Submitted: 6 June 2018; Revised: 13 July 2018; Accepted: 13 July 2018; Published online first: 20 July 2018
Reference biologicals are originator medicinal products made by or derived from living organisms using biotechnology. When the patent and exclusivity rights on a reference biological expire, biosimilar medicines can enter the market. A biosimilar is a biological product that contains a version of the active substance of an already authorized reference biological medicinal product . On the one hand, the European Medicines Agency (EMA) and regulatory authorities guarantee the quality, safety and efficacy of registered biosimilars. After a decade of experience with biosimilar products, no unexpected concerns have emerged [2, 3]. Also, health economists of international organizations refer to the important savings potential of a competitive off-patent biologicals and biosimilars market and to the opportunity to improve patient access. On the other hand, the market access, uptake and price evolution of off-patent biologicals and biosimilars stay heterogeneous between countries and between therapeutic classes, e.g. erythropoiesis-stimulating agents, granulocyte colony-stimulating factors, human growth hormones, antitumour necrosis factors, follitropin alfa and insulins .
This implies that European countries are not realizing the full potential of the off-patent biologicals and biosimilars market. In this respect, the European Commission and the Organisation for Economic Co-operation and Development (OECD) have argued that competition in the off-patent biologicals and biosimilars market could yield substantial savings to healthcare systems [5, 6]. To capture these savings, the European Commission (Directorate-General for Internal Market, Industry, Entrepreneurship and small and medium-sized enterprises [SMEs]) has supported a multi-stakeholder approach and has hosted multiple workshops with a view to facilitating access to and uptake of biosimilars [7, 8]. The European Commission also issued a consensus information paper in 2013, an information document for patients in 2016, and an information guide for healthcare professionals in 2017 .
However, the development of a competitive market for off-patent biologicals and biosimilars is not certain because of numerous factors including the risk of non-recognition of the difference between biosimilars and generics, physician and patient lack of confidence, and unbalanced payer pricing and procurement policies. In particular, after a decade of experience with these products, it seems clear that a simple logic whereby price reductions multiplied by prescribed volumes of reference biologicals will lead to potential savings is misleading and inappropriate. Price reductions alone do not appear to be the key factor guaranteeing greater market penetration of biosimilars . On the contrary, price reductions can lead to a race to the bottom, preventing manufacturers to enter the market.
It is also important that policymakers keep in mind that biosimilars (where the reference product is a biological medicine) are inherently different from generics (where the reference product is a chemically synthesized medicine), due to their more elaborate size and structure of the molecule, higher risks and costs of research and development, more complex manufacturing processes, extended development times, and the need to institute post-marketing pharmacovigilance programmes . Therefore, policy must be adapted to the specific needs of the off-patent biologicals and biosimilars market.
Developing a competitive market for off-patent biologicals and biosimilars in Europe is a necessary condition for stakeholders to reap the benefits that such competition may create. These benefits include more control of drug expenditure for healthcare payers, expanded access to health care for patients, increased treatment choices for physicians, and headroom for innovation for industry. The development of such a market requires the implementation of a long-term, sustainable and specific policy framework based on a multi-stakeholder approach. Thus, the aim of this manuscript is to provide guidance to policymakers with a view to fostering a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe, taking into account the role of all stakeholders.
This manuscript has been commissioned by the Belgian National Institute for Health and Disability Insurance. Individuals and stakeholder representatives from patient groups, clinicians, healthcare professional organizations, government bodies, and industry have participated in a series of roundtable discussions in 2016−2017 which have contributed to the development of the manuscript. These discussions were held under Chatham House Rules. This manuscript represents the authors’ views on the topic which have been informed by their participation in the roundtable discussions and do not represent the position of their respective organization/institution.
When developing guidance to policymakers, the focus of this manuscript is specifically on those product classes for which patent expiry and loss of exclusivity has recently occurred or is imminent, such as monoclonal antibodies for the treatment of inflammatory diseases (rheumatoid arthritis, inflammatory bowel diseases, psoriasis) and cancers.
Guidance to policymakers
A building block of a fair, competitive and sustainable market for off-patent biologics and biosimilars in Europe, see Box 1, relates to the need to put in place appropriate supply-side incentives. In particular, policymakers need to design smart procurement and reimbursement mechanisms with a view to allowing physicians to prescribe off-patent biologicals and biosimilars based on scientific evidence and clinical experience. The design of such mechanisms needs to be anchored in good clinical practice, which will evolve with knowledge, and needs to respect the European legislative framework on public procurement [10, 11]. Physician involvement in procurement and reimbursement mechanisms is vital to ensure that physicians maintain the freedom to prescribe. Also, there is a need to build up technical and practical expertise, and exchange experiences between countries with respect to designing smart procurement and reimbursement mechanisms.
Box 1: Recommendations for developing policy on off-patent biologicals and biosimilars in Europe
In the hospital setting, tendering mechanisms (i.e. public procurement mechanisms for medicines based on competition between pharmaceutical suppliers ) can be applied to off-patent biologicals and biosimilars nationally or locally, although future studies need to provide guidance to policymakers on how to optimize the features of these mechanisms, such as the frequency of tenders, the criteria to grant the tender, the reward for the winner(s), and the number of winners. For example, tendering may lead to a market where only one medicine is available (i.e. the ‘winner takes all’ principle) and shortages may occur if that supply fails. Thus, tendering mechanisms need to be monitored to ensure that several pharmaceutical suppliers participate and that the market does not fail .
In the ambulatory care setting, off-patent biologicals and biosimilars can be included in a reference pricing system, which sets a common reimbursement level for a group of medicines. Policymakers need to appreciate that the application of a reference pricing system could imply that off-patent biologicals and biosimilars included in the same reference group could be used interchangeably (which indicates that a patient can be alternated between products whilst expecting the same clinical outcomes in respect to efficacy and safety as if no alternation were to occur) . In such cases, the relevant policymaker should clarify the status of the medicine.
If implemented, smart tendering mechanisms and/or reference pricing systems need to be sufficiently flexible to permit the prescribing physician to act in the best interests of the patient, including the availability of choice between products. In our opinion, this also implies that physicians are in charge of any switching protocols and that no forced switching occurs. Although procurement and reimbursement mechanisms may generate price competition and produce short-term savings, policymakers also need to consider the possible impact of these mechanisms on the sustainability and the level of competition in the market for off-patent biologicals and biosimilars in the long run.
In our opinion, a key challenge relates to how physicians should use off-patent biologicals and biosimilars in real-life, clinical practice. It is clear that biosimilars can be administered to treatment-naïve patients in all approved indications. However, there is debate and concern about whether it is appropriate to introduce incentives that encourage patients to be switched from a reference biological product to a biosimilar; from one biosimilar to another biosimilar; and about switching on multiple occasions. Although such incentives purport to encourage price competition between manufacturers, there remains residual uncertainty and resistance from different stakeholders to these various forms of switching.
Therefore, we believe that the clinical profession, academia and patients need to be involved in the policy framework for off-patent biologicals and biosimilars, see Box 1. Due to the complex nature of off-patent biologicals and biosimilars, it is clear that the appropriate use of these products needs to be a clinical decision made by a treating physician for an individual patient on the basis of shared decision-making with that patient . The decision needs to balance the physician’s freedom to prescribe with his/her therapeutic and budgetary accountability based on scientific evidence, clinical experience and expert judgement. In order to make an informed and documented decision, physicians need to be supported by developing the evidence base around switching, including real-world data, pharmacovigilance data, switching data and outcome data . Scientific and medical societies have a particular responsibility to provide detailed guidance on appropriate use through position statements . Furthermore, the role of hospital pharmacists is important as they provide a ‘hub of information’ in respect of the uptake, good use and evidence base (monitoring of outcomes, real-world use and reporting of adverse events).
A number of European countries have implemented other physician incentives such as quota . From those experiences applied in countries with social health insurance systems clearly results that sufficient success will only be realized as far as a formal involvement of the medical profession and other relevant stakeholders is put in place.
In Europe, pharmacist substitution, i.e. the practice of a pharmacist dispensing a different, but similar biological medicine other than that which was prescribed, is a Member State responsibility. Today, the majority of European countries do not favour pharmacist substitution of a biosimilar for a reference biological medicine, although several countries are experimenting with various pharmacist substitution policies . Pharmacist substitution should only be considered in well-defined circumstances, motivated by specific needs and informed by high quality evidence. If a country would consider pharmacist substitution, policymakers need to ensure that any substitution policies guarantee that the prescribing physician is aware of and approves which specific product is dispensed, that pharmacists are trained to provide unbiased information about off-patent biologicals and biosimilars, and that patients are fully informed and agree with substitution.
A third building block that can align different supply- and demand-side stakeholders in promoting a competitive and sustainable market for off-patent biologicals and biosimilars relates to the recent trend of ‘gainsharing’, see Box 1. Several European countries are experimenting with gainsharing arrangements, which share the savings generated from off-patent biological and biosimilar competition between stakeholders (e.g. healthcare payers, hospitals, physicians and patients) . For instance, savings can be invested in supporting physicians and nurses when switching patients or in providing additional services to patients. Today, the experience with gainsharing arrangements is limited and future studies need to investigate the optimal design and impact of such arrangements.
In our opinion, policymakers need to introduce a long-term, sustainable and specific policy framework based on a multi-stakeholder approach with a view to fostering a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe. Although there exists residual uncertainty regarding the appropriate terms for switching off-patent biologicals and biosimilars, we believe that such issues will be clarified and resolved over the coming years with the development of new studies, data and experience with these products. Additionally, we advocate that a policy framework for the off-patent biological and biosimilar market needs to be founded on multiple building blocks including the implementation of supply- and demand-side incentives, and the prospective evaluation of gainsharing arrangements.
For patients summary
Competition among off-patent biologicals and biosimilars in Europe benefits patients as it may help to control drug expenditure, expand access to health care, increase treatment choices, and encourage pharmaceutical innovation. However, there remains uncertainty about switching patients from a reference biological product to a biosimilar; from one biosimilar to another biosimilar; and about switching on multiple occasions. Therefore, we believe that the clinical profession, academia and patients need to be involved in developing a policy framework for off-patent biologicals and biosimilars. Due to the complex nature of off-patent biologicals and biosimilars, it is clear that the appropriate use of these products needs to be a clinical decision made by a treating physician for an individual patient on the basis of shared decision-making with that patient.
The authors would like to thank John Bowis, Laura Batchelor and Johan Van Calster from FIPRA for facilitating and chairing the roundtable discussions.
This work was enabled by Amgen, MSD and Pfizer.
Provenance and peer review: Not commissioned; externally peer reviewed.
Disclosure of Conflict of Interest Statement is available upon request.
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