- Regulations concerning pharmacovigilance activity


- Guideline for procedure to be followed by Competent Authorities on undertaking pharmacovigilance activities


- Guideline for procedure to be followed by marketing Authorization Holder on undertaking the pharmacovigilance activities




- Guideline for procedure to be followed by Competent Authorities on undertaking pharmacovigilance activities


1.      Introduction 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.
In accordance 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 Agency.
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.

2.      Establishment 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.
National Medicines 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).

3.      Management of pharmacovigilance data
This section describes the following procedures:
Management of spontaneous reporting system
Management of pharmaceutical company derived pharmacovigilance data
Management of pharmacovigilance data from other sources
Procedures for communications and evaluation of pharmacovigilance issues within the EU

3.1.    Spontaneous reporting system

3.1.1.  Introduction
National Medicines 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).
National 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:
Reporting of adverse reactions to the designated centre is made as simple as possible;
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:
regular publishing 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.

3.1.2.  General principles of spontaneous reporting system
Physicians or 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, etc.
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.
The following procedures relate to the NMA-NPVC and are independent of the structure of the national pharmacovigilance system.
These procedures are divided into:
case report collection and validation and case report storage;
case report processing (evaluation and presentation for transmission), feedback information;
protection of data confidentiality and security, data quality control and quality assurance.

3.1.3.  Case report collection and validation
 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 be followed.
Case report collection
A pharmacovigilance 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
If 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).
Completeness of reports should be evaluated according to data required or forms for data transmission (see Individual Case Presentation for Transmission).
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.
A 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 storage
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 terminologies.
Data entry
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.
Audit trail
Storage 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 verified.

3.1.5.  Case report processing: evaluation of seriousness/expectedness and presentation for transmission
Case 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 individual cases
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.
Management 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.
Database 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 for transmission
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.
Competent 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.

3.1.6.  Information
NMA-NPVC 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.
NMA-NPVC 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.
NMA-NPVC should ensure that proper and timely information is provided to international bodies, in particular to WHO, in accordance with the European guidelines.

3.1.7.  Quality 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.

3.1.8.  Data 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 legislation.
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 transfers.

3.2.    Company derived pharmacovigilance data
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.
Company derived pharmacovigilance information will be presented in one of the following formats:
1.      Adverse reaction case reports
2.      Periodic safety update reports
3.      Company sponsored post-authorization safety studies.
This section deals with the procedures, to be undertaken the NPVC for handling company-derived pharmacovigilance data.

3.2.1.  Adverse 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.

3.2.2.  Periodic 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.

3.2.3.  Company sponsored post-authorization safety studies
These 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.
On completion 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

3.3.    Pharmacovigilance data from other sources

3.3.1.  Intensive monitoring schemes
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 place.
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 format.

3.3.2.  Data on misuse/abuse of medicinal products
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.

3.3.3.  Other pharmacovigilance data
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.

3.4.    Procedures 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 signals.
The presented aspects refer to:
Transmission of serious and other adverse reactions reports – general principles.
Procedures for transmitting and management of detected signals.
Procedures for the final report evaluation of company sponsored post-authorization safety studies.
Procedures for the evaluation of PSUR.
Special safety monitoring of medicinal products.
Technologies on data transmission to facilitate the implementation of the procedures conforming the European Pharmacovigilance System.

3.4.1.  Transmission 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).
Transmission 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.

3.4.2.  Procedures for transmission and management of detected signals
Once 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 information.
Rapid alert
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.
The 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.
This should also include any such action initiated by the MAH.
Non-urgent exchange of pharmacovigilance information
The criteria for non-urgent exchange of pharmacovigilance information are:
Requests 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 SPC.
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 authorized products.
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.
The procedure 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.
The reason for sending the information should be clearly stated.
Any information required of recipients should be specified clearly.
Responses should only be sent to the originator of the request and the EMEA.
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.

3.4.3.  Procedures for the final report evaluation of company-sponsored post-authorization safety studies
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).
All 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.
If any 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.

3.4.4.  Procedures 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.
An assessment 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 centralized procedure.

4.Changes to marketing authorization
The 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 NMA.
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.
In 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.