[Federal Register Volume 61, Number 67 (Friday, April 5, 1996)]
[Notices]
[Pages 15352-15357]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-8475]
[[Page 15351]]
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Part IV
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guideline on Clinical
Safety Data Management: Periodic Safety Update Reports for Marketed
Drugs; Availability; Notice
Federal Register / Vol. 61, No. 67 / Friday, April 5, 1996 /
Notices
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[[Page 15352]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0041]
International Conference on Harmonisation; Draft Guideline on
Clinical Safety Data Management: Periodic Safety Update Reports for
Marketed Drugs; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
guideline entitled ``Clinical Safety Data Management: Periodic Safety
Update Reports For Marketed Drugs.'' The draft guideline was prepared
under the auspices of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH). The draft guideline provides a unified standard for the
format, content, and reporting frequency for postmarketing periodic
safety update reports. The draft guideline also provides definitions
and terms for key aspects of postmarketing periodic safety reporting.
The guideline is intended to help harmonize collection and submission
of postmarketing clinical safety data.
DATES: Written comments by July 5, 1996.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm.1-23, Rockville, MD 20857. Copies of the draft
guideline are available from the Division of Communications Management
(HFD-210), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1012.
An electronic version of this guideline is also available via Internet
by connecting to the CDER file transfer protocol (FTP) server
(CDVS2.CDER.FDA.GOV).
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: -Murray M. Lumpkin, Center for Drug
Evaluation and Research (HFD-2), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-6740.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
At a meeting held on November 29, 1995, the ICH Steering Committee
agreed that a draft guideline entitled ``Clinical Safety Data
Management: Periodic Safety Update Reports for Marketed Drugs'' should
be made available for public comment. The draft guideline is the
product of the Efficacy Expert Working Group of the ICH. Comments about
this draft will be considered by FDA and the Efficacy Expert Working
Group. Ultimately, FDA intends to adopt the ICH Steering Committee's
guideline and to amend its regulations to fully implement the
guideline. Until such time as the agency's regulations are amended,
sponsors must continue to comply with the existing regulations.
The draft guideline provides guidance on the content, format, and
reporting frequency for postmarketing periodic safety update reports.
The draft guideline also defines basic terms for postmarketing periodic
reporting, such as ``company core data sheet,'' ``company core safety
information,'' ``data lock-point (data cut-off date),'' ``international
birth date,'' ``listed adverse drug reaction,'' ``spontaneous adverse
drug reaction report (spontaneous notification),'' and ``unlisted
adverse drug reaction.'' The draft guideline is designed primarily for
medicinal products authorized recently or in the future. It is most
relevant for products marketed in more than one ICH country.
In the past, guidelines have generally been issued under
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of
guidelines to state procedures or standards of general applicability
that are not legal requirements but are acceptable to FDA. The agency
is now in the process of revising Sec. 10.90(b). Although this
guideline does not create or confer any rights for or on any person and
does not operate to bind FDA, it does represent the agency's current
thinking on periodic safety update reports for marketed drugs.
Interested persons may, on or before July 5, 1996, submit written
comments on the draft guideline to the Dockets Management Branch
(address above). Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. The draft guideline and received comments may be seen in the
office above between 9 a.m. and 4 p.m., Monday through Friday.
The text of the draft guideline follows:
Clinical Safety Data Management: Periodic Safety Update Reports for
Marketed Drugs
1. Introduction
1.1 Objectives of the guideline
The main objective of ICH is to harmonize technical
requirements before registration or marketing approval. However,
because new products are introduced at different times in different
markets and the same product may be marketed in one or more
countries and still be under development in others, reporting and
use of clinical safety information should be regarded as part of a
continuum. The ICH Steering Committee has decided that the
harmonization of format, content, and time span covered in periodic
safety update reports for marketed drugs should be addressed by ICH,
as an extension of the ICH topic on Clinical Safety Data
[[Page 15353]]
Management: Definitions and Standards for Expedited Reporting.
The regulatory requirements, particularly regarding frequency
of submission and content of periodic safety updates, are not the
same in the three regions. To avoid duplication of effort and to
ensure that important data are submitted with consistency to
competent authorities, it is proposed to establish an international
consensus on the format and content for periodic safety updates of
marketed medicinal products.
1.2 Background
-When a new medicinal product is submitted for marketing
approval, the demonstration of its efficacy and the evaluation of
its safety are based at most on several thousand patients, except in
special situations. The limited number of patients included in
clinical trials, the exclusion at least initially of patients at-
risk, the lack of significant long-term treatment experience, and
the limitation of concomitant therapies do not allow a thorough
evaluation of the safety profile. Under such circumstances, the
detection or confirmation of rare adverse reactions is particularly
difficult, if not impossible.
Medicinal products must be closely monitored, especially during
the first years of commercialization to develop a comprehensive
picture of clinical safety. Surveillance of marketed drugs is a
shared responsibility between regulatory authorities and marketing
authorization holders (MAH). They record information on drug safety
from different sources, and procedures have been developed to ensure
timely detection and mutual exchange of safety data. Because all
information cannot be evaluated with the same degree of priority,
regulatory authorities have defined the information to be submitted
on an expedited basis; in most countries this rapid transmission is
usually focused on the expedited reporting of adverse drug reactions
(ADR's) that are both serious and unexpected.
-Reevaluation of the benefit/risk ratio of a drug is usually not
possible for each individual ADR case, even if serious. Therefore,
periodic safety update reports (PSUR's) present the worldwide safety
experience of a medicinal product at defined times postauthorization
to:
Report all the relevant new information from
appropriate sources;
Relate these data to patient exposure;
Summarize the market authorization status in different
countries and any significant variations related to safety;
Create periodically the opportunity for an overall
safety reevaluation;
Decide whether changes should be made to product
information to optimize the use of the product.
-However, if the PSUR's required in the different countries
where the product is on the market require a different format,
content, period covered, and filing date, MAH would be forced to
prepare on an excessively frequent basis different reports for the
same product. In addition, under such conditions, different
regulators could receive different kinds and amounts of information
at different times. Thus, efforts are needed to harmonize the
requirements for PSUR's, which will also improve the efficiency with
which they are produced.
-The current situation for periodic safety reports on marketed
drugs is different among the three ICH regions. For example:
The United States requires quarterly reports during the
first 3 years, then annual reports. FDA has recently published
proposed rules \1\ that take into account the Council for
International Organizations of Medical Sciencesse (CIOMS) Working
Group II proposals. \2\
\1\ Adverse experience reporting requirements for human drug and
licensed biological products; proposed rule, Federal Register,
October 27, 1994 (59 FR 54046 to 54064).
\2\ International reporting of periodic drug-safety update
summaries; final report of CIOMS, Working Group II, CIOMS, Geneva,
1992.
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In the European Union, Council Directive 93/39/EEC and
Council Regulation 2309/93 require reports with a periodicity of 6
months for 2 years, annually for the 3 following years, and then
every 5 years.
In Japan, the authorities require a survey on a cohort
of a few thousand patients established by a certain number of
identified institutions during the 6 years following authorization.
Systematic information on this cohort, taking into account a precise
denominator, must be reported annually. Regarding other marketing
experience, ADR's that are both nonserious and unlabeled must be
reported every 6 months for 3 years and annually thereafter.
-Following a discussion of the objectives and general principles
for preparing and submitting PSUR's, a model for their format and
content is presented.
-Appended is a glossary of important relevant terms.
1.3 Scope of the Guideline
-This guideline on the format and content of PSUR's is designed
primarily for medicinal products approved/authorized recently or in
the future.
-Although this guideline could be applied to other drugs,
modifications in accord with local regulations may be appropriate.
(See section 1.4.4 for additional discussion.)
-This guideline is most relevant to products marketed in more
than one ICH country.
1.4 General Principles
1.4.1 One report for one active substance
Ordinarily, all dosage forms and formulations as well as
indications for a given pharmacologically active substance should be
covered in one PSUR. Separate presentations of data for different
dosage forms, indications, or populations (e.g., children versus
adults) may be appropriate.
-For combinations of substances also marketed individually,
safety information for the fixed combination might be reported
either separately or included in the reports for each of the
separate components, depending on the circumstances. Cross-
referencing the relevant reports is appropriate.
1.4.2 General scope of information
-With the exception of regulatory status information on
authorization applications and renewals, which should be cumulative,
all relevant clinical and nonclinical safety data should cover only
the period of the report (interval data).
-The main focus of the report should be ADR's. For spontaneous
reports, unless indicated otherwise by the reporting health-care
professional, all adverse experiences should be assumed to be ADR's;
for clinical study and literature cases, only those judged not
related to the drug by both the reporter and the manufacturer/
sponsor should be excluded.
-Lack of efficacy, especially in the treatment of serious or
life-threatening conditions, may be reported as a ``safety issue.''
These types of cases, especially if isolated, are not expected to be
included in the PSUR ADR data presentation (e.g., line listings or
summary tabulations). However, such findings should be discussed
somewhere within a PSUR, particularly if they represent a potential
risk to the treated population (see section 2.8.1).
-An increase in the frequency of reports for known ADR's has
traditionally been considered as relevant new information. Although
attention should be given in the PSUR to such increased reporting,
no specific quantitative criteria or other rules are recommended.
Judgment should be used in such situations to determine whether the
data reflect a meaningful change in ADR occurrence or safety
profile.
1.4.3 Products manufactured and/or marketed by more than one company
-Each MAH is responsible for submitting PSUR's, even if
different companies market the same product in the same country.
When companies are involved in contractual relationships (e.g.,
licensor-licensee), respective responsibilities for sharing safety
information and for safety reporting to regulators should be clearly
specified between the parties to ensure that all relevant data are
duly reported to appropriate regulatory authorities.
-When available data received from partner company(ies) might
contribute meaningfully to the safety analysis and influence any
proposed or effected changes in the reporting company's product
information, these relevant data should be summarized in a PSUR even
if it is known that they are included in another company's PSUR.
1.4.4 International birthdate and frequency of review and reporting
-Each medicinal product should have as an international birth
date (IBD) the date of a company's first marketing authorization in
any country in the world. When a report contains information on
different dosage forms, formulations, or uses (indications, routes,
populations), the date of the first marketing authorization for any
of the various authorizations should be regarded as the IBD and,
therefore, determine the data lock point for purposes of the unified
PSUR. The data lock point is the date designated as the cutoff for
data to be included in a PSUR. During the initial years of
marketing, the MAH should generally freeze its data base (and have a
data lock point) every 6 months thereafter.
-The need for a report and the frequency of report submission to
authorities are subject to
[[Page 15354]]
local regulatory requirements. However, independent of the required
reporting frequency, preparation of PSUR's for all regulatory
authorities should be based on data sets of 6 months or multiples
thereof.
-The age of a drug on the market may influence this process;
during the initial years of marketing, a drug will ordinarily
receive authorizations at different times in different countries. It
is during this early period that harmonization of reporting is
particularly important. Once a drug has been marketed for several
years, the need for a comprehensive PSUR may be reviewed, depending
on local regulations or requests, while maintaining one IBD for all
regulatory authorities.
-In addition, approvals beyond the initial one for the active
substance may be granted for new indications, dosage forms,
populations, or prescription status (e.g., children versus adults;
prescription to nonprescription status). The potential consequences
on the safety profile raised by such new types and extent of
population exposures may influence the requirements for periodic
reporting.
-The MAH should submit a PSUR within 60 days of the data lock
point.
1.4.5 Reference product information
-The objective of a PSUR is to establish whether information
recorded during the reporting period is in accord with previous
knowledge on the drug's safety, and to decide whether changes should
be made to product information. Reference information is needed to
perform this comparison. In addition, having one reference source of
information in common for the three ICH regions will facilitate a
practical, efficient, and consistent approach to the safety
evaluation and make the PSUR a unique report accepted in all areas.
-Based on the common practice for MAH's to prepare their own
``Company Core Data Sheet''(CCDS), a practical option for the
purpose of periodic reporting is to use, as a reference, the safety
information contained within that central document. In addition to
this safety information, a full company CCDS covers material
relating to indications, dosing, pharmacology, and other areas that
are not necessarily safety related. Reference safety information
will therefore be referred to as ``Company Core Safety Information''
(CCSI).
-For purposes of periodic safety reporting, CCSI forms the basis
for determining whether an ADR is already ``Listed'' or is still
``Unlisted,'' terms that are introduced to distinguish them from the
usual terminology of ``expectedness'' or ``labeledness'' that is
used in association with official labeling. Thus, the local approved
product information continues to be the reference document upon
which labeledness/expectedness is based for the purpose of
``expedited'' postmarketing safety reporting.
1.4.6 Presentation of data on individual case histories sources of
information
-Generally, data from the three following sources of ADR case
information are potentially available to a MAH and could be included
in the PSUR:
(a) Direct reports to MAH (or under MAH control):
Spontaneous notifications from health care
professionals;
Spontaneous notifications from nonhealth care
professionals or from consumers (nonmedically substantiated);
MAH-sponsored clinical studies or named-patient
(``compassionate'') use.
(b) Literature.
(c) Other sources: Regulatory authorities; data from exchange
between contractual partners (e.g., licensors-licensees) holding
their own marketing authorizations; special registries such as organ
toxicity monitoring centers, poison control centers, and
epidemiological data bases.
Description of the reaction
Until an internationally agreed coding terminology (dictionary)
is available and its use broadly implemented, the event terms used
in the PSUR will generally be derived from whatever standard
terminology (``controlled vocabulary'' or ``coding dictionary'') is
used by the reporting company (e.g., WHO-ART, COSTART).
Whenever possible, the notifying reporter's event terms should
be used to describe the ADR. However, when the notifying reporter's
terms are not medically appropriate or meaningful, MAH's should use
the best alternative compatible event terms from their ADR
dictionaries to ensure the most accurate representation as possible
of the original terms. Under such circumstances, the following
should be borne in mind:
To make it available on request, the ``verbatim''
information supplied by the notifying reporter should be kept on
file (in the original language and/or as a medically sound English
translation, if applicable).
In the absence of a diagnosis by the reporting health-
care professional, a suggested diagnosis for a symptom complex may
be made by the MAH and used to describe a case, in addition to
presenting the reported individual signs, symptoms, and laboratory
data.
If a MAH disagrees with a diagnosis that is provided by
the notifying health care professional, it may indicate such
disagreement within the line listing of cases (see below).
It is incumbent on the MAH to report and try to
understand all information provided within a case report, such as
laboratory abnormalities possibly drug related but not identified as
such by the notifying reporter.
Therefore, when necessary and relevant, two descriptions of the
signs, symptoms, or diagnosis could be presented in the line
listing: First, the reaction as originally reported; second, when it
differs, the MAH's medical interpretation (identified by asterisk or
other means).
Line listings and/or summary tabulations
Depending on their type or source, available ADR cases should
be presented as individual case line listings and/or as summary
tabulations.
A line listing provides key information but not necessarily all
the details customarily collected on individual cases; however, it
does serve to help regulatory authorities identify cases that they
might wish to examine more completely by requesting full case
reports.
There are other issues regarding the content of line listings:
MAH's can prepare line listings of consistent structure
and content for cases directly reported to them (or under their
control) (see 1.4.6(a)); they can usually do the same for published
cases (ordinarily well documented; if not, followup with the author
is possible). However, inclusion of individual cases from second- or
third-hand sources, such as contractual partners and special
registries (see section 1.4.6(c)) might not be: (1) Possible without
standardization of data elements, or (2) appropriate due to the
paucity of information, and might represent unnecessary re-entry/
reprocessing of such information by the MAH. Therefore, summary
tabulations or possibly a narrative review of these data in these
circumstances is acceptable.
An exception to the above consideration is the case
reports received directly by regulatory authorities (but not by MAH)
that might be transmitted to the MAH.
-In addition to individual case line listings, summary
tabulations of the various signs, symptoms, and diagnoses across all
patients should usually be presented to provide an overview. Such
tabulations should be based on the data in line listings (e.g., all
serious ADR's and all nonserious unlisted ADR's), but also on other
sources for which line listings are not requested (e.g., nonserious
listed ADR's). Details are found in Section 2.6.4.
-It is worth noting that work in progress may in the future
enable routine electronic transmission of detailed ADR case report
information on a regular basis between MAH and regulatory
authorities. When implemented, this may obviate the need for line
listings within a PSUR, which for some products might be very
extensive.
2. Model for a PSUR
-The following sections are organized as a sample PSUR. In each
of the sections, guidance is provided on what should be included:
Sample Title Page
Periodic safety update report for: (product);
MAH's name and address (corporate headquarters or other
company entity responsible for report preparation);
- Period covered by this report: (dates);
- International birth date: date (country of IBD);
- Date of report;
(Other identifying information at the option of MAH,
such as report number).
Table of Contents for Model PSUR
- Introduction;
- Worldwide market authorization status;
- Update of regulatory authority or MAH actions taken
for safety reasons;
- Changes to reference product information;
- Patient exposure;
- Presentation of individual case histories;
- Studies;
- Other information;
- Overall safety evaluation;
- Conclusion;
- Appendix: Company Core Data Sheet.
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2.1 Introduction
-The MAH should briefly introduce the product so that the report
``stands alone'' but is also placed in perspective relative to
previous reports and circumstances.
-Reference should be made not only to product(s) covered by the
report but also those excluded. Exclusions should be explained; for
example, they may be covered in a separate report (e.g., for a
combination product).
-If it is known that a PSUR on the same product(s) will be
submitted by another MAH, some of whose data are included in the
report (see section 1.4.6), the possibility of data duplication
should be noted.
-For multiple dosage forms, indications, populations, etc., one
report is preferred in most cases. When appropriate, data
presentations within the report may be separated accordingly.
2.2 Worldwide Market Authorization Status
This section of the report is ordinarily the only one that
provides cumulative information.
-Information should be provided, usually as a table, on all
countries in which a regulatory decision about marketing has been
made related to the following:
Dates of market authorization or renewal;
- Any qualifications surrounding the authorization, such
as limits on indications if relevant to safety;
- Treatment indications and special populations covered
by the market authorization, when relevant;
- Lack of approval by regulatory authorities;
- Withdrawal by the applicant of a submission;
- Dates of launch when known;
- Trade name(s).
-Typically, indications for use, populations treated (e.g.,
children versus adults), and dosage forms will be the same in many
or even most countries where the product is authorized. However,
when there are important differences, which would reflect different
types of patient exposure, such information should be noted. This is
especially true if there are meaningful differences in the newly
reported safety information that are related to such different
exposures. If more convenient and useful, separate regulatory status
tables for different product uses or forms would be appropriate.
-Country entries should be listed in chronological order of
regulatory authorizations. For multiple authorizations in the same
country (e.g., new dosage forms), the IBD for the active substance
and for all PSUR's should be the first (initial) authorization date.
-Table 1 is an example, with fictitious data for an antibiotic,
of how a table might be organized. The drug was initially developed
as a solid oral dosage form for outpatient treatment of adults with
various infections.
2.3 Update of Regulatory Authority or MAH Actions Taken for Safety
Reasons
This section should include details on the following types of
activity during the reporting period:
- Application withdrawal or marketing authorization
suspension;
- Failure to obtain a marketing authorization renewal;
- Restrictions on distribution;
- Clinical trial suspension;
- Dosage modification;-
Changes in target population or indications;
- Formulation changes.
The safety related reasons that led to these actions should be
described, and documentation appended when appropriate.
2.4 Changes to Reference Product Information
The CCDS with its CCSI should be numbered and dated and include
the date of last revision. The version in effect at the beginning of
the period covered by the report should be used as a reference; a
copy should be included as an appendix with the PSUR.
Changes to the CCSI, such as new contraindications,
precautions, warnings, ADR's, or interactions, already made during
the period covered by the report, should be clearly described, with
presentation of the modified sections. The new document should be
used as the reference for the next report and the next period.
With the exception of emergency situations, it may take some
time before intended modifications are introduced in the product-
information materials provided to prescribers, pharmacists, and
consumers. Therefore, during that period the amended reference
document (CCDS) may contain more ``listed'' information than the
existing product information in many countries.
When meaningful differences exist between the CCSI and the
safety information in the official data sheets/product information
documents approved in a country, a brief comment should be prepared
by the company, describing the local differences and their
consequences on the overall safety evaluation and on the actions
proposed or initiated. This commentary may be provided in the cover
letter or other addendum accompanying the local submission of the
PSUR.
2.5 Patient Exposure
Where possible, the estimation of patient exposure should cover
the same period as the interim safety data. Ideally it should give
the number of patients or prescriptions, and duration of exposure,
data that are admittedly difficult to obtain and to validate.
However, a reasonable method should be used with proper explanation
and justification, particularly if it is not the same as used in the
previous report(s). Attempts should be made to obtain the most
useful and relevant quantification. Examples include patient-months
or patient-days of exposure, number of dosage units by form and
strength, or if other more precise measures are not available, bulk
sales (tonnage). The concept of a defined daily dose may be used in
arriving at exposure estimates.
If available, details by country (with locally recommended
daily dose) or other segmentation (e.g., indication, dosage form)
should be presented when relevant (e.g., when a pattern of reports
indicates a potential problem).
When ADR data from clinical studies are included in the PSUR,
the relevant denominator(s) should be provided. For ongoing and/or
blinded studies, an estimation of patient exposure may be made.
2.6 Presentation of Individual Case Histories
2.6.1 General considerations
- Followup data on individual cases may be obtained
subsequent to their inclusion in a PSUR. If such information is
relevant to the interpretation of the case (significant impact on
the case description or analysis, for example), the new information
should be presented in the next PSUR, and the correction or
clarification noted relative to the earlier case description.
- With regard to the literature, MAH's should monitor
standard, recognized journals for safety information on their
products and/or make use of one or more literature search/summary
service(s) for that purpose. Published cases may also have been
received as spontaneous cases, be derived from a sponsored clinical
study, or arise from other sources. Care should be taken to include
such cases only once. Also, no matter what ``primary source'' is
given a case, if there is a publication, it should be noted and the
literature citation given.
- In some countries, there is no requirement to submit
medically unconfirmed spontaneous reports that originate with
consumers or other nonhealth care professionals. However, such
reports are acceptable or requested in other countries; therefore,
medically unconfirmed reports should be submitted as addenda line
listings and/or summary tabulations only on specific request by
regulatory authorities.
2.6.2 Cases presented as line listings
-The following types of cases should be included in the line
listings (Table 2):
- All serious reactions, and nonserious unlisted
reactions, from spontaneous notifications;
- All serious reactions (attributable by either
investigator or sponsor), available from studies or named-patient
(``compassionate'') use;
- All serious reactions, and nonserious unlisted
reactions, from the literature;
- All serious reactions from regulatory authorities
Collection and reporting of nonserious, listed ADR's may not be
required in all ICH countries. However, a line listing of
spontaneously reported nonserious listed reactions that have been
collected should be submitted as an addendum to the PSUR only when
requested by a regulatory authority.
2.6.3 Presentation of the line listing
The line listing(s) should include each patient only once
regardless of how many adverse event/reaction terms are reported for
the case. If more than one adverse event/reaction term, they should
all be mentioned but the case should be listed under the most
serious presenting sign, symptom, or diagnosis, as judged by the
MAH. The cases should be organized (tabulated) by body system
(standard organ system classification scheme).
The following headings should usually be included in the line
listing:
MAH case reference number;
Country in which case occurred;
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Source (e.g., clinical trial, literature, spontaneous,
regulatory authority);
Age and sex;
Daily dose of suspected drug (and, when relevant,
dosage form or route);
Date of onset of the reaction. If not available, best
estimate of time to onset from therapy initiation. For an ADR known
to occur after cessation of therapy, estimate of time lag if
possible (may go in Comments section);
Dates of treatment. If not available, best estimate of
treatment duration;
Description of reaction as reported, and when necessary
as interpreted by the MAH (English translation when necessary) (See
section 1.4.6 for guidance.);
Patient outcome (at case level) (e.g., resolved, fatal,
improved, sequelae, unknown);
Comments, if relevant (e.g., 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).
Depending on the product or circumstances, it may be useful or
practical to have more than one line listing, such as for different
dosage forms or indications, if such differentiation facilitates
presentation and interpretation of the data.
2.6.4 Summary tabulations
An aggregate summary for each of the line listings should
usually be presented. These tabulations ordinarily contain more
terms than patients. It would be useful to have separate tabulations
(or columns) for serious reactions and for nonserious reactions, for
listed and unlisted reactions; other breakdowns might also be
appropriate (e.g., by source of report). (See Table 3 for an example
of a data presentation.)
A summary tabulation should be provided for the nonserious,
listed, spontaneously reported reactions. (See also section 2.6.2.)
The terms used in these tables should ordinarily be those used
by the MAH to describe the case. (See section 1.4.6.)
Except for cases obtained from regulatory authorities, the data
on serious reactions from other sources (see section 1.4.6(c))
generally should be presented only as a summary tabulation. If
useful, the tabulations may be sorted by source of information or
country, for example.
When the number of cases is very small, or the information
inadequate for any of the tabulations, a narrative description
rather than a formal table is suitable.
2.6.5 MAH's analysis of individual case histories
This section may be used for brief comments on the data
concerning individual cases. For example, discussion can be
presented on particular serious or unanticipated findings (e.g.,
their nature, medical significance, mechanism, reporting frequency).
The focus here should be on individual case discussion and should
not be confused with the global assessment in the Overall Safety
Evaluation (section 2.9).
2.7 Studies
All completed studies (nonclinical, clinical, epidemiological)
yielding safety information with potential impact on product
information, and studies specifically planned or in progress that
address safety issues, should be discussed.
2.7.1 Newly analyzed company-sponsored studies
All relevant studies containing important safety information
and newly analyzed during the reporting period should be described,
including those from epidemiological, toxicological, or laboratory
investigations. The results should be clearly presented with
attention to the usual standards of data analysis and description
that are applied to nonclinical and clinical study reports. Copies
of full reports should be appended only if deemed appropriate.
2.7.2 Targeted new safety studies planned, initiated, or continuing
during the reporting period.
New studies specifically planned or conducted to examine a
safety issue (actual or hypothetical) should be described (e.g.,
objective, starting date, projected completion date, number of
subjects, protocol abstract).
When possible and relevant, interim results of ongoing studies
may be presented. When completed and analyzed, the results should be
presented in a subsequent PSUR as described under 2.7.1.
2.7.3 Published safety studies
Reports in the scientific and medical literature containing
important safety findings (positive or negative) should be
summarized. Published abstracts from relevant meetings should also
be discussed.
2.8 Other Information
2.8.1 Efficacy-related information
Any information relating to a product's efficacy that has
implications or consequences for safety should be described, such as
unexpected significant lack of efficacy in the population under
treatment for a life-threatening disease.
2.8.2 Late-breaking information
Any important, new information received after the data base was
frozen for review and report preparation may be presented in this
section. Examples include significant new cases or important
followup data. These new data should be taken into account in the
Overall Safety Evaluation (section 2.9).
2.9 Overall Safety Evaluation
A concise analysis of the data presented, followed by the MAH
assessment of the significance of the data collected during the
period, should highlight any new information on:
Serious unlisted reactions;
Nonserious unlisted reactions;
An increased reporting frequency of listed reactions,
including comments on whether it is believed the data reflect a
meaningful change in ADR occurrence.
The report should also explicitly address any new safety issue
or new information on the following (lack of significant new
information should be mentioned for each):
- Drug interactions;
- Experience with overdose and its treatment;
- Drug abuse;
- Positive or negative experiences during pregnancy or
lactation;
- Experience in special patient groups (e.g., children,
elderly, organ impaired);
- Effects of long-term treatment.
2.10 Conclusion
The conclusion should:
- Indicate which safety data do not remain in accord
with the previous cumulative experience, and with the reference
safety information (CCSI);
- Specify and justify any action recommended or
initiated.
Appendix: Company Core Data Sheet
-The Company Core Data Sheet should be appended to the PSUR.
3. Glossary of Special Terms
-Company Core Data Sheet (CCDS)-A document prepared by the MAH
containing, in addition to all relevant safety information, material
relating to indications, dosing, pharmacology, and other areas that
are not necessarily safety related.
Company Core Safety Information (CCSI)-All relevant safety
information contained in the CCDS prepared by the MAH and which the
MAH requires to be listed in all countries where the company markets
the drug, except when the local regulatory authority specifically
requires a modification. It is the reference information by which
listed and unlisted are determined for the purpose of periodic
reporting for marketed products, but not by which expected and
unexpected are determined for expedited reporting.
Data Lock Point (Data Cut-off Date)-The date designated as the
cut-off date for data to be included in a PSUR. It is based on the
International Birth Date (IBD) and should usually be in 6 monthly
increments.
International Birth Date (IBD)-The date of first marketing
authorization for a company's new medicinal product in any country
in the world.
Listed Adverse Drug Reaction (ADR)-An ADR whose nature and
severity are consistent with the information in the CCSI.
Spontaneous Adverse Drug Reaction Report or Spontaneous
Notification-An unsolicited communication to a company, regulatory
authority, or other organization that describes an adverse medical
reaction in a patient given one or more medicinal products and which
does not derive from a study or any organized data collection
scheme.
Unlisted Adverse Drug Reaction-An ADR, the nature or severity
of which is not consistent with the information included in the
CCSI.
[[Page 15357]]
Table 1.--Example of Presentation of Worldwide Market Authorization Status
----------------------------------------------------------------------------------------------------------------
Country Action-Date Launch Date Trade Name(s) Comments
----------------------------------------------------------------------------------------------------------------
Sweden A1 - 7/90 12/90 Bacteroff -
AR - 10/95 - - -
Brazil A - 10/91 2/92 Bactoff -
A - 1/93 3/93 Bactoff-IV IV dosage form
United Kingdom AQ - 3/92 6/92 Bacgone Elderly (> 65) excluded
(PK) Topical cream
A - 4/94 7/94 Bacgone-C (skin infs) .........................
Japan LA - 12/92 - - To be refiled
France V - 9/92 - - Unrelated to safety
Nigeria A - 5/93 7/93 Bactoff -
A - 9/93 1/94 Bactoff New indication
Etc. ................... ................... ...................... .........................
----------------------------------------------------------------------------------------------------------------
\1\Abbreviations for Action: A = authorized; AQ = authorized with qualifications; LA: lack of approval; V =
voluntary marketing application withdrawal by company; AR = Authorization renewal.
Table 2.--Presentation of Individual Case Histories
(See sections 2.6.2 and 2.6.4 for full explanation)
------------------------------------------------------------------------
Line Listing and
Source Type of Case Only Summary Summary
Tabulation Tabulation
------------------------------------------------------------------------
1. Direct .............. .................... ................
Reports to MAH
S - +
Spontaneous ADR
reports1
NS U - +
NS L2 + -
MAH SA - +
sponsored
studies
2. Literature S - +
NS U - +
3. Other sources .............. .................... ................
S - +
Regulatory
Authorities
S + -
Contractual
partners
S + -
Registries
------------------------------------------------------------------------
\1\Medically unconfirmed reports should be provided as a PSUR addendum
only on request, as a line listing and/or summary tabulation.
\2\Line listing provided as PSUR addendum only on request by regulatory
authority. S = serious; L = listed; A = attributable to drug (by
investigator or sponsor); NS = nonserious; U = unlisted.
Table 3.--Number of Reports by Term (Signs, Symptoms and Diagnoses) from Spontaneous (Medically Confirmed),
Clinical Trial and Literature Cases: All Serious Reactions
----------------------------------------------------------------------------------------------------------------
Body system ADR term Spontaneous/regulatory bodies Clinical trials Literature
----------------------------------------------------------------------------------------------------------------
CNS ............................. ............................... ........................
-hallucinations1 2 0 0
-etc. ............................. ............................... ........................
-etc. ............................. ............................... ........................
-------- ---- ---- ----
Sub-total ............................. ............................... ........................
CV ............................. ............................... ........................
-etc. ............................. ............................... ........................
-etc. ............................. ............................... ........................
---- ---- ---- ----
Sub-total ............................. ............................... ........................
Etc. ............................. ............................... ........................
TOTAL ............................. ............................... ........................
----------------------------------------------------------------------------------------------------------------
\1\ Indicates an unlisted term
In a footnote (or elsewhere), the number of patient cases that
represent the tabulated terms might be given (e.g., x-spontaneous/
regulatory, y-clinical trial, and z-literature cases).
Dated: March 29, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-8475 Filed 4-4-96; 8:45 am]
BILLING CODE 4160-01-F
