and legal basis
The present Guideline is a translation
and adaptation in Romanian of the guideline CPMP/PhWP/175/95
regarding the procedure to be followed by Competent Authorities
when undertaking the pharmacovigilance activities and it is
in accordance with the Decision no. 12/24.03.2000 regarding
the approval of “Regulations on pharmacovigilance activity”,
document approved by the Scientific Council of the National
Medicines Agency Scientific Council in March 2000.
with the SC Decision no. 12/24.03.2000, the National Medicines
Agency organizes the national pharmacovigilance system for collection
and evaluation of information on adverse reactions to medicinal
product. Furthermore, National Medicines Agency takes all appropriate
measures to encourage physicians to report suspected adverse
reactions and to oblige Marketing Authorization Holders (MAH)
to systematically collect information on risks related to their
medicinal products and to transmit those to National Medicines
The requirements and procedures involved in the national
pharmacovigilance system are described in this guideline, which
relates to authorized medicinal products by covering collection
and evaluation of all useful information in the surveillance
of medicinal products.
of a pharmacovigilance system
National Medicines Agency organizes
in accordance with “ Regulations on pharmacovigilance activity”
above mentioned the national pharmacovigilance system having
headquarters in the structure of the National Medicines Agency
(hereafter referred to as “National Pharmacovigilance Centre”)
for receipt and evaluation of all pharmacovigilance data. This
centre must be in a position to handle these pharmacovigilance
data in a way which is compatible with the procedures undertaken
in the European Union and the European Agency for the Evaluation
of Medicinal Products (EMEA) in order that pertinent data may
be transferred between interested parties.
Agency will co-operate with the WHO Collaborating Centre for
International Drug Monitoring, EMEA and EU competent authorities
and CADREAC through the National Pharmacovigilance Centre (NPVC).
of pharmacovigilance data
This section describes the following
Management of spontaneous reporting system
of pharmaceutical company derived pharmacovigilance data
of pharmacovigilance data from other sources
communications and evaluation of pharmacovigilance issues within
3.1. Spontaneous reporting
Agency should have in place a system for collection of spontaneous
suspected adverse reaction reports from physicians (e.g., postal
system) and MAH.
NPVC should co-operate with physicians
to increase the awareness of the reporting system, stressing
its importance and encouraging reporting (e.g., by the provision
of an easy system of reporting and feedback after each report).
Pharmacovigilance Centre should cooperate with physicians to
ensure adequate reporting of adverse reactions to the National
Medicines Agency. To this end, it is desirable that National
Medicines Agency (NMA) through NPVC should ensure the following:
of adverse reactions to the designated centre is made as simple
All adverse reactions are acknowledged where
appropriate and further information requested by physicians
is forwarded as requested;
Regular contact is maintained
between the NPVC and physicians through:
of the pharmacovigilance bulletins, sending of “Dear Doctor”
letters, where appropriate (either by the NMA and/or MAH), provision
of requested information on a case-by-case basis where possible.
principles of spontaneous reporting system
MAH report a suspected adverse reaction related to one or more
medicinal products, to the NMA-NPVC. Reports are made in writing,
electronically, or by other approved ways (in accordance with
the report forms).
Reports are collected and validated by
the NPVC and are entered into a database. Serious adverse reactions
should be handled with the highest priority. The database is
used to identify potential signals and analyze data in order
to clarify risk factors, apparent changes in reporting profiles,
Case reports must be made accessible to the EMEA, competent
authorities of other EU member states, CADREAC and to the concerned
MAH according to the criteria laid down in the European legislation.
following procedures relate to the NMA-NPVC and are independent
of the structure of the national pharmacovigilance system.
procedures are divided into:
case report collection and validation
and case report storage;
case report processing (evaluation
and presentation for transmission), feedback information;
of data confidentiality and security, data quality control and
3.1.3. Case report collection
This concerns the collection and validation
of primary data, e.g., the data transmitted from the reporter
to the NMA-NPVC. For the validation and management of electronically
transmitted reports, the specific operational procedure should
Case report collection
spontaneous report concerns a single case, one patient, one
identifiable reporter, one or more suspected reaction(s), and
one or more suspected medicinal product(s). According to European
Directives and Regulations, only serious cases reported by physicians
will be received on an expedited basis.
Case report validation
the initial report is oral or made by phone, it should be confirmed
in writing by a physician. When several suspected reactions
to one or more suspected drugs occur in one patient, but are
considered to be independent reactions, they should be treated
as separate reports. If considered appropriate, especially in
the case of serious or unexpected reactions, data in the report
concerning the patient, the medicinal products taken, the reactions,
including signs and symptoms and laboratory reports, should
be confirmed by copies of most important and relevant original
documents (e.g., hospital discharge forms, specialist report,
laboratory tests, prescriptions and post mortem reports).
of reports should be evaluated according to data required or
forms for data transmission (see Individual Case Presentation
Incomplete reports, especially when concerning
serious or unexpected reactions, should be followed up promptly
and carefully by obtaining further information from initial
reporter or other available sources. In some cases, it would
also be appropriate to conduct further follow-up to obtain data
on the long-term outcome of the reaction.
An adverse drug
reaction must contain the following information: an identifiable
physician, an identifiable patient, at least one suspected substance/medicinal
product and at least one suspected adverse reaction. This is
the minimum information, which allows the case to be entered
into a database and become available for signal generation in
order to facilitate evaluation of cases. Every effort should
be made to obtain complete information where possible.
reaction is suspected if either the reporting physician or the
MAH believes there is a possible causal relationship between
it and the drug in question. If a reaction is spontaneously
reported, this usually implies a positive judgement from the
reporter unless the reporter explicitly gives a negative judgement
on a causal relationship.
3.1.4. Case report
Initial raw data (paper based) must be stored and
treated in the same way as other medical documents, with appropriate
respect for confidentiality.
Case reports should be stored
in a database by the NPVC.
Data storage should ensure permanent
accessibility of data at all reasonable times. Recommendations
cover individual data entry, audit trail, and correct use of
Conformity of stored data with
the initial report should be ensured. This should be made by
a quality control procedure, which provides validation against
the original data or images thereof.
should ensure traceability of all data entered or modified,
including dates and sources of received data, dates and destination
of transmitted data.
The ICH medical terminology
Med-DRA adopted by International Conference of Harmonization
should be used. Until Med-DRA becomes available and its use
widely implemented, the terminologies used to code diseases
and adverse reactions must ensure the compatibility of reports
between involved parties. Reports entered into database should
be coded according to internationally accepted terminologies
(Med-DRA, WHO ART, ICD 9) or with mutually accepted terms enabling
connections with internationally accepted terminologies, which
are compatible with Med-DRA, version2.
Reaction terms should
be entered as the closest term available in the terminology,
and, if possible, also in the original reporter’s words. Use
of terminologies should be monitored and validated, either systematically
or by regular random evaluation. Data entry staff should be
instructed in the use of terminologies, and its proficiency
3.1.5. Case report processing: evaluation
of seriousness/expectedness and presentation for transmission
report processing concerns evaluation of data in individual
cases, identification of individual cases requiring specific
handling, recognition and processing of alerts, and any other
data processing of multiple cases.
Evaluation of data in
Data evaluation includes validation of the
case report and determination of seriousness, and of expectedness
of the suspected reaction. These terms (seriousness and expectedness)
have specific meanings in the context of ADR report evaluation.
Evaluation of the probability of the causal relationship between
medicinal product and the suspected reaction(s) is undertaken
when considered appropriate. All method used to evaluate these
parameters should be documented. Evaluators should be trained
in the methods used and their training verified.
of duplicate reports
Some cases, especially those, which
are serious, will probably be reported to NMA-NPVC from more
than one source or from a single source through more than one
channel. The NMA-NPVC should make every effort to ensure that
case reports contain sufficient information to identify such
duplicates, e.g., from patient/reporter initials (or names if
allowed), addresses, date of birth, other dates.
should be reviewed regularly to identify duplicates in accordance
with NMA-NPVC’s procedures. After identification, duplicates
should be flagged as such.
Identification of individual cases
requiring specific handling
Database management should ensure
compliance with regulations, e.g., identification of cases flagged
as serious or unexpected and any other circumstance requiring
specific handling or transmission. Procedures should be in place
to ensure that cases previously identified and processed are
identified as such and not processed or transmitted repeatedly
as new cases (see Audit trail).
Individual case presentation
Cases sent to other competent authorities
or MAH should be transmitted according to the approved formats,
as defined by European guidelines.
Multiple case processing
and alert identification
Database management should enable
users to identify multiple cases or trends indicating a signal.
Once a possible signal has been identified, the possibility
of a causal relationship should be assessed. In these cases,
all adverse drug reaction reports should be classified according
to national preferences or requirements, using nationally or
internationally accepted methodologies. All reports fulfilling
the minimum information requirement must be included in the
overall analysis. Certain analyses (e.g., those concerning the
role of risk factors) may be confined to cases where enough
information is available, but it should be made clear that this
is a subset of the data.
Multiple case processing should
allow case grouping by accepted terms (see Terminologies). The
terminology used for multiple case should be specified.
authorities and MAH should inform each other of identified signals,
which may impact on the risk-benefit profile of the medicinal
product. The rapid alert should be used by NMA-NPVC when applicable.
should ensure that the reporter(s) of a case is informed of
its receipt and registration with a certain number and additional
information submitted, if requested.
NMA-NPVC should ensure
that adverse reaction data are transmitted to the MAH as required.
should also ensure that the physician (and when necessary, treated
patients) is informed of any significant changes where appropriate
in the SPC and any suspected hazards requiring vigilance.
should ensure that proper and timely information is provided
to international bodies, in particular to WHO, in accordance
with the European guidelines.
control and quality assurance
Quality control and quality
assurance concern every step in the processes described above.
Quality control and quality assurance should be ensured by NMA-NPVC,
which should devise and implement the necessary procedures.
confidentiality and security
Confidentiality of patient records
including its personal identity, if given, should always be
maintained; where possible, identifiable personal details of
reporting health care professionals should be kept in confidence
and appropriate and in accordance with national and European
At each stage of storage and processing of pharmacovigilance
data, all care must be taken to ensure data security and confidentiality.
This involves strict control of access to documents and to database
to authorized personnel keeping the medical and administrative
confidentiality of the data. This security extends to the complete
data path. Case report information should only be provided in
an anonymous form.
In addition, procedures should be taken
to ensure security and noncorruption of the data during data
3.2. Company derived
According to aforementioned
legislation, the MAH of any medicinal product must ensure that
he has an appropriate system of pharmacovigilance in place in
order to ensure responsibility for this product on the market
and to ensure that appropriate action can be taken, when necessary.
derived pharmacovigilance information will be presented in one
of the following formats:
reaction case reports
safety update reports
sponsored post-authorization safety studies.
deals with the procedures, to be undertaken the NPVC for handling
company-derived pharmacovigilance data.
reactions case reports
NPVC should ensure that all reports
submitted by the MAH conform to the requirements as laid out
in the legislation, in order to ensure conformity of reporting
of adverse reactions by the MAH. NPVC must ensure the validation
and verification of all data included in these case reports
as far as possible. NPVC should ensure that these reports are
followed up by the MAH where appropriate, in order to improve
the quality of data available and to facilitate causality assessment.
NMA-NPVC should ensure that they have the capability to send
and receive ADR reports electronically and to encourage MAH
to do so in a defined format.
safety update reports
A periodic safety update report is
intended to provide the NMA-NPVC with an update of the entire
safety experience of a medicinal product at defined times post-authorization.
It is the responsibility of NPVC to evaluate these reports
– for authorized products.
sponsored post-authorization safety studies
are normally conducted to asses the clinical safety of marketed
medicinal products in routine clinical practice; they may be
either hypothesis-generating or hypothesis-testing. MAH proposing
to perform such studies is advised to discuss the draft protocol
with the NMA.
NPVC may review studies, which are taking place
within its jurisdiction on a regular basis. All serious adverse
reactions, resulting from these studies, should be submitted
for examination in the usual way by the MAH/investigator and
should be in accordance with as outlined below.
of each study, the final report should be evaluated and all
relevant data (e.g., showing significant changes in the frequency
of known adverse reactions, the development of unexpected adverse
reactions, new interactions) should be incorporated in the SPC.
3.2.4. NMA-NPVC should
ensure that they communicate with MAH according to existing
European legislation and guidelines
data from other sources
3.3.1. Intensive monitoring
Intensive monitoring is defined as a system of report
collation in designated areas e.g., hospital units or by specific
physicians in community practice. NMA-NPVC may be involved in
the drawing up of the protocol to undertake this collection
of data or it will be informed that such monitoring is taking
It may be considered appropriate in the authorization
of certain medicinal products to impose specific requirements
in respect of reporting of serious or unexpected reactions of
prescribed medicinal products on the physician and to make these
requirements a condition of use of the product under the terms
of the marketing authorization.
NPVC should ensure that data
and reports are collected at agreed intervals and in an appropriate
3.3.2. Data on misuse/abuse of medicinal
Reports of suspected adverse reactions due to misuse
and abuse of medicinal products (associated with therapeutic
use), that are received by the NPVC (via spontaneous reports,
company reports, etc) should be handled in the same way as for
the other types of reactions.
These data include medicinal product
usage figures, published adverse reaction reports, pharmacoepidemiology
studies conducted by organizations – other than the MAH, pre-clinical
studies or significant quality data and reports on products
not currently marketed in the EU. These are important for determining
frequency, occurrence of unexpected adverse reactions, new interactions,
etc, and overall risk/benefit analysis.
In those cases (e.g.,
from pharmacoepidemiology studies) where significant data are
received from these sources, these findings may be transmitted
to the EU, CADREAC countries and the EMEA, as part of a routine
exchange of pharmacovigilance information, with a view to taking
action as appropriate.
It is also accepted the signaling
of adverse reactions from patients and pharmacists.
for communications and evaluation of pharmacovigilance issues
in the EU
This section describes the procedures
that should be implemented in order to improve the communication
of pharmacovigilance information within the EU and to optimize
human resources for identifying and evaluating pharmacovigilance
The presented aspects refer to:
of serious and other adverse reactions reports – general principles.
for transmitting and management of detected signals.
for the final report evaluation of company sponsored post-authorization
Procedures for the evaluation of PSUR.
safety monitoring of medicinal products.
data transmission to facilitate the implementation of the procedures
conforming the European Pharmacovigilance System.
of serious adverse reactions reports
All serious suspected
reactions, occurring within the EU and notified to the NPVC
should be transmitted to the MAH and in case of centrally authorized
products to the EMEA within 15 days of receipt by the NPVC.
In the case of centrally authorized medicinal products, it is
the responsibility of the EMEA to inform NMA-NPVC of serious
adverse reaction reports received from EU Member States. The
method of transfer of information to be used should be such
as to ensure that the information is transmitted within the
time frame outlined in the European legislation. The data transmitted
should be as complete as possible in order to facilitate assessment
but it is not obligatory for the NPVC to have made a formal
evaluation before this transmission (see Rapid alert).
of other adverse reaction reports
These include non-serious
expected or unexpected adverse reaction reports, which are received
from all sources.
Whenever appropriate, these data should
be available for transmission, in summary form, to all relevant
parties (MAH, EU Member States, EMEA), as outlined below (see
Urgent exchange of pharmacovigilance information). Only data,
evaluated by the NPVC are considered for transmission here.
for transmission and management of detected signals
a potentially serious safety problem (e.g., a series of unexpected
or serious adverse reactions or an increase in the reporting
rate of a known adverse reaction) for a certain product has
been detected by the NPVC, it should be transmitted to the Member
States, EU and EMEA. It is essential that the communication
of the problem be made at an early stage, before a national
decision is taken.
There are two ways for communicating this
kind of information: rapid alert and non-urgent exchange of
The purpose of the Rapid Alert
System (RAS) is to inform with the appropriate degree of urgency,
the EU Member States, the European Commission and the EMEA on
pharmacovigilance data of medicinal products. NMA-NPVC is responsible
for contacting the MAH, when appropriate. Rapid alerts concerning
batch problems are not considered in these guidelines.
criteria for sending a rapid alert is the concern about a change
in the balance between risks and benefits that could lead to
major changes in the authorization such as its urgent suspension
or withdrawal, the introduction of major contraindications,
restrictions in the indications or availability of a product.
should also include any such action initiated by the MAH.
exchange of pharmacovigilance information
The criteria for
non-urgent exchange of pharmacovigilance information are:
for information from EU Member States, the European Commission
and the EMEA, which may relate to a variety of safety issues
which, may require non-urgent actions or minor changes of the
Exchange of information between involved parties which
does not require any response.
Prior to circulation of such
information, if NMA-NPVC considers a pharmacovigilance hazard
it should contact the raporteur and the EMEA in case of centrally
Electronic transmission using the template
available on EudraNet web-page will be preferred mode of information
exchange. It is important that this exchange of pharmacovigilance
information is focused on important issues so that involved
parties do not become overloaded with information.
to be followed in this exchange of pharmacovigilance information
is as follows:
The information should be clearly labelled
as non-urgent exchange of pharmacovigilance information.
reason for sending the information should be clearly stated.
information required of recipients should be specified clearly.
should only be sent to the originator of the request and the
The originator of the request should collate the information
received and send this to all EU Member States, only if the
originator of the request wishes the issue to be considered
at the pharmacovigilance working groups.
for the final report evaluation of company-sponsored post-authorization
With regard to company-sponsored post-authorization
safety studies, a final study report has to be sent by the MAH
to the NMA-NPVC and in case of centrally authorized products
to the EMEA.
In case of studies conducted for nationally
authorized medicinal products the NMA-NPVC should be responsible
for the evaluation of the final report.
In case of medicinal
products authorized through centralized procedure, the raporteur
who evaluated the product for its authorization will normally
assess the final report. A co-raporteur may also be appointed
by the Committee for Proprietary Medicinal Products (CPMP).
data from the study have to be evaluated and an assessment report
will be elaborated as a result. This report has to be distributed
among EU Member States/CPMP/EMEA, as appropriate within three
months of receipt of the formal report from the MAH.
pharmacovigilance issue demanding an action is identified in
any phase of the evaluation, it will be communicated using the
appropriate procedure as described above, including at least
the minimal data and the assessment report.
for the evaluation of PSUR
In accordance with the in force
legislation, NMA-NPVC and the EMEA will receive regular safety
update reports from the MAH.
In the case of medicinal products
authorized through the centralized procedure, the rapporteur
who evaluated the product for its authorization will normally
assess the PSUR within the agreed timetable.
report will be elaborated and distributed by the rapporteur
to all EU Member States and EMEA according to the timetable
adopted by the CPMP for medicinal products authorized via the
4.Changes to marketing authorization
NMA-NPVC as part of its obligation to undertake ongoing evaluation
of risk/benefit assessment must ensure that all pharmacovigilance
data received and evaluated, as outlined above, are taken into
account on an ongoing basis.
In the case of nationally authorized
medicinal products, where updated pharmacovigilance data are
seen to adversely effect the benefit/risk profile of the medicinal
product, the NMA may wish to modify or withdraw the Marketing
Authorization or not to renew it as appropriate. Any significant
change to the Marketing Authorization status or SPC, undertaken
nationally as a result of these pharmacovigilance data should
be notified to the other EU Member States and the EMEA by the
In the case of centrally authorized medicinal products,
changes in the SPC or Marketing Authorization status are undertaken
according to Commission Regulation EC 542/95.
The MAH may
take provisional urgent safety restrictions in the event of
risk to public health. These must be notified to the EMEA and
the rapporteur (in case of centrally authorized products) within
24 hours before implementation. The EMEA and national authorities
have an opportunity to comment these measures. The change must
be submitted as type II variation as quickly as possible after
implementation. An urgent safety restriction for centrally authorized
products may also be initiated by the European Commission.
accordance with the European legislation (Art. 12, 15a and 15b
of Directive 75/319/EEC, as amended, and Art. 18 of Council
Regulation (EEC) 2309/93), NMA, European Commission or MAH may
refer a pharmacovigilance matter to the CPMP whenever the interests
of the community required so.