for Safety Reasons .......................................................... 15
4. Changes to Reference Safety Information .................................................................................... 15
5. Inventory of Clinical Trials Ongoing and Completed during the Reporting Period ....................... 17
6. Estimated Cumulative Exposure ................................................................................................... 18
6.1 Cumulative Subject Exposure in the Development Programme ............................................. 18
6.2 Patient Exposure from Marketing Experience .......................................................................... 18
7. Data in Line Listings and Summary Tabulations ........................................................................... 18
7.1 Reference Information .............................................................................................................. 18
7.2 Line Listings of Serious Adverse Reactions during the Reporting Period ................................ 18
7.3 Cumulative Summary Tabulations of Serious Adverse Events ................................................ 18
8. Significant Findings from Clinical Trials during the Reporting Period .......................................... 19
8.1 Completed Clinical Trials .......................................................................................................... 19
8.2 Ongoing Clinical Trials .............................................................................................................. 19
8.3 Long-term Follow-up ................................................................................................................. 19
8.4 Other Therapeutic Use of Investigational Drug ........................................................................ 19
8.5 New Safety Data Related to Combination Therapies ............................................................... 20
9. Safety Findings from Non-interventional Studies .......................................................................... 20
10. Other Clinical Trial/Study Safety Information .............................................................................. 20
11. Safety Findings from Marketing Experience ............................................................................... 20
12. Non-clinical Data ......................................................................................................................... 20
13. Literature ..................................................................................................................................... 21
14. Other DSURs ............................................................................................................................... 21
15. Lack of Efficacy ........................................................................................................................... 21
16. Region-Specific Information ........................................................................................................ 21
Cumulative summary tabulation of Serious Adverse Reactions ..................................................... 21
List of subjects who died during the reporting period ...................... Error! Bookmark not defined.
17. Late-Breaking Information ........................................................................................................... 22
18. Overall Safety Assessment ......................................................................................................... 22
18.1. Evaluation of the Risks .......................................................................................................... 22
18.2 Benefit-risk Considerations ..................................................................................................... 23
19. Summary of Important Risks ....................................................................................................... 23
20. Conclusions ................................................................................................................................. 24
Appendices to the DSUR
The order and nomenclature of the appendices are as per the DSUR guideline. Some appendices are
contained in the main body of the report.
 Appendix 1: Current and any revisions to the Reference Safety Information (RSI)
 Appendix 2: Cumulative Table of Important Regulatory Advice (refer to Section 3)
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<Trial acronym>
DSUR date: dd-mon-yyyy
 Appendix 3: Status of Ongoing and Completed Clinical Trials (refer to Section 5)
 Appendix 4: Cumulative Summary Tabulations (refer to Section 6)
 Appendix 5: A line listing of all Serious Adverse Reactions
 Appendix 6: A cumulative tabulation of all Serious Adverse Events
 Appendix 7: Scientific Abstracts (if relevant)
 Appendix 8: A cumulative tabulation of Serious Adverse Reactions
Page: 13 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
1. Introduction
Copy sections from Title Page and Executive Summary where applicable
Refer to section 3.1 of ICH E2F
Report Number:
<insert number; sequential,
starting at 1>
For the first DSUR after an Annual Safety Report,
insert <This is the first DSUR for the use of <insert
IMP/combination> in the <insert name> trial.
Annual Safety Reports were previously submitted.>
If this is the last DSUR insert <This is the final
DSUR for the use of <insert IMP/combination> in
the <insert name> trial <in the UK>. For
international trials state <All patients have now
completed treatment and this will be the final report
submitted in <specify member state>.>
Reporting Period:
e.g. 19-May-2011 to 18-May-2012
Report Date:
<insert date of finalised report>
CTA Approval Date:
<CTA date: insert date of competent authority approval. If the trial is
conducted in multiple countries this should be the first approval received>
IMP(s):
<list trial IMPs (as per CTA)> Include details of mode of action and
therapeutic class e.g.
Pegfilgrastim 6 mg solution for injection
Mode of action: binds to the G-CSF receptor. As a G-CSF analogue, it
controls proliferation of committed progenitor cells and influences their
maturation into mature neutrophils. Also stimulates the release of
neutrophils from bone marrow storage pools and reduces their maturation
time. Acts to increase the phagocytic activity of mature neutrophils. In
patients receiving cytotoxic chemotherapy, can accelerate neutrophil
recovery, leading to a reduction in duration of the neutropenic phase
Therapeutic class: blood modifying drug
<Where an IMP is supplied by the Sponsor, include statement of who is
providing IMP e.g. <supplied by Novartis> or <sourced locally via Trust
Pharmacy>>
Treatment Arms:
<insert different treatment arm(s). Include dose, route and formulation.>
Indication and
Population:
<insert indication and population e.g. relapsed refractory breast cancer in
post menopausal women aged over 60 years>
Scope:
This DSUR covers the <insert name of trial> trial
The following may apply where other DSURs have been referenced, e.g.
when information has been obtained from the Sponsor or in the rare
circumstance that there are multiple DSURs per trial (international studies):
<The above trial forms the scope of this DSUR and other relevant DSURs
are referenced in section 14.>
n most cases the following statement may apply unless data is contractually provided by a third party.
The <University of Birmingham or specify Sponsor> does not hold the Manufacturing or Marketing
Authorisations for the IMP(s) listed in this DSUR and therefore the <insert trials team> does not have
access to some of the requested data. Where information is not available the response ‘Data not
available’ or ‘Not applicable’ is provided.
2. Worldwide Marketing Approval Status
Refer to section 3.2 of ICH E2F
Page: 14 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
This section should provide a brief narrative overview including: date of first approval, indication(s),
approved dose(s), and where approved, if applicable.
The following statements may apply:
For a licensed IMP/Combination of IMPs: <IMP> has a Marketing Authorisation, but <the University of
Birmingham or specify Sponsor> are not the MA holder and therefore the <insert trials team> are not
aware of the worldwide approval status
Or
For an unlicensed IMP/Combination: <IMP> is currently in development with <insert company> and
<insert trials team> are not aware that it has a marketing approval>
3. Actions Taken in the Reporting Period for Safety Reasons
Refer to section 3.3 of ICH E2F
This section should include a description of significant actions related to safety that have been taken
during the reporting period.
For example: Refusal to authorise a clinical trial for ethical or safety reasons; Partial or complete
clinical trial suspension or early termination of an ongoing clinical trial; Recall of investigational drug or
comparator; Failure to obtain marketing approval for a tested indication including voluntary withdrawal
of a marketing application; Protocol modifications due to safety or efficacy concerns (e.g., dosage
changes, changes in study inclusion/exclusion criteria, intensification of subject monitoring, limitation
in trial duration); Restrictions in study population or indications; Changes to the informed consent
document relating to safety issues; Formulation changes; Addition by regulators of a special safetyrelated reporting requirement; Plans for new studies to address safety issues.
For marketed products (if known): Failure to obtain a marketing approval renewal; Withdrawal or
suspension of a marketing approval; New post-marketing study requirement(s) imposed by regulators.
Changes to the Investigator Brochure (IB) as a result of safety should not be discussed in this section
During Reporting Period
Insert <No actions taken.> or <The following actions were taken for safety reasons> and insert table
below.
Action
Reason (if known)
Update
<if resolved, say so>
<include summary and by which
body (e.g. REC, DMC)>
List all issues ongoing/resolved from previous reports in the table below. Once an action has been
taken during the course of the trial it must be included in the Cumulative Listing table.
Cumulative Listing can be deleted if this is the first DSUR
Action
Reason (if known)
Update
<if resolved, say so>
<include summary and by which
body (e.g. REC, DMC>
4. Changes to Reference Safety Information (RSI)
Refer to section 3.4 of ICH E2F
This section should list any significant safety-related changes to the RSI within the reporting period.
Such changes might include information relating to exclusion criteria, contraindications, warnings,
precautions, SARs, AEs of special interest, interactions, and any important findings from non-clinical
studies (e.g., carcinogenicity studies). Specific information relevant to these changes should be
provided in the appropriate sections of the DSUR.
Page: 15 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Attach current and any revisions to the RSI as an appendix.
RSI for Reporting Period:
Note: the RSI in effect at the start of the reporting period serves throughout the entire reporting period
<insert document ((sections of) IB/SmPC) name; version number and date><add <IMP> IB supplied
by <company>> where applicable
 <add lines if more than one document>
Changes to the RSI during the reporting period:
At present, the guidelines indicate that no changes to the RSI should be made during the reporting
period. For this section therefore insert <No changes to the RSI were made during the reporting
period>. If changes were made include <The following significant changes were made to the
<(sections of) IB/SmPCs> during the reporting period> and insert table.
Significant Changes
<insert document (e.g. (sections
of) IB/SmPC); name; revised
version number and date>
<summarise significant changes from previous version>
<insert document (e.g. (sections
of) IB/SmPC name); revised
version number and date>
<summarise significant changes from previous version>
Add more lines if required
Where applicable: RSI for the next reporting period:
The RSI needs updating should the safety information as embedded in the IB or SmPC have changed
over the last year in such a way that the expectedness of adverse reaction has changed as well. In
this case a substantial amendment would need to be submitted at the time of submitting the DSUR.
This section is to reflect the need of a change in the RSI. Include the following:
<The RSI has now been revised and the following document(s) will form the RSI for the next reporting
period (on approval from the competent authority)>
<insert document (IB/SmPC) name; version number and date>
 <add lines if more than one document>
 <add <IMP> IB supplied by <company>> where applicable
Page: 16 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
5. Inventory of Clinical Trials Ongoing and Completed during the Reporting Period
Refer to section 3.5 of ICH E2F
List for the trial included in this DSUR only.
EudraCT
No.
Phase
Status
<Country or
Countries>
Trial title
Trial
design
Regimen
and dose
<ongoing or complete>
Specify Country or Countries
Abbreviated title
e.g. randomised, blinded, uncontrolled
list regimen and dose IMPs
Trial
population
Age, sex, indication
Date of
clinical
start (First
Visit First
Patient)
First visit first patient
Planned
enrolment
Subject
exposure
(No.
recruited
patients)
Number patients recruited
Page: 17 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
6. Estimated Cumulative Exposure
6.1 Cumulative Subject Exposure in the Development Programme
Refer to section 3.6.1 of ICH E2F
For the trial included in this DSUR only
Cumulative exposure for the <insert name of trial> is summarised below:
Treatment
Number of subjects <registered/randomised> to treatment arm
<insert treatment arm 1>
<no. patients registered/randomised>
<insert treatment arm 2>
<no. patients registered/randomised>
Total
<no. patients registered/randomised>to trial
6.2 Patient Exposure from Marketing Experience
Refer to section 3.6.2 of ICH E2F
The following statements may apply:
For a licensed IMP/Combination of IMPs: <IMP> has a Marketing Authorisation, but <the University of
Birmingham or specify Sponsor> are not the MA holder and therefore the <insert trials team> are not
aware of the worldwide approval status
Or
For an unlicensed IMP/Combination: <IMP> is currently in development with <insert company> and
<insert trials team> are not aware that it has a marketing approval>
7. Data in Line Listings and Summary Tabulations
7.1 Reference Information
Refer to section 3.7.1 of ICH E2F
Coding document used to record Adverse Events
<e.g. National Cancer Institute Common
Terminology Criteria for Adverse Events (CTCAE)
version 4.0>
RSI used to assess expectedness
Note: the RSI in effect at the start of the reporting period serves throughout the entire reporting period
Effective from:
Effective to:
<insert document (IB/SmPC) name; version
number and date>
 <add lines if more than one document>
7.2 Line Listings of Serious Adverse Reactions during the Reporting Period
Refer to section 3.7.2 of ICH E2F
See Appendix 5.
Causality and expectedness were assessed as defined in the trial protocol effective at the time of the
event (see <insert reference to relevant section and version of the protocol>).
List any SARs that are excluded from this table in the DSUR and where necessary reference where
this data is summarised. SARs that are excluded from this table in the DSUR (refer to protocol)
7.3 Cumulative Summary Tabulations of Serious Adverse Events
Refer to section 3.7.3 of ICH E2F
Page: 18 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
See Appendix 6.
Causality and expectedness were assessed as defined in the trial protocol effective at the time of the
event (see <insert reference to relevant version and section of protocol>).
List any SAEs that are excluded from this table in the DSUR (e.g. disease related death) and where
necessary reference where this data is summarised. For example:
Please Note: The following events are excluded from the line listing of SAEs included in Appendix 5:


Disease related death as this data forms the primary end point for the trial. Appendix 9 lists
patients who have died during the reporting period
<insert other and explain why excluded>
8. Significant Findings from Clinical Trials during the Reporting Period
Refer to section 3.8 of ICH E2F
8.1 Completed Clinical Trials
Refer to section 3.8.1 of ICH E2F
The following statement may apply:
<Not applicable; no relevant completed trials included within this DSUR.>
8.2 Ongoing Clinical Trials
Refer to section 3.8.2 of ICH E2F
If the Sponsor is aware of clinically important information that has arisen from ongoing clinical trials
(e.g., learned through interim safety analyses or as a result of unblinding of subjects with adverse
events), this section should briefly summarise the issue(s). It could include information that supports or
refutes previously identified safety issues, as well as evidence of new safety signals.
This information should be based on the one trial for which the DSUR is prepared. This section needs
to be brief and can include recommendations from the DMC.
8.3 Long-term Follow-up
Refer to section 3.8.3 of ICH E2F
Where applicable, this section should provide information from long-term follow-up of subjects from
clinical trials of investigational drugs, particularly advanced therapy products (e.g., gene therapy, cell
therapy products and tissue engineered products).
This information should be based on the long term follow-up as defined in the protocol for the trial for
which the DSUR is prepared. This section needs to be brief and can include recommendations from
the DMC.
<Not applicable>
Or
<At present, patients are not subject to long-term follow-up>
Or
<Patients will be followed for <x> years however this trial is still open to recruitment and there are no
results available from long-term follow-up>
8.4 Other Therapeutic Use of Investigational Drug
Refer to section 3.8.4 of ICH E2F
This section of the DSUR should include clinically important safety information from other programmes
conducted by the Sponsor that follow a specific protocol (e.g., expanded access programmes,
compassionate use programmes).
The following statement may apply:
Page: 19 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
<Not applicable; this DSUR has been prepared for the trial described in the scope (section 1)
8.5 New Safety Data Related to Combination Therapies
Refer to section 3.8.5 of ICH E2F
The following statement may apply:
<This DSUR has been prepared for the trial described in the scope (section 1); other relevant DSURs
are referenced to in section 14.>
9. Safety Findings from Non-interventional Studies
Refer to section 3.9 of ICH E2F
This section should summarise relevant safety information from non-interventional studies that
became available to the Sponsor during the reporting period (e.g., observational studies,
epidemiological studies, registries and active surveillance programmes).
The following statement may apply:
<No information from non-interventional studies has become available to the <insert trial team> during
this reporting period.>
10. Other Clinical Trial/Study Safety Information
Refer to section 3.10 of ICH E2F
This section should summarise relevant safety information from any other clinical trial/study sources
that became available to the Sponsor during the reporting period (e.g., results from pooled analyses or
meta-analyses of randomised clinical trials, safety information provided by co-development partner).
It is not expected that additional information is actively sought from external sources. But, information
available to the TMG should be summarised.
<No information from clinical trials/studies has become available to the trials team during this reporting
period.>
11. Safety Findings from Marketing Experience
Refer to section 3.11 of ICH E2F
If the investigational drug has been approved for marketing in any country, this section should include
a concise summary of key safety findings that have arisen from marketing experience and that
became available to the Sponsor during the reporting period, particularly if the findings resulted in
changes to the product labelling, Investigator’s Brochure, informed consent document or amendments
to the product’s risk management plan. This includes not only safety findings relating to approved use
but also off-label use, administration to special populations (e.g., pregnant women), medication errors,
overdose and abuse.
It is not expected that additional information is actively sought from external sources. But, information
available to the TMG should be summarised.
The following statement(s) may apply:
<No information regarding safety findings from marketing experience has been brought to the attention
of trial team during this reporting period.>
Or
For an unlicensed IMP/Combination <<IMP> is currently in development with <insert company> and
the trial team are not aware that it has a marketing approval>
12. Non-clinical Data
Refer to section 3.12 of ICH E2F
Page: 20 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
This section should summarise major safety findings from non-clinical in vivo and in vitro studies (e.g.,
carcinogenicity, reproduction, or immunotoxicity studies) ongoing or completed during the reporting
period. Implications of these findings should be discussed in the Overall Safety Assessment.
It is not expected that additional information is actively sought from external sources. But, information
available to the TMG should be summarised.
<No information from non-clinical studies has become available to the trial team during this reporting
period.>
13. Literature
Refer to section 3.13 of ICH E2F
This section should summarise new and significant safety findings, either published in the scientific
literature or available as unpublished manuscripts, relevant to the investigational drug that the
Sponsor became aware of during the reporting period. This section should include information from
non-clinical and clinical studies and, if relevant and applicable, information on drugs of the same class.
It should also summarise significant new safety information presented at a scientific meeting and
published as an abstract; the Sponsor should provide a copy of the abstract, if possible.
It is not expected that additional information is actively sought from external sources. But, information
available to the TMG should be summarised.
Attach abstracts as Appendix 7 (if applicable)
<No new literature has become available to the trial team during this reporting period.>
14. Other DSURs
Refer to section 3.14 of ICH E2F
When available, the Sponsor should summarise significant findings from DSURs provided by other
Sponsors conducting clinical trials with the same investigational drug during the reporting period.
An attempt should also be made to obtain a summary of any other DSUR which have been prepared
for a trial a) with both the same Sponsor and which utilises the same IMP(s).
It is not expected that additional information is actively sought from external sources. But, information
available to the TMG should be summarised.
The following statement may be applicable: <<IMP> is manufactured/ marketed by <insert MA holder>
and the <insert the trials team> do not have access to the any other DSUR.>
15. Lack of Efficacy
Refer to section 3.15 of ICH E2F
Data indicating lack of efficacy, or lack of efficacy relative to established therapy(ies), for
investigational drugs intended to treat serious or life-threatening illnesses could reflect a significant
risk to clinical trial subjects and should be summarised in this section.
Insert a summary or <Not applicable>
16. Region-Specific Information
Refer to section 3.16 of ICH E2F
The following regional specific information is required for reports produced for submission to
competent authorities in the EU only. Additional information may be required if the report is submitted
to authorities within other ICH regions.
Cumulative summary tabulation of Serious Adverse Reactions
See Appendix 8
Page: 21 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
17. Late-Breaking Information
Refer to section 3.17 of ICH E2F
This section should summarise information on potentially important safety findings that arise after the
data lock point but while the DSUR is in preparation. Examples include clinically significant new case
reports, important follow-up data, clinically relevant toxicological findings and any action that the
Sponsor, a DMC, or a regulatory authority has taken for safety reasons. The Overall Safety
Assessment should also take these new data into account.
Insert a summary or <Not applicable>
18. Overall Safety Assessment
Refer to section 3.18 of ICH E2F
The overall safety assessment should be a concise, integrated evaluation of all new relevant clinical,
non-clinical, and epidemiologic information obtained during the reporting period relative to previous
knowledge of the investigational drug. This assessment should consider cumulative experience, new
information collected in the period covered by the DSUR and, for investigational drugs with a
marketing approval, clinically significant post-marketing data.
It should not summarise or repeat information presented in previous sections of the DSUR, but should
provide an interpretation of the information and its implications for the clinical trial population and the
development programme. If appropriate, separate assessments can be provided by therapeutic area,
route of administration, formulation and/or indication.
Do not enter data here but in sub-sections 18.1 and 18.2. Only include significant issues. Do not list
all. It is not expected that additional information is actively sought from external sources. But,
information available to the TMG should be summarised.
18.1. Evaluation of the Risks
Refer to section 3.18.1 of ICH E2F
In evaluating the risks, particular emphasis should be placed on interpretation of data related to newly
identified safety concerns or providing significant new information relative to previously identified
safety concerns. Relevant points to consider include (where applicable):
 newly identified safety issues (detailed description of adverse events or reactions; associated
laboratory values; risk factors; relationship to dose, duration, time course of the treatment;
reversibility; factors that could be useful in predicting or preventing reactions)
 meaningful changes in previously identified adverse reactions (e.g., increased frequency or
severity, outcome, specific at-risk populations)
 symptoms, signs, and laboratory evidence of newly and previously identified clinically significant
toxicities
 deaths that are an outcome of an adverse event
 study drug discontinuations because of adverse events, including abnormal laboratory values or
investigations
 drug–drug and other interactions
 important non-clinical safety findings
 manufacturing issues that could affect risk
 lack of efficacy where this would place trial participants at risk
 any specific safety issues related to special populations, such as the elderly, children, patients
with hepatic or renal impairment, or any other at-risk groups (e.g., slow or fast metabolisers)
 pregnancy and lactation exposure and outcomes
Page: 22 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
 safety findings arising from experience with long-term treatment
 evidence of clinically significant medication errors
 evidence of lack of patient compliance
 experience with overdose and its treatment
 occurrences of drug misuse and abuse
 any safety issues resulting from procedures required by the protocol (e.g., bronchoscopy, biopsy,
central line insertion) or associated with the conduct or design of a particular study (e.g.,
inadequate subject monitoring schedule, excessive period without active treatment)
 potential impact of significant new safety issues identified with another drug in the same class
18.2 Benefit-risk Considerations
Refer to section 3.18.2 of ICH E2F
This section should provide a succinct statement on the perceived balance between risks that have
been identified from cumulative safety data and anticipated efficacy/benefits and should note whether
there have been any changes in this balance since the previous DSUR. This section is not intended to
be a full benefit-risk assessment of the investigational drug.
Example text:




At the present stage of development, the risk of VGF-2 seems acceptable in light of its potential
benefit (amelioration of PAD)
With this DSUR, there is stronger evidence of a risk of hepatic injury, and we have made
appropriate changes in the protocol and informed consent, as noted in this report
By excluding subjects with a history of hepatic disease, and monitoring transaminases more
frequently, we hope to detect hepatic transaminase elevations at an earlier stage, and diminish
risk
These risks should be considered in light of the significant morbidity of PAD and VGF-2’s potential
to ameliorate claudication, improve function, and enhance limb salvage
19. Summary of Important Risks
Refer to section 3.19 of ICH E2F
This section should provide a concise, cumulative, issue-by-issue list of important identified and
potential risks, e.g., those that might lead to warnings, precautions, or contraindications in labelling.
Such risks might include, for example, toxicities known to be associated with a particular molecular
structure or drug class, or concerns based on accumulating non-clinical or clinical data. Each risk
should be re-evaluated annually and re-summarised as appropriate, based on the current state of
knowledge. New information should be highlighted. The appropriate level of detail is likely to be
dependent on the stage of drug development. For example, summaries covering drugs in early
development might include information on individual cases, whereas in later development, as more
knowledge and perspective are gained, the information on each risk might be less detailed.
The information in this section could provide the basis for the safety specification of a risk
management plan (ICH E2E).
Risks that have been fully addressed or resolved should remain in the summary and be briefly
described, e.g., findings from toxicology studies or early clinical trials that were not borne out by later
clinical data.
The information can be provided in either narrative or tabular format.
This section should only include the information which relates directly to the trial, the population being
studied and which is over and above the information contained within the RSI.
Page: 23 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Example text:
This section summarises the important identified or potential risks that have been recognised during
the conduct of the trial and identified in the scope of this DSUR. Identified risks will be as recorded in
the Reference Safety Information.
The following have been recognised as important potential risks during the reporting period:
•
•
•
•
Nephrotoxicity
Hepatotoxicity
Syncope
Pancreatitis
Additional details are provided below:
Risk
(New or updated risks
are denoted with an *)
Non-clinical data
Clinical data
Actions
20. Conclusions
Refer to section 3.20 of ICH E2F
The conclusion should briefly describe any changes to the previous knowledge of efficacy and safety
resulting from information gained since the last DSUR. The conclusion should outline actions that
have been or will be taken to address emerging safety issues in the clinical development programme.
Example text:
The risks remain fairly consistent with the experience described in our previous DSUR, and we
conclude that the information obtained in this reporting period justifies continuation of the trial, with the
modifications noted in this DSUR.
Page: 24 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Appendices to the DSUR
The order and nomenclature of the appendices are as per the DSUR guideline. Some appendices are
contained in the main body of the report.
 Appendix 1: Current and any revisions to the Reference Safety Information
 Appendix 2 – Cumulative table of important regulatory advice (refer to Section 3)
 Appendix 3 – Status of ongoing and completed clinical trials (refer to Section 5)
 Appendix 4 – Cumulative Summary Tabulations (refer to Section 6)
 Appendix 5: A line listing of all Serious Adverse Reactions
 Appendix 6: A cumulative tabulation of all Serious Adverse Events
 Appendix 7: Scientific abstracts (if relevant)
 Appendix 8: A cumulative tabulation of Serious Adverse Reactions
Page: 25 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Appendix 5: A line listing of all Serious Adverse Reactions
Refer to section table 5 of ICH E2F

Include a line listing of all SARs and SUSARs received within the reporting period. List each SAR only once regardless of how many AEs are reported per SAE
o If more than one AR has been reported on the SAE Form mention all but list under the most serious reaction term (where possible)

If data has not been collected in the required format then the best available data should be presented (e.g. ‘date last given’ instead of ‘treatment start and end dates’).
Each event reported for an individual subject must be listed as a separate event
Notes:
1.
2.
3.
4.
5.
Can be amended to reflect terminology used in the trial
Can be listed prior to line-listing if consistent throughout trial (e.g. all female subjects, all UK subjects)
Given for the most serious SAR
Outcome example: resolved; sequelae; ongoing; fatal; improved; unknown
Relevant comments may be causality assessment if the sponsor disagrees with the reporter; concomitant medications suspected to play a role in the
reactions directly or by interaction; indication treated with suspect drug(s); dechallenge/rechallenge results if available
Subject clinical
trial
identification
number1
Sponsor’s
adverse
reaction
case
reference
number1
Country2;
Gender2;
Age
SARs3
Outcome4
Date and/or
time of
onset 1,
Page: 26 of 29
Suspect
drug (if
blinded,
state
‘blinded)
Daily
dose;
Route;
Formulati
on
Dates of
treatment
and/or
best
estimate of
treatment
duration 1
Comments if
relevant 5
<Trial acronym>
DSUR date: dd-mon-yyyy
Page: 27 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Appendix 6: A cumulative tabulation of all Serious Adverse Events and for Appendix 8: A cumulative tabulation of all Serious Adverse
Reactions
Refer to section table 6 of ICH E2F
2 separate reports are required:

A tabulation of all SAEs (including SARs and SUSARs) that have occurred during the course of the trial (appendix 6)

A tabulation of all SARs (including SUSARs) that have occurred during the course of the trial (appendix 8)

Create a summary table as indicated below
o Include all SAEs/SARs (as applicable) reported throughout lifetime of trial
o Amend the number of columns as required to accommodate the appropriate number of treatment arms
o Report by coding terms that are referenced within section 7.1 of this document. If no coding has been used, group by body system as appropriate
o Include a sub-total for each category
Example 1 – for non-blinded trials
The exact detail will be dependent on the events reported.
Number of <insert Adverse Events or Adverse Reactions>
CTCAE Category
Adverse Event Term
Allergy / Immunology
Blood / Bone Marrow
<insert treatment arm 1>
<insert treatment arm 2 etc>
Allergic reaction/
hypersensitivity
(including drug fever)
1*
3
Vasculitis
4
1
Sub-total
5
4
Platelets
0
2
Sub-total
0
2
Page: 28 of 29
<Trial acronym>
DSUR date: dd-mon-yyyy
Example 2 – for blinded trials
The exact detail will be dependent on the events reported
Reactions should only be listed under the relevant treatment arms where results have been unblinded. All other adverse reactions will be classed as ‘blinded’.
Number of <insert Adverse Events or Adverse Reactions>
CTCAE Category
Allergy / Immunology
Blood / Bone Marrow
Adverse Event Term
Blinded
Unblinded
<insert treatment arm 1 >
<insert treatment arm 2 etc>
Allergic reaction/
hypersensitivity
(including drug fever)
1*
3
Vasculitis
4
1
7
7
Sub-total
5
4
14
Platelets
0
2
15
Sub-total
0
2
15
Page: 29 of 29