[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