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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS
FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
Draft (Step 2) ICH Guidance: Addendum to E2C: Periodic
Safety Update Reports for Marketed Drugs V1
Released for Consultation
at Step 2 of the ICH Process
on 12 September 2002
by the ICH Steering Committee
At Step 2 of the ICH Process, a consensus draft text or
guideline, agreed by the appropriate ICH Expert Working Group, is transmitted
by the ICH Steering Committee to the regulatory authorities of the three
ICH regions (the European Union, Japan and the USA) for internal and
external consultation, according to national or regional procedures.
ADDENDUM TO ICH E2C
CLINICAL SAFETY DATA MANAGEMENT
PERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS
Draft ICH Consensus Guideline
Released for Consultation, 12 September 2002, at Step
2 of the ICH Process
TABLE OF CONTENTS
1.0 INTRODUCTION
1.1 Objectives of the
Guideline
1.4. General Principles
1.4.1 One Report for
One Active Substance
1.4.4 International
Birthdate and Frequency of Review and Reporting
1.4.4.1 Synchronization
of National Birthdates with the IBD
1.4.4.2 Summary Bridging
Reports
1.4.4.3 Addendum Reports
1.4.4.4 Restarting
the Clock
1.4.4.5 Time Interval
Between the Data Lock Point and the Submission
1.4.5 Reference Safety
Information
2. MODEL FOR A PERIODIC
SAFETY UPDATE REPORT (PSUR)
2.1 Executive Summary
2.5 Patient Exposure
2.5.1 Off-Label Use
2.6 Presentation of Individual
Case Histories
2.6.1 General Considerations
2.6.2 Cases Presented
as Line Listings
2.6.3 Presentation of
the Line Listing
2.7 Studies
2.9 Overall Safety Evaluation
1.0 INTRODUCTION
The objective of this addendum is to provide guidance for the preparation
of the Periodic Safety Update Report (PSUR) as recommended in the
ICH Guideline E2C entitled Clinical Safety Data Management: Periodic
Safety Update Reports for Marketed Drugs that achieved Step 4 in November
1996. That guideline has been implemented in some but not all ICH
countries.
The PSUR should represent a practical and achievable mechanism to
summarize interval safety data, especially covering short periods
(e.g., 6 months or one year) in order to conduct an overall safety
evaluation. It serves as a stimulus for Marketing Authorization Holders
(MAHs) to conduct systematic analyses of safety data on a regular
basis. In addition to covering usual safety issues the PSUR also includes
updates on urgent safety issues, major signal detection/evaluation,
and changes in efficacy which have been or will be addressed in other
documents.
The ICH Guideline E2C was formulated to achieve harmonization of
PSURs and to permit acceptance by Regulatory Authorities of the same
report covering the same data for the same time intervals. However,
the original Guideline has been interpreted in different ways by both
MAHs and Regulatory Authorities. This has resulted in a perception
that the guideline was not sufficient to accommodate the broad range
of products and diverse circumstances which arise in practice.
Because PSURs are of value and importance to all parties in protecting
the public health, there was a need to reach agreement on the components
forming the PSUR. The Council for International Organizations of Medical
Sciences (CIOMS) Working GroupV1 made recommendations and developed
new concepts that harmonise the practice of summarizing data covering
long periods of time as well as the concept of a "summary bridging
report" that ties together information from shorter-period PSURs.
A wide range of issues pertaining to PSURs was considered in developing
this addendum. However, only those E2C provisions felt to be in need
of further clarification guidance or increased flexibility beyond
that provided in the ICH E2C guideline have been addressed in this
document. This document should always be used in conjunction with
the E2C Guideline.
In order to facilitate the use of this document, the numbering of
the sections and paragraphs are identical to those of the E2C guideline.
1.1 Objectives of the Guideline
PSURs contain proprietary information. With the exception of the
line listing or similar case information, which is comparable to data
provided by Regulatory Authorities to the public in some countries,
the Regulatory Authorities do not intend to release the remainder
of the contents of the PSUR unless there is a local legal
1 Report of CIOMS Working Group V: Current Challenges in Pharmacovigilance:
Pragmatic Approaches. CIOMS, 2001, Geneva.
requirement to do so. The title page of a PSUR should contain a clear
statement on the confidentiality of the data and conclusions included
in the report.
If, in addition to the usual safety analysis done in the PSUR, a
more comprehensive safety or risk-benefit analysis (e.g., all indications
reviewed) is considered appropriate this more comprehensive analysis
should be prepared and submitted as a "stand alone" document. The
results of this analysis should be included in the next PSUR.
1.4. General Principles
1.4.1 One Report for One Active Substance
It is strongly recommended that information on all indications, dosage
forms and regimens for the active substance be included in a single
PSUR, with a single data lock point common for all aspects of product
use. There is a great advantage to having a consistent, broad-based
examination of the safety information for the active substance(s)
in a single document. When relevant, data relating to a particular
indication, dosage form, or dosing regimen should be presented in
separate sections within the body of the PSUR and any safety issues
addressed accordingly without preparing a separate PSUR.
There are areas where separate PSURs might be considered appropriate.
Examples include:
- Fixed combinations: Options include a separate PSUR
for the combination with cross-reference to the single agent(s)
PSUR(s), or inclusion of the fixed combination data within one of
the single agent PSURs.
- When an active substance is used in two or more
different formulations (e.g. systemic preparations vs topical administration),
two or more PSURs, with the same or different International Birthdates
(IBD), can be useful.
1.4.4 International Birthdate and Frequency of Review
and Reporting
Whenever possible, PSURs should be based on the IBD. If, in the transition
period to a harmonized birthdate for that product, the use of a local
approval date is appropriate, the MAH can submit its already prepared
IBD-based PSUR plus:
- line-listings and/or summary tabulations covering the additional period
(i.e., when the additional period is less than 3 months for a 6 month
PSUR or 6 months for a longer duration PSUR) without further comment
unless, of course, the data reveal a new and important risk
- or an Addendum Report when the additional period is greater than 3
months for a 6 month PSUR or 6 months for a longer duration PSUR (see
section 1.4.4.3)
1.4.4.1 Synchronization of National Birthdates
with the IBD
For drugs that are on the market in many countries, the MAH might wish
to synchronize local or national birthdates with the IBD. Although such
a process can be difficult (e.g., it might require multiple applications
for a variation), such a step might be feasible and can be discussed with
the Regulatory Authorities.
For a drug where the IBD is not known, the MAH can designate the IBD
in order to allow synchronization of reports to all Regulatory Authorities
and to optimize PSUR
workload scheduling. Once the IBD is designated, the MAH should notify
the Regulatory Authorities, and the IBD should be adhered to thereafter.
It is recognized that the long interval between approvals could put the
drug in a 5 year cycle in one region and a 6 month cycle in the other
region(s). For practical purposes, if a single month, day and year for
the IBD is not attainable, the MAH can contact the Regulatory Authorities
to negotiate a mutually acceptable birth month and day. For example, where
there are different approval dates, it can be useful for reports to be
submitted on the same month and day (e.g. every January 18 and July 18),
whether every 6 months, yearly or every 5th year.
1.4.4.2 Summary Bridging Reports
A summary bridging report should be a concise document that integrates
two or more PSURs to cover a specified period over which a single report
is required by those Regulatory Authorities not requiring or desiring
PSURs on a more frequent basis. It should not contain any new data but
should provide a brief, bridging summary of two or more PSURs (e.g. 2
consecutive 6-month reports for a 1 year report or 10 consecutive 6-month
reports to make a 5-year report). It is intended to assist Regulatory
Authorities with a helpful overview of the appended PSURs. The data should
not be repeated but should be cross-referenced to individual PSURs. The
format/outline, which should be identical to the format of the usual PSUR,
should follow that of a usual PSUR but the content should consist of summary
highlights and an overview of data from the attached PSURs to which it
refers (See CIOMS V Report pages 154-6).
Summary bridging reports can be used in the situation where the MAH prepares
short duration reports (e.g. 6-month or 1-year reports) indefinitely,
especially if new indications or formulations are likely to be introduced
over the years. For those reports considered out of date relative to a
particular Regulatory Authority's requirement, an addendum report could
also be submitted (see 1.4.4.3).
The summary bridging report ordinarily should not include line listings.
If summary tables covering the period of the appended PSURs are considered
appropriate, there should be a clear understanding that such tables will
be generated from live databases, which change over time as cases are
updated (i.e. these tables will then have the most up to date data available
at the time they are generated). The case counts in these summary tables
can thus differ somewhat from the contents of the individual tables in
the appended PSURs.
1.4.4.3 Addendum Reports
MAHs should set IBDs for all their products and synchronise their local
renewals. However, there can be circumstances when a required or requested
report covers data that fall outside the defined period. An Addendum Report
is recommended for those situations.
An Addendum Report is an update to the most recently completed PSUR when
a Regulatory Authority requires a routine safety update outside the usual
IBD reporting cycle. It should be used when more than 3 months for a 6-month
report, and more than 6 months for an annual or longer-interval report,
have elapsed since the data lock point of the most recent PSUR. It might
also be appropriate to provide an addendum to the summary bridging report.
The Addendum Report should summarize the safety data received between
the data lock point of the most recent PSUR and the Regulatory Authority's
requested cut-off date. It is not intended that the addendum report provide
an in-depth analysis of the additional cases, as these should be included
in the next regularly scheduled PSUR. Depending on circumstances and the
volume of additional data since the last scheduled report, an Addendum
Report can follow the ICH E2C format or a simplified presentation. The
proposed minimal report should include the following sections, which should
contain any new information or changes beyond the most recent PSUR to
which the Addendum Report refers:
- Introduction (purpose; cross reference to most recent PSUR)
- Changes to the Company Core Safety Information (CCSI) (including a
copy of the most recent CCSI document if it differs from the one in
the PSUR)
- Significant regulatory actions bearing on safety
- Line listing(s) and/or summary tabulations
- Conclusions (brief overview of new information and any impact on the
known safety profile)
1.4.4.4 Restarting the Clock
For products in a long-term PSUR cycle, the return to 6-monthly or yearly
reporting could apply after important additions or changes in clinical
use are first approved in an ICH region, such as:
- A new clinically dissimilar indication, and/or
- A previously unapproved use in a special patient population, such
as children or pregnant women or elderly, and/or
- A new formulation and/or new route of administration.
Even if the clock "restarts," the analyses in the PSUR should focus on
the newly-indicated population by identifying and characterizing any differences
from the established safety profile in the previously indicated populations.
For the above circumstances, a decision on whether to restart the clock
should be discussed with the Regulatory Authority no later than the time
of approval of the relevant application dossier.
1.4.4.5 Time Interval Between the Data Lock Point
and the Submission
To facilitate the preparation of both current and future PSURs, as well
as safety reports outside of the PSUR, the Regulatory Authority reviewers
intend to attempt to send any comments on the PSUR to the MAH :
- As rapidly as possible if any issues of non-compliance with the ICH
format and content of a PSUR are identified (particularly those that
preclude review)
- As rapidly as possible if additional safety issues are identified
that could prompt further evaluation by the MAH that should either be
included in the next PSUR or provided as a separate stand-alone report
- Before the next data lock point if any additional analyses or issues
of content are identified that should be included in the next PSUR
Additional Time for Submissions
ICH E2C recommends that PSURs be submitted to Regulatory Authorities
within 60 days of the data lock point. However, in rare circumstances,
an MAH should make a special request to the Regulatory Authority for a
30 additional calendar days to submit a PSUR. Ideally, this request should
be made before the data lock point. The Regulatory Authority intends to
respond as rapidly as possible.
The basis of such a request should be justified and could include:
- A large number of case reports for the reporting period, provided
that there is no new significant safety concern
- Issues raised by Regulatory Authorities in the previous PSUR for
which the MAH is preparing additional or further analysis in the next
PSUR
- Issues identified by the MAH that might require additional or further
analysis
The MAH should make such a request only for the single PSUR in question
and not for subsequent PSURs. The Regulatory Authority will generally
expect subsequent PSURs to be submitted on the appropriate date and to
retain their original periodicity.
1.4.5 Reference Safety Information
For 6 month and 1 year reports, the version of the Company Core Safety
Information (CCSI)2 in effect at the beginning of the period covered by
the report should be used as the reference.
When producing a longer duration PSUR, such as a 5 year report, it is
often impractical to base the analysis of listedness on the CCSI that
was in effect at the beginning of the 5 year period. There can be considerable
variation in listedness over 5 years, depending on when the assessment
of listedness is made (i.e. on an ongoing basis, such as at AE/ADR case
entry, or when a PSUR is compiled). The latest CCSI in effect at the end
of the period can be used. The MAH should ensure that all changes to the
CCSI made over the 5-year period are described in Section 4 of the PSUR
(Changes to the Reference Safety Information).
When listedness is assessed at the time of PSUR preparation it is generally
considered acceptable to use the current version of the CCSI as the reference
document, as long as that choice is made clear in the PSUR text.
MAHs assessing listedness at case entry or on an ongoing basis throughout
the 5-year period should include the current version of the CCSI and comment
on the reasons for the change in listedness assessment over time. In both
cases, changes added since the previous PSUR should be explained in Sections
4 (Changes to Reference Safety Information) and/or 9 (Overall Safety Evaluation).
If a long duration PSUR is prepared using several shorter duration PSURs
(e.g. a 5-year report using 10 consecutive 6-month PSURs), the CCSI in
force at the beginning of each shorter duration report should be used.
A discussion of the changes that occurred in the CCSI and its implications
over the long duration should be included in the summary bridging report.
Whether listedness is assessed at case entry or as a batch process at
the time of preparing the PSUR, there will be an impact on Section 6 of
the PSUR. For example, as non-serious unlisted ADRs are added to the CCSI
over the 5 year period, they
2 Report of CIOMS Working Group III and V, CIOMS, Geneva, 1999
become listed, and therefore cease to appear in the line listing. Instead,
they should be included in the summary tabulation of non-serious listed
ADRs.
Please refer to section 2.4 of the E2C document regarding highlighting
of the differences between the CCSI and the local product information/local
labeling in the cover letter or other document accompanying the local
submission of the PSUR.
2. MODEL FOR A PERIODIC SAFETY UPDATE REPORT (PSUR)
2.1 Executive Summary
MAHs should prepare a brief (e.g., one page), stand-alone overview of
each PSUR to provide the reader with a description of the most important
information. The Executive Summary should be placed at the beginning of
the PSUR immediately after the title page. An example of an Executive
Summary can be found in CIOMS V page 333.
2.5 Patient Exposure
Estimating patient exposure data for marketed drugs often relies on gross
approximations of in-house or purchased sales data or volume to determine
patient exposure. This is not always reliable or available for all products.
For example, hospital-based (inpatient exposure) statistics from the major
use-monitoring sources are frequently unavailable. It is also difficult
to obtain accurate data for drugs for which there is use of generic versions.
For nonprescription drugs, use is often on an as-required basis, and individual
packages are frequently used by multiple family members of different ages
and weights. Background information, detailed explanations, and examples
of patient exposure estimations are given in the CIOMS V report (pages
167 181).
When the exposure data are based on information from a period that does
not fully cover the period of the PSUR, the MAH can make extrapolations
using the available data. When this is done it should be clearly indicated
what data were used and why it is valid to extrapolate for the PSUR period
in question (e.g., stable sales over a long period of time, seasonality
of use of the product, etc.).
The MAH should be consistent in its method of calculation across PSURs
for the same product. If a change in the method is appropriate, then both
methods and calculations should be shown in the PSUR introducing the change.
In a summary bridging report every effort should be made to avoid patient
exposure data and calculations that overlap time periods.
2.5.1 Off Label Use
Estimating the extent of off-label use of a product is difficult. Without
careful, separate studies, such as special prescription surveys or drug-utilization
audits, data covering off-label use can be misleading. Although suspect
ADR reports involving unapproved uses are received and processed by the
MAH as usual, the extent of underreporting is unknown.
Clearly, if an important safety signal arises with regard to off-label
use, special attempts should be made to understand the scope of use and
the problem; however, such efforts are generally not considered appropriate
for routine PSUR purposes and should be made only if there is evidence
of off-label use associated with a suspected safety issue.
2.6 Presentation of Individual Case Histories
There is no specific guidance in E2C on the presentation of individual
case report narratives. It is sometimes impractical to present all individual
case safety reports for the reporting period and/or for specific issues
in this section. A brief description of the criteria used to select cases
for presentation should be given.
This section should contain a description and analysis of selected cases
containing new or relevant safety information and grouped by medically
relevant headings/System Organ Classes (SOCs).
2.6.1 General Considerations Consumer and Other
Non-healthcare Professional Reports
MAHs should prepare standard line listings/tabulations that are acceptable
to all Regulatory Authorities as described in E2C.
In order to achieve this goal, MAHs should follow a consistent practice
across all PSURs for all products by presenting consumer and other non-healthcare
professional reports in separate line listings. When consumer reports
are included in the analysis of safety issues in section 6 and/or 9, they
should clearly be identified as such.
2.6.2 Cases Presented as Line Listings Solicited
Reports
A solicited report is one that does not come to an MAH spontaneously
from a consumer or health care professional. It is one in which the MAH
or its agent has made an effort to elicit safety information from the
patient, his or her health care provider, or his or her representative
(e.g. a family member). Such cases should be handled as follows:
- Solicited reports, if not medically confirmed, should be treated as
consumer reports, and thus not reported in the PSUR unless specifically
requested by the authorities (same as for spontaneous consumer reports)
- Solicited reports should be processed separately and categorized in
the data base as solicited reports. The reports should also be identified
as solicited cases in any reports or tabulations that are prepared.
All AEs from solicited reports should be handled in the same way as similar
reports from clinical trials.
Recognition of medically important information from the aggregate data
of solicited reports can on rare occasions be possible. Therefore, the
MAH should review the data on an ongoing basis, particularly at the time
of periodic report preparation, to ensure that potential signals are captured.
The MAH should follow a consistent practice across all PSURs for all
products by presenting solicited reports in separate line listings. When
solicited reports are included in the analysis of safety issues in section
6 and/or 9, they should clearly be identified as such.
2.6.3 Presentation of the Line Listing
"Comments" field
E2C indicates that the "Comments" field should be used only for special
information that helps to clarify individual cases. That field should
not be routinely used to convey causality assessment conclusions and other
non-essential information.
2.7 Studies
Only those company-sponsored studies and published safety studies, including
epidemiology studies, that produce relevant or new safety results with
potential impact on product information, should be included, with any
final or interim results discussed. The MAH should not routinely catalog
or describe all the studies.
2.9 Overall Safety Evaluation
Discussion and analysis for the Overall Safety Evaluation should be organized
by SOC rather than by listedness or seriousness; the latter properties
should, of course, still be covered under each SOC. Although related terms
might be found in different SOCs, they should be reviewed together for
clinical relevance.
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