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European Pharmaceutical Contractor

A New Mindset

When the new EU pharmacovigilance legislation came into force in July 2012, it led to an abundance of new administrative procedures and work practices – but also paved the way for a fresh mode of thinking, for an entirely new mindset. Innovative paradigms were introduced or supported by the legislation – for example, pharmacovigilance became an integrated discipline, was made more transparent, and increased the involvement of patients and citizens. This article summarises the main milestones leading to this highly innovative framework and provides insight into the first experiences, viewed from a regulator’s perspective.

The development of the new EU pharmacovigilance legislation has been a long process, from the very first ideas being exchanged between European legislators and regulators, to the law coming into force in July 2012. The kick-off took place shortly after the finalisation of an extensive review of pharmaceutical legislation in 2001 – a review which primarily focused on the licensing component of the European legislative framework, and only to a minor extent included the post-licensing pharmacovigilance element.

Looking Back

At the time of the 2001 review, the European Commission (EC) took stock of pharmacovigilance across the EU. Based on a wide range of data, the EC concluded that there were important reasons for strengthening pharmacovigilance in the interest of public health.

Some of these data derived from extensive national surveys performed in 2003 and 2004 in the 15 member states which comprised the EU prior to its enlargement in 2004, as well as in the 10 countries which joined in 2004. The outcome of these surveys revealed that the workload was huge and the human resources in regulatory agencies were scarce. Furthermore, the work practices differed between member states, but had two conspicuous and prominent features in common: the majority of resources were spent on data collection and registration, with little time and resources being paid to data usage. Work was also still largely paper-based, and far from digitalised.

Other data sources revealed that adverse drug reactions (ADRs) were a huge burden. Ten years ago, it was estimated that as many as 5% of hospital admissions were caused by ADRs. Some 5% of hospitalised patients experienced such reactions and they were the fifth most common cause of hospital death. This figure corresponded to almost 200,000 deaths caused by ADRs in the EU annually. A rough estimate of the total societal cost amounted to 80 billion Euro.

Besides public health concerns, the function of the EU pharmaceuticals internal market also had a significant impact on the decision to revise the legislative framework. Despite the creation of a European market comprising 500 million inhabitants, and the establishment of the EMA in 1995 – an important milestone leading to far-reaching and extensive cooperation and coordination within the EU – the outcome was not satisfying. The competitiveness of the European pharma industry was not boosted as anticipated. At the start of the 21st century, the EU market was still in second position worldwide, behind the US.

All in all, something had to be done. That something turned out to be new and better regulation. Based on the obligatory impact assessment (which must be performed prior to development of new legislation), it was evident that more and improved regulation was the optimal way forward.

Process of Creation

The new legislation has evolved following extensive involvement of all relevant stakeholders. The creation of the framework occurred via an open and transparent process. In principle, each and every citizen in Europe could have their say and contribute to the process.

The launch of draft legislation for consultation in December 2007 was preceded by numerous interactions between legislators, regulators, industry, healthcare professionals and patient organisations. These interactions took place at numerous face-to-face meetings and online, and included various consultation procedures. The surveys conducted by national regulatory authorities were also supplemented by the research of an external consultancy (Frauenhofer).

Following the consultation procedure, a proposal for a regulation and a directive was finally published in December 2008, and negotiations were initiated between the EC, member states and the European Parliament.

The new legislation was finally adopted by co-decision procedure in September 2010 and came into force in July 2012. The legislative provisions of the regulation and directive were supplemented by a detailed implementing regulation which was published in June 2012. This provided a wide range of technical details – for example, the format and scope of the most important tools, such as pharmacovigilance system master files, periodic safety update reports (PSURs), risk management plans (RMPs), and so on.

A comprehensive set of guidance documents were developed and published shortly before the legislation came into force. The initial guidance has since been updated and revised, and additional guidance has been published or will be published in the near future.

Also, an additional regulation and directive have been adopted to further strengthen the legal basis for pharmacovigilance, and recently another implementing regulation has been adopted in relation to the new system of additional monitoring.

Streamlined Procedures

A thorough evaluation of the impact and outcome of the new legislative framework cannot be done until some years have passed and a sufficient dataset has accumulated. Currently, the evaluation is in a preparatory phase, in which key performance indicators are being identified.

But the starting point and future reference frame are the expected achievements of the legislation. What is particularly noteworthy is that the new system provides clarity with regard to the roles and responsibilities of various stakeholders, and facilitates a more rational use of resources. These objectives are tentatively fulfilled by the implementation of streamlined procedures with timetables, and a more systematic and proactive approach to the overall handling of tasks. Needless to say, in the preceding system there was a considerable overlap among stakeholders. Procedures were less clear and without legally binding timetables, hampering their effectiveness.

The new legislation has provided clarity with regard to the role and responsibilities of various stakeholders, in particular those of the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee for Human Medicinal Products (CHMP), the Coordination Group for Mutual Recognition and Decentralised Procedures – human (CMD(h)), and the EMA.

The mandate of the new PRAC is clearly defined – it covers all steps in the pharmacovigilance lifecycle, including risk detection, assessment, communication and minimisation. Assessment of safety-related referrals, PSURs, RMPs, post-authorisation safety studies and renewals are now the responsibility of the PRAC. These tasks were previously the responsibility of the CHMP.

Besides the mandate of the PRAC, the new framework also includes assessment of efficacy data, and the PRAC is mandated to carry out benefit/risk assessments, and decide whether or not marketing authorisations should be maintained, varied, suspended or revoked. A new tool, the postauthorisation efficacy study, is also comprised within the mandate of the PRAC. Furthermore, in relation to pharmacovigilance inspections, the role and responsibility of the PRAC has added clarification and strength.

It is also important to realise that the new legislation has widened our focus, so that more resources are spent on proactive use of data, and not primarily on data collection and registration – although these steps are still very important. This is exemplified by the way we perform signal management today; every month the PRAC prioritises and considers all new signals which have been identified from various sources, most often from the spontaneous reporting system and databases.

Sharing the Workload

The CHMP has been struggling with a huge and continuously increasing workload for many years. If this development were to continue, there could be concern for the quality and robustness of the CHMP. Therefore, it was considered in the interest of public health that the responsibility of the CHMP be shared within the network. This share of work and responsibility is now a fact of life, with a large amount of pharmacovigilance-related tasks having been transferred to the PRAC.

With the new legislation, the CMD(h) is, for the first time, allocated pharmacovigilance tasks of its own – as recommendations of the PRAC for procedures (for example, referrals, PSURs or signals) involving only nationally authorised medicinal products are forwarded to the CMD(h) for formal adoption. Likewise, PRAC recommendations involving only centrally authorised medicinal products, or a mixture of centrally and nationally authorised products, are forwarded to the CHMP in the same way.

Before the legislation came into force, the EMA had an important coordinating role in the EU network. With the new framework, this role was further elaborated and strengthened. One example is the future coordination by the EMA of safety announcements across the EU for both centrally and nationally approved products. This coordination will ensure consistent and harmonised safety information is distributed across the EU, simultaneously. The EMA will also be responsible for new tasks, such as taking care of literature monitoring and organising public hearings at the request of the PRAC.

New Legislation and Paradigms

As is apparent from the above, the new legislation has provided significant change to the entire system. This is true when it comes to administrative procedures and work practices. Everyone who has been actively involved in the process of implementing the new legislation, whether on the regulatory or industry side, has witnessed significant changes in administrative procedures, and an abundance of new templates and workflow figures have been developed and are now in use.

No doubt all these changes from time to time have been perceived as quite troublesome and frustrating. But, despite this, it is evident that the new legislation has paved the way for a new way of thinking – it has introduced fresh paradigms and will gradually change our mindset. One new paradigm is pharmacovigilance’s position as an integrated benefit/risk discipline. Prior to the new laws, it was purely a risk analysis discipline. This development is exemplified by the scope of PSURs, which has changed significantly. The PSUR should now contain a thorough presentation and integrated evaluation of benefits and risks. In effect, the PSUR has become the document which, post-marketing, forms the basis for an evaluation of whether or not a product should stay on the market.

The first significant example underlining this fact emerged early in 2013, following an assessment of a PSUR for the medicinal product strontium ranelate, which is approved for treatment of postmenopausal osteoporosis. The PSUR revealed an increased risk of serious cardiac disorders, including myocardial infarction, in patients treated with the drug. Based on the PSUR data, the PRAC had to consider if the benefit/risk balance had changed to a degree which justified a suspension of the marketing authorisation.

The PRAC concluded – and recommended to the CHMP – that the marketing authorisation was varied, with the implementation of a contraindication for use in patients with increased cardiac risk profile. But the variation was followed up by a referral procedure triggered by the EC. This referral aimed at performing an in-depth review of the benefit/ risk profile of strontium ranelate and determining its place in the therapeutic spectrum. At the January meeting of the PRAC, it was concluded that a suspension of the marketing authorisation was deemed necessary. At the February 2014 CHMP meeting, following further analyses of additional responses from the marketing authorisation holder, the CHMP recommended to the EC to maintain the marketing authorisation.

Another paradigm shift was effected by the very important and innovative transparency provisions of the new legislation. In comparison to previously established committees in the network, the PRAC works according to an extremely high level of transparency. The PRAC agenda is published on the EMA website hours before its monthly meeting commences, and the minutes are published one month later, following adoption at the subsequent PRAC meeting. Highlights from the meeting and information on initiation of referrals are published the day after the PRAC meeting has ended. A detailed list of signals (either new or follow-up) assessed by the PRAC, as well as subsequent recommendations, are published immediately after the CHMP/ CMD(h) meetings two weeks later.

A third example of a new paradigm is the strong involvement of new stakeholders – patients and healthcare professionals. For instance, the new legislation introduced patient reporting schemes in the EU. In Denmark, patients have been able to report directly to their agency since 2003. From 2012, patient reporting has become EU standard. Another example is that patients and health professionals today are involved in the decision-making process through representative members of the PRAC. It is of great value that patient and health professional expertise and perspectives are included in the overall process.

Final Remarks

The full impact of the new pharmacovigilance legislation and its new paradigms on the most important endpoints – public health and competiveness of Europe’s pharma industry – are still largely unknown. Only the future can tell. Obviously, factors like other parts of the legislation, non-legislative initiatives and general economic development in Europe will influence the outcome.

One of the key questions to be addressed in future assessments is whether the attempt to provide better regulation and reduce the administrative burden has been achieved. It will also be important to determine the added value of the PRAC’s new mandate and the new way of cooperation and coordination within the EU regulatory network. Has it been able to adapt to the highly innovative new mindset which the new legislation has introduced? A third key factor to be analysed is what we gain through transparency. Finally, it will be interesting to know to what extent the involvement of new stakeholders can, in fact, improve the safe use of medicines.

While we are waiting for the outcome of future assessments, we can observe that Europe still has great difficulty in preserving competitiveness and stimulating economic growth. This is in sharp contrast to the development in Asia. Economic forecasts predict that, by 2017, China will be the second-largest market for pharmaceuticals, with the US still in the lead and the EU in third position. But we have reason to believe that the new pharmacovigilance legislation will, ultimately, make a huge difference.


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Doris Stenver, MD, MPA, is Chief Medical Officer at the Danish Health and Medicines Authority. She holds a medical degree from Copenhagen University’s Faculty of Medicine, and a Master’s degree in Public Administration from Copenhagen Business School. Her clinical experience covers a wide range of medical specialities, including nephrology, endocrinology, haematology, cardiology and infectious diseases. Doris joined the Danish regulatory authorities and the EU Pharmacovigilance Working Party in 1998. In 2002, she became a member of the European Risk Management Strategy Facilitation Group and, as of July 2012, a member of the Pharmacovigilance Risk Assessment Committee.
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