Download DSUR Template - CTT55 - Leeds Teaching Hospitals NHS Trust

Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
(Below is the CTT55 template including additional directions for completion for each section
listed on the DSUR index.)
DSUR Report Number: xxxxx
Trial Title:
Reporting Period: (E.G. 1st September 2010 – 31st August 2011)
* The DSUR must be compiled annually for the duration of the clinical trial until the regulator has been notified of the end of the trial. This
process must commence on the anniversary of the first MHRA approval. Reporting must occur within 60 days of this date.
Name of IMP(s)
Sponsor
University of Leeds or Leeds Teaching Hospitals NHS Trust
Chief Investigator
Address
Sponsor Address
Leeds Sponsor Office
Research and Development
Leeds Teaching Hospitals and NHS Trust
34 Hyde Terrace
Leeds
LS2 9LN
Date of Report
(This can be up to 30 days after the end of the reporting period)
Signed:
………………………………………………..
Name:
Note: This developmental Safety Update Report may contain confidential information, including
unblinded adverse event data.
EXECUTIVE SUMMARY
Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
This section should provide to the reviewer a concise summary of the relevant and important
information contained in the report as whole. This section of the DSUR will serve as part of your
annual report which must also be submitted to the Research Ethics Committee responsible for your
study. When you submit this section to the REC is should also include any relevant line listings of
Serious Adverse Event (SAEs) and Serious Adverse Reactions (SARs) which can also be added from this
report’s appendices.
The executive summary should contain the following information;








Brief introduction to the report describing content, report number and report period.
Confirmation that this report refers to the trial named and not all the sponsor
activity with this IMP
Detail on the IMP(s – why are you using this IMP in this patient group?), mode of
action, therapeutic class, indication(s), doses used, route of administration (sub-cut,
oral etc.), any relevant formulation data.
The estimated cumulative exposure of patients to the IMP in the study (is this more
or less than normal if the IMP is licensed?)
Has the IMP marketing approval? If so where – EU and/or beyond?
Summary of safety assessment (this will be detailed in the main report – section 19)
to include a brief description of the main risks.
Any safety changes to the protocol or Investigator Brochure (IB) – that have resulted
in amendments sent to the MHRA or other competent authority to be described
briefly here (not REC only amendments)
Conclusions – safe to continue, risks seem acceptable as potential benefits still
significant in the patient group.
Try and keep this section concise – two sides of A4 should in most cases cover everything. This is a
summary section.
Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Introduction
World Wide Marketing Approval Status
Actions taken in the Reporting period for Safety Reasons
Change to Reference Safety information (e.g. – IB)
Other Trials On-going with this IMP during this reporting period.
Estimated Cumulative Exposure
6.1. Cumulative Subject Exposure in this Trial
6.2. Patient Exposure from Previous Marketing Experience
Data in Line Listings and Summary Tabulations
7.1. Reference Information
7.2. Line Listings of Serious Adverse Reactions (SARs) during Reporting Period.
7.3. Cumulative Summary of all Serious Adverse Events (SAEs) during Reporting Period.
Significant Findings from Clinical Trials during reporting period
8.1. Completed Trials
8.2. Ongoing Trials
8.3. Long Term follow-up
8.4. Other Therapeutic Uses of IMP
8.5. New Safety Data related to any combination therapies using the IMP
Safety findings form non-interventional studies (Safety or PK studies)
Any other Clinical Trial/Safety Study data
Any Safety Issues form Marketing Experience
Any relevant non-clinical data
Literature
Other related DSURs
Lack of Efficacy
Any regional specific information
Late breaking Information
Overall Safety Assessment
18.1.
Evaluation of Risks
18.2.
Risk – benefit considerations
Summary of Important risks
Conclusions
Appendices:
Development Safety Update Reporting for IMP Clinical Trials
Title
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
1. Introduction
This section should include the following details of the study:
 Background information, earlier work and objective

Reporting period and sequential number of the report;

Brief description of the drug - therapeutic class, mechanism of action, route of
administration, formulation; e.g. a lyophilised powder (x mg/vial) re-constituted in saline
prior to infusion.

A brief description of the indications and populations being studied;

A short summary of the scope of the clinical trials covered by the report (e.g. all trials with
the investigational drug, indication-specific trials, trials with combination products);

A brief description and explanation of any information that has been excluded
(e.g., when written agreements with a partner company do not provide for exchange of all
safety data).
2. Worldwide Marketing Authorisation
Is the IMP marketed within the EU?
If the IMP is not yet marketed in the EU, please highlight anywhere else worldwide where the IMP is
currently marketed. If this information is unknown please clearly state this in the report.
3. Actions taken in the Reporting Period for Safety Reasons
Within the study have there been any changes to the protocol in response to the events that
occurred in the trial?
Examples;
(a) Changes to the inclusion / exclusion criteria to refine groups who recruited to the study?
(b) A series of Adverse Events that in light of other data (possibly received from the IMP
manufacturer / provider) indicated that more tests or more frequent testing were needed to
monitor a particular side effect.
(c) SAR(s) occurred which caused the safety profile of the study to be re-assessed.
(d) Safety related changes to the IB or SPC that meant the study conditions have to be altered.
Any substantial amendment submitted to the MHRA in this reporting period should be described
here including detail of the changes to the study documentation.
4. Changes to Reference safety Information
Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
Please list any new IB or SPC here – if this is not applicable please clearly state.
This section should list any significant safety-related changes to the Information Brochure (IB) or
other reference safety information within the reporting period. Such changes might include
information relating to exclusion criteria, contraindications, warnings, precautions, serious adverse
drug reactions, adverse events of special interest, interactions, and any important findings from nonclinical studies (e.g. carcinogenicity studies).
5. Inventory of Clinical Trials On-going and Completed During the Reporting Period.
Please state that this DSUR covers a single study; include the full name of the study, the EudraCT
number and REC reference number.
Describe whether the study is single site or multi-site (if the latter state how many sites and if they
are all in England, EU or worldwide.)
Describe briefly the type of study: Phase, status (ongoing, completed, follow up), design (blinded,
open etc), the study regimen including doses in each arm, date of first patient recruited, recruitment
to date and estimate of dose for each groups (estimate if blinded).
E.g. Study status: first patient was recruited 21-Jul-2009. As of end of this report date, 18 subjects
have been enrolled (enrolment is behind schedule due to change in staffing – now amended).
Group 1 – placebo –n=9
Group 2 – IMP – (10k/kg) n= 9
6. Estimated Cumulative Exposure
6.1 Cumulative Subject Exposure in the Study.
If your study is blinded you can only estimate this on the basis of the randomisation scheme. A table
of exposure can be used. If there are only two arms this will be straightforward – if there are several
blinded arms some thought will be needed to describe the possible numbers exposed at each dose.
This should be completed for all patients recruited to date.
Explain the method used to estimate subject exposure and the overall number of subjects exposed,
if available
.
1.2 Patient Exposure from Marketing Experience
It is unlikely that the Trust or University will be marketing the IMP so this is one section than can be
answered “Not Applicable”.
7. Data in line Listings and Summary Tabulations
7.1 Reference Information
Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
Describe how you are grading or coding your adverse events – this may be the MedDRA system or
you may be using a protocol defined system based on the IB or SPC of the IMP. This influences how
you assess expectedness.
7.2 Line listing of Serious Adverse Reactions (SARs) during the reporting period.
The MHRA require information on any DRUG related Serious Adverse Events. This section should
summarise how case reports were selected for inclusion in the line listings. A brief narrative of the
SAE should occur here including whether it is a SAR or SUSAR.
The line listings should be provided in an appendix (this will aid the annual report to ethics who only
require the executive summary and line listings from this report).
E.g. Subject 037 is a 39 year old male who presented to A&E at St Mary’s London on 17-Mar-2011 at
3pm (24 hours after receiving medication) with symptoms (describe). He was treated (describe) and
kept in overnight. He was diagnosed with acute xxx which is a rare expected side-effect of the IMP in
this patient group however the seriousness was not unexpected. The CI determined the reaction to be
related to the IMP, it was serous as described in the protocol but was not unexpected. This event has
been recorded as a SAR. The treatment was not un-blinded.
Repeat as necessary.
8. Significant Findings from the Clinical Trial during the Reporting period
E.g. This trial is on-going – the study is monitored by a Trial Steering Committee (TSC) and or Data
Monitoring Committee (DMC) – no significant findings have been identified in this period.
8.1 Completed Trials: Should provide a brief summary of clinically important emerging
efficacy and safety findings from clinical trials completed during the reporting period.
8.2 Ongoing Trials: Should provide details of clinically important safety 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).
8.3 Long Term Follow up: Where applicable, this section should provide information from
long-term follow up of subjects from clinical trials of investigational drugs
8.4 Other uses of the Drug (therapeutic or combination therapies: Any information that
has come to light in the literature that might affect the study if applicable.
8.5 New Safety Data Related to Combination Therapies: If this DSUR is for an
investigational drug that is also under development as a component of a fixed
combination product or a multi-drug regimen, this section should summarise important
safety findings from the combination therapy DSUR.
Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
9. Safety Findings from Non-Interventional Studies
If applicable, describe any observational or epidemiological data that you are aware of that has
influenced the safety aspects of the trial in the reporting period.
10. Other Clinical Trial Study Information
If your study IMP is not licensed/being used in a new indication and is being supplied by a
commercial company you will need to request this information from the company in order to
complete this section. Please state if not applicable.
11. Safety Findings from Marketing Experience
As outlined in section 10.
12. Non- Clinical Data
Any new major safety findings from in vivo or in vitro work that you become aware of should be
listed here and can be discussed in the Overall Safety Assessment in section 18.
13. Literature
This section should summarise any new safety related information on the IMP that has been
published during the reporting period, that the team are aware of. This section can also include
unpublished data, perhaps from a scientific meeting, that is relevant to the safe administration of
the IMP.
The information included in this section can be from clinical or non-clinical studies
14. Other DSURs
The investigator should contact the sponsor via the QA team for information on any other DSUR
submitted in the period for the same IMP. It is possible although unlikely that related information
may need to be included – this might include reports of SUSARs in other trials using the same IMP.
Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
15. Lack of Efficacy
Any evidence of lack of efficacy, or lack of efficacy relative to established gold standard therapies
should be discussed here. E.g. increased incidence of nausea means compliance can be poor,
resulting in overall lack of efficacy. Where compliance is good efficacy appears high alongside
comparator. This may mean that a change to the dose might need to be considered.
16. Region Specific Information
Things to be covered for UK submission are;





List of subjects who died
List of any subjects who drop out of the study due to adverse events
Any phase I modifications
Any significant manufacturing changes
Description of plan for the next year (projected recruitment rates, predicted end of
study dates)
The answer to these may all be not applicable.
17. Late Breaking Information
Any safety related events that have occurred from the end of the reporting period to the submission
date of the DSUR that may relate to the safety of the IMP.
18. Overall Safety Assessment
This section is probably the most important. A coherent argument must be made for continuing the
study in its current form. There should be a coherent narrative here describing all new relevant
safety data compared to the previous knowledge of the IMP. It should not repeat previous
information but should provide an interpretation of the information and its implications for the
clinical trial population. You should evaluate the risks and weigh up the benefits taking the following
points into consideration.
18.1.







Evaluation of the Risks
NEW safety issues – possibly related to dose, duration of exposure, new lab or
genetic associations
Changes in rate or severity of adverse events and in particular adverse reactions to
the IMP
Study drop outs due to adverse events
Manufacturing issues (danger to supply)
Evidence of lack of efficacy
Evidence of clinically significant medication errors
Lack of compliance
Title
Development Safety Update Reporting for IMP Clinical Trials
Template


Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
Evidence of IMP misuse or abuse
New safety information from a related drug in the same class
18.2.
Risk- benefit Considerations
This section should contain a succinct and clear statement on perceived balance between
the risks identified in the reporting period and the anticipated benefits. You should make a
clear statement that the potential benefits still outweigh the risks even with the new
information taken into account. You should detail how any amendments have mediated risk
in the previous year.
19. Summary of Important Risks
You should outline the main safety risk factors related to the IMP that have been influential in your
decision to continue or amend the study in this reporting period. There may be one or several or no
such risk factors.
E.g. Hypotension - an increase in hypotension was noted in 12% of patients taking this IMP in a
study reported in the BMJ. The IMP was being used in a different patient group, however after taking
this into consideration we amended the inclusion / exclusion to exclude patients with confirmed
coronary artery disease.
20. Conclusions
This should be very brief and describe any changes to the previous knowledge or efficacy and safety
resulting from information gained since the last DSUR. The conclusions should outline the actions
that have been or will be taken to address emerging safety issues
E.g. The risks remain consistent with experience described in previous DSUR (or in our application to
the regulator) and we conclude that in the information obtained in this reporting period warrants
continuation of the study, with the modifications outlined in this DSUR.
Appendices
Possible appendices:
1.
2.
3.
4.
5.
6.
Investigators Brochure;
Cumulative Table of Important Regulatory Requests;
Cumulative Summary Tabulations of Demographic Data;
Line Listings of Serious Adverse Reactions (mandatory – please see template 1);
Cumulative Summary Tabulation of Serious Adverse Events;
Scientific Abstracts (if relevant).
Development Safety Update Reporting for IMP Clinical Trials
Title
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55
Template 1: Example Line Listing of All Serious Adverse Events
Study
Subject ID
Country/
gender
diagnosis
Outcome
Time to Onset from
administration
Suspected drug
Dose, route of Date of
administration treatment
and
formulation
Comments
0023*
UK - male
hypotension
resolved
2 hours
IMP
10mg/kg, x3,
IV
Describe event.
0168
UK male
ongoing
3 months
blinded
10mg/kg, x3
IV or placebo
0109**
UK female
Metastatic
prostate
cancer
neutropenia
sequale
3 days
blinded
10mg/kg, x3
IV or placebo


* Indicates event suspected to be related to the IMP – a serious adverse reaction (SAR)
** Indicates event reported as a Suspected Unexpected Serious Adverse Reaction (SUSAR).
10-Apr-2011
11-Apr-2011
14-May-2011
21-feb-2011
18-Mar-2011
15-June -2011
06-May-2011
07-May 2011
12-May-2011
Describe event
Describe event
Title
Development Safety Update Reporting for IMP Clinical Trials
Template
Scope
Template DSUR form including additional guidance
Version
2.0
Date
120209
WI ID
CTT55