This article first appeared in the Canadian Pharmacy Newsletter, March 2019.
Biosimilars and the European Regulatory System
In the 1990s, governments and regulators in Europe began thinking about how to regulate biological medicines once patents expired and market exclusivity ended. Given the extensive experience regulators already had at that time assessing the manufacturing changes of biologics, they concluded that a simple generic pathway would not be advisable. As a result, Directive 2001/83/EC (translated in the laws of all EU member states) was amended with the addition of Article 10(4), which introduced the concept of “similarity.”
It is worth noting that the primary objective of the European Union is to foster free trade and the movement of services and professions between member states. This has led to common standards being developed across Europe for food, industrial goods, and medicines. In addition, the European Medicines Agency (EMA) was founded. However, there are many areas that are not under the jurisdiction of Europe. Most notable is healthcare.
Although the Treaty of Rome states that every European citizen is entitled to receive basic healthcare and access to medicines, the level of such care is regulated by the individual member states. This applies, for instance, to the types of healthcare and medicines that are reimbursed under (semi-)national insurance schemes. It is important to consider this background to understand why EMA has no say in interchangeability or substitution: these are national matters.
The Case for Biosimilars and its Initial Results
The cost of healthcare in all European countries (and elsewhere) is increasing rapidly, and the reasons are well known. People are getting older and living longer with chronic and debilitating diseases, and new medicines as well as expensive innovative services in healthcare are growing at an astounding pace.
In particular, the cost of biological medicines is a major concern, yet this is a situation where biosimilars could actually offer large savings, as market exclusivities of the largest blockbusters have already expired or will expire shortly. However, prescribers feel comfortable with innovator products, as do their patients. Prescribing a lower-cost alternative has no direct benefit for prescribers or patients. And without such a clear advantage for prescribers or patients, biosimilars require support from other parties with a broader societal interest, namely governments and third-party payers.
After licensing the first biosimilar in 2006, the European Union began closely monitoring the uptake of biosimilars in member states, and extreme differences were observed (IMS 2012), ranging from nearly zero uptake in some countries to virtually universal uptake in others. The findings sparked considerable research to pinpoint the reasons for this discrepancy. It appeared that where there was no incentive within the healthcare system to use biosimilars, then uptake was low. Another important reason was that physicians were very reluctant to switch patients under chronic treatment, complaining that there were no proper clinical trials available to support the safe switching of patients.
Ebbers et al. (2012) responded to that claim by publishing a review showing that for the available biosimilar molecules, a large number of clinical studies showed no safety signals after switching. It was clear that much more education was needed for prescribers, as were stronger incentives underscoring the societal value of prescribing biosimilars.
Education on Biosimilars: The Role of Medical Societies, Patient Organizations, and Regulators
A number of medical specialty societies had been analyzing the available clinical evidence supporting biosimilars and were not satisfied. As a result, they advised against changing treatment of patients to biosimilars. Regulators were disappointed at the mistrust expressed by medical societies with regard to biosimilars.
Subsequently, EMA decided to work on a consensus document to educate physicians. At the same time, it began work on an educational program for patients. Both early initiatives failed. The physician document was almost impossible to find online, and if you did manage to unearth it, it was unlikely the very carefully worded document, often in very political language, would change your mind.
The patient educational document suffered the same fate: it was not reader-friendly and was almost impossible to find. It was clear from these two failures that a more sophisticated communication effort was needed to inform doctors and patients alike. In the second round, EMA, together with the EU Commission, took a multi-stakeholder approach in revising the two documents. Eventually the revisions were published, and appeared to be much easier to access: https://www.ema.europa.eu/en/news/improving-understanding-biosimilars-eu.
In the meantime, more switch trials became available and, starting in 2015, medical societies began to take a more positive view. Most medical societies started recommending the use of biosimilars as an equal alternative for the indications for which they are licensed, and trust in regulators was restored.
Patient organizations felt it their duty to inform their members about the new phenomenon of biosimilars. This led, initially, to very negative recommendations, but as it turned out, they were based on poor advice and lack of knowledge.
The EU Commission, in collaboration with EMA, decided it was time to take responsibility for developing information material for doctors and patients. In addition, regulators started to actively participate in educational events aimed at prescribers and patients. Since 2017, the landscape has started to change. There is now such a wealth of experience in biosimilar use—more than 700 million patient days without a serious incident—that most medical and patient organizations have recognized the advantages of biosimilars for the healthcare system, and more positive revisions of position papers have started to appear.
Over the years, the argument was often heard: Why is EMA not recommending the use of biosimilars if it is so confident? However, this is not part of EMA’s mandate, which is to license medicines, not to interfere with local healthcare policies. Eventually, Finland and The Netherlands took the lead, and in 2015 they clearly recommended the prescribing of biosimilars as an equal alternative for similar innovative products. Since then, most EU countries have followed suit.
An overview of the various European recommendations can be found on the website of Medicines for Europe, and is free to download here (updated in January 2019).
Supporting Biosimilars: The Example of the Netherlands
One example of how concerted action among government, regulators, and insurance companies has changed the landscape for biosimilars completely is Biosimilars the Netherlands (www.biosimilars-nederland.nl), a collaboration of insurance companies, healthcare professionals, and scientists that was founded in 2013. The goal was to provide independent science-based information on biosimilars.
In 2014, the Dutch Ministry of Health made it clear to medical societies that prescribers had a responsibility in curbing spending on expensive medicines, and that lower-cost biosimilars were a safe and effective way to reduce spending.
In 2016, the Dutch Medicines Board revised its rather conservative view regarding the use of biosimilars and advised that switching from originator to biosimilar—and between biosimilars—was a safe option. In 2017, a Biosimilars Toolbox for Hospitals was developed jointly by medical specialists and hospital pharmacists.
In 2018, the Ministry of Health awarded an €800,000 grant to launch a three-year intensive education project at the hospital level, directed not only at prescribers, but also at support staff such as nurses and pharmacy-technicians.
The result of these initiatives has been impressive, as the uptake of biosimilars in hospitals has grown very rapidly, approaching 100% for some molecules (like rituximab and trastuzumab). Plus, the savings are more than €100 million for a small country like the Netherlands, and are expected to grow to around €250 million per year. The uptake of biosimilars outside hospitals (notably insulin) is still very low, underlining the need for active education and promotion.
What We Have Learned in Europe about Supporting Biosimilars
The above examples show that active stimulation of the use of biosimilars by governments, regulators, and insurance companies can make a huge difference in the potential savings afforded by biosimilars. Exploding healthcare budgets require drastic measures, and in most European countries, such measures have been taken, resulting in benefits for patients, namely, greater access at lower cost.