U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2004
ICH
Guidance for
Industry
Addendum to E2C Clinical Safety Data Management:
Periodic Safety Update Reports for Marketed Drugs
Additional copies are
available from:
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Division of Drug Information, HFD-240
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Food and Drug Administration
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(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
Office of Communication,
Training and
Manufacturers Assistance, HFM-40
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http://www.fda.gov/cber/guidelines.htm
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System at 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
February 2004
ICH
Guidance for Industry
Addendum to E2C Clinical Safety Data Management:
Periodic Safety Update Reports for Marketed Drugs
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if that
approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of
this guidance.
This addendum is intended to provide
practical
guidance for the preparation of periodic safety update
reports (PSURs) as recommended in the ICH guidance E2C Clinical
Safety Data Management: Periodic Safety Update Reports for
Marketed Drugs, which was endorsed by the ICH in November 1996
and published by the FDA in May 1997. The E2C guidance has been
implemented in some but not all ICH countries.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
The PSUR is a practical and achievable
mechanism for summarizing interval safety data, especially
covering short periods (e.g., 6 months or 1 year), and for
conducting an overall safety evaluation. It is a tool for
marketing authorization holders (MAHs) to conduct systematic
analyses of safety data on a regular basis. In addition to
covering ongoing safety issues, the PSUR should also include
updates on emerging and/or urgent safety issues, and major signal
detection and evaluation that are addressed in other documents.
PSURs are of value and importance to all
parties in protecting the public health. The ICH E2C guidance was
developed to harmonize PSURs submitted to
the regulatory authorities in terms of content and format
as well to introduce the concept of international birth date (IBD).
However, the original
E2C guidance has been interpreted in different ways by both
MAHs and regulatory authorities. These differing interpretations
have resulted in a perception that the guidance was not sufficient
to accommodate the broad range of products and diverse
circumstances that arise in practice. The Council for
International Organizations of Medical Sciences (CIOMS) Working
Group V made several recommendations and developed new concepts to
harmonize the practice of preparing PSURs that have been taken
into account in preparing this addendum.
This addendum addresses only those E2C
provisions considered to need further clarification, guidance, or
increased perceived flexibility beyond that provided in the ICH
E2C guidance. This document should always be used in conjunction
with the E2C guidance. To facilitate the use of this document, the
numbering of the sections and paragraphs corresponds to the
numbering in the E2C guidance.
This addendum addresses the following
concepts not previously addressed by E2C:
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
a separate section within the body of the PSUR and any safety
issues addressed accordingly without preparing a separate PSUR.
There are instances when separate PSURs might
be considered appropriate. In these cases, the regulatory
authorities should be notified and their agreement obtained at the
time of authorization.
Examples include:
·
Fixed combinations: Options include either 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 versus topical
administration), two or more PSURs, with the same or different
IBDs, can be useful.
Whenever possible, PSURs should be based on
the IBD. If, in the transition period to a harmonized birth date
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 (when the additional period is less than 3
months for a 6-month or annual PSUR, or 6 months for a longer
duration PSUR) with comment on whether 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 or annual PSUR, or 6 months for a longer
duration PSUR (see section 1.4.4.3)
For drugs that are on the market in many
countries, the MAH can synchronize local or national birth dates
with the IBD.
For a drug where the IBD is not known, the
MAH can designate an IBD to allow synchronization of reports to
all regulatory authorities. Once an IBD is designated, the MAH
should notify the regulatory authorities, and the IBD should be
adhered to thereafter.
It is recognized that long intervals between
approvals could put the drug in a 5-year cycle in one region and a
6-month cycle in another region. For practical purposes, if a
single date (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, annually, or every 5th year.
A summary bridging report is intended
to be a concise document integrating the information presented in
two or more PSURs to cover a specified period over which a single
report is requested or required by regulatory authorities. The
report should not contain any new data but should provide a brief
summary bridging two or more PSURs (e.g., 2 consecutive 6-month
reports for an annual report or 10 consecutive 6-month reports to
make a 5-year report). The summary bridging report is intended to
assist regulatory authorities with a helpful overview of the
appended PSURs. The PSUR data should not be repeated but should be
cross-referenced to individual PSURs. The format of the summary
bridging report should be identical to that of the 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, pp. 154-156).
Upon request from the regulatory authority, a summary tabulation
of serious, unlisted reactions should be included in the summary
bridging report.
Summary bridging reports can be used in
situations where the MAH prepares short duration reports (e.g.,
6-month or annual reports) indefinitely, especially if new
indications or formulations are likely to be introduced over the
years. For reports considered out of date relative to a
particular regulatory authority’s requirement, an addendum report
could also be submitted (see section 1.4.4.3). For a PSUR that
spans longer time intervals (e.g., 5 years), an addendum report
would only be considered appropriate if the time since preparation
of the 5-year PSUR and the locally-required report is greater than
6 months.
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 the tables will be generated from live
databases, which change over time as cases are updated. These
tables will then reflect the most up-to-date data available at the
time they are generated. It is recognized that the case counts in
these summary tables can differ somewhat from the contents of the
individual tables in the appended PSURs. A general statement
describing the differences should be provided.
MAHs should set IBDs for all their products
and can synchronize their local renewals. However, when a
requested or required report covers data that fall outside the
defined period, use of an addendum report is recommended.
An addendum report is an update to the
most recently completed PSUR when a regulatory authority requests
or requires a safety update outside the usual IBD reporting cycle.
An addendum report should be used when more than 3 months for a
6-month or an annual report, and more than 6 months for a
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 can 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 containing 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)
For products in a long-term PSUR cycle, the
return to 6-month or annual 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
- A previously unapproved use in a special patient population,
such as children, pregnant women, or the elderly
- A new formulation or new route of administration
The decision on whether to restart the clock
should be discussed with the regulatory authority no later than
the time of granting the relevant marketing authorization.
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.
In regions where they are required, PSURs are to be submitted
within 60 days of the data lock point. To facilitate the
preparation of both current and future PSURs, as well as safety
reports outside of the PSUR, the regulatory authority will attempt
to send comments to the MAH:
- as rapidly as possible, if any issues of noncompliance 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
In rare circumstances, an MAH can make a
special request to the regulatory authority for 30 additional
calendar days to submit a PSUR. Ideally, this request should be
made before the data lock point. The regulatory authority will
attempt to send response to MAH 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 for 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.
It is important to highlight the differences
between the CCSI and the local product information/local labeling
in the cover letter accompanying the local submission of the PSUR,
as described in E2C section 2.4.
PSUR covering a period of 6 months or 1
year
For 6-month and annual reports, the version
of the CCSI in effect at the beginning of the period covered by
the report should be used as the reference.
PSUR covering a period of over 1 year
When producing a longer duration PSUR or a
summary bridging report, it is often impractical to base the
analysis of listedness on the CCSI that was in effect at the
beginning of the period. There can be considerable variation in
listedness over the reporting period, depending on when the
assessment of listedness is made (e.g., on an ongoing basis, such
as at adverse event/adverse drug reaction (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 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 after the data lock point, it is generally
considered appropriate 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 reporting period should include the
current version of the CCSI and comment on the reasons for
any changes in listedness assessment over time. In both
cases, changes
made to the CCSI since the previous PSUR should be
explained in sections 4 (Changes to Reference Safety Information)
and/or 9 (Overall Safety Evaluation).
PSURs contain proprietary information.
Therefore, the title page of a PSUR should contain a statement on
the confidentiality of the data and conclusions included in the
report.
MAHs should prepare a brief overview, or
executive summary, of each PSUR to provide the reader with a
description of the most important information. This 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 the CIOMS V report, p. 333.
Estimations of patient exposure for marketed
drugs often rely on gross approximations of in-house or purchased
sales data or volume. This information 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 generics, nonprescription drugs, or
multiple drug regimens. Background information, detailed
explanation, and examples of patient exposure estimations are
given in the CIOMS V report, pp. 167-181.
When 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, seasonal use of
the product).
The MAH should use a consistent method of
calculation across PSURs for the same product. If a change in the
method is appropriate, both previous and current methods and
calculations should be shown in the PSUR introducing the change.
In summary bridging reports, recalculation of
patient exposure data to cover the entire reporting period can be
appropriate if the exposure periods used in the individual PSURs
overlap.
As described in E2C, when the pattern of
reports indicate a potential safety problem, detailed presentation
by clinical indication, approved or unapproved, should be provided
when available.
There is no specific guidance in E2C on the
presentation of individual case report narratives. As it is
impractical to present all case reports for the reporting period
in this section of the PSUR, 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, including fatalities, presenting new
and relevant safety information and grouped by medically relevant
headings or system organ classes (SOCs).
Consumer and Other Nonhealthcare
Professional Reports
MAHs should prepare standard line listings
and tabulations that are considered acceptable by all regulatory
authorities, as described in E2C. To achieve this goal, MAHs
should follow a consistent practice across all PSURs for all
products by presenting consumer and other nonhealthcare
professional reports in separate line listings. When included in
the analysis of safety issues in section 6 or 9, consumer reports
should clearly be identified as such.
“Comments” field
E2C indicates that the “Comments” field
should be used only for information that helps to clarify
individual cases.
Only those company-sponsored studies and
published safety studies, including epidemiology studies, that
produce findings with potential impact on product safety
information should be included with a discussion of any final or
interim results. The MAH should not routinely catalogue or
describe all the studies.
When an MAH has specific risk management
programs in place, they can be discussed in this section.
When a more comprehensive safety or
benefit-risk analysis (e.g., all indications reviewed) has been
conducted separately, a summary of the analysis should be included
in this section.
Discussion and analysis for the overall
safety evaluation should be organized by SOC rather than by
listedness or seriousness. Although related terms might be found
in different SOCs, they should be reviewed together for clinical
relevance.
This guidance was developed within the Expert Working Group
(Efficacy) of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH) and has been subject to consultation by the
regulatory parties, in accordance with the ICH process. This
document has been endorsed by the ICH Steering Committee at
Step 4 of the ICH process, February 2003. At Step 4 of the
process, the final draft is recommended for adoption to the
regulatory bodies of the European Union, Japan, and the USA.