Ich E2f Dsur
Ich E2f Dsur
June 2008
EMEA/CHMP/ICH/309348/2008
Step 3
1. INTRODUCTION................................................................................................................ 4
1.1 OBJECTIVE OF THE GUIDELINE ..................................................................................... 4
1.2 SCOPE OF THE DSUR.................................................................................................... 4
2. GUIDANCE....................................................................................................................... 5
2.1 WHEN SHOULD A DSUR BE PREPARED? ...................................................................... 5
2.2 PERIODICITY AND DSUR DATA LOCK POINT ............................................................... 5
2.3 CHANGE OF DSUR DATA LOCK POINT ........................................................................ 5
2.4 INTERRUPTION OR DISCONTINUATION OF CLINICAL TRIALS ......................................... 6
2.5 FINAL DSUR ................................................................................................................ 6
2.6 RESPONSIBILITIES FOR PREPARING AND SUBMITTING A DSUR .................................... 6
2.6.1 Sponsor’s responsibilities ........................................................................................ 6
2.6.2 Shared responsibilities............................................................................................. 6
2.6.3 Non-commercial sponsor responsibilities................................................................ 6
2.6.4 Responsibilities of multiple sponsors in formal agreements.................................... 6
2.7 DSURS FOR COMBINATION PRODUCTS ........................................................................ 6
2.8 REFERENCE SAFETY INFORMATION .............................................................................. 7
2.9 FORMAT AND PRESENTATION OF DSUR....................................................................... 7
2.9.1 Format...................................................................................................................... 7
2.9.2 Table of Contents ..................................................................................................... 7
2.10 GUIDANCE ON CONTENTS OF DSUR............................................................................. 8
3. UPDATE ON ACTIONS TAKEN IN THE REPORTING PERIOD FOR SAFETY9
6. ESTIMATED EXPOSURE............................................................................................ 11
6.1 CUMULATIVE SUBJECT EXPOSURE IN DEVELOPMENT PROGRAMME .................................. 11
6.2 PATIENT EXPOSURE FROM MARKETING EXPERIENCE ........................................................ 11
7. PRESENTATION OF SAFETY DATA FROM CLINICAL TRIALS ..................... 11
7.1 GENERAL CONSIDERATIONS ............................................................................................. 12
7.2 INTERVAL LINE LISTINGS OF SERIOUS ADVERSE REACTIONS (SARS) ............................. 12
7.3 CUMULATIVE SUMMARY TABULATIONS ..................................................................... 12
7.4 DEATHS IN THE REPORTING PERIOD ........................................................................... 12
7.5 SUBJECTS WHO DROPPED OUT IN ASSOCIATION WITH ANY ADVERSE EVENT IN THE
REPORTING PERIOD ................................................................................................................ 13
APPENDIX A ......................................................................................................................... 17
GLOSSARY ............................................................................................................................. 17
APPENDIX B.......................................................................................................................... 20
TABLE 1 - EXAMPLES OF TABLE HEADINGS FOR CLINICAL TRIAL STATUS
LISTINGS ............................................................................................................................ 20
TABLE 2 - EXAMPLES OF DEMOGRAPHIC DATA TABLES....................................... 21
TABLE 3 - EXAMPLES OF HEADINGS FOR INTERVAL LINE LISTINGS OF
SERIOUS ADVERSE REACTIONS ................................................................................... 22
TABLE 4 - EXAMPLES OF CUMULATIVE TABULATIONS OF SERIOUS ADVERSE
EVENTS............................................................................................................................... 23
The main objective of a DSUR is to present an annual review and evaluation of pertinent
safety information collected during the reporting period to: (1) summarise the current
understanding and management of identified and potential risks; (2) describe new safety
issues that could have an impact on the protection of clinical trial subjects; (3) examine
whether the information obtained by the sponsor during the reporting period is in accord with
previous knowledge of the product’s safety; and (4) provide an update on the status of the
clinical investigation/development programme. This guideline defines the content and format
of a DSUR and provides an outline of points to be considered in its preparation and
submission.
The DSUR should provide safety information from all ongoing clinical trials that the sponsor
is conducting or has completed during the review period including:
1
The term investigational drug is used in this guideline to indicate only the experimental product under study or development.
2
For detailed discussion see: The Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety
Reporting During Clinical Trials: Report of CIOMS Working Group VII, Geneva 2007.
3
ICH Topic E6(R1). Guideline for Good Clinical Practice http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf
The DSUR should focus primarily on the investigational drug, providing information on
comparators only where relevant to the safety of trial subjects. A DSUR should be concise
and provide information to assure regulators that sponsors are adequately monitoring and
evaluating the safety profile of the investigational drug. It should not contain initial
notification of any significant new safety issues, as these should have been communicated to
regulatory authorities via expedited reporting.
2. GUIDANCE
The DSUR should be submitted no later than 60 calendar days from the DSUR data lock
point. The data lock point of the DSUR should be based on the date of the sponsor’s first
authorisation to conduct a clinical trial in any country. This date is termed the “Development
International Birth Date” (DIBD). 5 For administrative convenience, if desired by the sponsor,
the DIBD can be designated as the last day of the month of authorisation.
Where clinical trials are ongoing in one country and are later initiated in another country(ies),
one DSUR based on the same DIBD should be used for all countries.
4
For classification of clinical trials see ICH E8 General considerations for clinical trials.
5
This is analogous to the International Birth Date (IBD) for a PSUR, defined as the date of first marketing approval worldwide.
6
For the purposes of this document, we use the term “authorisation/ authorised” to refer to approvals of clinical trials, and “approved/
marketing approval” to refer to marketing authorizations.
When unavoidable, multiple sponsors can agree in writing to prepare separate DSURs for the
same investigational drug. This can include situations where different indications, routes of
administration, or formulations are being investigated. The rationale for separate DSURs
should be provided in each report.
For trials involving drug combinations that are not fixed, it can be appropriate to prepare a
stand-alone DSUR. Alternatively, information on the multidrug regimen trials can be included
in the DSUR of one or all of the components.
Although medical devices are outside the scope of the DSUR, specific local regulations can
require a DSUR for certain drug-device combinations, depending upon whether the principal
therapeutic effect is achieved by the drug or the device.
The Investigator’s Brochure (IB) in effect at the start of the reporting period should serve as
the reference safety information for the DSUR for an investigational drug whether or not the
drug has a marketing approval. The report should clearly indicate the version number and date
of the IB used for this purpose. If the IB has been revised during the reporting period and not
previously submitted to the relevant regulatory authority, the sponsor should provide a copy
of the revised version of the IB as an attachment to the DSUR. When an IB is not required for
the trial by local regulations (e.g., non-commercial sponsors conducting a clinical trial with a
marketed product) the applicable local product label 7 or another suitable document should be
used as the reference safety information.
2.9.1 Format
The format and content of the DSUR should follow the table of contents below. For each
heading where information is available, the information should be presented concisely; when
no information is available, this should be stated. Guidance on the content of each section is
provided below. Note that the section numbers below reflect the numbering in the DSUR.
7
In the EU this would be the Summary of Product Characteristics (SmPC); in Japan this would be the Japanese Package Insert; and in the
US this would be the US Package Insert.
Title page
The title page of the DSUR should include the following information:
• DSUR number (reports should be numbered sequentially);
• Investigational drug(s);
• Reporting period;
• Date of the report;
• Sponsor name and address;
• Confidentiality statement; and
• Note regarding the inclusion of unblinded information in the DSUR.
Executive Summary
This section should provide a concise summary of the important information contained in the
report. Together with the title page, it should serve as a “stand-alone” document suitable for
submission to ethics committees and other stakeholders, if required by local regulations.
Information on the following should be included in the Executive Summary:
• Introduction – report version and reporting period;
• Investigational drug – mode of action, class, indications, dose, route of administration;
• Estimated cumulative clinical trial exposure;
• Marketing authorisation(s)? (yes/no) – If yes, number of countries;
• Summary of overall safety assessment;
• Summary of important risks (based on section 15 of the DSUR);
• Actions taken for safety reasons including significant changes to IB;
© EMEA 2008 Page 8/23
• Conclusion.
All sections should be completed; when no information is available, this should be stated.
Table of Contents
Introduction
This section should include:
• Reporting period and sequential number of the report;
• Brief description of the drug, e.g., therapeutic class, mode of action, route of
administration, formulation;
• Whether the report covers a development programme or a single clinical trial. This
section should also note the scope of the trials covered by the report (e.g., all trials
with the investigational drug, or indication-specific trials);
• A brief description of the indications and populations being studied;
• 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).
In addition to the above, for drugs with a marketing approval, examples of significant
actions due to safety reasons include:
• Failure to obtain a marketing approval renewal;
• Marketing approval withdrawal or suspension for safety reasons;
• Risk management activities including:
o Significant restrictions on distribution or introduction of risk minimisation
measures;
o Significant changes in labelling documents that could affect the development
programme, e.g., restrictions to indication or population or a new warning;
o Communications to health care professionals as a result of the above actions;
and
o New postmarketing study requirement(s) imposed by regional authorities.
5. Status of clinical trials ongoing and completed during the reporting period
This section should refer to an appendix that presents a listing of each clinical trial in
progress and each clinical trial completed during the reporting period. Separate tables
can be provided by indication, formulation, and study population if appropriate. In
addition, where required by local authorities, similar information should be provided
for other therapeutic use of an investigational drug in the reporting period e.g.,
compassionate use or expanded access.
The table(s) should include the following information for each trial:
• Protocol number or other trial identifier;
• Clinical trial phase (I, II, III, or IV);
• Status:
o Ongoing (study has begun; study has begun but is currently on hold; study is
completed, but final clinical study report is not yet available);
o Completed (final clinical study report is available);
• Countries/regions where there is at least one investigational site for the protocol;
• Abbreviated study title ;
• Study design (uncontrolled, controlled, open, single blind, double blind, parallel,
cross-over, etc., including treatment arms);
• Dose and regimen of study drug and any comparators;
• Subject population as appropriate (age; sex; indication(s); specific patient groups,
e.g., trial subjects with impaired renal function or trial subjects resistant to
treatment);
• Date of first visit for first patient;
• Planned enrolment for study as a whole;
• Estimates of cumulative numbers of exposed subjects where available for each
treatment arm. The actual enrolment numbers for open or completed trials, and/or
6. Estimated exposure
The sponsor should clearly explain in the DSUR the method used to estimate
subject/patient exposure.
When the data are available, the DSUR should provide cumulative exposure data
giving the number of trial subjects by age group, gender, and ethnic origin 9 for the
development programme. Tabulation of demographic characteristics for a single trial
can be useful if the trial is of particular importance, e.g., a pivotal phase III trial.
These exposure tables provide context for the cumulative summary tabulations of
serious adverse events (SAEs). Therefore, if the summary tabulations are presented by
indication, the exposure data should also be presented by indication where available.
If important and appropriate, the report should also include adverse reactions of
special interest within the line listings and adverse events of special interest in
summary tabulations. The basis for selection of such events/reactions should be
explained.
Certain adverse events can be excluded from the summary tabulations and line
listings, but such exclusions should be explained in the report. For example, adverse
9
Ethnic factors are defined as those factors relating to the genetic and physiologic (intrinsic) and the cultural and environmental (extrinsic)
characteristics of a population as described in ICH E5(R1): Ethnic Factors in the Acceptability of Foreign Clinical Data.
10
For DSURs to be submitted to an EU Member State, a regional appendix should be provided. It should contain a summary tabulation of
all SARs, specifying the number of SARs by: a) SOC, b) reaction term and c) treatment arm, if applicable. Unexpected adverse reaction
terms should be identified.
12.3 Literature
The commercial sponsor is expected to review the scientific literature periodically for
new safety information. This section should summarise new and significant safety
findings from non-clinical studies and clinical trials that have been published during
the reporting period. When available, this section should also include relevant new
information on drugs of the same class. Significant new safety information published
as an abstract for a scientific meeting should be summarised and a copy provided if
possible.
14.3 Conclusions
The section should present a brief conclusion, addressing any changes to the previous
knowledge of safety and risks resulting from information gained since the last DSUR.
Finally, the conclusion should describe how risks have been managed in the trials and
any additional actions that should be taken to address emerging safety issues.
Appendix A. Glossary
5. Development CIOMS VII Glossary Date of first approval (or authorisation) for conducting an interventional clinical trial in any
International Birth country.
Date
6. Identified risk Volume 9A Rules An untoward occurrence for which there is adequate evidence of an association with the
Governing Medicinal medicinal product of interest.
Products in the EU
Examples of identified risks include:
-an adverse reaction adequately demonstrated in non-clinical studies and confirmed by
clinical data;
-an adverse reaction observed in well designed clinical trials or epidemiological studies for
which the magnitude of the difference compared with the comparator group (placebo or
active substance or unexposed group) on a parameter of interest suggests a causal
relationship;
-an adverse reaction suggested by a number of well documented spontaneous reports where
causality is strongly supported by temporal relationship and biological plausibility, such as
anaphylactic reactions or application site reactions.
7. Important identified Volume 9A Rules An identified risk or potential risk that could impact on the risk-benefit balance of the product
risk; Governing Medicinal or have implications for public health.
Important potential Products in the EU
risk
8. Investigational drug The term investigational drug is used in this guideline to indicate only the experimental
product under study or development.
9. Non-commercial For the purposes of this guideline, examples of non-commercial sponsors include the
sponsor following: (a) university, (b) healthcare centre, (c) a public scientific organisation, (d) a non-
profit institution, (e) a patient organisation, and (f) an individual researcher who is responsible
for the design, initiation, conduct, recording and publishing of the clinical trial.
10. Non-interventional Based on EU A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance
clinical study Directive 2001/20/EC with the terms of the marketing authorisation. The assignment of the patient to a particular
on Clinical Trials therapeutic strategy is not decided in advance by a trial protocol but falls within current
practice and the prescription of the medicine is clearly separated from the decision to include
Estimated cumulative subject exposure to [study drug] in all clinical studies by ethnic origin*
Ethnic origin Number of subjects
Caucasian
Black
Oriental
Other
Total
* data from completed studies as of [date]
* Study/centre/patient
** ‘Primary’ SADR only