Annex 4
to Procedure for Surveillance over
Adverse Reactions to Medicinal
Products Permitted for Medical Use
FORMAT OF PERIODIC SAFETY UPDATE REPORT ON MEDICINAL
PRODUCT PERMITTED FOR MEDICLA USE
І. Cover page
Periodic safety update report on medicinal product (periodic report)____________
(serial number)
International name, АТС: Code(s)
Trade name of Composition
medicinal
of medicinal
product
product
1
2
Number of
registration
certificate
(in Ukraine)
3
Date of issue of
registration
certificate
(in Ukraine)
4
Holder of
registration
certificate
5
STATUS OF MEDICINAL PRODUCT IN UKRAINE: Registration/re-registration
AUTHORIZATION PROCEDURE IN EС: Centralized/mutual recognition/national
INTERNATIONAL BIRTH DATE (IBD): Date
REPORTING PERIOD: From <Date> – to <Date>
DATE OF REPORTING: <Date>
VOLUME: <Number/total number of volumes>
OTHER INFORMATION: <Other descriptive information>
DATA LOCK POINT OF NEXT REPORT:
<Date>
APPLICANT’S NAME AND ADDRESS:
< Name>
<Address>
AUTHORIZED PERSON, RESPONSIBLE FOR PHARMACOVIGILANCE
(including that in Ukraine), CONTACT DETAILS:
< Full name>
< Address>
< Phone/fax>
< E-mail>
SIGNATURE:
List of serial numbers
< Serial number>
< Period covered by this report >
DISTRIBUTION LIST
Regulatory authority
ІІ. Report’s content
List of abbreviations (if necessary)
Number of copies
2
Annex 4, continued
1. Basic statements/explanatory note (a brief description of each safety report in
the form of explanatory note which includes summary; licensing status in the world;
important regulatory information (e.g., information about any urgent safety restrictions
related to use of medicinal product); data about use, number of new reports received
during reporting period, as well as summarized data).
2. Introduction.
3. World-wide market authorization status (table format: country, registration
certificate’s number, date of issue of marketing authorization and subsequent reregistration; any restrictions of license conditions; indications for use; date of entering
the market; trade name(s)).
4. Update of actions taken by regulatory authorities or registration certificate
holder for safety reasons (marketing authorization withdrawal or suspension; rejection
in re-registration; restrictions for use; change of dosage regimen; change of indications
for use; formulation changes, etc. The safety-related reasons that caused the appropriate
decision being taken should be indicated and the required documentation submitted;
with copies of relevant reports).
5. Changes to reference safety information (the applicant may use list of
applicant’s core data together with the applicant’s core safety data as reference safety
information). The changes to applicant’s safety data related to contraindications,
warnings and adverse reactions to medicinal product or due to its interaction with other
medicinal products already made during reporting period should be clearly described
with submission of the modified sections. When essential differences exist between the
instructions for medical use and EC safety data of medicinal product (or official data
sheets/product information document approved in Ukraine), a brief comment should be
prepared by the applicant describing the present differences and their consequences to
the overall safety evaluation and actions proposed or initiated. This comment shall be
provided as a cover letter or addendum to the periodical report).
6. Patient exposure (an estimate of the number of patients exposed should be
provided along with the method used to derive the estimate: patient-days, number of
prescriptions or number of dosage units of medicinal product, etc. If these or other more
precise measures are not available the bulk sales (packaging, presentation unit or
tonnage) may be used. If the number of patients is impossible to estimate the
appropriate explanations and justifications shall be presented. The estimation of patient
exposure and estimation method used to derive the estimate (adverse reaction incidence
during medical use of this medicinal product, etc.) should be presented. When data
reported indicate a potential problem, details by countries (locally recommended daily
dose) or other segmentations (e.g., indications, pharmaceutical forms) should be
presented.
7. Presentation of individual case histories (description and analysis of cases which
contain new and/or important safety information related to medicinal product. Such
cases should be classified according to MedDRA terminology by System Organ Classes
(SOC). The inclusion criteria used for analysis shall be described).
7.1. Cases of adverse reactions to medicinal product are to be presented as line
listings.
The line listings should include:
а) all serious adverse reactions and non-serious unregistered adverse reactions
received through spontaneous reporting;
3
Annex 4, continued
b) all serious adverse reactions (which investigator or sponsor relates to the use of
medicinal product), which have been received from safety or other studies (including
those being a part of risk management plan) or programs for use of medicinal product in
exceptional circumstances (use of product by specific patient);
c) all serious adverse reactions and non-serious unregistered adverse reactions;
d) all serious adverse reactions submitted to the applicant by the country regulatory
authorities.
All types of cases presented below should be annexed to the periodic report:
а) all non-serious registered adverse reactions received through spontaneous
reporting;
b) all serious and non-serious registered adverse reactions reported by patients and
other non-health workers (not proved by health worker/physician).
The suspected transmission of any infectious agent during use of medicinal product
shall be considered as serious adverse reaction.
The line listings should include each patient only once, regardless of how many
adverse reaction terms are reported for the case. If there is more than one reaction, they
should all be mentioned but the case should be listed under the most serious ADR
(symptom, diagnose) as judged by the applicant.
Cases should be classified (summarized in table-list) according to MedDRA
terminology by System Organ Classes (SOC).
The list should include the following information: applicant’s case reference
number; country, in which case occurred; source of report; patient’s age and sex; dosage
regimen of suspected medicinal product; date of onset of adverse reaction; date of start
and end of therapy (duration of treatment); description of reaction as reported; patient
outcome (e.g., fatal, resolved, complicated); comment (causal effect assessment, if the
applicant disagrees with the reporter; concomitant medications, suspected to play a role
in the reaction development; indications for prescription of the given medicinal product;
dechallenge/rechallenge results, etc.
7.2. Cases presented in summary tabulations (provide an aggregate summary for
each case of adverse reaction to medicinal product in line listings where serious and
non-serious reactions being registered or not registered are specified. When there is a
lack of information for summary tabulation the data should be presented in optional
form. If necessary, the summary tabulations may be sorted by source of information or
by country of report).
7.3. Analysis of individual case histories by applicant (the comment to individual
case histories shall be provided. Analysis of serious or unexpected adverse reactions
shall be conducted – its character, medical significance, mechanism, incidence, etc.).
8. Studies (information about all studies (nonclinical, clinical, epidemiological,
which contain safety data (including information about lack of efficacy) with possible
effect to product information shall be provided; specially planned studies, those being
conducted and published studies, where the safety issues are considered, should be
included in discussion of any intermediate and final results. The studies which are a part
of risk management plan shall be provided).
8.1. Newly analyzed studies (all studies containing important safety information
and reanalyzed during the reporting period should be described including data from
epidemiological, toxicological or laboratory investigations. Add copies of complete
study reports which contain significant safety and efficacy results (if necessary).
4
Annex 4, continued
8.2. New target safety studies (planned, initiated or ongoing during the
reporting period).
8.3. Published study data (notifications/reports in scientific and medical literature
including appropriate published paper abstracts of workshops/conferences, which
contain important safety results (positive or negative) with references to the appropriate
publications).
8.4. Other studies (any important information about data obtained from registers of
pregnant exposure and the comment on positive and negative experience of use of
medicinal product during pregnancy shall be provided).
9. Other information.
9.1. Efficacy-related information (information about cases of lack of efficacy shall
be provided).
9.2. Late-breaking information (any important new information received after data
lock point shall be submitted for study and report. New data shall also be considered in
“Overall safety evaluation” of periodic report).
9.3. Risk management plan (risk management plan shall be discussed if it exists;
the efficacy of risk management system shall be evaluated).
9.4. Report on analysis of risk/benefit ratio (provide summary of analysis of
risk/benefit ratio or safety analysis if such analysis had been conducted).
10. Overall safety evaluation.
10.1. The applicant should present a concise analysis of data along with assessment
of significance of the data collected during this period. The collected data about adverse
reactions should be analyzed and the following information should be presented:
a) changes in characteristics of adverse reactions to medicinal product (severity,
outcome, target population) registered by the applicant (specified in applicant’s core
safety information);
b) number of serious adverse reactions to medicinal product not registered by the
applicant (not mentioned in applicant’s core safety information);
c) number of non-serious adverse reactions to medicinal product not registered by
the applicant (not mentioned in applicant’s core safety information);
d) an increased occurrence of reported adverse reactions to medicinal product
registered by the applicant (mentioned in applicant’s core safety information), including
comments on whether the data are believed to reflect essential changes in adverse
reaction frequency.
10.2. Information should explicitly address any new safety issue related to the use
of medicinal product with comment and assessment of significance of such information
regarding:
а) drug interactions;
b) experience with overdose (deliberate or accidental) and appropriate treatment;
c) drug abuse, accidental or irrational use of medicinal product;
d) experience of using medicinal product during pregnancy or lactation;
e) experience of using medicinal product in special patient groups (children,
elderly, organ and system impaired);
f) effects of long-term treatment;
g) reports from patients and other non-health workers (if necessary);
h) if there are errors in prescription/treatment including errors with trade names or
packaging of medicinal product which affect the safety of medicinal product.
5
Annex 4, continued
11. Conclusion:
а) indicate safety data which do not comply with the previously obtained data and
with the reference safety information about use of medicinal product;
b) specify and justify any action recommended or initiated;
c) make overall conclusion about safety of medicinal product at medical use during
reporting period.
When decision is taken about introduction of changes to instructions for medical
use of medicinal product, the applicant should submit application on introduction of
changes along with periodical report or if this is not possible present a schedule of
submission of these documents.
Note. If the periodic report has been submitted in English, sections 4, 5 and 11
shall be provided in Ukrainian or Russian. Section 10 of periodic report should be
provided in Ukrainian or Russian, if requested by the Center.