The Process of Regulatory Pharmacovigilance in the EU

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Chapter: Pharmacovigilance: Regulatory Pharmacovigilance in the EU

Regulatory pharmacovigilance is dependent on the availability of information on the clinical effects of medicines in representative populations as used in normal practice.


Regulatory pharmacovigilance is dependent on the availability of information on the clinical effects of medicines in representative populations as used in normal practice. In addition to systems for collect-ing and handling suspected ADRs, processes for iden-tifying and investigating signals are necessary. All potentially important hazards are investigated with a view to taking appropriate action based on the avail-able scientific evidence. The most important outputs of the process are actions to promote safer use of medicines. These include, for example introducing warnings, contraindications, information on ADRs or changes to dosing recommendations. Indications or methods of supply may also be restricted, although withdrawal of a medicinal product from the market on safety grounds is relatively unusual (Jefferys et al., 1998). Informing users and explaining the reasons for the action taken is a critical determinant of the effec-tiveness of these measures. The process of regulatory pharmacovigilance is summarised in Figure 14.1.


With a view to increase proactivity, the recently revised legislation has introduced the concept of risk management which is defined in the EU as a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those interventions. Some of its elements have already been agreed by the ICH in guideline E2E on pharmacovigilance planning and, together with current thinking, incorporate a ‘best evidence’ approach of the excellence model in pharma-covigilance (Waller and Evans, 2003). In terms of risk management, there is a need for use of best expertise and methods in safety studies and epidemiology to take this forward.


Potentially important safety issues can be identi-fied at any stage of drug development. In the post-authorisation phase, they are particularly likely to be identified in the first few years after marketing, although new issues also arise with long-established medicines. To ensure that safety problems which have not been recognised or fully understood pre-marketing are handled promptly, proactive processes are used for screening emerging data for potential issues and bring-ing together all the available information from multiple sources. In regulatory practice, a signal is an alert from any available source that a medicine may be associated with a previously unrecognised hazard or that a known hazard may be quantitatively (e.g. more frequent) or qualitatively (e.g. more serious) different from existing expectations.

The commonest source for identification of signifi-cant safety concerns arising with marketed medicines is spontaneous ADR reporting. These are individual case reports from health professionals of adverse events which the reporter considers may be related to the medicine(s) being taken. Reporters are not asked to provide all adverse events that follow administration of the medicine but to selectively report those which they suspect were ADRs. There is frequently confu-sion between the terms ‘adverse event’ and ‘adverse reaction’ which can be avoided by using the term ‘suspected adverse reaction’ when referring to a case or series of cases reported through a spontaneous report-ing scheme. The term ‘adverse event’ should be used in the context of studies where all events are being collected regardless of whether or not they are suspected to be related to a drug. This approach is underpinned by standard definitions given in EU legislation (Title I of Directive 2001/83/EC) and is also consistent with definitions proposed by the ICH in guidelines E2A and E2D (International Conference on Harmonisation, 2005).

Although formal studies of drug safety are partic-ularly used in the investigation of signals identi-fied by methods such as spontaneous ADR report-ing (i.e. hypothesis-testing), they may also provide the initial evidence producing a safety concern. Signals may also be detected from other sources such as literature reports and from screening of the international spon-taneous reporting database operated by the Uppsala Monitoring Centre in Sweden, a Collaborating Centre of the World Health Organization (Uppsala Monitoring Centre, 2005) to which EU Member States contribute data. Whatever the source of the signal, the aim is to identify it as rapidly as possible. The next steps are to inform other Member States, gather further information and conduct an evaluation.


When there is sufficient evidence of a hazard to warrant further investigation, detailed consideration is given to causality, possible mechanisms, frequency and preventability. Assessment of these issues may require new epidemiological studies, but the hypothesis may be strengthened or weakened using immediately available sources of retrospective information such as worldwide spontaneous reporting, published literature and epidemiological databases.

The broad principles relating to post-authorisation studies have been set out in guidelines for marketing authorisation holders (European Commission, 2006). When new data become available from purpose-designed studies, it is important that they are reviewed in the context of the existing data. An assessment is made of whether and how the new evidence changes the previ-ous evaluation, focusing particularly on the strength of the evidence for a drug-related association and possible approaches to prevention. In the latter respect, detailed analysis of the data to identify possible risk factors for the hazard is important.

The output of an evaluation is an assessment report that brings together the key information on the hazards and facilitates discussion of the risks and benefits of the medicine and possible measures which may facil-itate safe use. Experts in pharmacoepidemiology and relevant therapeutic areas are consulted and involved in such discussions both at national and EU level.


The objective of the EU competent authorities is to take regulatory actions which are justified by scien-tific evidence and allow users to make informed deci-sions and to use medicines safely. Sometimes, the balance of risks and benefits will be sufficiently clear to allow firm recommendations (such as contraindica-tions), whereas in other situations less directive advice will be warranted.

The types of action which may be taken vary accord-ing to potential means of preventing the ADR. In particular, hazards may be minimised by targeting the medicine at patients least likely to be at risk of the ADR and by specifically contraindicating it in patients with identifiable risk factors. Dose and duration of treatment are often important issues as the risk of many hazards is related to one or both of these parameters. It is quite common for dosage regimens to change during the post-marketing period in response to safety concerns, and many medicines have been initially recommended at doses higher than necessary. In re-evaluating dose in response to a safety concern, consideration is also given to the evidence of efficacy at lower doses.

The identification of a new ADR or the accumulation of important new evidence about a recognised reaction leads to a need to make changes to the product infor-mation and hence to vary the marketing authorisa-tion(s). Variations to marketing authorisations on safety grounds may be proposed by the competent author-ity or the pharmaceutical company. Regardless of who proposes the changes, there is exchange of informa-tion and discussion between the parties before a vari-ation is submitted to facilitate rapid implementation. When the competent authorities and companies are in agreement about the nature and impact of a drug safety issue, changes can be made on a voluntary basis by the marketing authorisation holder. However, if companies do not agree about the actions required, then the competent authorities may exercise compul-sory powers. In situations of particular urgency, the legislation provides for rapid processing of safety vari-ations where either the marketing authorisation holder or the competent authority can initiate an urgent safety restriction (USR) procedure that enables a change to the product information within 24 hours and is followed within 2 weeks by a formal variation (Commission Regulation (EC) No. 1084/2003; Commission Regu-lation (EC) No. 1085/2003). Exceptionally, when the issue has urgent public health implications, the author-ities may immediately withdraw the product(s) from the market. This can be effected either by suspen-sion of the authorisation(s) or by its revocation. The option to suspend is considered in situations whereby an urgent temporary measure is required as a precau-tion to protect public health whilst awaiting new data to emerge. Revocation is foreseen when data are already available demonstrating an unfavourable benefit–risk balance even in different sub-groups of patients.


Communicating information to users of medicinal prod-ucts is a vital step in the process of handling a safety issue with a marketed medicine. An important consideration is how quickly information needs to be made available to users. A new life-threatening ADR requires imme-diate communication, whereas the addition of informa-tion relating to a non-serious ADR could be added at the next routine revision of the product information. The distribution of safety information may be targeted at specialists or generalists or both, other relevant health professionals and at patients. The recently revised legis-lation has introduced new obligations for the Member States’ authorities and the EMEA in relation to such communication to the public. Additional requirements are also imposed on the companies and will even be enforced by penalty legislation. A particularly impor-tant aim in communications about drug safety is to ensure that essential information is clearly conveyed and not obscured by other less important information. Every effort is therefore made to word the key facts and recommendations unambiguously.

The key principles with patient information are that it should, in substance, be the same as the informa-tion provided to health professionals and it should be presented in language that the patient can understand. Good patient information adds to and reinforces the main issues that should be discussed between health professionals and patients and does not make state-ments which could interfere with that relationship. To respond appropriately to the patients’ demands, an EMEA/CHMP Working Group with Patient Organisa-tions is in operation since 2003 with one of its aims to provide overall recommendations and specific input to guidelines on communication and to new proce-dures, for example for testing of product information (EMEA/CHMP Working Group with Patient Organisa-tions, 2005). Similar initiatives have been undertaken at national level in some Member States and there is fruitful exchange of all experience gained.

Any change to the marketing authorisation and prod-uct information which has significant safety implica-tions is actively drawn to the attention of the rele-vant health professionals, usually by circulating the new product information under cover of a ‘Dear Doctor/Pharmacist’ letter (Direct Healthcare Profes-sional Communication). With regard to information targeted at health professionals, the EMEA has initi-ate dialogue with health professional organisations at EU level to support and complement national activities. When the changes being made are vital for ensuring patient safety, they are implemented very quickly, and it is normal practice to make information available to the media and general public through press releases and/or the Internet. Improvements in dissemination mecha-nisms are planned for the future.

The competent authorities recognise that successful communication about drug safety is a vital component of the pharmacovigilance process and needs EU-wide co-ordination. This is a particular challenge because of the need to translate messages into all the official languages used in the EU (currently 20), and consid-erable attention is being paid to improving this aspect of the process. Intensive thought is currently given to the enforcement of existing and establishment of new procedures to optimise EU-wide co-ordination of safety communication as well as to the assessment of public health impact of such communication. In terms of risk minimisation, targeted information to healthcare professionals and patients is seen as an important tool.

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