The pharmacovigilance (PV) legislation and the supporting guidelines define the required level of PV activities to ensure that the product is safe and effective. Today, in almost every country, it is mandatory for the pharmaceutical companies to demonstrate the safety and efficacy of the medicinal product to the local authorities to be allowed to distribute their product to patients.

In this blog post, we briefly look at some of the key milestones in recent decades of the evolution of legislation and what it meant for pharmacovigilance operations in EU. The legislative (and non-legislative) acts are cornerstones of the pharmacovigilance industry and an understanding of the legislative framework should be helpful for anyone who believes an update is necessary. We are advocates of change in PV on both the industry stakeholder level as well as the regulatory level and history of the legislative background is where we can start.

The background of the current pharmacovigilance legislation in the European Union (EU)

The first PV legislation in the EU was adopted in the 1960s[i]. The rules pertaining to PV had become gradually more complex for 40 years, until the EU lawmakers realized that the system had turned too complex and too expensive to maintain.

At this point, EU had 15 member states and the Directive 2001/83/EC relating to medicinal products for human use was the basis of the PV legislation in EU member states.

2004 Regulation – “2001-Review”

The year 2001 kicked off the “Review of the Directive 2001/83/EC”, also dubbed as ‘2001–Review’. This review led to amendments and a new Regulation (EC) 726/2004 [ii], which is one of the cornerstones of PV regulations today.

726/2004 introduced the centralized authorization procedure which has had a great impact in simplifying the authorisation of medicinal products in the EU, and has become mandatory for originators.

On the PV side, according to a later assessment by the European Commission [iii], this 2001–Review did not in fact include a systematic review of the PV requirements, nor did it assess the effectiveness of the requirements. The changes brought by the 2001-Review and the 2004 Regulation in reality “increased administrative burden without necessarily improving public health protection”.[iv]

For example, the 2004 Regulation included a requirement for the marketing authorization applicants to submit a detailed description of their PV system at the time of the authorization which needed to be maintained, submitted for regulatory review and best of all, the MAHs had to pay variation fees to the authorities for even the smallest changes to the system.

Modernizing Pharmacovigilance

The latest major update, Commission Implementing Regulation No 520/2012, to the PV legislation is actually a “non-legislative act [v]” and there have been later updates, but from PV perspective, we consider this to be the latest update with a major influence on the day-to-day activities. According to the EMA it was “the biggest change to the regulation of human medicines in the EU since 1995.” [vi]

This Commission Implementing Regulation 520/2012 is a result of a long project ‘Modernising Pharmacovigilance for Pharmaceuticals’ which started in 2005 and culminated in 2008 with Commission staff Impact Assessment [vii] to amend the Regulation 726/2004 [viii] and Directive 2001/83/EC[ix].

The project included, among other things, a working group, two public consultations, stakeholder consultation, and an independent study. According to the impact assessment, the results of the first public consultation were demanding for change:

“The consultation response provided compelling arguments that the current system is over complex, that resources are not best used often being focused on meeting bureaucratic requirements rather than proactively gathering data and information about the safety and risks of medicines. There was a strong and clear demand from stakeholders for the Community pharmacovigilance system to be strengthened and rationalised.”

The main issues with the EU PV legislation in 2008

At the time of the Commission Staff Impact Assessment in 2008, the project working group proposed that the weaknesses of the EU PV legislation needed to be fixed because of the significant impact that the ADRs have in public health. The assessment report listed the following points as the significant weaknesses of the then current EU PV system:

• A lack of clear roles and responsibilities and a lack of clear obligations resulting in poor compliance
• Slow EU decision-making specifically for nationally authorised products and difference in actions taken by the Member States
• Lack of transparency in PV
• Lack of EU coordination of communication about the safety of medicines
• Complex product information with poor penetration of key warnings
• Cumbersome oversight of MAHs’ PV systems by the authorities
• A lack of proactive and proportionate monitoring, including a lack of risk management and structured data collection in the form of post authorisation safety studies (PASS)
• Duplicative reporting rules for the MAHs and authorities relating to both 15-day, literature and periodic (PSUR) reporting of ADRs
• Lack of inclusiveness of stakeholders
• Lack of direct patient reporting of ADRs
• Absence of patients from decision-making

“The Problem”

According to the Commission Staff Impact Assessment in 2008, the legislation update was aimed to improve the situation with the main problem, the impact that ADRs have in public health [x].

It was estimated based on different articles and sources, that in the EU 3 – 10 % (2.5 – 8.4 million annually) of hospital admissions were caused by ADRs. According to these same estimates, out of all hospitalised patients 2.1 – 6.5 % (1.8 – 5.5 million annually) suffered an ADR and 0.12 – 0.22 % (100,800 – 197,000 annually) of hospital admissions resulted in death due to an ADR. [xi]

The Commission Staff Impact Assessment presented estimates that the annual societal economic burden of ADRs occurring in the EU was €79 billion. ADR-related costs other than those caused by hospitalization were estimated at €63 billion annually in the EU and the total costs of preventable ADRs at €23 billion. [xii]

Side note:

While it is certainly true that ADRs have a significant impact on public health and with reduction of preventable ADRs we can decrease the number of hospitalizations and deaths, reading these documents have raised some questions at Tepsivo. We have researched the available data on the hospitalization and death rates and also the effectiveness of the PV legislation in reduction of ADRs and we will be following up on these topics in future blog posts.

Improvements to the legislation

As we now know, this impact assessment led to amendments of the Regulation 726/2004 and Directive 2001/83/EC during the years before 2012 when the Commission Implementing Regulation (EU) No 520/2012 came into force. In 2012, we also saw the publication of the EMA GVP guidelines that have become an important cornerstone of PV activities globally.

The Good

The roles are clearly defined in the legislation and in the guidelines. The responsibilities are split between the MAH and the authorities.

Product information has become clearer and is much easier to access by the patients and the healthcare professionals.

The decision-making might still not be completely harmonized among the NCAs, but the processes are already quite similar. So even if you are not a local expert, it is possible to at least start the discussion with the respective NCA. EMA has taken a larger role as a coordinator and central authority in Europe and is still looking to increase their role. This has made it easier for the NCAs to follow the same set of rules.

On the process side, there is now a relatively good level of transparency within PV. This also means that the authorities have a good oversight of the MAHs’ PV systems.

There is, however, still lack of visibility into the impact and cost-effectiveness of the PV activities, which should be a major quality concern.

The Bad

The risk monitoring and data collection has improved, but there is a lot of room for improvement. EudraVigilance (EV) has become a good tool for risk monitoring and the medical literature monitoring (MLM) service has reduced the effort needed from the MAHs. However, there are still activities with low value or duplicative activities required to be performed by the MAHs (for example local literature screening).

The amount of duplicative reporting has been reduced, especially now thanks to central reporting to EV but a great amount of effort is still wasted on reporting the same cases from literature, re-reporting cases coming in from EV, duplicative reporting to EV and unnecessary follow-ups. Read our blog posts on 2020 EV Annual Report and Local Literature Screening for more information on these topics.

EMA has been trying to include the patient organizations in their decision making [xiii] but we cannot comment how successful this has been. It is clear however, that there is still much to do with ADR reporting by the patients.

Our wild guess is that 99 % of the patients do not know that they can report their ADRs to the authorities. As we reported in our previous blog about the 2020 EV Annual Report, the number of ICSRs from patients was 117,167. This is about 7 % of all the cases reported to EV. There is still much that can be done to make patients aware of their right to report and of the importance of reporting.

Updates are needed

One can appreciate the current process for creating and maintaining a PSMF after reading about the 2004 Regulation and burdensome and expensive process for maintaining detailed description of the PV system. But then again, this was almost 20 years ago. How much has the world changed since then? Shouldn’t this type of improvement be expected? Should we expect more from the legislators?

Taking PSMF as an example. Why is it still required that the PSMF has a physical location when in practice we all work electronically, and all our documents are in the cloud? The pharmaceutical companies are actually struggling to keep their systems in the stone-age of the computing just to meet the legal requirements. Even the UK PSMF needs to be accessible by the MHRA inspectors from a UK address. This might be just one of those Brexit-things, though.

Updating the legislation and guidelines by the authorities needs to become leaner and more harmonized. As we wrote in our blog about the EMA/HMA Joint Network 2025 [xiv] strategy, the authorities are aware of the issues and they are trying to fix everything. When will we see these updates in practice? According to some estimates, the 2001/83 Directive and 726/2004 Regulation could be updated in 2022 [xv].