Legislative base on pharmacovigilance is Regulation 726/2004 and Directive 2001/83, amended by Directive 2004/24/EC and Directive 2004/27/EC.

The obligations regarding to pharmacovigilance is applicable to all medicinal products registered in EU including those registered before 1995 whatever of the authorization procedure used; it is not applicable to simplified registration, according to article 4 from 2001/83/EC Directive, for homeopathic medicinal products.


1. Roles and responsibilities of Marketing Authorization Holder


The marketing Authorization Holder (MAH) should ensure that it has an appropriate system of pharmacovigilance in place in order to assume responsibility and liability for his products on the market and to ensure that appropriate action may be taken when necessary. The MAH should therefore ensure that all information relevant to the risk- benefit balance of medicinal products is reported to the competent Authorities and the Agency fully and promptly in accordance with legislation.


When submitting an application for a marketing authorization, the Applicant, in preparation for the role and responsibilities as MAH, should submit a description of the pharmacovigilance system and submit proof that the services of a Qualified Person Responsible for Pharmacovigilance, residing in EU, hereafter to as QPPV, are in place.


•  The Role and Responsibilities of the Qualified Person Responsible for Pharmacovigilance

  • establishing and maintaining/managing the Marketing Authorization Holder's pharmacovigilance system
  • having an overview of the safety profile concerns in relation to the medicinal products for which the Marketing Authorization Holder holds authorizations;
  • Acting as a single contact point for the Competent Authorities

Pharmacovigilance system established and maintained by QPPV consists of:

  • ensuring that information about all suspected adverse reactions which are reported to the personnel of the Marketing Authorization Holder, and to medical representatives are collected and collected in order to be accessible at least one point within the EU
  • the preparation for Competent Authorities of the Member States, where the medicinal product is authorized, of the reports referred to in Article 104 of Directive 2001/83/EC and in case of centrally authorized products the preparation for the Agency and Competent Authority of the Member State of the reports referred to in Article 24 of Regulation 726/2004/EC . These reports are: Individual Case Safety Reports (ICSRs), Periodic Safety Update Reports (PSURs); reports on company sponsored post-authorization safety studies
  • the conduct of continuous overall pharmacovigilance evaluation during the post-authorization period
  • the provision to the Competent Authorities of any information relevant for the evaluation of the benefits and risks afforded by a medicinal product, and any at request information about the volume of sales or prescriptions of the medicinal product concerned

The MAH should adequately support the QPPV and ensure that there are appropriate processes, resources, communication mechanism and access to all sources of relevant information in place for the fulfillment of the QPPV's responsibilities and tasks.

A MAH may transfer any or all of the pharmacovigilance tasks and functions, including the role of the QPPV, to another person(s) or organization, but ultimate responsibility for the fulfillment of all pharmacovigilance obligations and the quality and integrity of this always resides with the MAH.


2. Description of the Pharmacovigilance System to be included in theMarketing Authorization Application


The Article 8(3)(ia) of Directive 2001/83/EC requires the Applicant for a marketing authorization to provide a detailed description of the system of pharmacovigilance and, where appropriate, of the risk management system which the Applicant will introduce.

The detailed description of the pharmacovigilance system, including the proof of the availability of the services of the QPPV and the proof that the MAH has the necessay means for the collection and notification of any adverse reaction, should be provided in Module 1/section 1.8.1 of the application dossier.

Updates to the information provided in the detailed description of the pharmacovigilance system should be made as type II variations.

Elements of the detailed description of the pharmacovigilance system

2.1 Qualified Person Responsible for Pharmacovigilance- should be located in the European Economic Area (EEA), the business address and contact details should be provided in the Marketing Authorization Application form. Also, a summary Curriculum Vitae of the QPPV with the key information relevant to their role, a summary of the job description of the QPPV and a description of the back-up procedure to apply in the absence of the QPPV should be provided.

2.2 Organization

  • identification and location of the Company Units or other organizations where the principal EEA and global pharmaceutical activities are undertaken (in particular those sites where the main databases are located, where Individual Case Safety Reports are collated and reported and where PSURs are prepared and processed for reporting to the Competent Authorities
  • identification of the point in the Community at which pharmacovigilance data are accessible
  • high-level organization chart providing an overview of the global and EEA pharmacovigilance units and organizations and illustrating the relationships between them
  • flow diagrams indicating the flow of safety reports and how are process and reported from the sources to the point of receipt by the Competent Authorities
  • written procedures for: the activities of QPPV, the collection, processing, quality control, coding, classification, medical review and reporting of ICSRs, organized data collection scheme (solicited, unsolicited, clinical trial, literature), reports from different sources, the follow-up reports, detection of duplicate reports, expedited reporting, electronic reporting, PSURs, continuous monitoring of the safety profile of authorized medicinal products, relations between safety profile and a product nonconformity; responses to request for information from regulatory authorities, handling of urgent safety restriction and safety variations, global pharmacovigilance activities, managementul and use of databases and other recording system, internal audit, training, archiving

2.3 Databases- a listing of the main databases used for pharmacovigilance purposes and their validation; a copy of the registration of the QPPV with EudraVigilance system and identification of the process used for electronic reporting to the Competent Authorities.

2.4 Contractual agreement with other persons or Organizations involved in the fulfillment of pharmacovigilance obligations- a brief description of the nature of the agreements the company establishes with co-marketing partners and contractors for pharmacovigilance activities

2.5 Training- attending training of pharmacovigilance staff and other persons involved: sales and clinical studies personnel

2.6 Documentation- a brief description of the locations of the different types of pharmacovigilance source documents, including archiving arrangements.

2.7 Quality management system- a brief description of the Quality management system making cross-reference to the elements of pharmacovigilance )corrective and preventive actions, audit)

2.8 Supporting documents - documents to ensure that the pharmacovigilance system is clearly documented, the system functions properly, that the role and responsibilities and the required tasks are clear to all parties involved and that there is provisions for proper control and, when needed, change of the system.


3. Risk management


Risk management is a set of pharmacovigilance activities and interventions designed to ensure that the benefits of a particular medicine exceed the risk for the individual patient and for the target population as a whole. The management of a single risk can be considered as having four steps, risk detection, risk assessment, risk minimization and risk communication. A positive risk-benefit balance can be done either by increasing the benefits or by reducing the risk but, by its definition, risk management focuses upon the risk reduction approach.

The description of a risk management system should be submitted in the form of an EU- Risk Management Plan (EU-RMP). The EU-RMP contains two parts:

Part I:

•  a safety specification

•  a pharmacovigilance Plan

Part II:

•  an evaluation of the need for risk minimization activities

•  a risk minimization plan

In Part II of the EU-RMP, on the basis of the safety Specification, the Applicant/MAH should consider necessary the need for “routine activities” or “additional activities”. If only “routine risk minimization activities” are required there is no need to submit a risk minimization plan. If “additional activities” are necessary , sending the risk minimization plan should be considered and should contain both the routine and additional activities for each safety concern.

3.1 Situations requiring an EU-RMP

An EU-RMP may need to be submitted at pre-authorization, post-authorisation and in the following particular situations:

  • with the application for a new marketing authorization for:
    • any product containing a new active substance
    • a similar biological products
    • a generic/hybrid medicinal product where a safety concern requiring additional risk minimization activities has been identified with the reference medicinal product

•  with an application involving a significant change in a marketing authorization (e.g. new dosage form, new route of administration, new manufacturing process of a biotechnologically-derived product, significant change in indication) unless it has been agreed with the Competent Authority that submission is not been required

•  on request from a Competent Authority

•  at the initiative of an Applicant/MAH when identify a safety concern with a medicinal product at any stage of its life cycle.

For significant changes to an existing centralized marketing authorization, the MAH should discuss the need for an EU-RMP with the Agency at least two months in advance of the submission; if an EU-RMP is not mandatory the Applicant/MAH should submit a brief justification of this along with the application.

In cases of Marketing authorization via the mutual recognition or decentralized procedures, the Competent Authority of the Member State and of the Reference member State should be consulted.

3.2 Safety specification

The Safety Specification should be a summary of the important identified risks of a medicinal product, important potential risk and important missing information. The Safety Specifications is intended to help industry and regulators identify any need for specific data collection and also to facilitate the construction of the Parmacovigilance Plan.

Safety Specification should consist of:

  • non-clinical part of the Safety Specification
    • toxicity (including repeat-dose toxicity, reproductive/developmental toxicity, nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenity)
    • general pharmacology
    • drug interaction
    • other toxicity- related information or data

•  clinical part of the safety specification

•  limitation of safety database to populations likely to be exposed during the intended or expected use of the product in medical practice

•  populations not studied in the pre-authorisation phase (children, the elderly, pregnant and lactating women, patients with relevant co-morbidity such as hepatic or renal disorders, patients with disease severity different from that studied in clinical trials

•  sub-population carrying known and relevant genetic polymorphism

•  patient of different racial and/or ethnic origins

•  adverse events/adverse reactions (identified risks that require further evaluation, potential risks that require further evaluation, presentation of the risk data)

•  identified and potential interactions including food- drug and drug- drg interactions

•  epidemiology

•  pharmacological class effects

•  additional EU requirements: potential for overdose, potential for transmission of infectious agents, potential for misuse for illegal purposes, potential for off- label use, potential for of-label pediatric use

•  summary- at the end of the safety Specifications, a summary should be provided of the: important identified risks, important potential risks and important missing information.

3.3 Pharmacovigilance Plan

Pharmacovigilance Plan should be based on the Safety Specification and propose actions to address the safety concerns identified. There is a Routine Pharmacovigilance Plan and an Additional Plan for medicinal products with important identified risks, important potential risk and important missing information.

3.4 Evaluation of the need for Risk Minimization Activities

For each safety concern, the Applicant/MAH should assess whether any risk minimization activities are needed. Some safety concerns may be adequately addressed by the proposed actions in the Pharmacovigilance Plan, but for others the risk may be of a particular nature and seriousness that risk minimization activities are needed.

For some risks, routine risk minimization activities will not be sufficient and additional risk minimization activities will be necessary. If these are required, they should be described in the risk minimization plan which should be included in Part II of the EU-RMP.

Methods for risk minimization

  • provision of information to Healthcare Professionals and/or Patients on the specific risk of a product and the measures on how to reduce them (information in Summary of Product Characteristic, Package Leaflet, additional educational material if needed)
  • legal status of medicine- controlling the conditions under which a medicine may be made available to the Patients
  • the control at pharmacy level by informing patients
  • control of prescription size or validity
  • informed content and other patient aspects
  • restricted access programs- to those patients who agree to take part in a specific surveillance program
  • patient registries- to control access to a medicine


4. Expedited Reporting of Individual Case Safety Reports


The MAH is expected to validate all adverse reactions reported by Healthcare Professionals to ensure, prior to reporting to the competent Authorities, that the minimum information required is included in the report:

•  an identifiable Healthcare Professional reporter (name or initial, address or qualification, contact details)

•  an identifiable Patient (initials, patient number, date of birth, age, age group or sex)

•  at least one suspected active substance/medicinal product

•  at least one suspected adverse reaction

The MAH should transmit all ICSRs requiring expedited reporting promptly and no later than 15 calendar das from receipt.

Other sources for adverse reactions should be reports published in the worldwide literature, internet, data collection systems (clinical studies, post-authorization studies, management disease programs, information about patients compliance).

Electronic reporting by Eudravigilance is a must.

4.1 Requirement for reporting in special situations

Adverse reactions should be reported regardless of whether or not the medicinal product was used in accordance with the authorized Summary of Product Characteristics (SPC) and/or any other conditions laid down for the marketing of the product.

In addition to routine expedited and periodic reporting requirement the MAH should be aware of the following additional reporting requirement relating to world wide experience with the medicinal product:

  • reporting in the period between the submission of the marketing authorization application and the granting of the marketing authorisation
  • reporting of outcomes of use of a medicinal product during pregnancy
  • reporting of pediatric data
  • reporting for compassionate/named-patient use
  • reporting of lack of efficacy
  • reporting of suspecting transmission of infectious disease
  • reporting in relation to overdose, abuse, misuse
  • reporting of medication errors.


5. Requirements for Periodic Safety Update Reports (PSURs)


A Period Safety Update Report is intended to provide an update of the worldwide safety experience of a medicinal product to Competent Authority at defined point time post-authorization.

At these times, MAHs are expected to provide succinct summary information together with a critical evaluation of the risk-benefit balance of the product in the light of new changing information. This evaluation should ascertain whether further investigations need to be carried out and whether changes should be made to the marketing authorization and product information.

5.1 Frequency of reporting

Regular and ad hoc submission of PSURs

  • before initial placing on the EU market- immediately upon request from a Competent Authority or the Agency and at least every 6 months after authorization
  • after initial placing on the EU market- 6- monthly for the first two years, then yearly for the following two years and thereafter at 3 yearly intervals
  • immediately upon request from a Competent Authority or for centrally authorized product, from the Agency

When yearly or 3-yearly PSURs are due for submission, multiple 6-monthly or yearly PSUR are acceptable, provided that the MAH submits a PSUR Summary Bridging Report; the MAH should sent them only at the required due date (yearly or 3-yearly).

If a time gap occurs between the data lock point of a regular PSUR and a request form a Competent Authority, a PSUR Addendum Report should also be submitted. For a PSUR that spans longer time intervals, e.g. 3 years, an Addendum Report would only be considered if the time since preparation of the 3-year PSUR and the locally required report is greater than 6 months.

Submission of PSURs for Renewal of marketing Authorization

The MAH should submit safety data with renewal application at least 6 months before the expiry date of the marketing authorization in the EU; the MAH should lock the data no more than 60 days before submitting the PSUR

Circumstances where the periodicity may be amended

  • less frequent submission:
    • products authorized through line0extensions to existing medicinal products
    • newly authorized generic medicinal product

•  more frequent submission:

•  variations introducing new indications, populations, dosage forms and route of administrations

•  an active substance which is a different salt/ester or derivative (with the same therapeutic moiety)

•  the presence of an excipient without an established safety profile

•  a Risk management Plan in place for a corresponding originator product requiring specific monitoring of a safety profile

In order to harmonize the PSURs submission internationally, the MAH may use the International Birth Date- IBD to determine the dates of the data lock point for the PSUR submission schedule.

The IBD is the date of first marketing authorization of a medicinal product granted to the MAH anywhere in the world.

5.2 Model for a Periodic Safety Update Report (PSUR)

5.2.1 “Executive Summary”

  • the worldwide marketing authorization status (a list of countries where the product is authorized/marketed and the authorized indications
  • other relevant regulatory information related to the period covered by the PSUR (e.g. any urgent safety restriction should be highlighted)
  • exposure data
  • number of new case reports received during the period covered by the PSU and the cumulative numbers
  • particular issues and safety concerns investigated
  • overall findings of the PSUR
  • conclusions

5.2.2 “Introduction”

The MAH should briefly introduce the product so that the PSUR “stands alone” but is also placed in perspective to previous PSURs and circumstances.

5.2.3 “Worldwide Marketing Authorization Status”- provide cumulative information, usually for all countries where the product granted an authorization

5.2.4 “Update of Regulatory Authority or Marketing Authorisation Holder Actions taken for Safety Reasons”

  • marketing authorization withdrawal, revocation or suspension
  • failure to obtain a marketing authorization renewal
  • restrictions on distribution
  • clinical trial suspension
  • dosage modification
  • changes in target population or indications
  • formulation changes
  • urgent safety restriction

5.2.5 “Changes to Reference Safety Information”- Company Core Data Sheet (CCDS) with its Company Core Safety Information (CCSI) should normally be used as the reference information

5.2.6 “Patient Exposure” – Patient exposure often relies on gross approximations of in –house or purchased sales data or volume

5.2.7 “ Presentation of Individual case Histories” – This section should contain a description and analysis of selected cases containing new or relevant safety information and grouped preferably by medically relevant headings/MedDRA System organ Classes (SOCs).

5.2.7 (a) “Cases presented as Line –Listings” –The types of cases referenced below should be included in the line –listings:

•  all serious adverse reactions and non-serious unlisted adverse reactions form spontaneous reporting and post-authorization safety studies (PASS)

•  all serious adverse reactions ) attributable to the medicinal product by either investigator or sponsor) available from studies (including those which are part of the Risk Management Plan) or named- patient/compassionate use

•  all serious adverse reactions and non-serious unlisted adverse reactions form literature

•  all serious adverse reactions transmitted to the MAH by worldwide regulatory authorities

Line- listing(s) should include each Patient only once regardless of how many adverse reactions terms are reported for the case. If there is more than one reaction, they should all be mentioned but the case should be listed according to the most serious adverse reactions (signs, symptom or diagnosis), as judged by the MAH.

It is possible that the same Patient may experience different adverse reactions on different occasions (e.g. week apart during a clinical trial). Such experience should be treated as separate reports. Under such circumstances, the same patient might then be included in a line –listing more than once, and the line-listings should be cross-referenced when possible.

Where common PSUR are submitted, the line-listings should still reflect the invented name of the medicinal product (or the active substance name if the invented name of the medicinal products is not available) as reported by the original reporter.

The following headings should usually be included in the line-listings:

  • MAH case reference number
  • Country in which the case occurred
  • Source (e.g. clinical trial, literature, spontaneous, regulatory authority)
  • Age and sex of the Patient
  • Daily dose of the suspected medicinal product (and, where relevant, dosage form or route)
  • Date of onset of the adverse reaction
  • Dates of treatment
  • Description of adverse reaction as reported and when necessary as interpreted by the MAH
  • Patient outcome
  • Comments if relevant

5.2.7 (b) “Case presented as Summary Tabulations”

5.2.7 (c ) “ Marketing Authorization Holder's Analysis of Individual Case Histories”

5.2.8 “Description of all studies” ( non-clinical, clinical, epidemiological ) yielding safety information (this includes lack of efficacy data) with a potential impact on product information.

5.2.9 “Other information”

  • Efficacy-related information
  • Late- breaking information
  • Risk-management plan
  • Risk-benefit analysis report

5.2.10 “Overall safety evaluation”

5.2.11 ”Conclusion”


6. Rapid alert


A rapid alert (RA) should be used when a member State has a safety concern, which potentially has a major impact on the known risk-benefit balance of a medicinal product and which warrant prompt regulatory action and communication to Healthcare Professionals and the general public




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