[Federal Register Volume 61, Number 67 (Friday, April 5, 1996)]
[Notices]
[Pages 15352-15357]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-8475]




[[Page 15351]]

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Part IV





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Draft Guideline on Clinical 
Safety Data Management: Periodic Safety Update Reports for Marketed 
Drugs; Availability; Notice

  Federal Register / Vol. 61, No. 67 / Friday, April 5, 1996 / 
Notices  
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[[Page 15352]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
 [Docket No. 96D-0041]


International Conference on Harmonisation; Draft Guideline on 
Clinical Safety Data Management: Periodic Safety Update Reports for 
Marketed Drugs; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
guideline entitled ``Clinical Safety Data Management: Periodic Safety 
Update Reports For Marketed Drugs.'' The draft guideline was prepared 
under the auspices of the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH). The draft guideline provides a unified standard for the 
format, content, and reporting frequency for postmarketing periodic 
safety update reports. The draft guideline also provides definitions 
and terms for key aspects of postmarketing periodic safety reporting. 
The guideline is intended to help harmonize collection and submission 
of postmarketing clinical safety data.

DATES: Written comments by July 5, 1996.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm.1-23, Rockville, MD 20857. Copies of the draft 
guideline are available from the Division of Communications Management 
(HFD-210), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1012. 
An electronic version of this guideline is also available via Internet 
by connecting to the CDER file transfer protocol (FTP) server 
(CDVS2.CDER.FDA.GOV).

FOR FURTHER INFORMATION CONTACT:
     Regarding the guideline: -Murray M. Lumpkin, Center for Drug 
Evaluation and Research (HFD-2), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-6740.
     Regarding the ICH: Janet J. Showalter, Office of Health Affairs 
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville, 
MD 20857, 301-827-0864.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote international harmonization of regulatory 
requirements. FDA has participated in many meetings designed to enhance 
harmonization and is committed to seeking scientifically based 
harmonized technical procedures for pharmaceutical development. One of 
the goals of harmonization is to identify and then reduce differences 
in technical requirements for drug development among regulatory 
agencies.
     ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
consumer representatives and others. ICH is concerned with 
harmonization of technical requirements for the registration of 
pharmaceutical products among three regions: The European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission, the European Federation of Pharmaceutical Industries 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, the Centers for Drug 
Evaluation and Research and Biologics Evaluation and Research, FDA, and 
the Pharmaceutical Research and Manufacturers of America. The ICH 
Secretariat, which coordinates the preparation of documentation, is 
provided by the International Federation of Pharmaceutical 
Manufacturers Associations (IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization, the Canadian Health Protection Branch, and the 
European Free Trade Area.
    At a meeting held on November 29, 1995, the ICH Steering Committee 
agreed that a draft guideline entitled ``Clinical Safety Data 
Management: Periodic Safety Update Reports for Marketed Drugs'' should 
be made available for public comment. The draft guideline is the 
product of the Efficacy Expert Working Group of the ICH. Comments about 
this draft will be considered by FDA and the Efficacy Expert Working 
Group. Ultimately, FDA intends to adopt the ICH Steering Committee's 
guideline and to amend its regulations to fully implement the 
guideline. Until such time as the agency's regulations are amended, 
sponsors must continue to comply with the existing regulations.
    The draft guideline provides guidance on the content, format, and 
reporting frequency for postmarketing periodic safety update reports. 
The draft guideline also defines basic terms for postmarketing periodic 
reporting, such as ``company core data sheet,'' ``company core safety 
information,'' ``data lock-point (data cut-off date),'' ``international 
birth date,'' ``listed adverse drug reaction,'' ``spontaneous adverse 
drug reaction report (spontaneous notification),'' and ``unlisted 
adverse drug reaction.'' The draft guideline is designed primarily for 
medicinal products authorized recently or in the future. It is most 
relevant for products marketed in more than one ICH country.
    In the past, guidelines have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidelines to state procedures or standards of general applicability 
that are not legal requirements but are acceptable to FDA. The agency 
is now in the process of revising Sec. 10.90(b). Although this 
guideline does not create or confer any rights for or on any person and 
does not operate to bind FDA, it does represent the agency's current 
thinking on periodic safety update reports for marketed drugs.
    Interested persons may, on or before July 5, 1996, submit written 
comments on the draft guideline to the Dockets Management Branch 
(address above). Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. The draft guideline and received comments may be seen in the 
office above between 9 a.m. and 4 p.m., Monday through Friday.
    The text of the draft guideline follows:

Clinical Safety Data Management: Periodic Safety Update Reports for 
Marketed Drugs

 1. Introduction

1.1 Objectives of the guideline

     The main objective of ICH is to harmonize technical 
requirements before registration or marketing approval. However, 
because new products are introduced at different times in different 
markets and the same product may be marketed in one or more 
countries and still be under development in others, reporting and 
use of clinical safety information should be regarded as part of a 
continuum. The ICH Steering Committee has decided that the 
harmonization of format, content, and time span covered in periodic 
safety update reports for marketed drugs should be addressed by ICH, 
as an extension of the ICH topic on Clinical Safety Data

[[Page 15353]]
Management: Definitions and Standards for Expedited Reporting.
     The regulatory requirements, particularly regarding frequency 
of submission and content of periodic safety updates, are not the 
same in the three regions. To avoid duplication of effort and to 
ensure that important data are submitted with consistency to 
competent authorities, it is proposed to establish an international 
consensus on the format and content for periodic safety updates of 
marketed medicinal products.

1.2 Background

    -When a new medicinal product is submitted for marketing 
approval, the demonstration of its efficacy and the evaluation of 
its safety are based at most on several thousand patients, except in 
special situations. The limited number of patients included in 
clinical trials, the exclusion at least initially of patients at-
risk, the lack of significant long-term treatment experience, and 
the limitation of concomitant therapies do not allow a thorough 
evaluation of the safety profile. Under such circumstances, the 
detection or confirmation of rare adverse reactions is particularly 
difficult, if not impossible.
     Medicinal products must be closely monitored, especially during 
the first years of commercialization to develop a comprehensive 
picture of clinical safety. Surveillance of marketed drugs is a 
shared responsibility between regulatory authorities and marketing 
authorization holders (MAH). They record information on drug safety 
from different sources, and procedures have been developed to ensure 
timely detection and mutual exchange of safety data. Because all 
information cannot be evaluated with the same degree of priority, 
regulatory authorities have defined the information to be submitted 
on an expedited basis; in most countries this rapid transmission is 
usually focused on the expedited reporting of adverse drug reactions 
(ADR's) that are both serious and unexpected.
    -Reevaluation of the benefit/risk ratio of a drug is usually not 
possible for each individual ADR case, even if serious. Therefore, 
periodic safety update reports (PSUR's) present the worldwide safety 
experience of a medicinal product at defined times postauthorization 
to:
     Report all the relevant new information from 
appropriate sources;
     Relate these data to patient exposure;
     Summarize the market authorization status in different 
countries and any significant variations related to safety;
     Create periodically the opportunity for an overall 
safety reevaluation;
     Decide whether changes should be made to product 
information to optimize the use of the product.
    -However, if the PSUR's required in the different countries 
where the product is on the market require a different format, 
content, period covered, and filing date, MAH would be forced to 
prepare on an excessively frequent basis different reports for the 
same product. In addition, under such conditions, different 
regulators could receive different kinds and amounts of information 
at different times. Thus, efforts are needed to harmonize the 
requirements for PSUR's, which will also improve the efficiency with 
which they are produced.
    -The current situation for periodic safety reports on marketed 
drugs is different among the three ICH regions. For example:
     The United States requires quarterly reports during the 
first 3 years, then annual reports. FDA has recently published 
proposed rules \1\ that take into account the Council for 
International Organizations of Medical Sciencesse (CIOMS) Working 
Group II proposals. \2\

    \1\ Adverse experience reporting requirements for human drug and 
licensed biological products; proposed rule, Federal Register, 
October 27, 1994 (59 FR 54046 to 54064).
    \2\ International reporting of periodic drug-safety update 
summaries; final report of CIOMS, Working Group II, CIOMS, Geneva, 
1992.
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     In the European Union, Council Directive 93/39/EEC and 
Council Regulation 2309/93 require reports with a periodicity of 6 
months for 2 years, annually for the 3 following years, and then 
every 5 years.
     In Japan, the authorities require a survey on a cohort 
of a few thousand patients established by a certain number of 
identified institutions during the 6 years following authorization. 
Systematic information on this cohort, taking into account a precise 
denominator, must be reported annually. Regarding other marketing 
experience, ADR's that are both nonserious and unlabeled must be 
reported every 6 months for 3 years and annually thereafter.
    -Following a discussion of the objectives and general principles 
for preparing and submitting PSUR's, a model for their format and 
content is presented.
    -Appended is a glossary of important relevant terms.

 1.3 Scope of the Guideline

    -This guideline on the format and content of PSUR's is designed 
primarily for medicinal products approved/authorized recently or in 
the future.
    -Although this guideline could be applied to other drugs, 
modifications in accord with local regulations may be appropriate. 
(See section 1.4.4 for additional discussion.)
    -This guideline is most relevant to products marketed in more 
than one ICH country.

 1.4 General Principles

 1.4.1 One report for one active substance

     Ordinarily, all dosage forms and formulations as well as 
indications for a given pharmacologically active substance should be 
covered in one PSUR. Separate presentations of data for different 
dosage forms, indications, or populations (e.g., children versus 
adults) may be appropriate.
    -For combinations of substances also marketed individually, 
safety information for the fixed combination might be reported 
either separately or included in the reports for each of the 
separate components, depending on the circumstances. Cross-
referencing the relevant reports is appropriate.

 1.4.2 General scope of information

    -With the exception of regulatory status information on 
authorization applications and renewals, which should be cumulative, 
all relevant clinical and nonclinical safety data should cover only 
the period of the report (interval data).
    -The main focus of the report should be ADR's. For spontaneous 
reports, unless indicated otherwise by the reporting health-care 
professional, all adverse experiences should be assumed to be ADR's; 
for clinical study and literature cases, only those judged not 
related to the drug by both the reporter and the manufacturer/
sponsor should be excluded.
    -Lack of efficacy, especially in the treatment of serious or 
life-threatening conditions, may be reported as a ``safety issue.'' 
These types of cases, especially if isolated, are not expected to be 
included in the PSUR ADR data presentation (e.g., line listings or 
summary tabulations). However, such findings should be discussed 
somewhere within a PSUR, particularly if they represent a potential 
risk to the treated population (see section 2.8.1).
    -An increase in the frequency of reports for known ADR's has 
traditionally been considered as relevant new information. Although 
attention should be given in the PSUR to such increased reporting, 
no specific quantitative criteria or other rules are recommended. 
Judgment should be used in such situations to determine whether the 
data reflect a meaningful change in ADR occurrence or safety 
profile.

 1.4.3 Products manufactured and/or marketed by more than one company

    -Each MAH is responsible for submitting PSUR's, even if 
different companies market the same product in the same country. 
When companies are involved in contractual relationships (e.g., 
licensor-licensee), respective responsibilities for sharing safety 
information and for safety reporting to regulators should be clearly 
specified between the parties to ensure that all relevant data are 
duly reported to appropriate regulatory authorities.
    -When available data received from partner company(ies) might 
contribute meaningfully to the safety analysis and influence any 
proposed or effected changes in the reporting company's product 
information, these relevant data should be summarized in a PSUR even 
if it is known that they are included in another company's PSUR.

 1.4.4 International birthdate and frequency of review and reporting

    -Each medicinal product should have as an international birth 
date (IBD) the date of a company's first marketing authorization in 
any country in the world. When a report contains information on 
different dosage forms, formulations, or uses (indications, routes, 
populations), the date of the first marketing authorization for any 
of the various authorizations should be regarded as the IBD and, 
therefore, determine the data lock point for purposes of the unified 
PSUR. The data lock point is the date designated as the cutoff for 
data to be included in a PSUR. During the initial years of 
marketing, the MAH should generally freeze its data base (and have a 
data lock point) every 6 months thereafter.
    -The need for a report and the frequency of report submission to 
authorities are subject to

[[Page 15354]]
local regulatory requirements. However, independent of the required 
reporting frequency, preparation of PSUR's for all regulatory 
authorities should be based on data sets of 6 months or multiples 
thereof.
    -The age of a drug on the market may influence this process; 
during the initial years of marketing, a drug will ordinarily 
receive authorizations at different times in different countries. It 
is during this early period that harmonization of reporting is 
particularly important. Once a drug has been marketed for several 
years, the need for a comprehensive PSUR may be reviewed, depending 
on local regulations or requests, while maintaining one IBD for all 
regulatory authorities.
    -In addition, approvals beyond the initial one for the active 
substance may be granted for new indications, dosage forms, 
populations, or prescription status (e.g., children versus adults; 
prescription to nonprescription status). The potential consequences 
on the safety profile raised by such new types and extent of 
population exposures may influence the requirements for periodic 
reporting.
    -The MAH should submit a PSUR within 60 days of the data lock 
point.

 1.4.5 Reference product information

    -The objective of a PSUR is to establish whether information 
recorded during the reporting period is in accord with previous 
knowledge on the drug's safety, and to decide whether changes should 
be made to product information. Reference information is needed to 
perform this comparison. In addition, having one reference source of 
information in common for the three ICH regions will facilitate a 
practical, efficient, and consistent approach to the safety 
evaluation and make the PSUR a unique report accepted in all areas.
    -Based on the common practice for MAH's to prepare their own 
``Company Core Data Sheet''(CCDS), a practical option for the 
purpose of periodic reporting is to use, as a reference, the safety 
information contained within that central document. In addition to 
this safety information, a full company CCDS covers material 
relating to indications, dosing, pharmacology, and other areas that 
are not necessarily safety related. Reference safety information 
will therefore be referred to as ``Company Core Safety Information'' 
(CCSI).
    -For purposes of periodic safety reporting, CCSI forms the basis 
for determining whether an ADR is already ``Listed'' or is still 
``Unlisted,'' terms that are introduced to distinguish them from the 
usual terminology of ``expectedness'' or ``labeledness'' that is 
used in association with official labeling. Thus, the local approved 
product information continues to be the reference document upon 
which labeledness/expectedness is based for the purpose of 
``expedited'' postmarketing safety reporting.

 1.4.6 Presentation of data on individual case histories sources of 
information

    -Generally, data from the three following sources of ADR case 
information are potentially available to a MAH and could be included 
in the PSUR:
     (a) Direct reports to MAH (or under MAH control):
     Spontaneous notifications from health care 
professionals;
     Spontaneous notifications from nonhealth care 
professionals or from consumers (nonmedically substantiated);
     MAH-sponsored clinical studies or named-patient 
(``compassionate'') use.
    (b) Literature.
     (c) Other sources: Regulatory authorities; data from exchange 
between contractual partners (e.g., licensors-licensees) holding 
their own marketing authorizations; special registries such as organ 
toxicity monitoring centers, poison control centers, and 
epidemiological data bases.

 Description of the reaction

     Until an internationally agreed coding terminology (dictionary) 
is available and its use broadly implemented, the event terms used 
in the PSUR will generally be derived from whatever standard 
terminology (``controlled vocabulary'' or ``coding dictionary'') is 
used by the reporting company (e.g., WHO-ART, COSTART).
     Whenever possible, the notifying reporter's event terms should 
be used to describe the ADR. However, when the notifying reporter's 
terms are not medically appropriate or meaningful, MAH's should use 
the best alternative compatible event terms from their ADR 
dictionaries to ensure the most accurate representation as possible 
of the original terms. Under such circumstances, the following 
should be borne in mind:
     To make it available on request, the ``verbatim'' 
information supplied by the notifying reporter should be kept on 
file (in the original language and/or as a medically sound English 
translation, if applicable).
     In the absence of a diagnosis by the reporting health-
care professional, a suggested diagnosis for a symptom complex may 
be made by the MAH and used to describe a case, in addition to 
presenting the reported individual signs, symptoms, and laboratory 
data.
     If a MAH disagrees with a diagnosis that is provided by 
the notifying health care professional, it may indicate such 
disagreement within the line listing of cases (see below).
     It is incumbent on the MAH to report and try to 
understand all information provided within a case report, such as 
laboratory abnormalities possibly drug related but not identified as 
such by the notifying reporter.
     Therefore, when necessary and relevant, two descriptions of the 
signs, symptoms, or diagnosis could be presented in the line 
listing: First, the reaction as originally reported; second, when it 
differs, the MAH's medical interpretation (identified by asterisk or 
other means).

 Line listings and/or summary tabulations

     Depending on their type or source, available ADR cases should 
be presented as individual case line listings and/or as summary 
tabulations.
     A line listing provides key information but not necessarily all 
the details customarily collected on individual cases; however, it 
does serve to help regulatory authorities identify cases that they 
might wish to examine more completely by requesting full case 
reports.
     There are other issues regarding the content of line listings:
     MAH's can prepare line listings of consistent structure 
and content for cases directly reported to them (or under their 
control) (see 1.4.6(a)); they can usually do the same for published 
cases (ordinarily well documented; if not, followup with the author 
is possible). However, inclusion of individual cases from second- or 
third-hand sources, such as contractual partners and special 
registries (see section 1.4.6(c)) might not be: (1) Possible without 
standardization of data elements, or (2) appropriate due to the 
paucity of information, and might represent unnecessary re-entry/
reprocessing of such information by the MAH. Therefore, summary 
tabulations or possibly a narrative review of these data in these 
circumstances is acceptable.
     An exception to the above consideration is the case 
reports received directly by regulatory authorities (but not by MAH) 
that might be transmitted to the MAH.
    -In addition to individual case line listings, summary 
tabulations of the various signs, symptoms, and diagnoses across all 
patients should usually be presented to provide an overview. Such 
tabulations should be based on the data in line listings (e.g., all 
serious ADR's and all nonserious unlisted ADR's), but also on other 
sources for which line listings are not requested (e.g., nonserious 
listed ADR's). Details are found in Section 2.6.4.
    -It is worth noting that work in progress may in the future 
enable routine electronic transmission of detailed ADR case report 
information on a regular basis between MAH and regulatory 
authorities. When implemented, this may obviate the need for line 
listings within a PSUR, which for some products might be very 
extensive.

 2. Model for a PSUR

    -The following sections are organized as a sample PSUR. In each 
of the sections, guidance is provided on what should be included:

Sample Title Page

     Periodic safety update report for: (product);
     MAH's name and address (corporate headquarters or other 
company entity responsible for report preparation);
    - Period covered by this report: (dates);
    - International birth date: date (country of IBD);
    - Date of report;
     (Other identifying information at the option of MAH, 
such as report number).

Table of Contents for Model PSUR

    - Introduction;
    - Worldwide market authorization status;
    - Update of regulatory authority or MAH actions taken 
for safety reasons;
    - Changes to reference product information;
    - Patient exposure;
    - Presentation of individual case histories;
    - Studies;
    - Other information;
    - Overall safety evaluation;
    - Conclusion;
    - Appendix: Company Core Data Sheet.
    
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 2.1 Introduction

    -The MAH should briefly introduce the product so that the report 
``stands alone'' but is also placed in perspective relative to 
previous reports and circumstances.
    -Reference should be made not only to product(s) covered by the 
report but also those excluded. Exclusions should be explained; for 
example, they may be covered in a separate report (e.g., for a 
combination product).
    -If it is known that a PSUR on the same product(s) will be 
submitted by another MAH, some of whose data are included in the 
report (see section 1.4.6), the possibility of data duplication 
should be noted.
    -For multiple dosage forms, indications, populations, etc., one 
report is preferred in most cases. When appropriate, data 
presentations within the report may be separated accordingly.

 2.2 Worldwide Market Authorization Status

     This section of the report is ordinarily the only one that 
provides cumulative information.
    -Information should be provided, usually as a table, on all 
countries in which a regulatory decision about marketing has been 
made related to the following:
     Dates of market authorization or renewal;
    - Any qualifications surrounding the authorization, such 
as limits on indications if relevant to safety;
    - Treatment indications and special populations covered 
by the market authorization, when relevant;
    - Lack of approval by regulatory authorities;
    - Withdrawal by the applicant of a submission;
    - Dates of launch when known;
    - Trade name(s).
    -Typically, indications for use, populations treated (e.g., 
children versus adults), and dosage forms will be the same in many 
or even most countries where the product is authorized. However, 
when there are important differences, which would reflect different 
types of patient exposure, such information should be noted. This is 
especially true if there are meaningful differences in the newly 
reported safety information that are related to such different 
exposures. If more convenient and useful, separate regulatory status 
tables for different product uses or forms would be appropriate.
    -Country entries should be listed in chronological order of 
regulatory authorizations. For multiple authorizations in the same 
country (e.g., new dosage forms), the IBD for the active substance 
and for all PSUR's should be the first (initial) authorization date.
    -Table 1 is an example, with fictitious data for an antibiotic, 
of how a table might be organized. The drug was initially developed 
as a solid oral dosage form for outpatient treatment of adults with 
various infections.

 2.3 Update of Regulatory Authority or MAH Actions Taken for Safety 
Reasons

     This section should include details on the following types of 
activity during the reporting period:
    - Application withdrawal or marketing authorization 
suspension;
    - Failure to obtain a marketing authorization renewal;
    - Restrictions on distribution;
    - Clinical trial suspension;
    - Dosage modification;-
     Changes in target population or indications;
    - Formulation changes.
     The safety related reasons that led to these actions should be 
described, and documentation appended when appropriate.

 2.4 Changes to Reference Product Information

     The CCDS with its CCSI should be numbered and dated and include 
the date of last revision. The version in effect at the beginning of 
the period covered by the report should be used as a reference; a 
copy should be included as an appendix with the PSUR.
     Changes to the CCSI, such as new contraindications, 
precautions, warnings, ADR's, or interactions, already made during 
the period covered by the report, should be clearly described, with 
presentation of the modified sections. The new document should be 
used as the reference for the next report and the next period.
     With the exception of emergency situations, it may take some 
time before intended modifications are introduced in the product-
information materials provided to prescribers, pharmacists, and 
consumers. Therefore, during that period the amended reference 
document (CCDS) may contain more ``listed'' information than the 
existing product information in many countries.
     When meaningful differences exist between the CCSI and the 
safety information in the official data sheets/product information 
documents approved in a country, a brief comment should be prepared 
by the company, describing the local differences and their 
consequences on the overall safety evaluation and on the actions 
proposed or initiated. This commentary may be provided in the cover 
letter or other addendum accompanying the local submission of the 
PSUR.

 2.5 Patient Exposure

     Where possible, the estimation of patient exposure should cover 
the same period as the interim safety data. Ideally it should give 
the number of patients or prescriptions, and duration of exposure, 
data that are admittedly difficult to obtain and to validate. 
However, a reasonable method should be used with proper explanation 
and justification, particularly if it is not the same as used in the 
previous report(s). Attempts should be made to obtain the most 
useful and relevant quantification. Examples include patient-months 
or patient-days of exposure, number of dosage units by form and 
strength, or if other more precise measures are not available, bulk 
sales (tonnage). The concept of a defined daily dose may be used in 
arriving at exposure estimates.
     If available, details by country (with locally recommended 
daily dose) or other segmentation (e.g., indication, dosage form) 
should be presented when relevant (e.g., when a pattern of reports 
indicates a potential problem).
     When ADR data from clinical studies are included in the PSUR, 
the relevant denominator(s) should be provided. For ongoing and/or 
blinded studies, an estimation of patient exposure may be made.

 2.6 Presentation of Individual Case Histories

 2.6.1 General considerations

    - Followup data on individual cases may be obtained 
subsequent to their inclusion in a PSUR. If such information is 
relevant to the interpretation of the case (significant impact on 
the case description or analysis, for example), the new information 
should be presented in the next PSUR, and the correction or 
clarification noted relative to the earlier case description.
    - With regard to the literature, MAH's should monitor 
standard, recognized journals for safety information on their 
products and/or make use of one or more literature search/summary 
service(s) for that purpose. Published cases may also have been 
received as spontaneous cases, be derived from a sponsored clinical 
study, or arise from other sources. Care should be taken to include 
such cases only once. Also, no matter what ``primary source'' is 
given a case, if there is a publication, it should be noted and the 
literature citation given.
    - In some countries, there is no requirement to submit 
medically unconfirmed spontaneous reports that originate with 
consumers or other nonhealth care professionals. However, such 
reports are acceptable or requested in other countries; therefore, 
medically unconfirmed reports should be submitted as addenda line 
listings and/or summary tabulations only on specific request by 
regulatory authorities.

 2.6.2 Cases presented as line listings

    -The following types of cases should be included in the line 
listings (Table 2):
    - All serious reactions, and nonserious unlisted 
reactions, from spontaneous notifications;
    - All serious reactions (attributable by either 
investigator or sponsor), available from studies or named-patient 
(``compassionate'') use;
    - All serious reactions, and nonserious unlisted 
reactions, from the literature;
    - All serious reactions from regulatory authorities
    Collection and reporting of nonserious, listed ADR's may not be 
required in all ICH countries. However, a line listing of 
spontaneously reported nonserious listed reactions that have been 
collected should be submitted as an addendum to the PSUR only when 
requested by a regulatory authority.

 2.6.3 Presentation of the line listing

     The line listing(s) should include each patient only once 
regardless of how many adverse event/reaction terms are reported for 
the case. If more than one adverse event/reaction term, they should 
all be mentioned but the case should be listed under the most 
serious presenting sign, symptom, or diagnosis, as judged by the 
MAH. The cases should be organized (tabulated) by body system 
(standard organ system classification scheme).
     The following headings should usually be included in the line 
listing:
     MAH case reference number;
     Country in which case occurred;
    
[[Page 15356]]

     Source (e.g., clinical trial, literature, spontaneous, 
regulatory authority);
     Age and sex;
     Daily dose of suspected drug (and, when relevant, 
dosage form or route);
     Date of onset of the reaction. If not available, best 
estimate of time to onset from therapy initiation. For an ADR known 
to occur after cessation of therapy, estimate of time lag if 
possible (may go in Comments section);
     Dates of treatment. If not available, best estimate of 
treatment duration;
     Description of reaction as reported, and when necessary 
as interpreted by the MAH (English translation when necessary) (See 
section 1.4.6 for guidance.);
     Patient outcome (at case level) (e.g., resolved, fatal, 
improved, sequelae, unknown);
     Comments, if relevant (e.g., concomitant medications 
suspected to play a role in the reactions directly or by 
interaction; indication treated with suspect drug(s); dechallenge/
rechallenge results if available).
     Depending on the product or circumstances, it may be useful or 
practical to have more than one line listing, such as for different 
dosage forms or indications, if such differentiation facilitates 
presentation and interpretation of the data.

 2.6.4 Summary tabulations

     An aggregate summary for each of the line listings should 
usually be presented. These tabulations ordinarily contain more 
terms than patients. It would be useful to have separate tabulations 
(or columns) for serious reactions and for nonserious reactions, for 
listed and unlisted reactions; other breakdowns might also be 
appropriate (e.g., by source of report). (See Table 3 for an example 
of a data presentation.)
     A summary tabulation should be provided for the nonserious, 
listed, spontaneously reported reactions. (See also section 2.6.2.)
     The terms used in these tables should ordinarily be those used 
by the MAH to describe the case. (See section 1.4.6.)
     Except for cases obtained from regulatory authorities, the data 
on serious reactions from other sources (see section 1.4.6(c)) 
generally should be presented only as a summary tabulation. If 
useful, the tabulations may be sorted by source of information or 
country, for example.
     When the number of cases is very small, or the information 
inadequate for any of the tabulations, a narrative description 
rather than a formal table is suitable.

 2.6.5 MAH's analysis of individual case histories

     This section may be used for brief comments on the data 
concerning individual cases. For example, discussion can be 
presented on particular serious or unanticipated findings (e.g., 
their nature, medical significance, mechanism, reporting frequency). 
The focus here should be on individual case discussion and should 
not be confused with the global assessment in the Overall Safety 
Evaluation (section 2.9).

 2.7 Studies

     All completed studies (nonclinical, clinical, epidemiological) 
yielding safety information with potential impact on product 
information, and studies specifically planned or in progress that 
address safety issues, should be discussed.

 2.7.1 Newly analyzed company-sponsored studies

     All relevant studies containing important safety information 
and newly analyzed during the reporting period should be described, 
including those from epidemiological, toxicological, or laboratory 
investigations. The results should be clearly presented with 
attention to the usual standards of data analysis and description 
that are applied to nonclinical and clinical study reports. Copies 
of full reports should be appended only if deemed appropriate.

 2.7.2 Targeted new safety studies planned, initiated, or continuing 
during the reporting period.

     New studies specifically planned or conducted to examine a 
safety issue (actual or hypothetical) should be described (e.g., 
objective, starting date, projected completion date, number of 
subjects, protocol abstract).
     When possible and relevant, interim results of ongoing studies 
may be presented. When completed and analyzed, the results should be 
presented in a subsequent PSUR as described under 2.7.1.

 2.7.3 Published safety studies

     Reports in the scientific and medical literature containing 
important safety findings (positive or negative) should be 
summarized. Published abstracts from relevant meetings should also 
be discussed.

 2.8 Other Information

 2.8.1 Efficacy-related information

     Any information relating to a product's efficacy that has 
implications or consequences for safety should be described, such as 
unexpected significant lack of efficacy in the population under 
treatment for a life-threatening disease.

 2.8.2 Late-breaking information

     Any important, new information received after the data base was 
frozen for review and report preparation may be presented in this 
section. Examples include significant new cases or important 
followup data. These new data should be taken into account in the 
Overall Safety Evaluation (section 2.9).

 2.9 Overall Safety Evaluation

     A concise analysis of the data presented, followed by the MAH 
assessment of the significance of the data collected during the 
period, should highlight any new information on:
     Serious unlisted reactions;
     Nonserious unlisted reactions;
     An increased reporting frequency of listed reactions, 
including comments on whether it is believed the data reflect a 
meaningful change in ADR occurrence.
     The report should also explicitly address any new safety issue 
or new information on the following (lack of significant new 
information should be mentioned for each):
    - Drug interactions;
    - Experience with overdose and its treatment;
    - Drug abuse;
    - Positive or negative experiences during pregnancy or 
lactation;
    - Experience in special patient groups (e.g., children, 
elderly, organ impaired);
    - Effects of long-term treatment.

 2.10 Conclusion

 The conclusion should:
    - Indicate which safety data do not remain in accord 
with the previous cumulative experience, and with the reference 
safety information (CCSI);
    - Specify and justify any action recommended or 
initiated.
 Appendix: Company Core Data Sheet
    -The Company Core Data Sheet should be appended to the PSUR.

 3. Glossary of Special Terms

    -Company Core Data Sheet (CCDS)-A document prepared by the MAH 
containing, in addition to all relevant safety information, material 
relating to indications, dosing, pharmacology, and other areas that 
are not necessarily safety related.
     Company Core Safety Information (CCSI)-All relevant safety 
information contained in the CCDS prepared by the MAH and which the 
MAH requires to be listed in all countries where the company markets 
the drug, except when the local regulatory authority specifically 
requires a modification. It is the reference information by which 
listed and unlisted are determined for the purpose of periodic 
reporting for marketed products, but not by which expected and 
unexpected are determined for expedited reporting.
     Data Lock Point (Data Cut-off Date)-The date designated as the 
cut-off date for data to be included in a PSUR. It is based on the 
International Birth Date (IBD) and should usually be in 6 monthly 
increments.
     International Birth Date (IBD)-The date of first marketing 
authorization for a company's new medicinal product in any country 
in the world.
     Listed Adverse Drug Reaction (ADR)-An ADR whose nature and 
severity are consistent with the information in the CCSI.
     Spontaneous Adverse Drug Reaction Report or Spontaneous 
Notification-An unsolicited communication to a company, regulatory 
authority, or other organization that describes an adverse medical 
reaction in a patient given one or more medicinal products and which 
does not derive from a study or any organized data collection 
scheme.
     Unlisted Adverse Drug Reaction-An ADR, the nature or severity 
of which is not consistent with the information included in the 
CCSI.

[[Page 15357]]


                   Table 1.--Example of Presentation of Worldwide Market Authorization Status                   
----------------------------------------------------------------------------------------------------------------
      Country            Action-Date          Launch Date           Trade Name(s)               Comments        
----------------------------------------------------------------------------------------------------------------
Sweden               A1 - 7/90            12/90                Bacteroff               -                        
                     AR - 10/95           -                    -                       -                        
Brazil               A - 10/91            2/92                 Bactoff                 -                        
                     A - 1/93             3/93                 Bactoff-IV              IV dosage form           
United Kingdom       AQ - 3/92            6/92                 Bacgone                 Elderly (> 65) excluded  
                                                                                        (PK) Topical cream      
                     A - 4/94             7/94                 Bacgone-C (skin infs)   .........................
Japan                LA - 12/92           -                    -                       To be refiled            
France               V - 9/92             -                    -                       Unrelated to safety      
Nigeria              A - 5/93             7/93                 Bactoff                 -                        
                     A - 9/93             1/94                 Bactoff                 New indication           
Etc.                 ...................  ...................  ......................  .........................
----------------------------------------------------------------------------------------------------------------
\1\Abbreviations for Action: A = authorized; AQ = authorized with qualifications; LA: lack of approval; V =     
  voluntary marketing application withdrawal by company; AR = Authorization renewal.                            


           Table 2.--Presentation of Individual Case Histories          
           (See sections 2.6.2 and 2.6.4 for full explanation)          
------------------------------------------------------------------------
                                                        Line Listing and
     Source        Type of Case       Only Summary           Summary    
                                       Tabulation          Tabulation   
------------------------------------------------------------------------
1. Direct         ..............  ....................  ................
 Reports to MAH                                                         
          S               -                     +               
 Spontaneous ADR                                                        
 reports1                                                               
                  NS U            -                     +               
                  NS L2           +                     -               
  MAH     SA              -                     +               
 sponsored                                                              
 studies                                                                
2. Literature     S               -                     +               
                  NS U            -                     +               
3. Other sources  ..............  ....................  ................
          S               -                     +               
 Regulatory                                                             
 Authorities                                                            
          S               +                     -               
 Contractual                                                            
 partners                                                               
          S               +                     -               
 Registries                                                             
------------------------------------------------------------------------
\1\Medically unconfirmed reports should be provided as a PSUR addendum  
  only on request, as a line listing and/or summary tabulation.         
\2\Line listing provided as PSUR addendum only on request by regulatory 
  authority. S = serious; L = listed; A = attributable to drug (by      
  investigator or sponsor); NS = nonserious; U = unlisted.              


   Table 3.--Number of Reports by Term (Signs, Symptoms and Diagnoses) from Spontaneous (Medically Confirmed),  
                           Clinical Trial and Literature Cases: All Serious Reactions                           
----------------------------------------------------------------------------------------------------------------
 Body system ADR term   Spontaneous/regulatory bodies          Clinical trials                 Literature       
----------------------------------------------------------------------------------------------------------------
CNS                     .............................  ...............................  ........................
-hallucinations1        2                              0                                0                       
-etc.                   .............................  ...............................  ........................
-etc.                   .............................  ...............................  ........................
--------                ----                           ----                             ----                    
Sub-total               .............................  ...............................  ........................
CV                      .............................  ...............................  ........................
-etc.                   .............................  ...............................  ........................
-etc.                   .............................  ...............................  ........................
----                    ----                           ----                             ----                    
Sub-total               .............................  ...............................  ........................
Etc.                    .............................  ...............................  ........................
TOTAL                   .............................  ...............................  ........................
----------------------------------------------------------------------------------------------------------------
\1\ Indicates an unlisted term                                                                                  

    In a footnote (or elsewhere), the number of patient cases that 
represent the tabulated terms might be given (e.g., x-spontaneous/
regulatory, y-clinical trial, and z-literature cases).

    Dated: March 29, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-8475 Filed 4-4-96; 8:45 am]
BILLING CODE 4160-01-F