Submitted: 9 March 2018; Revised: 11 March 2018; Accepted: 12 March 2018; Published online first: 23 March 2018
Biosimilars to most blockbuster biologicals have now been licensed in the European Union (EU). The key biologicals have estimated sales of Euros 40 billion in 2016–2020 in the main European markets . Thus, the healthcare systems in the EU will soon get a relief provided by great savings and a better access to important medicines – or maybe not?
The problem is that EU Member States do not have a common master plan or shared idea as how to collect the reward for having biosimilars approved. Decisions for interchangeability, price, reimbursement, procurement and instructions to prescribers are made separately in each Member State . The final decisions to use biosimilars are usually made by individual hospitals and prescribers. By each step, different decisions are made. Because of this highly complicated situation, biosimilars have had a very modest and variable success in penetrating the markets dominated by originator products. At the moment, prescribers are the main gatekeepers for biosimilars into the health care.
In spite of the excellent safety and efficacy record of EU-approved biosimilars, many physicians still hesitate to prescribe biosimilars. The concept of biosimilarity seems to be difficult to understand and accept as it deviates from the conventional drug development concept . Thus, early position papers of various European and national medical societies failed to recognize the difference. As a result, prescribers were discouraged to use biosimilars in ‘extrapolated’ indications and to switch originators to biosimilars . Since then, more positive position papers [5–7] have been issued. Based on past experience, the understanding of biosimilarity will slowly reach the grass root level of prescribers. During this learning path, many prescribers will suffer from cognitive dissonance , i.e. evaluating biosimilars on the basis traditional drug development concept although being informed of biosimilarity. The mighty marketing machineries of pharmaceutical companies that are under threat of biosimilar competition seem to be very skilful in taking advantage of the non-rational aspects of prescription [9–12] in their campaign against biosimilars.
The lifespan of a biosimilar that is a copy of a 10+ years old original product is limited. The market of biosimilars is eroded by influx of new products, including new ‘improved’ or ‘biobetter’ versions of the original product. While the benefits of the latter ‘convenience products’, such as the new, more concentrated formulation of original glargin insulin, are often marginal , aggressive marketing has managed to convince prescribers to switch patients to the new product that is protected against biosimilar competition. Thus, biosimilar glargin insulins have a negligible market share in most EU countries [14, 15]. In 2016, about half of the epoetin market and two thirds of the filgrastim market were protected by biobetters and subsequently biosimilars were able to take only a modest slice of the total epoetin alfa and filgrastim markets . From the health economical point of view, biosimilars should be adopted to clinical use as soon as possible after marketing authorization in order to get the desired savings.
Interchangeability is the key factor determining the success of biosimilars whose main market is in chronic treatment. Tendering processes have led to switches between biosimilars and the originator products in several countries without safety problems. Data from controlled and uncontrolled switches have not raised any safety, immunogenicity, or efficacy concerns [16, 17]. Many national regulatory agencies have issued position papers supporting physician-guided switches .
O’Brien et al.  described the process that led to the prescription of a biosimilar infliximab and later to the switching of the originator infliximab to the biosimilar infliximab in an Irish teaching hospital. This project lasted three years after licensing of the product and was based mainly on clinical studies and position papers. Even then, the hospital pioneered switching in Ireland where negative attitudes against switches are still common . O’Brien et al.  predict that prescribers will also require switching studies from other biosimilars. This approach reflects the mistrust in the biosimilar development concept that aims to demonstrate physicochemical, structural, and functional similarity to the extent that the clinical performance will also be similar. Reliance on switch studies generates two problems. First, it will reduce the attractiveness of biosimilar development by increasing costs and narrowing the window of opportunity for biosimilars. Second, it is unlikely that reasonably sized switch studies will give reliable answers, as the potential differences in safety are small and significant problems very rare.
For the success of biosimilars, it will be critical whether clinicians will regard the clinical switching studies conducted thus far as the proof of concept or whether switching studies will always be required between an innovator product and its biosimilars or even between biosimilars of the same innovator product.
Payers and policymakers have noticed the slow uptake of biosimilars and have taken measures to control pricing and prescription. Setting a minimum price reduction compared to the originator and requesting prescription quotas for biosimilars sound logical but may be counterproductive as they will reduce the attractiveness of the local market, especially in small Member States, to biosimilar developers. The market dynamics of biosimilars is different from that in generics market [21, 22]. In the Nordic countries, Denmark and Norway apply national tendering processes that have managed to introduce biosimilars relatively fast and obtained significant price reductions as compared to Finland that requires 30% price reduction and has to wait longer for biosimilars to enter the market. The situation is further complicated by different goals of companies developing biosimilars .
Companies developing only biosimilars are ready to price competition whereas for other companies also developing original biologicals, biosimilars are only the plan B. The latter companies do not readily enter price competition and wish to keep regulatory requirements high and competition low.
Successful use of generics required the introduction of automatic substitution. Several old beliefs of insurmountable problems in copying biological medicines, such as characterization of complex molecules, extrapolation of safety and efficacy, and interchangeability have turned out to be unfounded or greatly overstated. Now, it is time to have a second look at automatic substitution. Irrespective of their attitude to physician-guided interchangeability, position papers of medical societies and anti-biosimilar industry-sponsored publications state categorically that automatic substitution is not appropriate. Automatic substitution at the pharmacy level is currently not possible in most Member States [2, 23]. Larkin et al.  listed several prerequisites for automatic substitution, including additional clinical data and designation as an interchangeable biosimilar. Such a requirement will raise the bar for biosimilar development so high that only ‘Big Pharma’ can afford it and, thus, reduces competition. As always with biosimilars, discussion of automatic substitution is often biased by the interests of stakeholders.
There is a fairly wide consensus in the interchangeability of biosimilars . Automatic substitution is a practical application of interchangeability that will be initiated at the political and administrative level when there are economic constraints and alternative ways to control costs are unpopular or harmful to public health. A prerequisite for automatic substitution is that the pharmacy staff will be able to provide information to patients and caregivers on biosimilars and, if necessary, training in the use of a new administration device. This is not an impossible hurdle for adequately staffed pharmacies. Another concern is traceability when a certain product is prescribed and later another is dispensed in the retail pharmacy. Information sharing between pharmacies, hospitals and prescribers outside hospitals may have to be improved to ensure traceability. This will require special arrangements that may include the development of local IT systems. These measures would be useful in improving traceability and adverse event reporting of biologicals in general. Thus, in most EU Member States, automatic substitution will require careful planning, sometimes changes to the legislation, and some support to pharmacies that will execute the substitution. A general scheme for the automatic substitution would be helpful and could be tailored for local circumstances in EU Member States.
Prescribers and other healthcare professionals, patients, payers, and healthcare administrators are slowly learning the value and nature of biosimilars. Biosimilars will probably be adopted sooner in hospitals where the choice of the medicinal product is not an individual prescriber’s choice and where the budget determines the access to medicines.
The experience from the biosimilar glargin insulin suggests that the adoption of other biosimilars that are prescribed outside hospitals may be slow. Thus, additional measures, carrots and sticks, are needed. It seems likely that an increasing number of EU Member States will consider automatic substitution. Prescribers have to reconsider their role in ensuring the sustainability of the pharmacotherapy in EU – an active player or a bystander.
In the long run, biosimilars will become a standard tool for controlling costs of biologicals produced by biotechnology. The market dynamics of biosimilars is not straightforward and depends on the number of biosimilars coming to the market, as well as attitudes of payers and prescribers. Thus far, the method of restoring healthy competition seems to have been trial and error. In the future, EU Member States will probably adopt more harmonized approach to biosimilar pricing, reimbursement, procurement, prescribing and dispensing policies.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
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Author Adjunct Professor Pekka Kurki, MD, PhD, University of Helsinki, 19 Lukupolku, FI-00680 Helsinki, Finland
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