[Federal Register Volume 62, Number 96 (Monday, May 19, 1997)]
[Notices]
[Pages 27470-27476]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-13065]
[[Page 27469]]
_______________________________________________________________________
Part VI
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Guideline on Clinical Safety
Data Management: Periodic Safety Update Reports for Marketed Drugs;
Availability; Notice
Federal Register / Vol. 62, No. 96 / Monday, May 19, 1997 / Notices
[[Page 27470]]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0041]
International Conference on Harmonisation; Guideline on Clinical
Safety Data Management: Periodic Safety Update Reports for Marketed
Drugs; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is publishing a
guideline entitled ``Clinical Safety Data Management: Periodic Safety
Update Reports for Marketed Drugs.'' The guideline was prepared under
the auspices of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH). The guideline recommends a unified standard for the format,
content, and reporting frequency for postmarketing periodic safety
update reports for drugs and biological products. The 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: Effective May 19, 1997. Submit written comments at any time.
ADDRESSES: Submit written comments on the guideline to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline
are available from the Drug Information Branch (HFD-210), Center for
Drug Evaluation and Research, Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-4573. Single copies of the
draft guideline may be obtained by mail from the Office of
Communication, Training and Manufacturers Assistance (HFM-40), Center
for Biologics Evaluation and Research (CBER), 1401 Rockville Pike,
Rockville, MD 20852-1448 or by calling the CBER Voice Information
System at 1-800-835-4709 or 301-827-1800. Copies may be obtained from
CBER's FAX Information System at 1-888-CBER-FAX or 301-827-3844.
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, 301-594-5400.
Regarding 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.
In the Federal Register of April 5, 1996 (61 FR 15352), FDA
published a draft tripartite guideline entitled ``Clinical Safety Data
Management: Periodic Safety Update Reports for Marketed Drugs.'' The
notice gave interested persons an opportunity to submit comments by
July 5, 1996.
After consideration of the comments received and revisions to the
guideline, a final draft of the guideline was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies at the ICH meeting held on November 6, 1996.
The guideline provides recommendations on the content, format, and
reporting frequency for postmarketing periodic safety update reports
for drugs and biological products. The 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 report (spontaneous notification),'' and
``unlisted adverse drug reaction.'' The 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.
This guideline represents the agency's current thinking on periodic
safety update reports for marketed drugs. It does not create or confer
any rights for or on any person and does not operate to bind FDA or the
public. An alternative approach may be used if such approach satisfies
the requirements of the applicable statute, regulations, or both.
As with all of FDA's guidelines, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guideline. The comments in the docket will be periodically
reviewed, and, where appropriate, the guideline will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
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 guideline and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. An electronic version of this draft guideline is
available on the Internet using the World Wide Web (WWW) (http://
www.fda.gov/cder/guidance.htm) or through the CBER home page (http://
www.fda.gov/cber/cberftp.html).
The text of the 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 make recommendations to
harmonize technical
[[Page 27471]]
requirements for 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 regulatory requirements, particularly regarding frequency of
submission and content of periodic safety updates, are not the same
in the three regions (EU, Japan, United States). To avoid
duplication of effort and to ensure that important data are
submitted with consistency to regulatory authorities, this guideline
on the format and content for comprehensive periodic safety updates
of marketed medicinal products has been developed.\1\
---------------------------------------------------------------------------
\1\ Guidelines are not legally binding. Some portions of this
guideline may not be reflected in existing regulations. To that
extent, until the regulations are amended, marketing authorization
holders (MAH's) must comply with existing regulations.
---------------------------------------------------------------------------
1.2 Background
When a new medicinal product is submitted for marketing
approval, except in special situations, the demonstration of its
efficacy and the evaluation of its safety are based at most on
several thousand patients. The limited number of patients included
in clinical trials, the exclusion at least initially of certain
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.
In order to develop a comprehensive picture of clinical safety,
medicinal products should be closely monitored, especially during
the first years of commercialization. Surveillance of marketed drugs
is a shared responsibility between regulatory authorities and MAH's.
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, in order 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;
Indicate whether changes should be made to product
information in order to optimize the use of the product.
However, if 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's would need 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 U. S. regulations require quarterly reports during
the first 3 years, then annual reports. FDA has recently published
proposed rules\2\ that take into account the Council for
International Organizations of Medical Sciences (CIOMS) Working
Group II proposals.\3\
---------------------------------------------------------------------------
\2\ Adverse Experience Reporting Requirements for Human Drug and
Licensed Biological Products; Proposed Rule, Federal Register,
October 27, 1994 (59 FR 54046 to 54064).
\3\ International Reporting of Periodic Drug-Safety Update
Summaries; Final Report of CIOMS, Working Group II, CIOMS, Geneva,
1992.
---------------------------------------------------------------------------
In the EU, 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, at the time of renewal of registration.
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, adverse reactions that are nonserious, but both mild in
severity 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 considered
particularly suitable for comprehensive reports covering short
periods (e.g., 6 months, 1 year) often prepared during the initial
years following approval/authorization.
This guideline might also be applicable for longer term
reporting intervals; however, other options may be appropriate.
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. Within the single 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 may be reported either
in a separate PSUR or included as separate presentations in the
report for one of the separate components, depending on the
circumstances. Cross-referencing all relevant PSUR's is considered
important.
1.4.2 General scope of information
All relevant clinical and nonclinical safety data should cover
only the period of the report (interval data) with the exception of
regulatory status information on authorization applications and
renewals, as well as data on serious, unlisted ADR's (see section
1.4.5), which should be cumulative.
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.
Reports of lack of efficacy specifically for drugs used in the
treatment of life-threatening conditions may represent a significant
hazard and, in that sense, be a ``safety issue''. Although these
types of cases should not be included with the usual ADR
presentations (i.e., line listings and summary tabulations), such
findings should be discussed within the PSUR (see section 2.8), if
deemed medically relevant.
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
and whether an explanation can be proposed for such a change (e.g.,
population exposed, duration of exposure).
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), arrangements for sharing safety information should be
clearly specified. In order to ensure that all relevant data will be
duly reported to appropriate regulatory authorities, respective
responsibilities for safety reporting should also be clearly
specified.
When data received from a 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 data should be included and discussed in the PSUR, even if it
is known that they are included in another company's PSUR.
[[Page 27472]]
1.4.4 International birth date and frequency of review and reporting
Each medicinal product should have as an international birth
date (IBD) the date of the first marketing authorization for the
product granted to any company in any country in the world. For
administrative convenience, if desired by the MAH, the IBD can be
designated as the last day of the same month. 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.
The need for a report and the frequency of report submission to
authorities are subject to local regulatory requirements. The age of
a drug on the market may influence this process. In addition, 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.
However, independent of the required reporting frequency,
regulatory authorities should accept PSUR's prepared at 6-month
intervals or PSUR's based on multiples of 6 months. Therefore, it is
recommended that the preparation of PSUR's for all regulatory
authorities should be based on data sets of 6 months or multiples
thereof.
Once a drug has been marketed for several years, the need for a
comprehensive PSUR and the frequency of reporting 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 should be discussed between regulatory
authorities and MAH's since they 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 safety 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 indicate whether changes
should be made to product information. Reference information is
needed to perform this comparison. Having one reference source of
information in common for the three ICH regions would facilitate a
practical, efficient, and consistent approach to the safety
evaluation and make the PSUR a unique report accepted in all areas.
It is a common practice for MAH's to prepare their own ``Company
Core Data Sheet'' (CCDS) which covers material relating to safety,
indications, dosing, pharmacology, and other information concerning
the product. A practical option for the purpose of periodic
reporting is for each MAH to use, as a reference, the safety
information contained within its central document (CCDS), which
would 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 local
expedited postmarketing safety reporting.
1.4.6 Presentation of data on individual case histories
Sources of information
Generally, data from the four following sources of ADR case
information are potentially available to an MAH and could be
included in the PSUR:
(a) Direct reports to MAH's (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\4\ or named-patient
(``compassionate'') use.
---------------------------------------------------------------------------
\4\ What constitutes a clinical study may not always be clear,
given the recent use of, for example, stimulated reporting and
patient-support programs. In some of these circumstances, the
distinction between spontaneous reporting and a clinical study is
not well defined. The MAH should specify how relevant data from such
sources are included.
---------------------------------------------------------------------------
(b) Literature.
(c) ADR reporting systems of regulatory authorities.
(d) Other sources of data:
Reports on ADR's exchanged between contractual partners
(e.g., licensors-licensees);
Data in special registries, such as maintained in organ
toxicity monitoring centers;
Reports created by poison control centers;
Epidemiological data bases.
Description of the reaction
Until an internationally agreed coding terminology becomes
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.
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 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 an 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).
MAH's should report and try to understand all
information provided within a case report. An example is a
laboratory abnormality not addressed/evaluated 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.
MAH's can prepare line listings of consistent structure and
content for cases directly reported to them (or under their control)
(see section 1.4.6(a)) as well as those received from regulatory
authorities. They can usually do the same for published cases
(ordinarily well documented; if not, followup with the author may be
possible). However, inclusion of individual cases from second- or
third-hand sources, such as contractual partners and special
registries (see section 1.4.6(d)) 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 is
considered acceptable under these circumstances.
In addition to individual case line listings, summary
tabulations of ADR terms for 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.
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.
[[Page 27473]]
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 safety information;
Patient exposure;
Presentation of individual case histories;
Studies;
Other information;
Overall safety evaluation;
Conclusion;
Appendix: Company Core Data Sheet.
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 to 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.
2.2 Worldwide Market Authorization Status
This section of the report 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, and subsequent 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, including explanation, by regulatory
authorities;
Withdrawal by the company of a license application
submission if related to safety or efficacy;
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 considered
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 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
actions relating to safety that were taken during the period covered
by the report and between data lock point and report submission:
Marketing authorization withdrawal or 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; any
communication with the health profession (e.g., Dear Doctor letters)
as a result of such action should also be described with copies
appended.
2.4 Changes to Reference Safety Information
The version of the CCDS with its CCSI in effect at the beginning
of the period covered by the report should be used as the reference.
It should be numbered, dated, and appended to the PSUR and include
the date of last revision.
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 revised CCSI 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, an estimation of accurate patient exposure
should cover the same period as the interim safety data. While it is
recognized that it is usually difficult to obtain and validate
accurate exposure data, an estimate of the number of patients
exposed should be provided along with the method used to derive the
estimate. An explanation and justification should be presented if
the number of patients is impossible to estimate or is a meaningless
metric. In its place, other measures of exposure, such as patient-
days, number of prescriptions, or number of dosage units are
considered appropriate; the method used should be explained. If
these or other more precise measures are not available, bulk sales
(tonnage) may be used. The concept of a defined daily dose may be
used in arriving at patient exposure estimates. When possible and
relevant, data broken down by sex and age (especially pediatric
versus adult) should be provided.
When a pattern of reports indicates a potential problem, details
by country (with locally recommended daily dose) or other
segmentation (e.g., indication, dosage form) should be presented if
available.
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 medical and scientific journals for safety
information on their products and/or make use of one or more
literature search/summary services 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 when required or requested
by regulatory authorities. However, it is considered that such
reports are not expected to be discussed within the PSUR itself.
[[Page 27474]]
2.6.2 Cases presented as line listings
The following types of cases should be included in the line
listings (Table 2); attempts should be made to avoid duplicate
reporting of cases from the literature and regulatory sources:
All serious reactions, and nonserious unlisted
reactions, from spontaneous notifications;
All serious reactions (attributable to drug 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. Therefore, a line listing of
spontaneously reported nonserious listed reactions that have been
collected should be submitted as an addendum to the PSUR only when
required or 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 there is more than one event/reaction, they should all
be mentioned but the case should be listed under the most serious
ADR (sign, symptom, or diagnosis), as judged by the MAH. It is
possible that the same patient may experience different ADR's on
different occasions (e.g., weeks apart during a clinical trial).
Such experiences would probably be treated as separate reports.
Under such circumstances, the same patient might then be included in
a line listing more than once, and the line listings should be
cross-referenced when possible. 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;
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). This field does not refer to the
criteria used to define a ``serious'' ADR. It should indicate the
consequences of the reaction(s) for the patient, using the worst of
the different outcomes for multiple reactions;
Comments, if relevant (e.g., causality assessment if
the manufacturer disagrees with the reporter; 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 a sample
data presentation on serious reactions.
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))
should normally 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 considered suitable.
As previously described, the data in summary tabulations should
be interval data, as should the line listings from which they are
derived. However, for ADR's that are both serious and unlisted, a
cumulative figure (i.e., all cases reported to date) should be
provided in the table(s) or as a narrative.
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,
etc.). 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, studies specifically planned or in progress, and
published studies 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 study design and results should be clearly and
concisely 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, if an interim analysis was part of
the study plan, the interim results of ongoing studies may be
presented. When the study is completed and analyzed, the final
results should be presented in a subsequent PSUR as described under
section 2.7.1.
2.7.3 Published safety studies
Reports in the scientific and medical literature, including
relevant published abstracts from meetings, containing important
safety findings (positive or negative) should be summarized and
publication reference(s) given.
2.8 Other Information
2.8.1 Efficacy-related information
For a product used to treat serious or life-threatening
diseases, medically relevant lack of efficacy reporting, which might
represent a significant hazard to the treated population, should be
described and explained.
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, taking into account
any late-breaking information (section 2.8.2), and followed by the
MAH assessment of the significance of the data collected during the
period and from the perspective of cumulative experience, should
highlight any new information on:
A change in characteristics of listed reactions, e.g.,
severity, outcome, target population;
Serious unlisted reactions, placing into perspective
the cumulative reports;
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
on the following (lack of significant new information should be
mentioned for each):
Drug interactions;
Experience with overdose, deliberate or accidental, and
its treatment;
Drug abuse or misuse;
Positive or negative experiences during pregnancy or
lactation;
Experience in special patient groups (e.g., children,
elderly, organ impaired);
[[Page 27475]]
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 in effect at the beginning of the
period covered 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 safety information, material relating to
indications, dosing, pharmacology, and other information concerning
the product.
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-month
increments.
International Birth Date (IBD)--The date of the first marketing
authorization for a new medicinal product granted to any company in
any country in the world.
Listed Adverse Drug Reaction (ADR)--An ADR whose nature,
severity, specificity, and outcome are consistent with the
information in the CCSI.
Spontaneous Report or Spontaneous Notification--An unsolicited
communication to a company, regulatory authority, or other
organization that describes an adverse 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 whose nature, severity,
specificity, or outcome are not consistent with the information
included in the CCSI.
Table 1.--Example of Presentation of Worldwide Market Authorization
Status
------------------------------------------------------------------------
Launch Trade
Country Action-Date Date Name(s) Comments
------------------------------------------------------------------------
Sweden A\1\-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)
A-4/94 7/94 Bacgone-C excluded
(skin infs) (PK)
Topical cream
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
Source Type of Case Only Summary and Summary
Tabulation Tabulation
------------------------------------------------------------------------
1. Direct Reports to MAH ..............
Spontaneous ADR S - +
reports\1\ NS U - +
NS L\2\ + -
SA - +
MAH sponsored
studies
2. Literature S - +
NS U - +
3. Other sources
Regulatory S - +
authorities S + -
Contractual S + -
partners
Registries
------------------------------------------------------------------------
\1\ Medically unconfirmed reports should be provided as a PSUR addendum
only if required or requested by regulatory authorities, as a line
listing and/or summary tabulation.
\2\ Line listing should be provided as PSUR addendum only if required or
requested by regulatory authority.
S = serious; L = listed; A = attributable to drug (by investigator or
sponsor); NS = nonserious; U = unlisted.
[[Page 27476]]
*Table 3.--(Example of summary tabulation)\1\ Number of Reports by Term
(Signs, Symptoms and Diagnoses) from Spontaneous (Medically Confirmed),
Clinical Study and Literature Cases: All Serious Reactions
(An * indicates an unlisted term)
------------------------------------------------------------------------
Spontaneous/
Body system/ADR term Regulatory Clinical Literature
bodies trials
------------------------------------------------------------------------
CNS
hallucinations* 2 0 0
etc.
etc.
________ ________ ________ ________
Sub-total
------------------------------------------------------------------------
CV
etc.
etc.
________ ________ ________ ________
Sub-total
------------------------------------------------------------------------
Etc.
------------------------------------------------------------------------
TOTAL
------------------------------------------------------------------------
\1\ This table is only one example of different possible data
presentations which are at the discretion of the MAH (e.g., serious
and nonserious in the same table or as separate tables, etc).
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: May 13, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-13065 Filed 5-16-97; 8:45 am]
BILLING CODE 4160-01-F
