Submitted: 29 May 2021; Revised: 22 July 2021; Accepted: 26 July 2021; Published online first: 30 July 2021
The rising cost of health care is a matter of global concern. Drug pricing has been a growing part of the discussion about this issue and the high cost of new biologics medicines has contributed to the concern. While these therapies have been medical breakthroughs, access to them because of cost has been a concern, as has the potential for bankrupting the funding for health care. Health authorities and payers are scrambling to find solutions to this dilemma.
Biosimilars – copies of biological drugs that are similar but not identical to the product on which they are based – have proliferated significantly over the past decade as the patents for several biologics have expired. Biosimilars have been developed across a variety of therapeutic areas globally, including oncology and inflammatory diseases. The rationale for creating biosimilars is to promote competition among manufacturers to lower prices, thereby increasing access to expensive biologic medicines. A competitive marketplace typically produces price competition in general, and for biologic medicine this is no exception. The unexpected challenge has been realizing the potential savings.
There has been the temptation to apply the lessons learned from the creation of generic versions of simple molecules to biological medicines and biosimilars. This is understandable because of the substantial saving resulting from price competition, price reductions, and the ability to freely substitute a much less expensive generic version is dispensed when a more expensive brand name product is prescribed. This model is not possible for biologicals because while highly similar, biosimilars are not identical to the reference product with which they compete. This has prompted many studies of the comparability of biosimilars to their reference product, including switching studies where patients are switched from the reference product to a biosimilar. These studies have confirmed the similarity of biosimilars to reference products but may have been inconclusive about important clinical differences that may affect patients being treated. As a result, there have been a variety of different regulatory and policy approaches to the use of biosimilars around the world.
Regulatory and policy approaches to the use of biosimilars are usually developed with the goal of reducing drug costs by stimulating their use. These approaches should, but do not always have a goal in assuring the effectiveness and safety when biosimilars are used in the clinical setting. Other considerations include maintaining an environment for future innovation, sustaining a competitive market, and assuring a reliable supply chain. Good regulations and policies consider all these factors.
As of 30 April 2021, Canada has approved 36 biosimilars, and another 13 are under review . While this is on par with the Food and Drug Administration’s (FDA) approval of 30 biosimilars  and the European Medicines Agency’s (EMA) approval of 73 biosimilars (13 of which are not considered biosimilars in the US) , Canada’s recent implementation of policies requiring a non-medical switch to biosimilar medicines in British Columbia, Alberta, New Brunswick, and Quebec stands in contrast to biosimilar substitution practices in the US and Europe and does not consider some of the factors used in other countries to foster the effective and safe use of biosimilars as ways to control rising healthcare costs are considered.
Health Canada originally issued their regulatory guidelines for biosimilars, Information and Submission Requirements for Biosimilar Biologic Drugs, in 2010 . Since then, 36 biosimilars based on 13 reference products have been approved, see Table 1. To improve the efficiency of the regulatory review of drugs and devices and to support timely access to biological products, Health Canada issued a Regulatory Review of Drugs and Devices initiative (also known as ‘R2D2’) in 2017 . A key objective of R2D2 was to work with local health partners, including health technology assessment organizations, to reduce the time between Health Canada approvals and reimbursement recommendations.
While the approval of biosimilars is regulated at the national level by Health Canada, decisions about biosimilar substitution are made at the provincial level. Policies requiring the switching of a patient’s medicine from an originator biological to a biosimilar primarily for economic reasons is referred to as ‘non-medical switching’ and have been avoided by Canadian payers until recently. Newer initiatives to realize potential savings opportunities offered by biosimilars have reflected a shift in the perspective of provincial payers, and four of Canada’s provinces, that are inhabited by approximately 50% of the country’s population, have begun implementation of biosimilar switching programmes, see Table 2. Other provinces are expected to consider similar biosimilar initiatives soon.
In May 2019, British Columbia announced that it would forcibly switch more than 20,000 of its arthritis, psoriasis and diabetes patients from their originator biological medicines to the government’s choice of preferred biosimilar products. In September of the same year, it was announced that an additional 1,700 patients with inflammatory bowel disease would be switched [6, 7]. The province of Alberta announced plans to switch at least 26,000 patients, including those being treated with infliximab for ulcerative colitis and Crohn’s disease, from biological therapies (etanercept, infliximab, insulin glargine, filgrastim, pegfilgrastim) to biosimilars by the summer of 2020 . The COVID-19 pandemic has delayed the implementation of these programmes. The recent implementation of forced non-medical switching policies by Canadian payers represents a departure are different from biosimilar substitution practices in the US and Europe in that they focus on economics, not clinical or marketplace factors.
In the US, pharmacy-level substitution of a biosimilar for an originator biological without physician consent is only permitted for biosimilars that have been designated ‘interchangeable’ by FDA.
To receive an interchangeable designation, the product must meet additional requirements beyond being biosimilar, which translates to more clinical development – including switching studies. The rationale for this policy is based on the acknowledgement that biosimilars are similar but not identical to the reference product and to protect patients, additional evaluation of comparability is needed. Prior to 26 July 2021, no biosimilars in the US had been approved as interchangeable, therefore, nonmedical switching has not existed in the US§.
In contrast, EMA does not have recommendations on interchangeability but the decision-making authority on substitution policies rests with the individual EU Member States. While automatic substitution is prohibited in most European countries, a few financially constrained countries in Central and Eastern Europe, e.g. Estonia, Latvia, Poland and Serbia, allow pharmacy-level substitution . Particularly in Bulgaria, Poland and Serbia, tendering procedures are applied for purchasing biologicals and dictate which product a patient will receive. However, the prescription of switching to a biosimilar medicine in Europe most commonly occurs under the supervision of a physician in consultation with the patient. These policies are based on the responsibility and accountability of the physician for the care of their patient, while acknowledging the need to consider cost when making treatment decisions.
Successful biosimilar markets in the EU and US have demonstrated that forced medical switching is unnecessary to achieve high uptake of biosimilars and the associated savings. While the global biologicals market is dominated by the US, which has a share above 50%, Europe is the leader in biosimilar approval and commercialization . The EU was the first to establish a regulatory framework in 2004 and has the largest biosimilar market in the world, representing ~60% of the global biosimilar market . Biosimilars have attained market shares as high as 91% for older products (before the approval of the first monoclonal antibody biosimilar in 2013) and as high as 43% for newer products (approved post-2013) in some European markets. The success of the European biosimilar markets reveals three common principles: physician choice, not mandating automatic substitution, and promotion of competition [11-13]. This fosters a robust and sustainable biosimilar market with multiple suppliers in any given product class. Tenders are designed to include value-based criteria in addition to price and award multiple contracts not single-winner tenders to ensure continuity of supply and healthy competition . Experience in the EU suggest that competition not regulation results in cost savings without compromising patient care .
The introduction of major reimbursement policy changes by Canadian payers that is intended to increase the use of biosimilars, has been criticized by various groups in Canada. Physicians, medical societies and patients themselves have argued that non-medical switching will adversely affect patient care. Furthermore, these policies conflict with principles believed to be the foundation for a sustainable biosimilars market.
At the behest of Quebec’s Ministry of Health and Social Services, the Institut National d’Excellence en Santé et Services Sociaux (INESSS) conducted a state-of-knowledge report about the risks associated with non-medical switching and the interchangeability of biologicals . The systematic review on which this report is based indicated that the available scientific data are insufficient to support the safety of switching between originator biological and biosimilar, particularly in inflammatory bowel diseases and oncology, and that larger studies are needed to address the uncertainty associated with switching between biologicals in these indications. Furthermore, the report indicated that non-medical switching is generally not supported by clinicians due to the potential destabilization of complex patients, along with many other patient-related concerns. While clinicians in Quebec support the use of biosimilars in patients who have not used the corresponding reference product, they believe that switching to a biosimilar should be carried out under medical supervision. A survey of Canadian prescribers of biologicals conducted by the Alliance for Safe Biologic Medicines indicated that 83% of physicians across 13 therapeutic specialties considered it ‘very important’ or ‘critical’ that the prescribing physician decide the most suitable biological for their patients . Most prescribers were not comfortable with a third-party switching a patient’s medicine for non-medical reasons.
In a joint statement from the Canadian Association of Gastroenterology and Crohn’s and Colitis Canada, non-medical switching was not recommended for patients who are stable on biological treatment . Further, gastroenterologists across Canada do not support automatic substitution of any kind but supported starting treatment-naïve patients on biosimilar products if they had active disease and the price differential between the originator biological and the biosimilar is significant. The Gastrointestinal Society stated that reimbursement policies must recognize and respect the physician’s right to prescribe based on clinical evidence and a patient’s right to choose the therapy that is best for them .
The Biosimilars Working Group of Canada, a key collaboration of diverse non-profit organizations, registered health charities, and healthcare advocacy coalitions dedicated to ensuring good outcomes for patients, stated that the cost-driven objective of the forced-switch policy is worrisome as it fails to put physician wisdom, patient choice, appropriateness of care, accessibility, and affordability at the forefront of health policy . When Canadian researchers surveyed patients with gastrointestinal diseases and their caregivers to determine their views on the use of biological and biosimilar drugs, 95% of those surveyed believed it was important that decisions regarding choice of medication be determined solely by the treating physician in collaboration with the patient .
The burden on healthcare systems is clear according to the Gastrointestinal Society’s report on the impact of British Columbia and Alberta’s non-medical switching policies. Patients reported experiencing delays with biosimilar doses, with some reporting shortages in availability, inadequate education on biosimilars, as well as the physical and mental toll they experienced in navigating their new treatment pathways .
It can be concluded that many Canadian physicians feel that non-medical switching of biological products poses a risk to patients [14-17]. As prescribers of biosimilar medicines, these physicians feel that it is critical for them to retain the right to make treatment decisions that best benefit their patients, see Table 3. While the opinions of these Canadian physicians are at odds with the forced non-medical switching policies of Canadian drug plans in British Columbia, Alberta, New Brunswick and Quebec, they are aligned with the views of experienced prescribers from the US and Europe [11, 14].
Health policy decisions in Canada affecting the clinical use of biosimilars focuses primarily on economic factors and a strategy to reduce rising healthcare costs. While this is a laudable aim, it does not consider other factors that are important when making regulatory decisions. Factors that must be considered include the effectiveness and safety of therapy, the supply chain, and sustaining a healthy market for innovation and price competition. Mandatory switching for non-medical reasons does not consider that not all patients respond the same way to medications and that this can increase the financial burden on healthcare systems. In a recent systematic literature review conducted to evaluate the economic impact of non-medical switching, Liu et al.  identified 17 studies that reported an overall increase in real-world costs associated with non-medical switching. Higher rates of surgery (11%) increased steroid use (13%) and biosimilar dose escalations (6% to 35.4%) were cited as some of the reasons for the cost increases. Most studies evaluating the economic impact of non-medical switching consider only drug costs; however, a comprehensive evaluation should incorporate all elements of healthcare service needs .
For example, Alberta’s switching policy resulted in many unintended consequences, the health and financial impacts of which the province has said it needs to investigate :
In Alberta, patients were switched from infliximab, etanercept, pegfilgrastim, and filgrastim originator biologics. They were also switched from insulin glargine originators, although in the United States there are no official biosimilars for these products yet§.
Alberta ran into some problems. For example, some pharmacies began stocking only preferred biosimilars, which meant that patients and their providers could not choose. Alberta has attempted to remedy this problem.
The government has succeeded in switching over 60% of patients from reference infliximab to biosimilar infliximab, but there has been opposition. In addition, more than 15% of patients moved to a different biologic and roughly 15% dropped or terminated their government coverage, [Alberta Health Assistant Deputy Minister, Chad Mitchell] said. The government is attempting to find out the reasons for these coverage departures and treatment changes.
For the originator insulin glargine product Lantus, more than 40% of patients moved to a different biologic after switching was initiated, and 15% of beneficiaries dropped or terminated their coverage. Mitchell said 10% to 20% of beneficiaries in other biosimilar categories terminated coverage. More investigation is needed to understand the significance of these trends, he said.
Non-medical switching to biosimilar products may also have a negative impact on patient safety in cases where administration devices for self-administered biosimilars differ from the reference product [22, 23]. Without proper guidance from a healthcare provider, biosimilar products available in different presentations compared to their reference products could lead to inappropriate use by patients or caregivers – again highlighting the need for physician responsibility in treatment decisions.
While the European biosimilars market has been credited with higher uptake compared to the US market, rates of uptake differ from country to country in Europe and can vary significantly by product class. A report by KPMG commissioned by Medicines for Europe to analyse the procurement of medicines in hospitals in eight European countries highlighted the variability in biosimilar sales against originator in these different Member States . An average of hospital biosimilar volume in March 2019 showed that Denmark achieved 63% overall biosimilar volume, with the UK coming in second at 45%. Germany had 40% biosimilar volume, France had 34%, and Belgium tied with Switzerland for last place among the countries studied at 14%. In a recent assessment of the impact of biosimilar competition in Europe, 16 European countries were reported to have achieved > 90% biosimilar utilization for filgrastim and pegfilgrastim in 2018, while utilization in Ireland was just 27%. Among antitumour necrosis factor biosimilars (adalimumab, etanercept and infliximab), Norway and Denmark had 81% and 96% biosimilar uptake, respectively, while every other country’s utilization was less than 50% . Variations in adoption rates among individual European countries as well as across therapeutic areas are influenced by government involvement, reimbursement structures and tender procurement policies.
In the US, biosimilars have gained significant share in the majority of therapeutic areas in which they have been introduced, ranging on average from 20% to 25% within the first year of launch, with some projected to reach greater than 50% within the first two years [26, 27]. As expected, first-to-market biosimilars tend to capture a greater portion of the segment compared to later entrants. Filgrastim biosimilars have been on the market the longest at five years and have achieved a 72% share, while bevacizumab and trastuzumab biosimilars have approximately 40% share. Rituximab and infliximab have had the most limited adoption, with approximately 20% market share .
Canada desires a robust biosimilar market share like that observed in Europe. While there may be short-term savings from non-medical switching, a long-term consequence of this policy may be decreased competition resulting from fewer products launches and a negative impact on patient safety. Potential drug shortage issues may develop in the absence of multiple suppliers of biologicals in each product class. There would also likely be undermining the confidence of both physicians and patients in biosimilars that creates an additional barrier to biosimilar uptake.
The successful uptake of biosimilars in Europe was not accomplished by limiting the choice of biological or forced non-medical switching, but through preserving choice for physicians and patients and by promoting competition among all products approved by regulatory authorities. To foster its success in creating a sustainable biosimilars market, Canadian payers can learn from the lessons learned in more mature markets and implement evidence-based transition policies that consider patients’ needs primary.
This paper is funded by the Alliance for Safe Biologic Medicines (ASBM).
The ASBM is an organization composed of diverse healthcare groups and individuals – from patients to physicians, innovative medical biotechnology companies and others – who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion.
The activities of ASBM are funded by its member partners who contribute to ASBM’s activities. Visit www.SafeBiologics.org for more information.
Professor Philip J Schneider1, MS, FASHP, FASPEN, FFIP
Michael S Reilly2, Esq, Executive Director
1College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA
2Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
Competing interests: Professor Philip J Schneider is a member of the International Advisory Board of Alliance for Safe Biologic Medicines (ASBM) since 2012 without compensation. From September 2014, Emeritus Professor Schneider has been the Chair of the International Advisory Board of ASBM and is paid a small stipend for that role. Mr Michael S Reilly, Esq is the Executive Director and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002 to 2008.
Provenance and peer review: Not commissioned; externally peer reviewed.
§On 26 July 2021, the US FDA approved its first interchangeable biosimilar, the insulin glargine product Semglee. To be designated interchangeable, a biosimilar must provide additional data to FDA demonstrating that a patient switched repeatedly between the biosimilar and the originator product can expect the same clinical result without additional risks, compared to a patient who remained on the originator product. As of April 2021, all US states permit interchangeable biosimilars to be substituted at the pharmacy level without prior physician authorization.
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Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
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