It has been 50 years since the idea of authorising pharmaceuticals at European Union (EU) level first took shape and while the present system has its critics, few would say that public health in Europe is not significantly better off as a result. The process was triggered by the thalidomide tragedy of the late 1950s and early 1960s, an experience which, says the European Commission, ‘shook public health authorities and the general public (and) made it clear that to safeguard public health, no medicinal product must ever again be marketed without prior authorisation’.
Manufacturing Chemist asked public health organisations, industry and the academic community what they felt had been achieved 50 years on. ‘The founding legislation is Directive 65/65/EEC, which is what we’re really celebrating,’ said Melanie Carr, Head of the Corporate Stakeholder Department at the London-based European Medicines Agency (EMA). ‘After the thalidomide disaster it became very clear there was a need to have an evidence-based review and authorisation of medicines going onto the market and that really set the scene to have this EU review of quality, safety and efficacy. The level of harmonisation was built up progressively,’ she said. Thalidomide was first sold in what was then West Germany in 1957, and was henceforth sold around the world, creating thousands of birth defects as a side-effect.
Some of the key milestones which led to the setting up of the EMA and a centralised procedure for EU-wide approvals of medicines in 1995 were the launch of the multi-state procedure in 1975. This was the first step in having an EU authorisation, involving a common committee looking at medicines approvals in the EU – and then in 1987 the introduction of the ‘concertation’ procedure which obliged member states to refer to an EU-level committee on marketing authorisation for innovative products. ‘That really set the scene for the framework which became what we know today as the centralised procedure, the mutual recognition and the decentralised procedure, so they are the stepping stones of where we are today with regulatory procedures,’ said Carr.
The recently-adopted clinical trials legislation will result in unprecedented levels of transparency on clinical trials and outcomes
A 1992 EU regulation 2309/93 laid down procedures for authorisation and established the medicines agency. ‘We opened our doors in January 1995,’ said Carr. Subsequently, the 1993 law was transposed and consolidated in 2004 into what EMA now calls its founding regulation 726/2004. More recently, the major 2010 review of the pharmacovigilance legislation ‘reinforced the way we supervised the safety of medicines on the market, established the PRAT pharmacovigilance risk assessment committee and formalised a number of the tools we have,’ Carr added. In terms of transparency, ‘the recently-adopted clinical trials legislation will result in unprecedented levels of transparency on clinical trials and outcomes. A lot more data is being put into the public domain than in the past’.
Carr noted that for the future the Commission had set up an expert group on safe and timely access to medicines for patients (STAMP) – to make better use of the regulatory tools to speed up the delivery of novel medicines throughout the EU member states.
At a one-day event in Brussels, Belgium on 18 March to mark the 50th anniversary, the European Federation of Pharmaceutical Industries and Associations’ (EFPIA) Director General Richard Bergström said the success of EU legislation had served as a springboard for further development of the pharmaceutical sector ‘due to new technical possibilities (IT), increasing globalisation in drug development and distribution, enhanced European and global cooperation within companies and authorities, as well as changing societal expectations’.
The time is ripe to examine whether the current regulations, their application and interpretation are favourable to the earliest possible regulatory approval and swift access to innovative medicines
A statement from the EFPIA added: ‘New technologies and advanced knowledge of disease mechanisms, which are driving the development of targeted therapies, bring with them new challenges...the time is ripe to examine whether the current regulations, their application and interpretation are favourable to the earliest possible regulatory approval and swift access to innovative medicines after the necessary benefit-risk assessment’. The Federation said this would require ‘a comprehensive discussion on the interface between European and national rules regarding the assessment of relative effectiveness, falling under the competence of EU member states’. Bergström said at the meeting that the EU legislative framework had served well for 50 years, ‘but new approaches in development and innovation mean that we must re-evaluate whether changes should be implemented to speed access to medicines for the benefit of patients’.
At the same meeting, which was sponsored by the EFPIA and the German state of Bavaria, representatives of pharmaceutical companies echoed the EFPIA in calling for shorter EU vetting procedures. Severin Schwan, CEO of Roche, agreed that EU legislation had had positive effects but said he was ‘equally emphatic that there could be no complacency going forward, and that the EU was in danger of being consistently out-performed by the US with regard to a number of regulatory aspects, including approval times’. In Europe, it took an average of six months longer to approve a novel cancer treatment than in the US and this was a matter that needed to be addressed swiftly if Europe were to keep pace with its transatlantic counterpart, he said.
The EU is turning towards the use of regulations to implement legislation, which must be implemented to the letter, so it doesn’t give the member states much option about whether they implement or not
Dr John Talbot, Senior Lecturer in Pharmacovigilance at the University of Hertfordshire, in the UK, said the pharmaceutical industry had been highly regulated and was becoming more so. A lot of new EU legislation came into play in 2012 and was being implemented over a three-year period, he stressed. But there were important changes, he added. The old system in the EU was through directives that relied on the member states introducing national legislation, over which they had some leeway. ‘In the UK we did that through statutory instruments and we’re actually very good at doing this, but not all member states are,’ he said. Now, however, the EU was turning towards the use of regulations to implement legislation, which must be implemented to the letter, ‘so it doesn’t give the member states much option about whether they implement or not’.
This was a good thing, said Dr Talbot. ‘Look at the clinical trials directive 2001/20 – not all member states implemented it properly. It’s a great idea to have uniform regulation clinical trials in Europe but because it was a directive it wasn’t done.'
There were good concepts in the new approach, such as decreasing the level of duplication ‘but it’s very daunting in terms of the guidances,’ he said. There were currently 12 guidelines, some of which were up to 100 pages long and more were coming out this summer. Companies were expected, by their national agencies and the EMA, to deal with a huge level of detail ‘and these things are by no means optional: you absolutely have to do them, and you have to have a lot of expertise in the area’.
Regulation of the safety of medicines was an extremely sensible thing ‘and certainly the companies I’ve worked for haven’t tried to dodge around the legislation; they’ve actually worked very, very hard to implement it in the right way,’ he said. It was more of a struggle for smaller companies which didn’t have the same level of expertise and nor did they necessarily have products, particularly generics, where the safety profiles were very well established.
In general, EU pharmaceutical legislation is well intended and very good but there is an immense level of detailed complexity
Dr Talbot welcomed the regulations brought in over the past half century. ‘Before that you could do clinical trials without authorisation. The big advantage of EU legislation is that it applies across all member states. I worked for Glaxo and we sent in applications to every single country in Europe – 30 or 40. Now you can send an application to the EMA and go through a single approval process and that’s got to be better,’ he said. In general, EU pharmaceutical legislation was well intended and very good, he said, ‘but there is an immense level of detailed complexity’.
Nevertheless, the present system, and what could emerge in the next year or two, is a cause for unease on the part of Seattle, US-based Health Alliance International (HAI), which is concerned with public health in a number of mostly African developing countries. Ancel-la Santos Quintano, HAI policy advisor, said the organisation had a number of concerns about clinical trial data transparency. While there had been positive developments in the EU with the new clinical trials regulation, the problem was that now in the proposed Transatlantic Trade & Investment Partnership (TTIP) between the EU and US, ‘they want to include the trade secrets protection,’ she said. There had been a big push for this from the EU ‘and of course companies in Europe have been lobbying for it for a long time. If this is included in TTIP we feel this will have an impact on clinical trial data if there are not adequate safeguards in a future trade secrets directive’.
The scope for trade secrets should be narrowed down and there should be strong exemption for data which is in the public interest
The European Commission had put forward a proposal for a directive on trade secrets where their definition was very broad and everything could be included and there were no adequate safeguards to exempt data in the public interest from the scope of the directive, she claimed. ‘We know that the pharmaceutical industry considers that some clinical trial data is considered confidential and is a trade secret and this is one of the main arguments that we feel they will use to redact data. Our position is that the scope for trade secrets should be narrowed down and there should be strong exemption for data which is in the public interest like clinical trade data,’ added Quintano.
In the meantime, HAI would continue monitoring implementation of the clinical trials regulation, with Quintano arguing: ‘It’s now very much up to the EMA because they’ll manage the EU database where all the results will be posted and made publicly available.’ Claiming under the current guidance, EMA has released ‘a broad definition of commercial confidentiality which includes information that may undermine the interests of the company,’ she said. ‘It should always say that the public interest comes first.’
The EMA did not want to comment on the issue directly, although it has released plenty of details on its position. It released a paper in February explaining that it was consulting the pharma industry on proposed transparency reforms to the European Union (EU) clinical trial regulation, regulation No 536/2014, saying it wanted to ‘balance carefully the information needs of patients and the public with the needs of academia and industry.’1,2
However, Quintano claimed that there has been a ‘big push from industry for fast-track procedures to speed up market authorisation procedures and we feel this is very worrying'. Early access is important for patients but should not be detrimental to patients, she said.
References
1. www.ema.europa.eu/docs/en_GB/document_library/Other/2015/01/WC500180618.pdf
2. www.ema.europa.eu/docs/en_GB/document_library/Other/2015/01/WC500180632.pdf
