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Recent Developments

The handling of medicinal product safety crises is generally managed at an EU level. Serious concerns with regard to product safety – especially where the product is on the market of more than one member state – are considered at European level. In December 2010, new pharmacovigilance legislation was adopted to reinforce the coordinating role of the European Medicines Agency (EMA), improve the possibilities for detection of signals (or potential safety concerns) and facilitate the operation of coordinated procedures at EU level to respond to safety concerns (1). A new committee – the Pharmacovigilance Risk Assessment Committee (PRAC) – was created at the EMA, while a coordination group of member state representatives – the Co-ordination Group for Mutual Recognition and Decentralised Procedures – human (CMDh) – was also formally established and tasked with examination of pharmacovigilance questions, as well as approving and monitoring risk management systems. 

With regard to companies holding or seeking marketing authorisations (MAs), the revisions aimed to strengthen companies’ pharmacovigilance systems, largely by concentrating information into a global ‘living’ document in the form of a pharmacovigilance system master file (PSMF), due by July 2015 at the latest. The revisions require companies to operate risk management plans (RMPs) for all new products – including generics, but excluding traditional use herbal medicinal products and simplified registration procedure homeopathic products – and for products with safety concerns. MA holders are also required to initiate proactive, structured pharmacovigilance data collection – including via conduct of required post-market studies.

The revisions also aimed to reduce the administrative burden of duplicative reporting and assessments by enabling companies to file safety reports centrally, via the EudraVigilance data processing network, and by gradually establishing a single assessment procedure (and EU repository) for periodic safety update reports (PSURs) for several centrally or nationally authorised medicines containing the same active substance(s). This is done through a harmonised European reference date list, operated by the Committee for Medicinal Products for Human Use (CHMP) and the CMDh. The latter became binding in April 2013, but the repository is still awaited. Furthermore, the promised efficiencies of centralised adverse drug reaction (ADR) reporting by MA holders are still a way off, as it is expected to take until 2015 before the EudraVigilance website functionality has been upgraded and satisfactorily audited, allowing this to begin.

One aim of these changes is to accelerate and increase the updating of product and patient information with important safety information derived from pharmacovigilance – thereby improving both the understanding and trust of patients and health professionals regarding pharmaceuticals, by increasing transparency and communication.

Early ‘Stress Testing’

Prior to the mandatory implementation of the new pharmacovigilance legislation (which started in July 2012), the European Commission introduced additional pharmacovigilance proposals in February 2012 to further reinforce the new measures, after the well-known Mediator case raised concerns about the adequacy of the new framework. This case became a strong media focus in 2011 and concerned the diabetes medicine, Mediator – manufactured by Laboratoires Servier – which was reported to have been frequently prescribed off-label for obesity, despite concerns about its safety profile.

The product was taken off the market in France in 2009, having previously been withdrawn in Spain and Portugal. Regulators in France, and also at the EMA, were criticised for having failed to adequately evaluate safety issues and for not intervening earlier by removing or restricting the product on the EU market. The Mediator case ultimately led to the reorganisation and re-naming of the French medicines regulatory authority in 2011.

This early ‘stress testing’ of the new pharmacovigilance measures led to the introduction of amending legislation imposing an automatic EU-level review of, and response to, safety concerns for all products (2) – whether authorised via mutual recognition or centrally – where safety concerns result from pharmacovigilance. This additional legislation requires MA holders to state reasons for any temporary or permanent interruption in, or cessation of, medicine supply. It also requires member states and the Commission to inform each other of, initiate an urgent EU procedure to verify and, if appropriate, react to safety concerns about a medicine, if questions arise from the evaluation of pharmacovigilance data. This obligation arises where the evaluation of the data causes the member state or the Commission to consider suspending or revoking an MA; to prohibit supply; or to refuse a renewal of an MA; or alternatively, where they have been informed by the holder that supply has been interrupted on safety grounds. Finally, member states and the Commission are also required to inform each other whenever dose reductions, new contraindications or restrictions are considered – and the urgent EU procedure may then be initiated where a member state or the Commission considers it necessary.

Alternative Measures

In addition to the main pharmacovigilance measures outlined above, the EU legislation package required the EMA to:

  • Collect specified information on all medicines authorised in the EU
  • Develop detailed implementation processes for pharmacovigilance in the form of 15 modules of guidelines on Good Pharmacovigilance Practices, the majority of which have now been finalised, together with product- or population-specific additional chapters
  • Increase transparency around the conduct of pharmacovigilance, including broadened access to the EU pharmacovigilance database – EudraVigilance – and publication of PRAC, CHMP and CMDh meeting agendas and minutes; and also, in some circumstances (currently being defined), via public hearings of the PRAC
  • Develop a European medicines web portal linked up to member states’ national web portals – in practice this will be the EMA’s own upgraded website

As part of the overall package, certain products are now required to carry an inverted black triangle symbol, indicating they are subject to additional five-year monitoring. This affects all new active substances, biologicals, and exceptionally or conditionally authorised products, but also products where there has been a Commission or member state request following consultation with the PRAC.

Member states are also required to promote reporting of suspected ADRs by patients and to encourage healthcare professionals to contribute to pharmacovigilance through reporting of ADRs, as well as by implementing risk minimisation advice received – for example, via updated product information or direct healthcare professional communications.

Meanwhile, in 2013, the Commission considered whether to exercise its option to adopt a delegated act in order to specify the situations in which post-market efficacy studies should be required to be undertaken by MA holders. Such studies are explicitly referred to in the new pharmacovigilance legislation and are now subject to a greater level of regulatory oversight, including review of study protocols by the PRAC at its meetings.

The proposal to provide guidance via a delegated act has been cautiously welcomed; concerns have been expressed that such a step could be seen by regulatory authorities as an invitation to regularly impose such studies – or else impose over-rigid requirements regarding study design – rather than considering the need for, or the design of, these studies on a case-by-case basis. Concerns have also been expressed regarding the Commission’s preference for randomised controlled trials and whether this will amount, in practice, to MA holders being required to re-run pre-market Phase 3 studies.

Many of the above measures are currently still being implemented. For example, MA holder, healthcare professional or patient access to certain parts of the EudraVigilance database is not yet effective, and is not expected until 2015-2016 – though patients do already have access to the EU database of suspected ADR reports (3).

The PRAC has met on a monthly basis since July 2012. Its published minutes demonstrate that it consistently considers all EU safety referral procedures (urgent or otherwise) and, in relation to individual medicines, signals assessment and prioritisation; RMPs; PSURs; post-authorisation safety studies; renewals; and product-related pharmacovigilance inspections. It also participates in the new international pharmacovigilance cluster teleconference with the Food and Drug Administration, which is attended by Health Canada and PDMA-J in Japan.

Other pharmacovigilance activities at EU level complement the changes introduced by the new legislative requirements, such as the public-private PROTECT project on pharmacovigilance, which introduced two new pharmacovigilance databases developed as part of the EU’s Innovative Medicines Initiative (4). These databases provide data resources for pharmacovigilance activities and pharmacoepidemiological studies via access to structured information on drug consumption in Europe, as well as to listings of all ADRs for medicinal products centrally authorised in the EU, based upon MedDRA terminology and combining different data sources. The goal of this database is to improve the efficiency of the detection process of ADRs by accelerating identification and filtering or flagging listed and unlisted ADRs, and to enable the integration and presentation of data on benefits and risks.

Outsourcing and Delegation Implications

With regard to companies, the legal obligations introduced or expanded by the legislation are largely carried directly by the MA holder and, of course, the Qualified Person for Pharmacovigilance (QPPV). EU pharmaceutical legislation has consistently recognised de facto outsourcing of pharmacovigilance activities by MA holders. For example, a MA holder is not required to directly employ a QPPV, provided one is continuously available. Similarly, the pharmacovigilance implementing regulation directly addresses and permits subcontracting by MA holders, although explicitly restricting delegation to performance only (5). No delegation of responsibility is allowed, and MA holders must draw up contracts with subcontractors and maintain within the PSMF lists of all activities, contracts and territories covered by any subcontracting.

In practice, delegation of pharmacovigilance performance can be either intra-group, to affiliates, to third-party alliance partners, and/or to contractors. Some regulatory affairs consultancies may operate comprehensive pharmacovigilance systems and services for their clients, while other contractors may only perform discrete pharmacovigilance-related activities, such as translation services concerning spontaneous reports. In all cases, however, the MA holder carries the legal responsibility to maintain the pharmacovigilance quality system and the PSMF, and it must capture all the relevant contracts in this. In all cases, and particularly where significant pharmacovigilance activity is outsourced, it is critical that the MA holder ensures that the PSMF is kept up-to-date, in order to meet the seven-day production deadline, following a request from a competent authority. It is therefore vital that pharmacovigilance contracts confirm that the MA holder’s PSMF can be promptly updated (with information concerning the contractor’s activity), and made available within this timeframe.

Wherever delegation is contemplated, MA holders must structure this to ensure they can fulfil their responsibilities for safety data collection and reporting. Where third-party contractors are selected this should be on the basis of:

  • A documented selection policy and procedure
  • An appropriately risk-based approach to auditing
  • A detailed contract:
    – Defining safety data exchange and reconciliation (where applicable) permitting oversight by the MA holder of the performance and content of the contractor’s own personnel training (to ensure pharmacovigilance is adequately covered)
    – Providing for appropriate training to be administered for specific projects by the MA holder, where appropriate
    – Containing appropriate mechanisms to ensure the MA holder’s oversight of the performance of the subcontracted activity
    – Providing the MA holder with sufficient rights of access (whether for purposes of audit by the MA holder or by a competent authority)

Where MA holders share a pharmacovigilance system, with alliance partners or with affiliates, each holder must have available a complete and up-to-date PSMF. If there is delegation of pharmacovigilance activity among the MA holders, the delegating holders may be able to cross-refer to the PSMF and pharmacovigilance system operated by the managing MA holder, provided appropriate access agreements are in place to allow the delegating holder the appropriate level of access for itself and competent authorities.

1. Directive 2010/84/EU and Regulation (EU) 1235/2010. These were subsequently supplemented by a technical Commission implementing Regulation (EU) 520/2012
2. Directive 2012/26/EU and Regulation (EU) 2012/1027, which came into mandatory effect in October 2013
3. Visit:
4. Pharmacoepidemiological research on outcomes of therapeutics by a European consortium. Visit: 5. Commission Implementing Regulation (EU) 520/2012

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Shuna Mason is a partner and Head of Regulatory at CMS, London. She is one of the few lawyers specialising in the law and regulation of life sciences and consumer products – covering pharmaceuticals, medical devices, in vitro diagnostic devices, human tissue, and cosmetic and plant protection products. She advises on international as well as national issues, and frequently manages and coordinates regulatory advice for companies across several different regions
Shuna Mason
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