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What’s New in Europe?

Brexit, EMA’s Move to Amsterdam, Clinical Trial Regulation Delay, Off-Label Uses

John Lisman
Global Forum
Europe Regional Editor

2017 ended with some important decisions in respect of Brexit. First, the UK finally managed to reach agreement about the conditions for leaving the EU. This agreement is merely about payments the UK must still make as a consequence of earlier commitments. The next step towards Brexit is to negotiate the future relationship between UK and EU. Second, Amsterdam in the Netherlands was chosen as the future seat of the European Medicines Agency (EMA). Next, perhaps as a consequence of EMA’s preparations for Brexit, new delays in the development of the clinical trial platform have pushed back the coming into actual use of the new Clinical trial Regulation (CTR). In addition, more and more attention is directed at off-label use of medicinal products and it consequences on public health.

Painful Divorce: Future UK – EU Trade Agreements


very divorce is painful. This might be even truer for breaking up the UK-EU bond.

Voters were told in the Brexit campaign that leaving the EU would lead to a better life, because the disadvantages of membership would disappear while not touching the benefits. However, the remaining member states will not allow the Britons to eat their cake and have it, too. This means that clear choices must be made about trade relations between an independent UK and the EU. The benefits of an open internal market, however, come alongside the disadvantages of EU membership which the majority of referendum voters wanted to get rid of.

The whole idea of the EU is free movement of goods, services, capital, and persons. For healthcare goods, free movement is only possible if all member states act upon the basis of the same standards and rules, because protecting public health is always a national responsibility. If you must accept healthcare products that have been authorized in another member state, you want guarantees about the quality, safety, and efficacy of those products. If common standards apply, and if decisions of other member states and EU institutions also apply, common supervision is necessary for another country to agree. If the UK wants to stay in the business of healthcare products without any barriers, they must comply with all applicable legislation. If the UK wants access to the single market, they must also pay their fair cost share and comply with case law of the European Court of Justice.

This is a heart-wrenching dilemma for UK politicians, because there is a segment of the voters that stands to lose no matter what direction they take. The optimal agreement from a European perspective means the least disturbance to the healthcare product systems of development, approval, and patient access.

Move Not Entirely on Track

The decision to move the EMA to Amsterdam has been made. Planning this strenuous relocation is not without practical problems, specifically around timing. The date for Brexit has been set at the end of March 2019, but the newly-built (or rather, to-be-built) seat of the EMA will not be ready before the end of 2019. Experience teaches that for megaprojects in the Netherlands (like other parts of the world), building sometimes takes more time than expected. This may be the reason why Dutch officials have rented an intermediate building for ten years, until 2028. Unfortunately, this “Spark” building can accommodate only half of the EMA, so the rest will be distributed across the region. Moreover, this unwieldy plan means that the EMA will have to move some parts of its staff at least twice instead of once.

The Executive Director of the EMA, Guido Rasi, hinted in his 29 January 2018 press conference that he was not amused and yet insisted that EMA has a duty to continuously protect the health of EU citizens. The Netherlands has committed to full cooperation with the EMA and the Commission in order to maintain the protection of humans and animals before, during, and after this move.

Hurry Up and Wait: Clinical Trial Regulation

In its 14 December 2017 meeting, the EMA management board was informed of further delay in setting up the EU platform for clinical trials. Regulation (EU) No. 536/2014 will only become applicable for all clinical trials in the EU six months after the Commission signs off the platform developed by the EMA. The date foreseen as the starting date for the new system was originally mid-2016. Now it is expected to be the second half of 2019.

European Attention to Off-Label Use

Not very long ago, regulators and politicians in the EU did not want to talk about off-label use of medicinal products. The reason may be the fact that off-label use is rather a threat for the regulatory system, because if the off-label use of medicinal product is not regulated, why would we bother with regulating on-label use? However, there is a good reason for managing off-label use as the physicians and the patients using a medicinal product for an unauthorized indication have the right to the same scrutiny by competent authorities as the on-label users.

Furthermore, the real safety, and therefore the real risk/benefit ratio, of a medicinal product depends on on-label and off-label use. After a Belgian study on off-label use, the Commission commissioned a report about the legal situation around off-label use. This last study gives a lot of information about the legal and practical aspects of off-label use, but provides no recommendations.

Legislators and regulators should pick this up and try to find ways to bring unauthorized applications of medicinal products to an authorized status. The process of authorizing off-label applications should be promoted under the title of drug rediscovery, drug repurposing, or some other name. The authorization of off-label use takes away the disadvantages of off-label use, the most important of which is to accept a medicine that has not been carefully scrutinized.

References available upon request.