A critical review of substitution policy for biosimilars in Canada

Author byline as per print journal: Professor Philip J Schneider1, MS, FASHP, FASPEN, FFIP; Michael S Reilly2, Esq

Canada has approved a total of 36 biosimilars. While the approval of biosimilars is regulated at the national level, decisions about biosimilar substitution are made at the provincial level. Four Canadian provinces, representing around 50% of the population in Canada, have now implemented policies requiring non-medical switching of biosimilars – switching from a patient from an originator biological to a biosimilar primarily for economic reasons. In this article, we compare biosimilar substitution policies in Canada to policies in Europe and the US, finding an enhanced focus on clinical and marketplace factors in these regions. We also find evidence that in some cases non-medical switching may pose a risk to patients and suggest that Canada could learn from more mature markets, such as those in Europe, where switching policies better consider patient needs, preserve physician choice and promote market competition.

Submitted: 29 May 2021; Revised: 22 July 2021; Accepted: 26 July 2021; Published online first: 30 July 2021

Introduction

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 biologicals 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 biologicals 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 biological medicines. A competitive marketplace typically produces price competition in general, and for biological 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 [1]. While this is on par with the Food and Drug Administration’s (FDA) approval of 30 biosimilars [2] and the European Medicines Agency’s (EMA) approval of 73 biosimilars (13 of which are not considered biosimilars in the US) [3], 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.

Overview of biosimilars in Canada

Health Canada originally issued their regulatory guidelines for biosimilars, Information and Submission Requirements for Biosimilar Biologic Drugs, in 2010 [4]. 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 [5]. 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.

Table 1

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.

Table 2

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 [8]. 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.

Policies in established biosimilars markets

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, non-medical 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 [9]. 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 [10]. 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 [10]. 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 [12]. Experience in the EU suggest that competition not regulation results in cost savings without compromising patient care [13].

Internal concerns about Canadian biosimilars policy

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 [14]. 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 [15]. 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 [16]. 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 [17].

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 [18]. 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 [19].

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 [20].

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].

Table 3

Discussion

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. [20] 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 [21].

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 [22]:

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 [24]. 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 anti-tumour 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% [25]. 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 [25].

Conclusion

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.

Funding sources

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.

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.

Authors

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

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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

Disclosure of Conflict of Interest Statement is available upon request.

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A white paper: US biosimilars market on pace with Europe

Abstract:
In the US, 28 biosimilars have been approved, with 10 in the last two years. The US is keeping pace with the EU who pioneered biosimilars approvals a decade earlier. Herein, current FDA regulations and hurdles encountered for US biosimilar approval and uptake are discussed.

Submitted: 12 October 2020; Revised: 28 October 2020; Accepted: 29 October 2020; Published online first: 9 November 2020

While many sources claim that Europe is winning the race when it comes to biosimilars, a broader assessment of the landscape reveals a more encouraging story for the US. Although the European Medicines Agency (EMA) pioneered the framework for biosimilar regulation, the US Food and Drug Administration (FDA) is moving at approximately the same pace as EMA based on the number of approvals at the same time after implementation of its regulatory pathway [1].

The biosimilar regulatory framework in Europe was implemented in 2004. Within this framework, the Committee for Medicinal Products for Human Use (CHMP) provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by EMA [2]. In the US, the Biologics Price Competition and Innovation Act of 2009 (BPCIA Act) created an abbreviated licensure pathway for biosimilars and granted FDA the authority to approve these near-identical biologicals [3]. This legislation was implemented in 2010 as part of the Patient Protection and Affordable Care Act signed by President Barack Obama.

As of September 2020, approximately 10 years after implementation of the bio­similar approval pathway, 28 biosimilars have been approved by FDA, with 18 of those approvals granted in the last two years [4]. In the 10-year time period following the creation of Europe’s biosimilar regulatory pathway, EMA approved 13 biosimilar products (some of which were marketed under several different brands) [5]. From this perspective, the US appears to be on a faster pace than the EU in terms of biosimilar approvals. Currently, there are 45 biosimilars approved in Europe; however, these estimates fall to 35 when products approved in the US as follow-on biologicals via the 505(b)(2) pathway, e.g. somatropin, insulin, teriparatide, or abbreviated new drug application (ANDA) are excluded, see Table 1. Furthermore, Europe’s filgrastim biosimilar Tevagrastim®/Ratiograstim® was approved as Granix® (tbo-filgrastim) in the US via a Biologic License Application (BLA) prior to the implementation of a biosimilar approval pathway and is not included in the US biosimilar count.

Biosimilars have been developed in various therapeutic areas, including oncology and rheumatology, and are based on nine reference products. For some reference products, numerous biosimilars have been developed; for example, five biosimilars of Genentech’s Herceptin® (trastuzumab) and Amgen’s Neulasta® (pegfilgrastim) have been approved in the US and Europe. A summary of the biosimilars landscape in the US and EU is presented in Table 1.

There are currently nine biosimilar appli­cations under CHMP evaluation, including biosimilar candidates for adalimumab (2), bevacizumab (5), pegfilgrastim (1), and trastuzumab (1) [6]. Unlike the transparency on biosimilar filings in Europe, FDA does not provide information on biosimilar candi­dates under review until they are approved.

Since the creation of a regulatory approval pathway, numerous guidance documents have been developed by both EMA and FDA to guide manufacturers in their development of biosimilar candidates. At least 10 documents have been released by FDA that provide guidance on scientific and quality considerations in the demonstration of biosimilarity and interchangeability [7]. EMA has published three overarching guidelines and nine product-specific guidelines for biosimilars manufacturers that address both non-clinical and clinical issues as well as quality-related issues [8].

Because EMA pioneered biosimilar regulations, the question has commonly been raised: To what extent does the European biosimilar experience translate to the US? Although the US and the EU are on a similar trajectory in terms of the number of biosimilar products approved, these markets differ in several respects. A critical point of divergence between the US and EU biosimilars terrain is the concept of interchangeability. Unique to the US, FDA may designate a product ‘interchangeable’ if it meets additional requirements beyond being biosimilar, which translates to more clinical development that includes switching studies and increased cost from a manufacturer’s perspective. To date, no biosimilar products have interchangeability status. Having a separate designation of interchangeability for an approved biological has been said to give the impression that interchangeable biosimilars are superior in quality to non-interchangeable biologicals ‒ which is not the case. A major focus area for the Association for Accessible Medicines’ Biosimilars Council has been educating physicians and payers on interchangeability designations as they are ‘waiting for interchangeability to really get on board with biosimilars’ [9].

Perceptions of prescribing physicians about the safety of biosimilars is an ongoing issue. There is a need for increased confidence, particularly around switching from a reference product to a biosimilar. Concerns are particularly heightened in the oncology therapeutic area, where treatments can be curative and clinicians fear the loss of efficacy and increased immunogenicity [10]. One of the key concerns around switching to a biosimilar is the negative counterpart of the placebo effect: the nocebo effect, a phenomenon in which negative expectations lead to worsening of symptoms [11]. Some physicians continue to have doubts regarding the rigorous approval process for biosimilars and switching studies that have been performed thus far and transfer these negative concerns to patients through body language or tone of voice when discussing treatment options. Raising awareness about the nocebo effect by educating healthcare professionals on this phenomenon may mitigate its effect in patients receiving biosimilar products [12, 13].

Table 1

The biosimilars marketplace

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 [14]. 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% [15]. 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 [16, 17]. 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 [16].

Biosimilar competition has a significant potential to impact overall drug spending, with the amount of savings per country based on the volume and list price of products prior to biosimilar entry [15, 17]. Manufacturers are reducing healthcare costs by launching biosimilars at a wholesale acquisition cost (WAC) that is generally 15% to 37% lower than the reference product WAC and 3% to 40% below the reference product average sales price (ASP). Manufacturers of originator products have had to adapt their strategies in order to stay competitive, whether it be launching a second-generation product, or a new formulation aimed at reducing side effects. Biosimilar competition and originator manufacturer responses are translating into significant savings. The annualized savings reached US$6.5 billion in the second quarter of 2020, where reference molecules sold US$20.8 billion (annualized) pre-biosimilar [18]. Savings over the next five years as a result of biosimilar alternatives are projected to exceed US$100 billion [17].

Biosimilars include both self-administered drugs obtained at retail pharmacies as well as provider-administrated drugs in inpatient and outpatient settings. In the US, the balance of cost savings to healthcare payers, providers and patients is different for each of these due to differences in payment and cost-sharing arrangements [19]. Most self-administered pharmacy-dispensed biologicals are paid for on a fee-for-service basis and the final amount paid by insurers reflects several transactions, including a confidential rebate payment. On the other hand, the costs associated with provider-administered biologicals are purchased directly from manufacturers and wholesalers or through group purchasing organizations either incorporated into prospective, bundled payments or under fee-for-service arrangements. Access to these biologicals (reference or biosimilar) is determined by formularies that may reflect the highest price concession rather than the lowest list price.

To date, there have been no self-administered biosimilars launched in the US. This is in stark contrast to Europe, where biosimilars administered via self-injection at home are available, including a recently approved subcutaneous form of infliximab [20]. It remains to be seen how self-administered biosimilars will fare in the US system where higher list price drugs may be ‘preferred’ on the formulary based on their profitability for those constructing the formulary.

Overcoming the hurdles

Despite having approved 28 biosimilars in 10 years, the US faces one of its biggest biosimilar hurdles when it comes to launching these products. So far, 18 of 28 biosimilars have been made available to patients, while the others have not been commercialized due to patent-related issues. In an effort to protect their originator products, brand manufacturers block competition by filing numerous follow-on patents. The expense of challenging these patents can serve as a deterrent to potential biosimilar competitors [21]. Brand manufacturers also disincentivize biosimilar utilization by leveraging a ‘rebate trap’ wherein brand manufacturers offer significant rebates for their products that disable competition from biosimilars coming on the market [22].

While there is work to be done to acceler­ate commercialization of biosimilars, FDA has taken active steps to mitigate some of these barriers to biosimilar utilization. In July 2018, Health and Human Services Secretary Alex Azar announced a Biosimi­lars Action Plan (BAP) to advance poli­cies that facilitate the development of the biosimilars market and increase competi­tion for biological drugs [23].

Key strategies of FDA’s BAP of 2018:

FDA’s most recent actions addressed biosimilar market competition in a joint statement issued by FDA and the Federal Trade Commission (FTC) that identified four goals to help combat anti-competitive practices [24]. In particular, the agencies noted their concern with false or misleading statements comparing biological reference products and biosimilars, which may be hampering biosimilar uptake by creating negative misperceptions about the safety and efficacy of biosimilar therapies. To further clarify how data and information about biosimilars should be presented in a truthful and non-misleading manner in regulated promotional materials, FDA announced the release of the ‘Draft guidance for industry: promotional labeling and advertising considerations for prescription biological reference and biosimilar products ‒ questions and answers’ and invited comment by stakeholders in the docket. As part of their efforts to promote greater competition, FDA and FTC held a public workshop in March 2020 to discuss their ‘collaborative efforts to support appropriate adoption of biosimilars, discourage false or misleading communications about biosimilars, and deter anticompetitive behaviors in the biological product marketplace’.

Targeting faster reviews, FDA issued new draft guidance in February 2020 detailing how it will speed its review of biosimilar or interchangeable application supplements, which can be used to update the initial biosimilar approval when it is for fewer than all the reference product’s licensed conditions of use [25]. At the time of submission, applicants may decide not to seek licensure of a proposed biosimilar for conditions of use that are protected by patent for the innovator. FDA had previously committed to reviewing and acting on original 351(k) BLA supplements with clinical data within 10 months of receipt; however, the agency now says such supplements will be reviewed and acted upon in a 6-month timeframe.

The US Centers for Medicare and Medicaid Services (CMS) have also revised a ­number of their payment policies in an effort to promote biosimilar competition. Three policy changes made under Medicare Part B to incentivize biosimilar uptake were: 1) BPCIA required Medicare Part B to pay for biosimilars at the ASP of the biosimilar plus 6% of the innovator product’s ASP [26]; 2) unique payment codes were provided for each biosimilar (reversing policy that grouped drugs under single codes) [27]; and 3) biosimilars were allowed ‘pass-through’ status under the 340B Drug Pricing Program, which meant they could be paid at ASP plus 6% rather than being heavily discounted (–22.5%) [28]. Furthermore, under Medicare Part D, the Bipartisan Budget Act of 2018 changed the treatment of biosimilars in the coverage gap (doughnut hole) discount programme, requiring manufacturers to give discounts for biosimilars [29]. Furthermore, in 2019, there was a lowering of the maximum copay amount on biosimilars to rates commensurate with generic copay amounts for lower income beneficiaries.

In parallel with updated regulatory policies that encourage development of the biosimilars market, a growing body of evidence has amassed to support the clinical safety of biosimilars. In a systematic review of primary data from 90 studies that enrolled 14,225 unique individuals, the nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference biological [30]. Similar results were observed in a systematic review of 57 switching studies evaluating the efficacy, safety and immunogenicity risk of transitioning between an originator biological and a biosimilar [31]. These results should increase confidence of patients, healthcare professionals and the public in biosimilars, leading to increased acceptance of these safe and effective medicines.

Conclusion

Although it has been suggested that biosimilars are not living up to their promise in the US, the current landscape suggests otherwise. FDA has approved 18 biosimilars in the past two years alone and a total of 28 since the implementation of a regulatory pathway just 10 years ago. Although getting these drugs into the hands of patients has hit some stumbling blocks due to anti-competitive behaviours from brand manufacturers, FDA has been proactive in addressing these ‘shenanigans’ and has created a BAP as well as additional guidances to mitigate such barriers to uptake and ensure the biosimilars market is poised for success. Clinical studies on the impact of switching between reference medicines and biosimilars have underscored the safety of biosimilars and impart confidence in their utilization for both physicians and patients.

In short, the overall outlook on biosimilars is positive. Pharmaceutical Research and Manufacturers of America (PhRMA), an organization representing biopharmaceutical manufacturers, believes that biosimilars are helping to bring down the cost of drugs in the US market and are positioned to achieve further savings. Katie Verb, Director of Policy and Research for PhRMA, says that federal policies are having a positive effect. These sentiments were echoed by Dr Leah Christl, Amgen’s Executive Director for Global Regulatory and Research and Development Policy, who believes the US biosimilars market is showing healthy vital signs.

Funding sources

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.

Competing interests: Dr Madelaine Feldman is the Chairperson of the Alliance for Safe Biologic Medicines. She has participated in advisory boards for Gilead, Lilly, Pfizer and Samsung. 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.

Authors

Madelaine Feldman, MD, FACR
Michael S Reilly, Esq

Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

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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

Disclosure of Conflict of Interest Statement is available upon request.

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European prescribers’ attitudes and beliefs on biologicals prescribing and automatic substitution

Introduction: The European Union (EU) and the European Medicines Agency (EMA) have led the development of a regulatory framework for biosimilars since 2004. By end of December 2019, 64 biosimilars of 15 originator biological medicines have a marketing authorization in Europe. Now, for the second time, the Alliance for Safe Biologic Medicines (ASBM) asked European prescribers for their views on the prescribing, adverse drug reaction reporting, automatic substitution and switching of biologicals and biosimilars.
Methods: In March 2019, the ASBM surveyed 579 prescribers in France, Germany, Italy, Spain, Switzerland and the UK. Prescribers were asked for their views on authority over prescribing and dispensing of biologicals/biosimilars, reporting biological/biosimilar use and adverse drug reactions (ADR) and switching. There were also questions related to their familiarity with, knowledge of, attitudes to, and beliefs in, biosimilars.
Results: Since the previous European prescriber study conducted in 2013, the percentage of respondents considering themselves highly familiar with biosimilar medicines has increased from 76% to 90%. Four out of five prescribers said they are legally required to report ADR that are brought to their attention and they file detailed ADR reports taking 10–20 minutes. Four out of five prescribers feel very strongly about having control over what is prescribed and dispensed to their patients. While highly comfortable prescribing biosimilars to naïve patients, physician comfort level decreased when switching a stable patient to a biosimilar. Comfort level decreased further when prescribers were asked about switching a patient to a biosimilar for non-medical reasons, e.g. cost, and further still if the switch is initiated by a third party.
Conclusion: European physicians have increased their familiarity with biosimilars since the 2013 survey. Physicians increasingly believe they should always have control of treatment decisions including the decision to switch to a biosimilar. It was also highlighted that governments should make multiple therapeutic options available through tenders.

Submitted: 9 Junly 2020; Revised: 9 August 2020; Accepted: 19 August 2020; Published online first: 26 August 2020

Introduction

Healthcare systems across the globe face resource and budget constraints. Biosimilar drug products offer less expensive alternatives to brand-name originator drug products and can thus offer some relief to healthcare costs. Biosimilars are highly similar and have no clinical meaningful differences; but are not identical to originator biologicals. As countries seek to control health costs and expand access to biological therapies, building physician confidence in biosimilars is critical to promoting their use and reaping the cost benefits.

The European Union (EU) and the European Medicines Agency (EMA) have led the development of a regulatory framework for biosimilars. In 2005, EMA established the first biosimilars approval pathway that was distinct from generics approval [1]. Since then, EMA has developed and refined a comprehensive set of regulatory guidelines on which biosimilar applications are reviewed and approved or rejected. By the end of 2019, 58 biosimilars of 15 originator biological medicines have a marketing authorization in Europe [2]. The European biosimilars market is currently the largest in the world, representing approximately 60% of the global biosimilar market and growing consistently year on year [3].

At present, once authorized, EMA applies a ‘same-label’ (generic) approach to biosimilar product labels [4]. However, there are concerns over whether this is sufficient to ensure appropriate drug switching and product traceability. There is ongoing debate about what information is appropriate in the naming and labelling of biosimilars. In the US, FDA released its requirements for the non-proprietary naming of biological products in January 2017 [4]. Prior to this, the Alliance for Safe Biologic Medicines (ASBM) carried out surveys of Australia and EU prescribers and US pharmacist perspectives on the naming of these products. Overall, both groups believed that naming should make biosimilars distinguishable from originator products [57]. The ASBM is an organization composed of diverse healthcare groups including patients, physicians and medical innovators. It is funded by its many member partners that are made up of international organizations and companies [8].

The interchangeability of biosimilars is viewed differently in countries across the world. This is particularly marked by the approaches to interchangeability and substitution in the US and Europe [9]. ‘In the US, insurance mandates can result in formulary changes requiring patients to be switched from a reference product to a biosimilar strictly for cost reasons’ . In Europe, automatic substitution of originator biologicals with biosimilars is rare as this practice excludes physicians from decisions regarding the treatment of patients. There have been a number of surveys and workshops carried out across the world (Australia [5], Europe [4, 6], South America [10] and the US [11]) that have asked for prescriber opinions on prescribing practices, naming and labelling of biologicals. In terms of naming, prescribers in Australia, Europe and the US, overall, agreed that there is a need for distinguishable non-proprietary names to be given to all medications. In South America, knowledge about biosimilars varied in different countries surveyed (Argentina, Brazil, Colombia and Mexico) and revealed gaps in understanding and in the use of distinguishable names for biologicals.

In 2019, the ASBM commissioned 15-minute web-based surveys to be carried out by biological prescribers in six Western European countries (France, Germany, Italy, Spain, Switzerland and the UK) to document their perspectives on biological substitution. This survey mirrors their previous European prescriber survey conducted in 2013 [6] (both survey reports can be found at www.safebiologics.org/surveys).

Overall, the 2019 survey showed that awareness of biosimilars in the countries had increased since the 2013 survey. Specifically, more physicians (90%) rated themselves as being ‘Familiar’ or ‘Very familiar’ with biosimilars than did in 2013 (76%). A strong majority of respondents (82%) felt that it is either ‘Very important’ or ‘Critical’ for them to decide which biological medicine is dispensed to their patients, representing a 10% increase over the results of the 2013 survey. Again, a strong majority of respondents (84%) considered authority to prevent a substitution either ‘Very important’ or ‘Critical’ , another 10% increase over the 2013 findings. In 2019, physicians remained uncomfortable with switching a stable patient to a biosimilar for non-medical reasons. Since the 2013 survey, there has also been a sharp increase in physicians who are highly uncomfortable with a non-medical substitution performed by a third party.

It is hoped that the findings of this study may serve as a resource for other countries in developing biosimilar policies that can build physician confidence in biosimilars. Confidence that will increase biosimilar uptake and reduce government expenditures on biological products.

Sample characteristics and methodology

In March 2019, 579 prescribers practising in six specified European countries (France, Germany, Italy, Spain, Switzerland and the UK) completed the 15-minute web-based survey that was administered in the respondents’ native language – French, ­German, Italian, Spanish, or English. The survey was commissioned by the ASBM and was a refreshed version of that carried out in 2013 [6]. The questionnaires were developed as a collaboration among ASBM management, ASBM membership and Industry Standard Research (ISR) management. No ‘validation’ was conducted as the instruments did not measure higher level ‘constructs’ . They are purely direct measures of opinion and attitude.

Potential respondents were identified in – and recruited from – a large, global, commercial database/panel of healthcare professionals. The response rate was high because people in this database/panel have already indicated a willingness to participate in market research. In addition, their specialties were known prior to recruitment, which decreased the rate of disqualification, as if someone was identified as representing a specialty that did not qualify for the study, they were not invited.

Respondents were paid a stipend for their participation. Stipends ranged from US$37.00 to US$48.00, depending on the specialty.

Prescriber eligibility criteria

  1. Must prescribe biological medicines in their practice
  2. Must practice in France, Germany, Italy, Spain, Switzerland, or UK
  3. Must specialize in one of 10 practice areas: Dermatology, Endocrinology, Gastroenterology, Haematology-Oncology, Immunology, Nephrology, Neurology, Oncology, Ophthalmology, Rheumatology
  4. Must have been in practice for one year or more

Online survey
The surveys were administered by ISR. In summary, prescribers were asked to rate:

  1. The importance of retaining sole authority to decide the most suitable biological for their patients.
  2. The importance of retaining the authority to deny/prevent a substitution by indicating “Do Not Substitute” or similar language when prescribing.
  3. Their comfort level with: a) prescribing a biosimilar to a new (treatment-naïve) patient; and b) switching a stable patient from an originator biological to a biosimilar.
  4. Their comfort level with a biosimilar switch for non-medical reasons, e.g. cost, coverage, a) when performed by the physician; and b) when performed by a third party.
  5. The importance of awarding government tenders on originator biologicals and biosimilars to multiple suppliers.
  6. The importance of national tender offers including factors besides price.

ISR provided statistical significance tests by country and practice area for most questions. The information from these tests made it possible to determine which answers were most significant amongst prescribers from different countries and working in different practice areas.

Information on survey participants
Participants were sourced from six countries and across 10 therapeutic areas. The detailed breakdown of this information is as follows. Table 1 provides details of the survey sample disposition.

Table 1

A total of 579 responses were received:

The breakdown of the practitioner’ s primary therapeutic areas is as follows:

Neurology (14%), Rheumatology (14%), Gastroenterology (13%), Ophthalmology (12%), Nephrology (12%), Endocrinology (11%), Dermatology (10%), Oncology (6%), Immunology (5%) and Haematology-Oncology (3%).

The largest group of prescribers (47%) practice in a hospital setting, with the remainder in academic medical centres (23%), private/family practice (18%), multi-specialty clinics (8%), community settings (3%), and other settings (1%).

Respondents’ mean experience level was 15.5 years in practice. Forty per cent of responders had been practising medicine for 11–20 years, 24% for more than 21 years, 23% for 6–10 years, and 13% for 1–5 years.

Seventy-nine per cent of responders said they commonly treat patients who are using biological medicines prescribed by another healthcare provider.

Respondents use different sources to learn about the details of a medicine for prescribing and monitoring, see figure 1.

All data refer only to those who completed the survey. All data were analysed in MS Excel and checked manually.

Figure 1

Results

Familiarity with biosimilars
Familiarity with biologicals versus biosimilars
When asked about familiarity with biological medicines, 58% of prescribers said they are ‘Very familiar’ , and have a complete understanding of them, compared to 41% who said the same about biosimilars. Thirty-seven per cent of prescribers said they are “Familiar”, with a basic understanding of biologicals, compared to 49% who said the same about biosimilars. And 4% had heard of biologicals but could not define them, compared to 8% who said the same about biosimilars. All prescribers had heard of biologicals whereas 2% of prescribers have not heard of biosimilars.

Since the 2013 European prescribers study, familiarity with biosimilar medicines increased from 76% to 90%; and a prescriber’ s awareness that a biosimilar may be approved for several or all indications of the reference product on the basis of clinical ­trials in only one of those indications increased from 63% (2013) to 83% (2019.) Strongest familiarity with biosimilars was among prescribers in Italy, Spain and Germany (48%, 47% and 44% are very familiar/have complete understanding). Prescribers in Switzerland had the lowest familiarity with only 31% stating they are very familiar/have complete understanding of biosimilars; 19% of Swiss prescribers either could not define biosimilars or have never heard of biosimilars.

Strongest familiarity with biological medicines was among Rheumatology and Gastrointestinal prescribers (96% and 88% are very familiar/have complete understanding) when compared to the other practice areas. Strongest familiarity of biosimilars was also among Rheumatology, Gastrointestinal and Endocrinology prescribers (70%, 61% and 60% are very familiar/have complete understanding).

Preferred route to familiarity
Of the respondents (n = 517) that said they were very familiar/familiar with biosimilar medicines. The top five sources of information were: 1) scientific publications (70%); 2) national medical conferences/symposia (70%); 3) international medical conferences/symposia (61%); 4) self-study (42%); and 5) CME/IME (40%).

The sources varied among the countries. For example, prescribers in the UK became more familiar with biosimilars through self-study (66%) and scientific publications (56%), while in Spain scientific publications (73%) and CME/IME (66%) were the most utilized.

The top five sources to learn about biosimilars among the respondents (n = 62) who had never heard of, nor could define biosimilar medicines were: 1) scientific publications (68%); 2) international medical conferences/symposia (61%); 3) national medical conferences/symposia (55%); 4) CME/IME (37%); and 5) reference product company sponsored education (35%).

There were no significant differences in the preferred method for becoming familiar with biosimilars among practitioners in different countries.

Biosimilar approval awareness
Prescribers in Italy (94%) had significantly higher biosimilar approval awareness compared to the rest of the countries. The specialties with the highest biosimilar approval awareness were Rheumatology (96%), Endocrinology (95%), Oncology (94%) and Gastrointestinal (92%) prescribers. All had significantly higher awareness than other specialties.

Adverse drug reaction reporting: mechanism, recording, information required, barriers
The survey showed that four out of five prescribers are legally required to report adverse drug reactions (ADRs) that are brought to their attention.

Italian prescribers rated the highest percentage for being required to report ADRs (96%), and French prescribers the ­lowest (69%). The practice areas in which the highest number of prescribers are required to report ADRs were Oncology (91%) and Immunology (90%).

More than half (54%) of prescribers said they are most likely to report an ADR to the National Competent Authority (NCA). The UK is significantly more likely to report to a combination of the NCA, the Marketing Authorization Holder (MAH), i.e. the manufacturer, and EMA (54%) as opposed to the NCA alone (29%).

ADR report mechanisms, time spent and follow-up
Email was utilized by almost half (49%) of prescribers (n = 550) to report ADRs to the NCA or MAH. However, when looking at specific countries, prescribers in Germany (58%) and the UK (52%) had a majority preference for paper. Prescribers in France (57%) and Italy (60%) had a preference for email, while Spain (53%) preferred a web-based tool/app.

Two-thirds (65%) of prescriber respondents said that the amount of time spent on filing a report ranged from 10 to 20 minutes, with 25% requiring less than 10 minutes and 10% requiring more than 20 minutes (average 36 minutes) While prescribers do file detailed reports, the time varies among the specialties. Dermatology (38%) prescribers need less time to file compared to other practice areas, whilst Neurology (19%), Immunology (17%) and Nephrology (14%) prescribers need more than 20 minutes to file the ADR report.

In terms of follow up from the NCA or MAH, 24% of prescribers responded they always receive follow-up, 21% very often, 30% sometimes, 19% rarely and 6% never. Prescribers in Switzerland have one of the highest rates of follow up from reporting entities (Always, 35%) compared to several other countries.

Information included in the ADR reports
When ADR reports are filed for a biological medication, 92% of practitioners responded that information about the ADR experienced by the patient are included, 84% include brand name of the biological suspected to have caused the incident, 80% include date and time of report, 72% include the non-proprietary name of the biological suspected to have caused the incident, 69% include batch number of the biological suspected to have caused the incident, including the manufacturer of the product suspected to have been associated with the reaction.

Prescribers in Italy (79%) are better about including batch ­number in the ADR report; Germany (74%) prescribers are ­better about including the manufacturer of the product; prescribers in the UK (90%) are better about including date and time.

When asked about how frequently the NCA or MAH follow-up to request the brand name or manufacturer of the product, 55% of prescribers responded either always or very often, 28% said sometimes, while 18% said rarely or never.

Fifty-five per cent of practitioners said that the level of detail required in ADR reports deters them from reporting minor events. When looking at the country specific data, prescribers in France are significantly more deterred from reporting minor events, while those in Italy are significantly less deterred.

Barriers to reporting ADRs
Fifty-five per cent of the prescribers responded that the amount of information necessary to report an adverse drug reaction deters them from reporting minor events. France (74%) is significantly more deterred from reporting minor events, while Italy (38%) is significantly less deterred.

More than half (56%) of prescribers responded that reporting infrastructure, e.g. the mechanism of reporting ADRs, was the biggest barrier to accurate reporting; another 20% responded no barriers exist. When looking at the country specific data, prescribers in Spain identified reporting infrastructure (70%) and lack of integration of electronic health records (55%) as barriers to accurate reporting more so than most countries.

Nearly all prescribers responded that they were somewhat confident (62%) or highly confident (36%) in the European pharmacovigilance system’ s ability to accurately identify the specific product at the brand-name level that might be responsible for the ADR. However, prescribers in the UK were less confident in the European pharmacovigilance system than the other countries surveyed, with only 24% reporting they were ‘highly confident’ the system would be able to accurately identify the product responsible.

Frequency of including batch number when reporting adverse events was mixed; 37% always, 27% very often, 20% sometimes, 17 % rarely/never. The survey showed that prescribers in Italy (55%) were best about including batch number (always) when compared to most of other countries. Of the prescribers who said they only included batch number sometimes, rarely, or never, more than half (53%) of prescribers responded that the reason for this was due to not having it available at time of reporting.

Automatic substitution, switching and physician choice
A high majority of prescribers (82%) feel very strongly about having control over what is prescribed and dispensed to their patients.

Opinion on sole authority for prescribers
Most prescribers agreed that it is either critical or very important (82%) that they had the sole authority, together with their patients, to decide on the most suitable biological medicine for their disease. When looking at each country, it is significantly more critical to have sole authority in deciding medicine for prescribers in Italy (94%), Switzerland (91%) and Germany (84%). When looking at specific fields, it was most important/critical to have sole authority in deciding biological medicine for Immunology (86%), Dermatology (86%) and Ophthalmology (86%) prescribers. It was least important/critical for Haematology-Oncology prescribers, 20% of whom considered it slightly/not important, compared to an average of 2% across all specialties which thought this, see figure 2.

Figure 2

It is significantly more critical to have sole authority in ­deciding medicine for Immunology, Rheumatology, Dermatology and Endocrinology.

Government tenders
Most prescribers stated that they believe it is very important or critical (63%) that government tenders for biosimilars are awarded to multiple suppliers. Prescribers in Spain and the UK, while considering this very important, do not think it is as critical for government tenders to be awarded when compared to the other countries surveyed. Only 7% and 9% considered this ‘critical’ compared to an 18% average across all other respondents.

Most prescribers agreed that it is either critical or very important (83%) that factors besides price to be taken into account in national tender offers, e.g. reliability of supply, patient support services, manufacturer reputation.

Prescriber authority to deny substitution
Most prescribers agreed that it is either critical or very important (84%) that, in a situation where substitution by a pharmacist was an option in their country, they have the authority to designate a biological medicine as ‘DISPENSE AS WRITTEN’ or ‘DO NOT SUBSTITUTE’ . It was significantly more critical for those in Switzerland (94%) to have authority to deny substitution for a biological medicine, and least so for those in the UK (73%), compared to those in the other countries. It was significantly less important for Haematology-Oncology prescribers to be able to deny substitution when compared to almost all other practice areas, see figure 3.

Figure 3

Identifying medicines
Eighty-five per cent of prescribers said that, when prescribing medicine including biologicals, they identify the medicine in the patient record by brand name. When looking at country and practice area responses, UK (68%) and Oncology (56%) identify medicine in a patient’ s record by brand name significantly less than those in other countries and practice areas, see figure 4.

Figure 4

Forty-three per cent of prescribers responded they rarely or never prescribe biological products by non-­proprietary name only. When compared to the other countries, prescribers in Switzerland (40%) are most likely never to use the non-proprietary name of a product. When compared to those in other practice areas, Dermatology (32%) and Rheumatology (28%) prescribers are more likely never to use the non-proprietary name of a product, see figure 5.

Figure 5

When asked about how confident a prescriber can be in their ability to know exactly what product is dispensed to a patient when using a non-proprietary name, 63% were very or somewhat confident, while 38% were slightly confident or not confident at all. Prescribers in Switzerland (26% are not confident at all) noted that they are significantly less confident in knowing what is dispensed when a non-proprietary name is used than those in Italy, Spain and the UK. Prescribers in the fields of Dermatology (55%) and Rheumatology (42%) are significantly less confident in knowing what is dispensed when a non-proprietary name is used compared to those in several other practice areas, see figure 6.

Figure 6

Dispensing in pharmacies
When asked about biological products dispensed directly to patients in a pharmacy, 61% of prescribers said that they were either very confident or somewhat confident that, if the pharmacy dispenses a drug that is different from the one that is prescribed (whether it is biosimilar 1, 2, or 3 or even the reference product), they have the ability to identify exactly what drug was dispensed to the patient. Thirty-nine per cent were either slightly confident or not confident at all. Prescribers in the UK (73%) said they are significantly more confident in knowing what is dispensed by pharmacy than those in Germany (49%) and Spain (60%); and those in Switzerland (24% not confident at all) are significantly less confident than several countries. It was shown that Oncology (82%) prescribers are significantly more confident in knowing what is dispensed than those in almost all of the other practice areas, see ­figure 7.

Figure 7

Eighty-three per cent of prescribers said it was critical or very important to be notified by the pharmacist if a patient has received a biological other than the one prescribed, if the patient was receiving chronic (repeated) treatment. It was shown to be significantly more critical for prescribers in Switzerland (80%) to be notified that a different biological was prescribed than for those in all other surveyed countries. It was also shown that it is significantly more critical for Rheumatology (84%) prescribers to be notified that a different biological was prescribed than those in several other practice areas; and it is significantly less important for Haematology-Oncology prescribers to be notified.

Only 5% of prescribers thought it was totally acceptable for a pharmacist to determine which biological (reference product or biosimilar) to dispense to a patient at the initiation of treatment. Fifty-eight per cent thought this was acceptable if the pharmacist’ s ability to determine the product was agreed to by clinicians in advance, and 37% thought it not acceptable. It was shown to be significantly not acceptable for a pharmacist to make the decision for prescribers in Spain (52%) and Switzerland (51%) when compared to the other countries surveyed. It was shown to be significantly not acceptable for a pharmacist to make decision more so for Rheumatology (60%) and Dermatology (52%) prescribers compared to those in other practice areas, see ­figure 8.

Figure 8

Prescribing biosimilars and switching
Seventy-four per cent of prescribers agreed that the correct definition for a ‘naïve’ patient is: a patient that has never received any biological treatment from this class of medicines. Eighty-four per cent of prescribers said they were very comfortable or somewhat comfortable in prescribing biosimilars to treat naïve patients. Prescribers in France, Germany, Italy, Switzerland and the UK are significantly more comfortable (very) than those in Spain (18%) in prescribing a biosimilar to a naïve patient. Rheumatology (60%) prescribers are more comfortable (very) than those of many other practice areas in prescribing a biosimilar to a naïve patient; Ophthalmology (10%) prescribers are the least comfortable.

Comfort level decreases when asked about switching a stable patient to a biosimilar versus to a naïve patient. While 17% are uncomfortable in prescribing a biosimilar to a naïve patient, see figure 9; twice as many (40%) are uncomfortable with switching a stable patient from an originator to a biosimilar. Spain (54%) prescribers are the least comfortable with switching a stable patient to a biosimilar. Haematology-Oncology prescribers are more comfortable switching a stable patient from an originator to a biosimilar than those in several other practice areas; Ophthalmology and Rheumatology prescribers are less comfortable, see figure 10.

Figure 9
Figure 10

Comfort level decreases further when asked about switching a patient to a biosimilar for non-medical reasons. More than half of prescribers (58%) said they are uncomfortable with switching their patients to a biosimilar for non-medical reasons. Prescribers in France are significantly more comfortable (very) switching a patient to a biosimilar for non-medical reasons than several other countries; prescribers in Italy and Spain are the least comfortable. Haematology-Oncology prescribers are significantly more comfortable (very) switching a patient to a biosimilar for non-medical reasons than those in most other practice areas, see figure 11.

Figure 11

Even more prescribers are uncomfortable (73%) when asked about a third party initiating such a switch. In the UK and France, prescribers were shown to be most comfortable with switching their patients (40% and 35% comfortable, respectively), while in Spain, prescribers are the least comfortable with having a third party make the switch (14%). Haematology-Oncology prescribers were shown to be significantly more comfortable with a third party switching a patient to a biosimilar for non-medical reasons (60% versus an average of 27%) than those in several other practice areas, see figure 12.

Figure 12

Conclusion

In summary, the survey reveals that European physicians have increased their familiarity with biosimilars since last surveyed in 2013. After 13 years of experience with biosimilars in Europe, physicians:

Key points of the 2019 European prescribers survey on biosimilar

  • More than half of prescribers are most likely to report an ADR to the National Competent Authority
  • Two-thirds of prescribers said amount of time spent on filing a report is 10 to 20 minutes
  • Prescribers do file detailed reports; this level of detail in turn deters 55% from reporting minor events
  • More than half of prescribers said reporting infrastructure was the biggest barrier to accurate reporting; another 20% said no barriers exist
  • Frequency of including batch number is mixed; not having the number available at time of reporting was selected by more than half of prescribers who said sometimes, rarely, or never
  • Control over prescribing and dispensing – four out of five prescribers feel very strongly about having control over what is prescribed AND dispensed to their patients. Italy prescribers expressed the highest importance in having sole authority to decide the medicine, while France prescribers expressed the least. Switzerland prescribers expressed the highest importance in having the ability to deny a pharmacist’ s substitution, while UK prescribers expressed the least. Having this level of control was most important to Immunology, Rheumatology, Endocrinology and Dermatology prescribers.
  • Product Name and Pharmacist Control
  • More than 40% of prescribers said they rarely or never prescribe biological products by non-proprietary name only
  • More than one-third said confidence would be lacking in knowing exactly what was dispensed to patient if they prescribed a product using non-proprietary name
  • Four out of five prescribers said it would be critical or very important to be notified by pharmacist that patient received a biological medication other than one they prescribed
  • Fifty-eight per cent of prescribers said it would be acceptable for a pharmacist to determine which biological to dispense on initiation of treatment, but would require clinician agreement in advance
  • Prescribe Biosimilar versus Switch to Biosimilar – comfort level decreases when asked about switching a stable patient to a biosimilar versus prescribing a biosimilar to a naïve patient. About 20% are uncomfortable in prescribing a biosimilar to a naïve patient; twice as many (40%) are uncomfortable with switching a stable patient from an originator to a biosimilar. France, Switzerland and UK prescribers are most comfortable with prescribing a biosimilar to a naïve patient, while Spain prescribers are the least comfortable with switching a stable patient to a biosimilar.
  • Prescriber Switch versus Third-Party Switch – Comfort level decreases when asked about switching a patient to a biosimilar for non-medical reasons. More than half of prescribers (58%) are uncomfortable with switching their patients to a biosimilar for non-medical reasons; this percentage increases to 73% when asked about a third party initiating such a switch. UK and France prescribers are most comfortable with switching their patients, while Spain prescribers are the least comfortable with having a third party make the switch.

Funding sources

The survey study was sponsored by Alliance for Safe Biologic Medicines (ASBM) and administered by Industry Standard Research, LLC.

This paper is funded by the 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.

Competing interests: Dr Madelaine Feldman is the Chairperson of the Alliance for Safe Biologic Medicines. She has participated in advisory boards for Gilead, Lilly, Pfizer and Samsung. 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 2002–2008.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Madelaine Feldman, MD, FACR
Michael S Reilly, Esq

Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

References
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2. Bird E. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(1):37-44. doi:10.5639/gabij.2020.0901.007
3. Schneider PJ, Reilly MS. Policy recommendations for a sustainable biosimilars market: lessons from Europe. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(2):76-83. doi:10.5639/gabij.2020.0902.013
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6. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi:10.5639/gabij.2014.0302.018
7. Schneider PJ, Reilly MS. Naming and labelling of biologicals – the perspective of hospital and retail pharmacists. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(4):151-5. doi:10.5639/gabij.2016.0504.040
8. Safe Biologics. Members partners [homepage on the Internet]. [cited 2020 Aug 9]. Available from: www.safebiologics.org/member-partners/
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10. Reilly MS, Gewanter HL. Prescribing practices for biosimilars: questionnaire survey findings from physicians in Argentina, Brazil, Colombia and Mexico. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):161-6. doi:10.5639/gabij.2015.0404.036
11. Gewanter HL, Reilly MS. Naming and labelling of biologicals – a survey of US physicians’ perspectives. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(1):7-12. doi:10.5639/gabij.2017.0601.003

Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

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Policy recommendations for a sustainable biosimilars market: lessons from Europe

Author byline as per print journal: Professor Philip J Schneider1, MS, FASHP, FASPEN, FFIP; Michael S Reilly2, Esq

Abstract:
Approximately 25% of all new medicines approved in recent years and in development today are biologicals. The complexity of biologicals, the investment needed to meet ever more stringent regulatory and payer requirements, combined with the needs of an ageing population, mean the cost of these medicines and the burden on governments and insurance companies is growing. However, the introduction of biosimilars has broadened treatment choices for physicians and their patients and, by increasing competition, reduced healthcare expenditures.
The biosimilar market in Europe is the largest in the world, representing approximately 60% of the global biosimilar market and growing consistently year on year. As of October 2019, 54 biosimilars of 15 originator biological medicines have marketing authorization in Europe. European countries, with their large biosimilar markets and diverse healthcare systems, serve as valuable examples of different approaches to biosimilar policy. Several studies, research papers and position statements have been published on such policies. These findings, along with real-world policy and procurement examples from European countries, provide an opportunity for other countries to learn from. This paper will review the different approaches to biosimilar policy across the European continent, highlighting principles which can be applied to develop an efficient and sustainable biosimilar market.

Submitted: 24 October 2019; Revised: 6 February 2020; Accepted: 17 February 2020; Published online first: 24 February 2020

Introduction

Approximately 25% of all new medicines approved in recent years and in development today are biologicals [1]. The biosimilar market in Europe is the largest in the world, representing approximately 60% of the global biosimilar market and growing consistently year on year [2].

Biosimilars are large and structurally complex molecules obtained from a biological source. Due to inherent biological variability, they can be reproduced to a high degree of – but not complete – similarity [3]. Compared to generics, their development requires additional quality and comparability studies as well as clinical studies on immunogenicity, safety and efficacy [4]. As a consequence, the cost to develop and gain approval for a biosimilar medicine ranges between US$100 million to US$200 million [5].

The European Union (EU) and the European Medicines Agency (EMA) developed a legal framework for the review and development of biosimilars in 2004 [6]. Based on this framework, EMA has a comprehensive set of regulatory guidelines for biosimilar review. One of the most challenging areas in the regulation of biosimilars is switching. So-called ‘switching studies’ where the originator medicine is substituted with the biosimilar candidate and vice versa are not part of the existing European regulatory approval requirements. Neither are studies where biosimilar medicines referencing the same originator medicine are substituted with each other. As a consequence, limited sufficiently powered randomized clinical trial data exist to inform on the risks of switching such as immunogenicity, treatment-emergent adverse events, or lack of efficacy. Because of these factors, the authors of the NOR-SWITCH study recommend caution in generalizing their findings to other biological agents. They also stated that more studies are needed ‘to examine multiple-sequenced as well as back-and-forth switches’ [7].

In summary, a biological medicine should generally not be substituted with another biological or biosimilar medicine that is made using a different bio-manufacturing process. Switching does occur in practice, but the decision to change a patient’s therapy (switch [4]) generally resides with the treating physician in consultation with the patient.

Because of the differences between generic and biosimilar medicines, different rules apply to their clinical use, e.g. procurement practices, prescriber authority and pharmacist involvement. These differences, along with the relative novelty of biosimilars, have resulted in a limited number of biosimilars being made available to date compared with small molecule generics. The limited amount of data available on switching between originator medicines and biosimilars and in-between biosimilars in particular results in a major challenge for all stakeholders – and physicians, patients and payers in particular – to establish policies and frameworks for efficient and patient-friendly long-term sustainable biosimilar markets. These policies must take into consideration: the uniqueness of biosimilar medicines, the educational needs of both physicians and their patients, the maintenance of physician choice and clinical decision-making, the guarantee of drug supply to ensure continuous patient care, pricing rules that do not discriminate against either originator or biosimilar medicines, purchasing mechanisms (procurement frameworks) which encourage companies to compete, and maintaining the correct balance of incentives for providers and prescribers while delivering savings.

Biosimilar competition in Europe

Europe’s legislative and regulatory leadership in biosimilars is evident in European biosimilar sales. While the global biologicals market is dominated by the US, which has a share above 50%, the global biosimilar market has been even more so dominated by the European market, which accounted for close to 90% of global biosimilar sales between 2012 and 2016, see Figure 1.

Figure 1

With the launch of 22 biosimilars on the US market since 2017 [8], Europe’s share has been dropping towards 60%, see Figure 1. Although in absolute terms the share of the global biosimilar market as a percentage of the global biologicals market was below 1% in 2016 (compared with 35% of global generics sales as a percentage of global non-biologicals sales), this figure has grown closer to 2.5% and is expected to grow further in the future.

While European biosimilar markets are more mature than those in the US, opportunities for biosimilar companies are smaller in Europe given the overall lower spending on biologicals. In the longer term, the US market represents the greater economic opportunity for these companies [9].

Sustainable biosimilar markets – policy considerations

Several research papers and position statements defining the factors and conditions required for sustainable biosimilar markets have been published in recent years, with the intent to inform policymakers and payers and to support them to develop, assess and refine biosimilar policies in the European Economic Area (EEA, i.e. EU Member States plus Iceland, Liechtenstein and Norway). These publications [10, 14] originate from diverse stakeholders, offering a comprehensive perspective on the necessary conditions for long-term sustainable biosimilar markets, see Appendix 1 on research papers and position statements defining the factors and conditions required for sustainable biosimilar markets in Europe, 2014−2019.

Based on these publications, we believe a ‘gold standard’ for a sustainable European market for off-patent biologicals can be derived, containing six policy requirements:

(1) Policies should be designed to incentivize and reward innovation in all types of biologicals.
(2) Healthcare financing must take into account societal benefits derived from biological medicines, as well as the unique characteristics of biologicals.
(3) Procurement practices must provide for multiple suppliers and a minimum term of 12 months.
(4) Physicians must have autonomy to choose the most appropriate medicine for their patient, including making decisions on switching, which must also be consented to by the patient; no automatic substitution.
(5) There should be mandatory brand- name prescribing to avoid unintended switches as well as a robust pharmacovigilance system to report adverse drug reactions (ADRs).
(6) Policies with potential to undermine sustainability, such as measures which induce biosimilar uptake or promote preferential treatment, thereby limiting physician choice, should be avoided.

When comparing the findings and recommendations from these papers, several key conditions to achieve sustainable biosimilar markets can be identified and may be considered as ‘must haves’ for the long-term success of these markets. These are:

(1) Physicians should have the freedom to choose between off-patent originator biologicals and available biosimilars and to act in the best interest of their patients based on scientific evidence and clinical experience.
(2) Tenders should be designed to include multiple value-based criteria beyond price, e.g. education, services, available dose strengths, and provide a sufficient broad choice (multi-winner tenders versus single-winner tenders) to ensure continuity of supply and healthy competition.
(3) A level playing field between all participating manufacturers is the best way to foster competition; mandatory discounts which place artificial downward pressure on manufacturers do not engender a sustainable market environment.

Elements or conditions recommended by some but not all of the above studies are:

(1) The provision of early access and swift market entry of approved biosimilars upon the innovator’s loss of exclusivity to expand access to treatment for patients while lowering costs.
(2) Incentives, e.g. gainsharing, where a portion of generated savings are returned to prescribers and/or an institution and prescribing targets should be carefully designed so as not to restrict physician choice nor limit competition between originator biologicals and their biosimilars.
(3) The pursuit of a multi-disciplinary team approach when designing payer purchasing policies to ensure the perspectives and needs of different stakeholders, i.e. payers, manufacturers, physicians and patients, are taken into consideration.
(4) Safeguarding the interest of patients and serving their needs as best as possible remains a critical consideration for health authorities, in particular considering the increasing numbers of self-administered biosimilars.

European biosimilar markets – policy examples and experience

Biosimilar policy varies within the 28 EU Member States and the three EEA countries.

Policies have evolved over time and are likely to continue to evolve based on experience, clinical data and the growing number of authorized biosimilars. Current policies are characterized by different supply and/or demand-side incentives as well as different degrees of competition and are determined either at the national, regional or hospital level, or a mixture of these.

Independent of the kind of policy which is pursued, data suggest that biosimilar price and use also depends on therapeutic area and the time the biosimilar has been on the market. This diversity is reflected in Figure 2, that shows differences in price reductions as well as volume increases for both originator and biosimilar relative to the period prior to when the first biosimilar within a product group was launched [15].

Figure 2

National tender markets
Norway and Denmark are the only European countries to pursue a national tender policy for biosimilar products such as adalimumab, etanercept, or infliximab. Denmark’s policy has been ambitious and restrictive, in that only the manufacturer with the lowest bidding price for a particular molecule will be reimbursed for a 12-month period, potentially requiring physicians to switch patients every 12 months (unless they provide clinical arguments not to do so). In comparison, Norway, which has a history of anti-tumour necrosis factor (anti-TNF) tendering, tenders all molecules in a single tender split by indication as well as application, i.e. infusion or intravenous (IV) (self-administered) based on bi-annual cost according to each product’s prescribing information. Norway then ranks products based on those bi-annual costs in each indication and urges physicians to prescribe the most economical product for new patients. However, the choice is ultimately left to the physician and all lower ranked products are still reimbursed if prescribed, i.e. switching is not explicitly mandated as it is in Denmark. Tenders in Norway tend to be in effect for one year.

Regional and hospital tender markets
In Sweden, hospital administered products are funded by county councils in each of the 21 Swedish counties. Each county runs their own tenders by molecule thus making the market more sustainable for all competitors, as they can compete in more than one tender. Resulting tender prices are communicated among hospital doctors with the intent to promote economic prescribing. As in the case of Norway, all available products continue to be reimbursed if prescribed and, while switching is encouraged, the decision remains with the treating physician and her patient. Tenders tend to run for 24 months and may be re-opened as new competitors enter the market. A recent study of infliximab prescribing in Sweden [16] showed that biosimilar infliximab prescribing varied between regions depending on the absolute difference in price between the originator and the biosimilar products, the opinion of key opinion leaders and clinic heads, local guidelines and hospital initiatives.

With the intent to increase competition, maintain choice for physicians and their patients and avoid shortages of supply from a single manufacturer, Italy passed a national law in December 2016 (2017 Budget Law) which forbids automatic substitution in the case of biologicals and gives priority to the physician’s freedom of prescription. Based on this law, if there are no more than three suppliers of a specific molecule on the market, each is available to physicians to be prescribed. In cases where there are more than three suppliers, the three lowest priced products may be prescribed. In both cases, prices are determined in hospital tenders for both IV and subcutaneous (SC) products in each of the Italian regions. For stable patients, physicians may choose to continue the current treatment under the condition that the respective medicine participated in the tender process.

As in Sweden, hospital tenders in France only apply to IV products. Tenders tend to promote a single winner based on price with a duration of 12 months. Physicians are encouraged to prescribe the most economical product for new patients as well as for stable patients, even though the decision to switch a patient is left at the physician’s discretion. However, while a single switch from the originator to a considerably lower priced biosimilar is seen as less controversial, multiple switches are looked upon unfavourably, unless a very substantial discount to the previously lowest priced biosimilar applies. Given that hospitals are paid a lump sum per patient per case, lower priced products offer a profit incentive to hospitals.

In Spain, similar to Italy, hospitals tender both IV and SC products by molecule, all products remain available for physicians to choose from, and all products are reimbursed. In addition to hospital tenders, some regions have pursued biosimilar prescribing targets, however, physicians’ responsibility to provide the best treatment for their patients remains paramount. Furthermore, physicians are liable for their treatment choices as regards patient outcomes.

In Poland, medicines are prescribed in the hospital. Every hospital is obliged to tender each molecule annually and only the winning bidder can generally expect to be used and reimbursed during each 12-month tender period. As a result, competition has been particularly fierce, and the longer-term sustainability of the biosimilar market may be affected. In addition, product choice for physicians and their patients is limited, both for new and stable patients.

In the UK, National Health Service (NHS) England in their September 2017 publication ‘Commissioning framework for biological medicines (including biosimilar medicines)’ stated that ‘… at least 90% of new patients will be prescribed the best value biological medicine within three months of launch of a biosimilar medicine, and at least 80% of existing patients within 12 months, or sooner if possible’. In England, which comprises 80% of UK citizens, NHS England has provided guidance in their Commissioning Framework for Biological Medicines. Based on tenders in each of the four regions within England, prices for originators and their biosimilars are determined for both IV and SC products. Commissioners are encouraged to promote switching where appropriate, incentivize prescribing and monitor biosimilar uptake. While all approved biologicals remain available for prescribing by physicians, various mechanisms have been put in place to promote the use of the best value biological medicine [17].

Retail and hospital contract markets
Germany, where both SC and IV biologicals are primarily prescribed by private doctors, is the largest retail market in Europe. Pricing is free allowing for price competition both at the list price level as well as towards individual sick funds based on discount agreements. German Statuary Health Insurance (GKV), which represents dozens of health insurers and the German National Association of Statutory Health Insurance Physicians (KBV), agrees national prescription volume targets for biosimilars. However, such quotas vary widely by region and molecule, as regional associations are not obliged to abide by national targets and are free to set higher or lower regional targets. To achieve set quotas, private doctors’ prescribing practices are monitored to encourage compliance. Despite these incentives, physicians remain free in their choice among all available products and are expected to base their decision on clinical data, experience and patient needs. All available products are reimbursed. For biologicals prescribed in the hospital, prices are typically determined by contracts agreed between hospitals and manufacturers.

In France, SC biologicals are prescribed by private doctors and reimbursed nationally. While certain quotas do apply, similar to Germany, French physicians are free to choose the best product for their patients and all available products are reimbursed.

In Sweden, hospital tenders apply only to IV products, but SC biologicals are prescribed in the hospital and reimbursed centrally. Prices for SC biologicals are determined in so-called managed entry agreements by way of three-party negotiations between The Dental and Pharmaceutical Benefits Agency, county councils and manufacturers. After an agreement is reached, prices apply nationwide. Managed entry agreements have durations of up to two years and may be re-visited when new competitors arrive. Savings resulting from these agreements are shared between the government (40%) and the counties (60%). Physicians are free to prescribe the most suitable product for their patients while taking economic arguments into consideration. Based on two recent studies of infliximab and etanercept in Sweden [16], see Table 1, biosimilar prescribing varied between regions to a larger degree in the case of infliximab probably due to a limited price difference between originator and biosimilar etanercept in comparison with infliximab. Overall, as in the case of infliximab, etanercept volume has increased, likely driven by a lower threshold to prescribe and by higher and more appropriate dosing.

Table 1

Solution

Understanding, acceptance, familiarity and use of biosimilars in Europe have evolved in recent years. Based on 13 years’ experience with biosimilars in off-patent biologicals markets in Europe, it can be stated that biosimilars have: (1) increased competition; (2) reduced unit cost of both originator and biosimilars compared to price levels prior to the arrival of biosimilars; (3) increased volume consumption of molecules with biosimilar competition thus expanding market access and optimizing patient dosing; and (4) alleviated budget pressures by providing headroom to fund novel treatment solutions.

While the policies by which this has been achieved vary between countries, all major European markets share the following principles:

(1) Automatic substitution for biologicals is forbidden.
(2) All approved biologicals, i.e. originators and their biosimilars, are available on the market and are reimbursed when prescribed.
(3) Reimbursement decisions on novel treatment solutions are independent from biosimilar use and uptake.
(4) The time from market approval to first product sales for biosimilars is shorter than the time to first sales of novel medicines [18].

Biosimilars have attained market shares in some European markets 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) [15]. However, this does not necessarily mean that countries with a more moderate biosimilar market share are less competitive. On the contrary, these markets tend to benefit not only from the use of lower cost biosimilars but equally from lower cost originators. Furthermore, markets with multiple manufacturers tend to be better positioned for the long term since market participation and price levels allow for a return on investment which will accommodate the development and launch of future biosimilars, the generation of real-world data and more patient-friendly devices and services. Last but not least, such markets allow physicians to choose among available products and act in the best interest of their patients based on clinical evidence, experience and patient preferences.

As countries decide on their biosimilar policies, they must strike the right balance between a desire for substantial immediate savings and more sustainable savings in the long term, as well as future innovations. The number of future off-patent biologicals offers an attractive savings outlook which should not be jeopardized by a short-term race to the bottom of the prices of today’s biosimilars. Policymakers should carefully design procurement measures such as tenders and contracting to ensure: (1) a wide and non-discriminatory choice of products; (2) selection criteria beyond price such as services and supply; (3) the avoidance of (forced) multiple switches [19]; and (4) the involvement of physicians, pharmacists and other stakeholders in the process. Any demand-side incentives to promote biosimilar prescribing, such as biosimilar market share targets, financial prescriber incentives or sanctions, should also be designed with care regarding their size and level of enforcement in order to ensure appropriate product use. This ultimately needs to be a clinical decision made by the treating physician for an individual patient on the basis of shared decision-making.

Conclusions

Creating a new market is a slow process. It took the generics sector over a decade to establish itself as the major volume driver in developed markets. After more than a decade of biosimilar experience in Europe, biosimilars have gained wider acceptance and the use of newly approved products has increased. While many blockbuster products with European sales above US$1 billion have lost market exclusivity during this decade, there will only be three such products going off patent in the decade to come. The majority of products will have sales between US$100 million to US$1 billion [20]. For future off-patent originator biologicals to offer a compelling investment for multinational biosimilar companies, regulatory and payer policies which help to foster a fair and sustainable environment will be crucial. Advocacy from patient and industry groups as well as healthcare providers will be important to convince market gatekeepers to develop a market with these characteristics.

The European experience is testament to the value of multi-stakeholder participation and engagement at every stage of the process, from the regulatory framework through education all the way to procurement policy decisions and treatment guidelines. Trust is at the core of matters such as the appropriate use of complex medicines for the treatment of chronic and life-threatening diseases; only an approach which is transparent and includes all stakeholders will facilitate the long-term acceptance of biosimilar products.

In their pursuit of savings and increased patient access in off-patent biologicals markets, stakeholders will need to strike the right balance between both short- and long-term savings, as well as the maintenance of patient care and physician and patient trust. Based on the European experience to date, the most suitable policies appear to be those which provide continuous, unbiased information on biosimilars, stimulate manufacturer competition, guarantee a sufficiently broad choice of products, are non-discriminatory towards either originator or biosimilar medicines and allow the treating physician to choose the most appropriate product in consultation with their patient. Given the required investment to develop a biosimilar medicine, their market access and participation should be supported by medical guidelines and incentives such as prescribing targets for biosimilars. While the use of biosimilars for bio-naïve patients is not controversial, some uncertainty remains about switching patients currently being treated with an originator product to a biosimilar (or vice versa), from one biosimilar to another, and about switching on multiple occasions [21]. Any incentives must take these uncertainties into account in order for prescriber and patient confidence in biosimilar medicines to evolve.

Funding sources

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.

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 2002–2008.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

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

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Appendix 1: Research papers and position statements defining the factors and conditions required for sustainable biosimilar markets in Europe, 2014−2019

In 2014, consultancy GfK Market Access published a study undertaken on behalf of the European Generics Association (EGA) now Medicines for Europe on Factors supporting a sustainable European biosimilar medicines market [10]. In this study, four elements for a Sustainability Policy Framework were identified, namely: (1) Education and Understanding; (2) Experience and Use; (3) Sustainable Pricing; and (4) Rational Decision-making. The core considerations under each of these elements were:

(1) Education and Understanding

(2) Experience and Use

(3) Sustainable Pricing

(4) Rational Decision-making

In 2015, the European Federation of Pharmaceutical Industries and Associations (EFPIA) published their Policy principles for off-patent biologic medicines in Europe [11] ‘to help healthcare systems to design and implement policies that can successfully create competitive off-patent biological markets’. The four principles identified by EFPIA and the core aspects in each of them were:
(1) Overarching principles for European off-patent biological markets

(2) Principles for creating sustainable competition

(3) Principles for prescribing frameworks

(4) Principles for specific market mechanisms

In 2016, consultancy Simon & Kucher published a report undertaken on behalf of Medicines for Europe titled Payers’ price & market access policies supporting a sustainable biosimilar medicines market [12]. In their comprehensive study based on data and interviews with payers and manufacturers, Simon & Kucher identified the following principles for a sustainable biosimilar medicines market:

(1) Biosimilars increase competition thus increasing access for more patients and funding for new innovative medicines
(2) Pricing and procurement policies should ensure continuous market participation of several manufacturers to maintain healthy competition
(3) Biosimilar policies should allow physicians to choose from different treatment alternatives

(4) Tender decisions should not be based only on price. They should take into consideration multiple value-based influencing factors, e.g. supply, education, services
(5) Procurement policies should allow parallel sourcing to sustain competition and supply
(6) Pricing and procurement policies for biosimilar markets must be commercially attractive to sustain competition and biosimilar investment long term
(7) Pricing and market access policies enforcing lower prices (compared to their originators) have to be accompanied by specific guidance on biosimilar use and prescribing incentives
(8) Voluntary and mandatory price discounts without volume compensation do not offer biosimilar manufacturers a sustainable market environment
(9) Gainsharing is considered a successful driver of biosimilar uptake
(10) Physician incentive policies are only sustainable if payers monitor physicians’ policy adherence

In 2018, pharmaceutical consultancy IQVIA published the multi-stakeholder assessment Advancing Biosimilar Sustainability in Europe [13], which was commissioned and funded by Pfizer. In this assessment IQVIA identified five key areas that have significant influence on the sustainability in the biosimilar marketplace: the current regulatory environment, clinical guidelines for biosimilars, product and supply features, incentives for biosimilar use and competitive market pressures such as pricing. Based on an analysis of policies in seven EEA countries (France, Germany, Italy, Norway, Poland, Spain, UK), the following key sustainability elements emerged:

(1) Regulatory environment and clinical guidelines favourable to biosimilar approval and uptake
(2) Guidelines and policies supporting a physician-guided therapy switch
(3) Prescription freedom for physicians enabling them to select therapy for patients, i.e. no automatic substitution
(4) Availability of multiple products, enabling physicians’ choice of approved therapies
(5) Well-designed incentives that foster biosimilar uptake, while safeguarding physician choice and patient input into treatment decisions, such as treatment switch
(6) Consideration of the long-term sustainability of the market as well as physician needs when designing incentives to facilitate budget release
(7) Incentivize biological manufacturers towards continued patient-friendly innovation
(8) Balance price pressures of payer purchasing mechanisms with requirements for long-term market sustainability; implement policies that address the needs of all market stakeholders
(9) Sustain healthy competition with multi-winner tenders as compared with single-winner tenders
(10) Sustain healthy product supply by enabling access for both originator and biosimilar products

In 2019, boutique consultancy Patch Consilium published the study Towards a sustainable European market for off-patent biologics [14] which was commissioned and funded by EFPIA. The objective of this study was to assess how policy and governance frameworks should be designed and implemented to ensure long-term sustainable off-patent biological markets through an analysis of the current policy ecosystem in 15 EEA countries (Belgium, Czech Republic, France, Germany, Greece, Hungary, Italy, Netherlands, Norway, Poland, Romania, Slovakia, Spain, Sweden, UK) regarding the pricing environment, procurement practices and the degree of physician autonomy and patient choice and through a survey among different stakeholders in these countries regarding their perceptions of the off-patent biologicals. The core findings are summarized below:

(1) Pricing environment

(2) Procurement practices

(3) Physician autonomy and patient choice

(4) Stakeholder* perception

*Stakeholders interviewed were: Healthcare Professionals, Patients/Patient Group Representatives, Government Institution Representatives and Industry/Trade Association Representatives; due to the limited number of responses (76) and uneven distribution between stakeholders, the study states that they may not reflect the common view of these stakeholder groups.

Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

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Medicines regulation in the MENA region and the importance of the World Health Organization’s INN proposal of Biological Qualifier

Author byline as per print journal: Peter J Pitts, BA; Michael S Reilly, Esq

Abstract:
The World Health Organization should finalize its Biological Qualifier guidance. Distinguishable naming will allow quick and accurate tracing of the manufacturer, should adverse events occur and improve patient safety by reducing confusion and mishaps. This will ensure that developing nations, including those in the MENA region, have access to high quality, affordable medicines.

Submitted: 1 June 2018; Revised: 29 October 2018; Accepted: 30 October 2018; Published online first: 2 November 2018

Introduction

When it comes to monitoring the quality, safety and efficacy of biological medicines, distinguishable naming is imperative because biosimilar therapies are similar to, but not exactly the same as, existing biological medicines. Since no biosimilar is perfectly identical to its innovator parent, every biological – whether reference product or biosimilar – must be fully distinguishable from other biologicals to permit quick and accurate tracing of its manufacturer, should an adverse event be observed. Precise naming of all biologicals will improve patient safety by reducing confusion and mishaps in prescribing and holding manufacturers accountable. Also, differential nomenclature helps enable national health authorities to collect and compare real-world data that measure the clinical effects of biologicals including biosimilars. Insights from such data, over time, will enable us to better measure a drug’s effectiveness in delivering successful health outcomes for patients.

The World Health Organization (WHO) must finalize their Biologic Qualifier guidance. It is this organization that has the responsibility to ensure that developing nations of the world have access to affordable, quality medicines. Safety is mission critical and the Biological Qualifier is a potent tool on behalf of global public health.

The primacy of medicines quality

Over the last few years we have travelled to many countries around the world, visiting with medicines regulators from Australia, Europe, Latin America and the Middle East. Although a wide range of topics were discussed with these regulators, one of the most pressing issues for all was the urgency of access to quality medicine.

This paper will focus on medicines regulation in the Middle East and North Africa, specifically Algeria, Egypt, Iraq, Jordan, Kuwait, Lebanon, Morocco, Oman, Qatar, Saudi Arabia, Turkey and the United Arab Emirates (UAE). We will also discuss the importance of the World Health Organization’s leadership around establishing a global nomenclature policy that will help maintain the quality, safety and efficacy of biological and biosimilar medicines for that region.

Without quality, safety and effectiveness are non-starters and access is without meaning. Without quality, healthcare spending is not just wasteful – but harmful. Without quality it is all about ‘lowest price tenders’ without any consideration for value. Without quality, regulation is a sham.

Medicines quality in the Middle East

Medicine quality is on the minds of leaders in the Middle East. At the Second Annual Arab Conference on Food and Drugs (Sharm El Sheikh, Egypt, 11-13 April 2015), a conference of regional regulatory agencies, Dr Rasha Ziada (Egyptian Ministry of Health) made the important point that if a pricing authority does not take outcomes into consideration; it will lead to overall price distortions. Amen! Dr Ola Ghaleb (Ministry of Health UAE), spoke about the UAE’s strategy of performance-based risk-sharing arrangements. Outcomes are now capitalized and bolded in the international lexicon of healthcare policy. The necessary precursor to positive outcomes is quality.

A significant number of the conference presenters discussed the value of sharing pharmaceutical economic data across borders, but there was not an equal counterbalancing discussion of the value of sharing clinical data for approvals and outcomes-based decision-making processes. The opportunity to enhance regulatory capacity and product quality through collaboration and information sharing is significant. Unfortunately, cost is too often the primary focus while other priorities such as quality are left to languish.

There was certainly an effort (both on many of the panels as well as during the breaks and after hours) to stress the urgency of the quality agenda. The good news is that speaker after speaker (sometimes in passing and other times passionately) made the point that it must not just be about ‘getting the lowest price’, but also appropriately pricing the most clinically effective treatments. Cost savings without quality are no bargain.

The crisis in drug quality is very real. In Saudi Arabia, according to Alhawassi et al. [1]:

The list of essential medicines from WHO is also considered essential in primary health care in Saudi Arabia. Yet, unfortunately, many medications from this list are among the most widely substandard and counterfeited [2]. For example, one study conducted in Saudi Arabia showed that amoxicillin has already been identified as substandard [3]. Consequently, one of the central aims of advancing pharmaceuticals and patient care in Saudi Arabia is the ‘safe use’ of quality medications [4].

Access to medicine alone is not enough; medicine quality is an essential element of patient care. Quality – even for relatively common and easily evaluated medicines like amoxicillin – is a challenge and must be a policy priority. As put forth by Alhawassi et al. [1]:

One initiative of the Saudi 2030 vision plan should be to advance patient care through a more robust, safety/quality-centred culture together with a more collegial relationship between local and international drug manufacturers and Saudi regulatory authorities. Such an enhanced working relationship would result in a higher quality care to the public (Saudi, 2030 [5]). This concept of aggressive attention to better patient care through greater attention to quality and safety is only now emerging in developed and less developed countries.

The observation of scientist W Edwards Deming applies today as it did decades ago. ‘Change is not required. Survival is not mandatory’.

As in the West, generic drugs provide greater access to medicine for millions of patients in the Middle East. As in other parts of the developing world, assuring quality through robust regulatory oversight is often at counter-point with available human and financial resources. As in every part of the world, Middle Eastern health officials (from national ministries of health to local inspectorates) recognize the imperative that ‘the most expensive drug is the one that does not work’. No nation can afford to buy low quality products.

Countries around the world are struggling to adequately monitor the quality of medicines available to their citizenry. From more regular manufacturing inspections, to risk-based investigations into the sourcing of ingredients, to a rethinking of post-marketing surveillance (pharmacovigilance), there is not one single solution.

Attention to quality cannot end at product approval. This dimension is clearly elucidated from the Jordan Food and Drug Administration (JFDA). In a recent journal article Dr Hayel Mohammad Obeidat, JFDA’s Director General writes, ‘We believe that 21st century pharmacovigilance must also include tighter and more regularly monitored post-approval bioequivalence measures. It is a new and difficult task and calls for better validated methodologies for both data collection and signal prioritization. It is the responsibility of JFDA to take the leadership role and help educate our various constituencies to the importance of 21st century Phase IV monitoring and interventions [6]’.

What we need are standards and systems that recognize the situation as it exists and provide both a path for convergence with global best practices and immediate tactical programmes that can address the true situation on the ground. In brief, regions such as the Middle East require tactical, pragmatic regulation that recognizes the asymmetries inherent in an evolving regulatory ecosystem. Global institutions can play an important role in facilitating this.

Quality, pharmacovigilance and biosimilars

A key issue driving the development of 21st century regulatory pharmacovigilance strategies is the need for updated post-marketing surveillance of biosimilars. Biological medicines have revolutionized the treatment of many serious and life-threatening diseases; as patents for these products expire around the world, biosimilars are becoming available. Biologicals are very complex medicines made using living cells and cannot be copied exactly, thus copies are called biosimilar, not generic drugs. Appropriate approval standards, specific to biological medicines, are a threshold requirement for all medicines that are deemed ‘biosimilar’. The problem of alleged copies approved outside of a scientifically sound biosimilar framework is a serious safety problem and a topic for another paper. However, even in the context of sound scientific standards, vigilance cannot stop at approval for any biological.

Issues related to the particularities of biologicals (sources, process, quality requirement and new safety profile) require sophisticated new thinking.

Fundamentally, all of the players in the pharmacovigilance ecosystem will have problems characterizing biosimilar issues since we do not have an existing, validated predictive models of potential ‘hot spot’ products, base ingredients and/or suppliers. Consequently, pharmacovigilance for biologicals will have to evolve at the same time as new medicines are launched into this space. Small numbers and the novelty of biological products and their safety profiles – alone and in combination with other medicines – for manufacturers, medical providers and patients will likely render monitoring challenging. This is where global institutions can step in.

We are in a situation of post-marketing ‘indetermination’ and the first step should be to develop new epidemiological approaches that based on a better understanding of the differences between the concepts of ‘generic’ and ‘biosimilar’. We understand there can be different safety profiles for generics (based on differing bioequivalence ranges, excipient and active pharmaceutical ingredient sourcing). When it comes to biosimilar pharmacovigilance, however, variability-induced iatrogenesis concerns, differences between batches by multiple manufacturers, and the elastic definition of ‘similarity’ is not a question of ‘safety profile’, but rather of ‘concept’ [7].

Biosimilar nomenclature and the unique role of WHO

It is into this maelstrom that the steady hand of WHO is needed. And nowhere is this more true or urgent than in the current debate over biosimilar medicines generally and product nomenclature specifically.

WHO has published a draft proposal for a global system to assign ‘biological qualifiers’ (BQs) to biologicals and biosimilars [8]. A BQ is a random four-letter code assigned to a biological manufactured at a specified site. WHO said the scheme would be voluntary for each regulatory authority and applicable retroactively. The qualifier would not be part of a biological’s International Nonproprietary Name (INN), although WHO’s INN expert group would oversee the scheme. WHO said the proposed scheme is intended to avoid separate national qualifier systems. It will also permit less developed national regulatory systems to institute a globally consistent protocol that will help to guarantee the quality, safety and efficacy of biological and biosimilar medicines.

Consider Lebanon, ‘the hospital of the Middle East’. Minister Ghassan Hasbani, Lebanon’s Deputy Prime Minister and Minister of Health, is revamping the medicines tendering programme for Lebanon and one of the key tenets being weighed in the new national decision-making process is value. As His Excellency said from the podium, ‘It is not only a cost, it is an investment’. And, as with any investment, it is impossible to understand the cost without proper consideration of the return.

Minister Hasbani recognizes that biosimilars represent an important tool in expanding access to patients in Lebanon. But, as in the West, it must be access combined with quality and safety.

When it comes to health care, clarity is better than confusion, especially when it comes to drug safety — the sine qua non of medicines regulation. And that means clarity in biosimilar nomenclature.

What is so important about a biosimilar’s name? Patient safety. According to the US Food and Drug Authority, distinct and precise nomenclature for all biologicals, innovator and biosimilar, will promote accurate prescribing and facilitate accurate attribution of adverse events [9].

Distinguishable naming is imperative because biosimilar therapies are similar to, but not exactly the same as, existing biological medicines. Since no biosimilar is perfectly identical to its innovator parent, every biological – whether reference product or biosimilar – must be fully distinguishable from other biologicals to permit quick and accurate tracing of its manufacturer, should an adverse event be observed. This facilitates manufacturer accountability.

On a global level, an INN [10] is used to identify the active ingredient in a drug, which in the case of a chemical/generic drug is equivalent. Biosimilars are not identical to their innovator parents; they are ‘highly similar’.

The differences, however, are crucially important since there is the potential for all biologicals to elicit dangerous immune responses. For this reason, if biosimilars use identical INNs and prescribing, dispensing or adverse event records identify products only by INNs, global regulators cannot recognize precisely which product is causing a problem. Testimony to WHO showed that there is a high level of ambiguity in attributing adverse events to a specific manufacturer when products share the same non-proprietary name [11]. Efforts to include other identifiers, such as batch number, that would distinguish between products and manufacturers routinely fail [12]. The addition of a unique suffix to the non-proprietary name provides a distinguishing feature that can be used to enhance traceability in a marketplace with multiple similar options.

Precise naming will improve patient safety by reducing confusion and mishaps in prescribing and dispensing; biosimilars are not identical to the reference product or one another, thus switching from one product to another may not be appropriate. Also, differential nomenclature helps enable national health authorities to collect and compare real-world data that measure the clinical effects of biologicals including biosimilars. Insights from such data, over time, will enable us to better measure a drug’s effectiveness in delivering successful health outcomes for patients.

WHO must finalize their BQ guidance. It is this organization, after all, that has the responsibility to ensure that developing nations of the world have access to affordable, quality medicines. Safety is mission critical and the BQ is a potent tool on behalf of global public health.

Concluding thoughts on the global regulatory fraternity

Our experience with healthcare regulators worldwide has reinforced our belief that health care and health policy professionals devoted to ensuring timely access to innovative medicines, quality generic drugs and biosimilars. It is not easy, and it is not only a job – it is a personal public health mission.

There are many issues surrounding the introduction of biosimilars into the global healthcare ecosystem: safety, effectiveness, interchangeability, potential adverse medical events, appropriate regulatory labelling and physician prescribing guidelines. But, even so, biosimilars are here. They are safe and effective. They are less costly. And they deserve a seat at the therapeutic table.

When it comes to biosimilar nomenclature, it is important for WHO to look … backwards. According to the 10th century Arab physician, Ibn Sina, ‘The time of action must be observed, so that essence and accident are not confused’.

Funding

This paper is funded by Alliance for Safe Biologic Medicines.

Competing interests: Mr Peter J Pitts declares no conflict of interest. Mr Michael S Reilly, Esq, is the Executive Director of and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002–2008.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Peter J Pitts, BA
Former Associate Commissioner, United States Food and Drug Administration
Visiting Professor, Université Paris Descartes Medical School
President, Center for Medicine in the Public Interest
757 Third Avenue, 20/F
New York, NY 10017, USA

Michael S Reilly, Esq
Executive Director
Alliance for Safe Biologic Medicines
PO Box 3691, Arlington
VA 22203, USA

References
1. Alhawassi TM, Abuelizz HA, Almetwasi M, Mahmoud MA, Alghamdi A, Alruthia YS, et al. Advancing pharmaceuticals and patient safety in Saudi Arabia: a 2030 vision initiative. Saudi Pharm J. 2018;26(1):71-4.
2. Caudron JM, Ford N, Henkens M, Macé C, Kiddle-Monroe R, Pinel J. Substandard medicines in resource-poor settings: a problem that can no longer be ignored. Trop Med Int Health. 2000;13(8):1062-72.
3. Salomon JA, Vos T, Hogan DR, Gagnon M, Naghavi M, Mokdad A. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet. 2012:15;380(9859):2129-43.
4. Australian Commission on Safety and Quality in Health Care. Medication Safety; Safety and Quality improvement Guide, Australia 2012 [internet]. 2012 [cited 2018 Oct 29]. Available from: https://www.safetyandquality.gov.au/wp-content/uploads/2012/10/Standard4_Oct_2012_WEB.pdf
5. Wikipedia. Saudi Vision 2030 [homepage on the Internet]. [cited 2018 Oct 29]. Available from: https://en.wikipedia.org/wiki/Saudi_Vision_2030
6. Al Kayyali L, Al Haqaish W, Bawaraesh N, Pitts PJ. The Jordan Food and Drug Administration: a culture of quality and continuous improvement. J Comm Biotechnol. 2014;20(4).
7. Pitts PJ, Louet HL, Moride Y, Conti RM. 21st century pharmacovigilance: efforts, roles, and responsibilities. Lancet Oncol. 2016;17(11):e486-e492.
8. World Health Organization. Essential medicines and health products. International Nonproprietary Name [homepage on the Internet]. [cited 2018 Oct 29]. Available from: http://www.who.int/medicines/services/inn/en/
9. U.S. Food and Drug Administration. Labeling for biosimilar products. [homepage on the Internet]. [cited 2018 Oct 29]. Available from: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf
10. World Health Organization. Essential medicines and health products. Biological qualifier [homepage on the Internet]. [cited 2018 Oct 29]. Available from: http://www.who.int/medicines/services/inn/inn_bio_bq/en/
11. World Health Organization. 63rd Consultation on International Nonproprietary Names for Pharmaceutical Substances. Geneva, 18-21 October 2016 [homepage on the Internet]. [cited 2018 Oct 29]. Available from: http://www.who.int/medicines/services/inn/63rd_Executive_Summary.pdf
12. World Health Organization. 64th Consultation on International Nonproprietary Names for Pharmaceutical Substances. Geneva, 4-7 April 2017 [homepage on the Internet]. [cited 2018 Oct 29]. Available from: http://www.who.int/medicines/services/inn/64th_Executive_Summary.pdf

Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

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A survey of Australian prescribers’ views on the naming and substitution of biologicals

Author byline as per print journal: Stephen P Murby, FRSA; Michael S Reilly, Esq

Introduction: As the number of biosimilar approvals in Australia increases, it is important to build on the existing regulatory framework to continue to bring high quality, safe and efficacious biosimilars to the widest number of patients most cost-effectively. As new policies regarding the regulation, reimbursement and uptake of biosimilars are being considered, the Alliance for Safe Biologic Medicines (ASBM) has asked Australian prescribers for their views on the naming, substitution and prescribing of biologicals and biosimilars. Currently, biologicals and biosimilars are approved by Australia’s Therapeutic Goods Administration (TGA). The country’s Pharmaceutical Benefits Advisory Committee (PBAC) has indicated it will consider pharmacy-level substitution of biosimilars for reference biological medicines on a ‘case-by-case basis’.
Methods: In June 2016, the ASBM surveyed 160 prescribers in Australia to gauge their opinions on the naming of biologicals and biosimilars and how the use of these medicines is recorded. Prescribers were also asked for their views on substitution of, as well as their familiarity with, knowledge of, attitudes to, and beliefs in, biosimilars.
Results: Nearly all (97%) respondents consider the best way for TGA to differentiate a biosimilar medicine from its reference biological is either with the same non-proprietary scientific name and a differing prefix or suffix, or with a completely unique name. Those surveyed used brand name (39%) and non-proprietary scientific name (38%) in about equal frequency when recording reference biologicals and biosimilars in patient records. 53% rarely or never include batch members when reporting adverse events. 89% of respondents thought it critical or very important that they be notified in the event of a pharmacy-level substitution. 61% thought that TGA should be responsible for providing the primary advice to the Australian Government that a product is suitable for pharmacy-level substitution, while only 33% thought that PBAC should be responsible.
Conclusion: Most respondents agreed that TGA should insist on distinct non-proprietary scientific names for all biosimilars and reference products, and most agreed that robust data are needed to support substitution rather than clinically supervised switching. While the prescribers surveyed use several different information sources to learn about the medicines they prescribe, the proportion of prescribers using any one of these sources was small. Perhaps because of this, half the prescribers surveyed thought, incorrectly, that biosimilars and originators are approved through the same regulatory process.

Submitted: 9 May 2017; Revised: 13 July 2017; Accepted: 19 July 2017; Published online first: 1 August 2017

Introduction

In Australia, biologicals and biosimilars are approved nationally by the Therapeutic Goods Administration (TGA). Aczicrit and Grandicrit (epoetin lambda) were the first products approved in Australia as biosimilars in 2010 [1]. To date, TGA has approved 13 biosimilars within the product classes of human growth hormone, granulocyte colony-stimulating factor (G-CSF), insulin, erythropoietin, follicle stimulating hormone (FSH) and tumour necrosis factor-inhibitor [1].

With an increasing number of biosimilars seeking entry to the Australian market, it is important to build on the existing regulatory framework established to continue to bring high quality, safe and efficacious biosimilars to the widest number of patients most cost-effectively. As new policies regarding the regulation, reimbursement and uptake of biosimilars are being considered, the Alliance for Safe Biologic Medicines (ASBM) has asked Australian prescribers for their views on the naming, substitution and prescribing of biologicals and biosimilars.

Australia’s Pharmaceutical Benefits Advisory Committee (PBAC), an independent expert body appointed by the Australian Government to recommend new medicines for listing on the PBS (Pharmaceutical Benefits Scheme), has indicated that it will consider pharmacy-level substitution of biosimilars for reference biological medicines on a ‘case-by-case basis’.

Some clinicians hold concerns with pharmacy-level substitution due to the current paucity of data on such practices, and also matters associated with tracking which product is dispensed. PBAC has stated that its ‘default position’ would be to advise that a biosimilar is suitable for substitution by a pharmacist ‘where the data are supportive of this conclusion’ and that a relevant consideration is ‘the absence of data to suggest significant differences in clinical effectiveness or safety compared with the originator product’ [2].

Biologicals are used in the prevention, diagnosis, or treatment of a range of chronic diseases. Since biologicals have large, complex, inherently diverse molecular structures made, or derived, from living organisms, they are always heterogeneous. Unlike non-biological medicines, there is a degree of natural variability in biologicals, and there are generally some differences between the reference and biosimilar products. Current methods to analyse physicochemical and structural differences are extremely sensitive. Analysis of different batches of reference products following a change in the manufacturing process has revealed differences between the pre- and post-change batches [3]. This molecular heterogenity within the originator biological is distinct from molecular differences between the originator and biosimilar.

A biosimilar is a version of the active substance of an already authorized original (or reference) biological, see Box 1.

Box 1: Biological medicines and biosimilars

Biological medicines are therapeutic proteins produced using living organisms. The active substances of biological medicines are larger and more complex than those of non-biological medicines. A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine (the ‘reference medicine’). While a biosimilar approved by a competent national regulator will be safe and effective, biosimilars nevertheless differ from generic versions of small molecule drugs in that they are not identical copies of their reference products.

Biosimilars introduce competition, which has the effect of lowering prices of both originator and biosimilar and increasing patients’ access to these therapies [3].

With a growing number of reference biologicals and biosimilars, regulatory authorities across the globe are in discussion over how biosimilar medicines should be named and labelled [4, 5]. Distinct names will be crucial in order to facilitate post-market safety monitoring and help minimize the potential for medication errors.

There is a clear need for sufficiently detailed and transparent labelling and product information to enable informed decision-making by physicians and patients, ensuring appropriate safe and effective use of these medicines [6].

International Nonproprietary Names (INNs) are intended for use in drug regulation, prescribing, dispensing, pharmacopoeias, labelling, pharmacovigilance and in scientific literature [7]. However, biologicals, due to their increased molecular complexity and structural micro-heterogeneity, are not categorized by the INN alone [7]. An INN Expert Group recommended that the World Health Organization (WHO) develop and implement a system for assignment of Biological Qualifiers (BQs) to similar biotherapeutic products (SBPs) [8]. WHO has proposed the development of a global BQ for biological medicines that will provide a unique identifier for all biological active substances that are assigned an INN [6]. While the INN is a common and public non-proprietary name for a given active substance, the BQ would be applied to a particular manufacturer’s active substance. The BQ would not be part of the INN and it is envisaged that it would enhance identification, prescribing, dispensing and pharmacovigilance of biological medicines.

The US Food and Drug Administration (FDA) issued its guidance for the non-proprietary naming of biological products in January 2017 [9] following the release of two draft guidance documents outlining proposed methods for biological product naming and biosimilar product labelling [10]. According to its latest guidance, FDA will assign a non-proprietary name for all reference biologicals, related biologicals and biosimilars that will include an ‘FDA-designated suffix’. The ‘proper name’ will consist of a combination of the ‘core name’ and distinguishable suffix, which will be ‘devoid of meaning’ and be ‘composed of four lower case letters’. A survey of prescribers of biologicals in the US, carried out before the release of this guidance, found that two thirds (66%) of the prescribers surveyed supported the introduction of distinct names. Of those, the majority would prefer a suffix that indicated the manufacturer [11]. The WHO and FDA emphasis stands in contrast to the EMA approach to biosimilar naming, under which an originator biological and all biosimilars to that product will share the same non-proprietary name.

In Australia, biologicals and biosimilars are approved nationally by TGA. TGA issued a biosimilars guidance in 2013 that includes a section on naming conventions for biosimilars [1214]. This guidance required the name of a biosimilar in Australia should be made up of the reference product Australian Biological Name (ABN), thus identifying the reference product with which the biosimilar has demonstrable comparability; and a biosimilar identifier, consisting of: the prefix sim(a)– and a three-letter code issued by the WHO INN Committee, according to its draft policy. This guidance was subsequently revoked and recently approved biosimilars to etanercept and infliximab have been given the same non-proprietary name as their reference products.

The country’s PBAC has indicated that it will consider pharmacy level substitution of biosimilars for reference biological medicines on a case-by-case basis, see Box 2. Since the introduction of this policy, two biosimilars to infliximab have been ‘a’ flagged, as has one biosimilar to etanercept.

Box 2: The role of the Pharmaceutical Benefits Advisory Committee

The Pharmaceutical Benefits Advisory Committee (PBAC) has indicated that it will consider pharmacy-level substitution of biosimilars for reference biological medicines on a ‘case-by-case basis’. Where a product is deemed suitable for pharmacy-level substitution (a process known as ‘a’ flagging), a patient can be switched by a pharmacist from the reference biological medicine to the biosimilar medicine and from the biosimilar medicine back to the reference biological medicine. This could potentially be done on multiple occasions. The prescriber can however prevent this substitution by selecting ‘no substitution’, and pharmacy guidelines reference consultation with the patient.

In June 2016, 160 prescribers in Australia completed a survey sponsored by the ASBM about their knowledge of, attitudes toward and beliefs regarding biosimilars. They were asked their opinions on the naming of biologicals and biosimilars and how these medicines are identified in the patient record and in adverse event reporting. They were also asked for their views on substitution.

Methods

Sample characteristics and methodology
In June 2016, 605 prescribers in Australia were invited to complete a 15-minute web-based survey on biologicals and biosimilars. Potential respondents were identified in, and recruited from, a large, global, commercial database of healthcare professionals. A high response rate was expected because prescribers in this database had previously indicated a willingness to participate in market research.

A total of 451 prescribers responded. Respondents were screened as follows: they had to specialize in one of seven therapeutic specialties, including dermatology, endocrinology, gastrointestinal, nephrology, neurology, oncology or rheumatology; they had to have been in practice for one year or more; and they had to have prescribed biological medicines in their practice. A total of 174 respondents were screened out because they did not meet these criteria. A further 80 prescribers did not qualify because they specialized in a therapeutic specialty for which data collection had closed. In addition, 37 started but failed to complete the survey. Any data they contributed are not included in the analysis and report.

A total of 160 prescribers completed the survey. All data collected refer only to those who completed the survey. Participants received a standard cash stipend of US$76 for their time.

Prescribers practised in public hospitals (46%); private hospital/private practice (42%); academic medical centre (11%); and other (1%). They had spent between one and 30 years in practice, see Figure 1.

Figure 1

A quarter (25%) of the prescribers were rheumatologists, 25% were oncologists, and 25% were gastroenterologists. The remaining 25% prescribers were divided equally among dermatologists, neurologists, nephrologists and endocrinologists, see Figure 2.

Figure 2

Regarding responses from participants to the question of how often they used different information sources to learn about the details of a medicine for prescribing and monitoring, 46% of prescribers said they always used published literature, whilst 43% said they never used published literature. Only 19% of prescribers said they always used information from TGA, and 27% said they always used information from PBAC. Only a fifth (19%) of those surveyed said they learnt about the details of a medicine by reading the product information label, and 13% from hospital formulary, see Figure 3.

Figure 3

Results

Reporting and naming of biologicals and biosimilars
Participants were asked how they identified biological medicines when they were prescribed or entered in patients’ records. Similar numbers of prescribers identified medicines by brand name or non-proprietary scientific name (39% and 38%, respectively). A smaller proportion identified medicines by brand name and non-proprietary scientific name (21%), and 2% identified them by Australian Register of Therapeutic Goods (ARTG) number. When adverse events (AEs) were reported, medicines were identified by brand name by 39% of prescribers, by brand name and non-proprietary scientific name by 34% of prescribers, by non-proprietary scientific name by 25% of prescribers, and by ARTG number by just 2% of prescribers, see Table 1.

Table 1

Respondents were asked how often they included batch numbers when reporting AEs. A total of 23% of prescribers said they never used batch numbers, almost a third of prescribers (30%) said they rarely included batch numbers, 20% sometimes used batch numbers and 28% said they always included batch numbers.

When prescribers were asked why a batch number was not always reported, they replied that the batch number was not available at time of reporting (41%); or they were not sure where to find the information (36%); or they had forgotten to include the information (19%).

Respondents were also asked whether a loss of efficacy should be reportable as an AE. Most prescribers (65%) said it should not, while 19% of prescribers thought it should, and 16% of prescribers had no opinion about whether a loss of efficacy should be a reportable AE.

Asked whether TGA should insist on a distinct non-proprietary scientific name for every biological or biosimilar medicine that it approves, three quarters of prescribers (76%) said yes, 18% of prescribers said no, and 7% of prescribers had no opinion.

Asked what the best way was for TGA to differentiate a biosimilar medicine from its reference product, a large proportion of physicians responded that it would be best if biosimilars had the same non-proprietary scientific name as their reference medicines but with either a differentiating prefix (38%) or suffix (29%). 30% of participants opted for entirely different non-proprietary scientific names for the biosimilar and its reference product.

Substitution attitudes and beliefs
Prescribers were asked what level of evidence would be supportive of pharmacy-level substitution, see Table 2. They were also asked what role they thought TGA should play in advising PBAC on the suitability of a product for pharmacy-level substitution, see Figure 4, and whether TGA or PBAC should be responsible for providing the primary advice to the Australian Government that a product is suitable for pharmacy-level substitution, see Figure 5.

Table 2

Figure 4

Figure 5

Prescribers completing the survey were asked how important it was for them to have the sole authority to decide, together with their patient, the most suitable biological medicine to be dispensed to the patient. Over half of prescribers (54%) thought it was very important and over a third (36%) thought it was critically important, see Figure 6. When the prescribing physicians were asked whether their prescription software/documentation included a box marked ‘brand substitution not permitted’, 61% responded that it did, 21% responded that it did not, and 18% were unsure.

Figure 6

Respondents were asked about switching between biological medicines for patients with chronic disease. Over half (51%) of prescribers said that pharmacy-level substitution was not acceptable for these patients, 9% thought it was totally acceptable, while 40% thought it was acceptable providing they were notified in advance.

Biosimilars familiarity and knowledge
In response to the question of how familiar survey respondents were with biosimilar medicines, 21% said they were very familiar and had a complete understanding, 73% said they had a basic understanding, 6% said that they could not define them (although they had heard of them), and 1% said they had never heard of them.

Prescribers were asked a series of questions to gauge their understanding of biosimilars, their awareness of and comfort with the biosimilars approval process, and their opinions on switching. Responses to these questions are given in Table 3.

Table 3

Respondents were asked how comfortable they would be prescribing a biosimilar medicine that had been approved for several or all of the indications of its reference medicine on the basis of clinical trials in only one of those indications, or in fewer indications than for which the biosimilar is approved, 73% would have some concerns, depending on data and indications; 16% would be comfortable; and 11% would not be comfortable.

Conclusion

Of the prescribers who completed the survey, over three quarters (76%) agreed that TGA should insist on distinct non-proprietary scientific names for all biosimilars and reference products. In addition, well over half (61%) of respondents believed TGA should be responsible for recommendations on pharmacy-level substitution, while only a third (33%) thought that PBAC should be responsible.

Nearly all the prescribers in this survey (98%) use either brand name or non-proprietary scientific name for recording and prescribing biosimilars and their reference biologicals. Most prescribers (61%) want TGA to play a major role in naming biosimilars.

It was clear that the reporting of biosimilars use via brand name and batch number varied between respondents. Respondents indicated that robust data are needed to support substitution, and the vast majority of prescribers (94%) said that the final decision over which biological to prescribe should rest with the prescriber and the patient, and strongly supported clinically supervised switching over pharmacy-level substitution.

Respondents used different information sources to learn about the details of a medicine for prescribing and monitoring, but each source was used by surprisingly few prescribers. Less than half of prescribers said they always used published literature, and a similar proportion said they never used published literature. Clearly there were gaps in how the regulatory process is understood since about half of those surveyed thought, incorrectly, that biosimilars and originators are approved through the same regulatory process.

Despite a spread of responses from the prescribers surveyed, there was general agreement that biosimilars should be distinguished from originators with either the same non-proprietary scientific name and a differing prefix or suffix, or with a completely unique name. The vast majority of prescribers thought that they and their patients should decide which biological is dispensed and that they should be notified of any substitution by the pharmacist.

Key points

  • 76% of respondents believe TGA should insist on distinct non-proprietary scientific names for all biosimilars and reference products.
  • 97% of respondents consider the best way for TGA to differentiate a biosimilar medicine from its reference biological is either with the same non-proprietary scientific name and a differing prefix or suffix, or with a completely unique name.
  • 98% of respondents prescribed identified biological medicines in patient records by either brand name (39%), nonproprietary scientific name (38%), or both (21%).
  • 53% of respondents rarely or did not include batch numbers when reporting adverse events.
  • Respondents generally agreed that statistically significant comparative clinical data are needed before pharmacy-level substitution can be recommended, but opinion was divided over the evidence required for a PBAC recommendation for substitution.
  • 61% of respondents believe TGA should be responsible for recommendations on pharmacy-level substitution compared to 33% for PBAC.
  • 90% of respondents believe it is critical or very important that the prescriber and patient hold the ultimate decision for which biological is dispensed.
  • 89% believe it is critical or very important that they be notified in the event of a pharmacy-level substitution.

Funding sources

The Alliance for Safe Biologic Medicines (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.

The Australia 2016 prescribers and biosimilars survey was sponsored by ASBM.

This paper is funded by ASBM.

Competing interests: Mr Stephen P Murby, FRSA, is a member of the International Advisory Board of Alliance for Safe Biologic Medicines (ASBM). Mr Michael S Reilly, Esq, is the Executive Director of and employed by ASBM. Mr Reilly served in the US Department of Health and Human Services from 2002–2008.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Stephen P Murby, FRSA, former Head of Consumers Health Forum of Australia; International Advisory Board Member of ASBM

Michael S Reilly, Esq, Executive Director, ASBM
Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

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14. World Health Organization. Biological Qualifier [homepage on the Internet]. [cited 2017 Jul 13]. Available from: http://www.who.int/medicines/services/inn/inn_bio_bq/en/

Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2017 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Source URL: https://gabi-journal.net/a-survey-of-australian-prescribers-views-on-the-naming-and-substitution-of-biologicals.html


Naming and labelling of biologicals – a survey of US physicians’ perspectives

Introduction: The US Food and Drug Association (FDA) released its requirements for the non-proprietary naming of biological products in January 2017. Before the FDA’s release, the Alliance for Safe Biologic Medicines (ASBM) asked physicians for their views on the labelling and naming of biosimilar medicines.
Study objectives: To determine the opinions of physicians who prescribe biologicals about labelling and naming of biologicals/biosimilars.
Methods: 400 prescribers of biologicals in the US were asked what information they would like to see included in a biological product label in order to choose between multiple biosimilars and their reference products. In a separate survey, 400 prescribers were asked how biosimilars should be named. In the labelling survey, prescribers were asked what information should be included in a label, such as what clinical data should be present; whether the product was a biosimilar; and whether or not it was interchangeable. In the naming survey, prescribers were asked for their opinion on product naming in general and on what were then FDA proposals (now FDA requirements) for biosimilar naming.
Results: All items queried in the labelling survey were considered very important for label inclusion. The fact that a drug was a biosimilar was considered the most important; whether it was interchangeable was marginally less important. In the naming survey, 66% of respondents thought that FDA should require a distinct non-proprietary scientific name for every FDA-approved biological product – whether originator or biosimilar. 60% thought that a manufacturer-specific suffix should be added to the name.
Conclusion: The physicians surveyed generally agree on the issue of the labelling of biosimilars. Two thirds of respondents to the naming survey agreed that FDA should require a distinct non-proprietary scientific name for every biological product they approve – whether originator or biosimilar. However, 53% did not support FDA’s proposal to add a random suffix to the name, and would prefer a suffix that indicated the manufacturer.

Submitted: 9 January 2017; Revised: 12 February 2017; Accepted: 13 February 2017; Published online first: 27 February 2017

Introduction

Biological medicines are therapeutic proteins produced using living cells. A copy of an original biological made by a different manufacturer is referred to as a biosimilar or follow-on biological rather than a generic drug because it will be similar, not identical, to the product it copies. Biosimilars are also referred to as subsequent entry biologics (SEBs) in Canada. As a result of the abbreviated biosimilar approval pathway [1], biosimilar medicines are now available in the US market.

The market uptake of biosimilars in the US will depend on regulatory policies [2], for which an agreed naming and labelling system will be key. A survey of the views of European physicians on familiarity of biosimilar medicines has demonstrated the need for distinguishable non-proprietary names to be given to all biologicals [3]. There have been calls for clear regulation in this area from Latin America [4], Malaysia [5] and beyond.

Since FDA has only distributed draft guidance on the naming of biosimilar medicines [6] at time of the survey, feedback from the physicians who prescribe biologicals may well be helpful in determining how these drugs are to be regulated. The Alliance for Safe Biologic Medicines (ASBM) invited 5,423 physicians in the US to complete a study on the naming of biologicals. A total of 433 physicians responded, of which 400 prescribers of biologicals qualified and completed the study. Prescribers were asked for their feedback on the non-proprietary biologicals naming proposal issued by FDA in August 2015 [6].

FDA has proposed a new policy that would require every biological – whether originator or biosimilar – to have a distinct non-proprietary scientific name. Prescribers concluded that FDA was right to require a distinct non-proprietary scientific name for every biological product – originator or biosimilar – that FDA had approved.

Product labelling is seen at the heart of building user confidence in biosimilars [7]. In a subsequent study, the ASBM invited 9,813 prescribers to complete a study on the labelling of biologicals. 624 of these responded, of which 400 qualified and completed the study. Physicians who completed the study were asked what information they would like to see in a biological product label in order to choose between multiple biosimilars and their reference products. Physicians were asked what information could be included in a label, such as what clinical data should be present; whether or not the product was a biosimilar; and whether or not it was interchangeable.

All the information included in the labelling survey was considered important by the physicians surveyed. The greatest importance was accorded to an indication that the drug was a biosimilar. Physicians responded that including information on interchangeability was slightly less important than this.

Sample characteristics and methodology

Physician biosimilars labelling survey
Four hundred physicians were recruited in the US to complete a 15-minute web-based questionnaire on biosimilar labelling. In a separate, independent study, 400 prescribers were recruited in the US to complete a 15-minute web-based questionnaire on biosimilar naming. Participants in both surveys received a standard cash stipend of US$25 for their time to complete the survey.

All participants in the labelling survey were located in the US. They were recruited from a large, reputable panel of physicians and were all board certified in one of the following six specialities: dermatology, endocrinology, nephrology, neurology, oncology, or rheumatology. All participants prescribed biological medicine.

Of the 400 physicians who completed the labelling survey, 23% specialized in dermatology, 15% in endocrinology, 16% in nephrology, 15% in neurology, 16% in oncology, and 16% in rheumatology.

Prescribers completing the labelling survey worked in different settings. Twenty-six per cent of respondents worked in a community setting, 24% worked in an academic medical centre, 22% worked in a multi-speciality clinic, 17% worked in a private or family practice, 8% worked in a hospital, see Figure 1.

Fig 1

A total of 7% of participants in the labelling survey had spent 1–5 years in practice, 26% had spent 6–10 years, 41% had spent 11–20 years, 22% had spent 21–30 years, and 4% had spent more than 30 years in practice.

Sample characteristics and methodology

Physician biosimilars naming survey
The 400 participants in the naming survey were also based in the US. They were recruited from a large, global panel of healthcare professionals. Participants specialized in one of the following seven therapeutic specialities: dermatology, endocrinology, gastrointestinal, nephrology, neurology, oncology or rheumatology.

Among physicians completing the naming survey, 13% specialized in dermatology, 15% in endocrinology, 14% in gastrointestinal, 14% in nephrology, 14% in neurology, 16% in oncology, and 14% in rheumatology.

Prescribers completing the naming survey worked in different settings. 26% of respondents worked in an academic medical centre, 25% in a community setting, 20% in a private or family practice, 18% in a multi-specialist clinic, 7% in a hospital, and 2% in a military/veterans affairs hospital, see Figure 2.

Fig 2

A total of 7% of the physicians completing the naming survey had spent 1–5 years in practice, 33% had spent 6–10 years in practice, 32% had spent 11–20 years, 21% had spent 21–30 years, and 6% had spent more than 30 years in practice.

Participants in the naming survey were asked about their familiarity with FDA’s ‘Orange Book’ [8], the resource for Approved Drug Products with Therapeutic Equivalence Evaluations. The ‘Orange Book’ is a reference that identifies drug products approved on the basis of safety and effectiveness by FDA. Only 13% considered themselves very familiar with the book, 33% somewhat familiar, 26% vaguely familiar, and over a quarter (28%) had never heard of it. Only 4% used the Orange Book on a daily basis, 17% used it weekly, 14% used it monthly, 28% used it rarely, and 37% never used it.

Asked about their familiarity with FDA’s ‘Purple Book’ [9], that is, the resources for Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations, 8% were very familiar, 23% were somewhat familiar, 28% were vaguely familiar, and 41% had never heard of it. Only 4% used the Purple Book daily, 11% used it weekly, 12% used it monthly, 23% used it rarely, and over half (51%) never used it. Information contained in the Purple Book is designed to help enable a user to see whether a particular biological product has been determined by FDA to be biosimilar to or interchangeable with a reference biological product.

All physicians questioned in the naming survey claimed that they identified all medicines that they prescribed (biological and chemical) in the medical record.

Asked how they identified a medicine in the patient record, 25% said by scientific name, 34% by brand name, and 39% said it varied by medicine. Asked whether they would report an adverse event by using a drug’s product name or National Drug Code (NDC) number, 47% said they would use the brand name, 38% said they would use the scientific name, 2% would use the NDC number, and 13% had no preference.

Participants in the naming survey were asked for their attitudes and beliefs on product naming for originator and biosimilar products. 72% of respondents thought that if medicines had the same non-proprietary scientific name then they were probably structurally identical, 16% thought they would not be structurally identical, and 12% had no opinion. If two products have the same non-proprietary scientific name then 68% of respondents thought that a patient could safely receive either product and expect the same result. Twenty-one per cent of respondents would not expect the same result, and 11% had no opinion.

Asked about switching (when a patient is switched from one medicine to another), 60% of respondents thought that patients could safely be switched between two medicines that had the same non-proprietary scientific name and expect the same results. A quarter of respondents (25%) thought that patients could not safely be switched between two medicines with the same non-proprietary scientific name, 14% of respondents had no opinion.

Results

Physician responses to biosimilar labelling survey
On a scale of 1–5, where 1 is not important at all and 5 is very important, 90% of the physicians questioned rated the importance of whether a product label for a biosimilar should clearly indicate that it is a biosimilar as either a 4 or 5, see Figure 3. On the question of post-marketing data, 79% of respondents rated the importance of including this data on the biosimilar label as either a 4 or 5, see Figure 4. On the question of interchangeability, 79% of respondents rated the importance of including whether or not a biosimilar is interchangeable as either a 4 or 5, see Figure 5. The responses of physicians to questions on biosimilar labelling are shown in Table 1.

Fig 3

Fig 4

Fig 5

Table 1

Physician responses to biosimilar naming survey
In the naming survey, prescribers were asked whether FDA should require a distinct non-proprietary scientific name for every biological product FDA had approved – whether originator or biosimilar. FDA has recently proposed a distinct non-proprietary scientific name for all products, whether originator or biosimilar. This is intended to aid the process of pharmacovigilance and accurate prescribing and dispensing of medicines.

Respondents were asked for their views on the information that should be included in a product name and for their attitudes and beliefs on substitution.

Responses to questions in the physicians’ naming survey are shown in Table 2.

Table 2

The spread of prescribers’ responses to questions related to the information contained in the representative suffix are given in Figure 6.

Fig 6

Conclusion

Generally speaking, all issues raised in the labelling survey were considered by the physicians surveyed to be very important for label inclusion. The inclusion of an indication of interchangeability was considered very important by 54% of the physicians. In fact, the physicians concluded that interchangeability was – of all the features included in the survey questions – the least important feature, with an average score of 4.1 out of 5. On average, the physicians gave the highest score, 4.4, to indicating that the drug was a biosimilar.

Segment differences were examined for all issues included in the survey. Segments among physicians included specialty, time spent working in health care, and practice setting. Very few specialty differences were noted and no differences for practice setting were noted. In general, the longer a physician had been in practice, the more important they thought it was to include the features mentioned in the survey on the biosimilar product label.

FDA proposal for a random suffix on a product’s name that does not indicate the manufacturer was not broadly welcomed, with only 9% of respondents agreeing with FDA. Instead, most physicians (60%) would prefer a suffix on the non-proprietary scientific name that is indicative of the product’s manufacturer. A third of respondents (32%) had no opinion.

In the naming survey, it was clear that respondents were not in complete agreement on how biological medicines, whether originators or biosimilars, are named. Reaching an agreement on the naming of these medicines will be key in building user confidence in biosimilars. The data presented here provide important feedback from a wide range of physicians who prescribe biologicals in the US. The findings will be helpful in determining how these biosimilar medicines are regulated in future.

Key points of the 2015 physicians naming and labelling survey

  • All items queried in the labelling survey were considered very important for label inclusion.
  • The fact that a drug was a biosimilar was considered the most important; whether or not it was interchangeable was slightly less important.
  • In general, the longer a physician has been practising, the more important they considered the inclusion of post-marketing data and a clear distinction between data generated by the biosimilar sponsor and by the originator sponsor.
  • 66% of physicians thought FDA should require a distinct non-proprietary scientific name for every biological product – whether originator or biosimilar – that FDA had approved. 11% of physicians did not, and 23% of physicians had no opinion.
  • 35% of respondents considered it very important they had the authority to designate a biological medicine as ‘dispense as written’ or ‘do not substitute’. Nearly all respondents considered it important and only 2% of respondents thought it was not at all important.

Funding sources

The Alliance for Safe Biologic Medicines (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.

Competing interests: Harry L Gewanter, MD, FAAP, FACR, Chairman of the Alliance for Safe Biologic Medicines (ASBM), and Mr Michael S Reilly, Esq, Executive Director; are employed by ASBM.

This paper is funded by ASBM.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Harry L Gewanter, MD, FAAP, FACR, Chairman
Michael S Reilly, Esq, Executive Director

Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

References
1. Biologics Price Competition and Innovation Act of 2009, Public Law 111-148, Sec. 7001–7003, 124 Stat. 119. Mar. 23, 2010.
2. Cohen JP, Felix AE, Riggs K, Gupta A. Barriers to market uptake of biosimilars in the US. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):108-15. doi:10.5639/gabij.2014.0303.028
3. O Dolinar R, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi:10.5639/gabij.2014.0302.018
4. Feijó Azevedo V, Mysler E, Aceituno Álvarez A, Hughes J, Javier Flores-Murrieta F, Ruiz de Castilla EM. Recommendations for the regulation of biosimilars and their implementation in Latin America. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):143-8. doi:10.5639/gabij.2014.0303.032
5. Abas A, Siew Khoon Khoo Y. Regulation of biologicals in Malaysia. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(4):193-8. doi:10.5639/gabij.2014.0304.044
6. GaBI Online – Generics and Biosimilars Initiative. FDA issues draft guidance on biosimilars labelling [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Feb 12]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-biosimilars-labelling
7. European Biopharmaceutical Enterprises. Tell me the whole story: the role of product labelling in building user confidence in biosimilars in Europe. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(4):188-92. doi:10.5639/gabij.2014.0304.043
8. U.S. Food and Drug Administration. Orange Book: approved drug products with therapeutic equivalence evaluations [homepage on the Internet]. [cited 2017 Feb 12]. Available from: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
9. U.S. Food and Drug Administration. Purple Book: lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations [homepage on the Internet]. [cited 2017 Feb 12]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm

Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2017 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Source URL: https://gabi-journal.net/naming-and-labelling-of-biologicals-a-survey-of-us-physicians-perspectives.html


Naming and labelling of biologicals – the perspective of hospital and retail pharmacists

Author byline as per print journal: Professor Philip J Schneider, MS, FASHP; Michael S Reilly, Esq

Introduction: To date, the US Food and Drug Administration (FDA) has offered only draft guidance on the naming of biosimilar medicines. The Alliance for Safe Biologic Medicines (ASBM) has asked pharmacists for their views on the labelling and naming of biosimilar medicines.
Study objective: To determine the opinions of pharmacists about labelling and naming of biosimilars.
Methods: A total of 3,525 pharmacists in the US were invited to complete a survey on the naming and labelling of biologicals. Responses were received from 849 pharmacists, of which 401 completed the survey. Of the pharmacists who completed the survey, 60% worked in hospitals or the healthcare system, 40% worked in retail. Pharmacists were asked for their feedback on a recent FDA non-proprietary biologicals naming proposal. They were also asked what information they would like to see included in a biological product label in order to choose between multiple biosimilars and their reference products.
Results: Of the 401 pharmacists who completed the survey, 68% responded that FDA should require a distinct non-proprietary scientific name for every biological product – originator or biosimilar – approved by them. A total of 77% of respondents thought that a manufacturer-specific suffix should be included in the name of each biological product. Respondents considered the following as very important for label inclusion: clinical data to support whether or not the product was a biosimilar and whether or not the biosimilar and originator are interchangeable. Noting that the drug was a biosimilar was considered the most important; whether or not it was interchangeable was slightly less important.
Conclusion: A total of 401 pharmacists (11.4% of all those invited) completed the survey. The respondents comprised of 241 hospital pharmacists (60%) and 160 retail pharmacists (40%). Of these the majority of total respondents (68%) think that originator biological and biosimilars should have distinguishable non-proprietary scientific names and 77% think the name should include a unique, distinguishing suffix specific to the manufacturer for future product approval.

Submitted: 28 September 2016; Revised: 28 October 2016; Accepted: 31 October 2016; Published online first: 14 November 2016

Introduction

The market uptake of biosimilars in the US and worldwide will depend on regulatory policies [1], for which an agreed naming and labelling system will be important [2]. A survey of the views of European physicians on familiarity of biosimilar medicines demonstrated the need for distinguishable non-proprietary names to be given to all biologicals [3]. This has been supported by a number of discussions surrounding the development of clear regulation in this area [47], and a number of countries across the globe from Latin America [8, 9], Australia [10] and beyond; have called for specific nomenclature to be developed. The results of these surveys reinforce the value of a global naming policy for biologicals and the importance of the World Health Organization (WHO) moving forward with its biological qualifier proposal.

Since the US Food and Drug Administration (FDA) has only distributed draft guidance on the naming of biological medicines [11] and biosimilar labelling [12, 13], feedback from the pharmacists who prepare and dispense them is also important in determining how these drugs are regulated. In Europe, product labelling is seen as important to build user confidence in biosimilars [14]. In response to concerns in Europe, the Alliance for Safe Biologic Medicines (ASBM) invited 3,525 pharmacists in the US to complete a survey that included questions related to the information that could be included in a label, such as whether or not the product was a biosimilar; what analytical/clinical data and clinical similarity data should be present; post-marketing data; approved and non-approved indications; data source; and whether or not it was interchangeable/substitutable.

FDA has proposed a new policy that would require every biological – whether originator or biosimilar – to have a distinct non-proprietary scientific name. Both pharmacists and prescribers concluded that FDA was right to require a distinct non-proprietary scientific name for every biological product – originator or biosimilar – that FDA had approved.

Methods

In 2015, the ASBM invited 3,525 pharmacists in the US to complete a survey on the naming of biological medicines and biosimilar labelling [15], including feedback on FDA draft guidance on non-proprietary biologicals naming [11]. A total of 849 pharmacists replied (a response rate of 24%). Of these, 448 pharmacists were screened out predominately for their lack of knowledge on biologicals or did not complete the survey. A total of 401 pharmacists (11.4% of all those invited) completed the survey, and are collectively termed ‘respondents’. Pharmacists were reimbursed US$22 for completing the survey.

Pharmacists were recruited from a large, global panel of healthcare professionals and were either employed in a hospital/health system pharmacy (60%) or retail pharmacy setting (40%). All 401 pharmacists that completed the study had dispensed biological medicines and had been in practice as a pharmacist for one year or more, see Figure 1.

Figure 1

Pharmacists were asked what information they would like to see included in a biological product label in order to choose between multiple biosimilars and their reference products. Data were analysed using MS Excel, and checked manually.

Results

Use of biological product reference material by pharmacists
The majority (64%) of pharmacist respondents were very familiar with the FDA ‘Orange Book’ [16], that is, the resource for Approved Drug Products, with Therapeutic Equivalence Evaluations. The ‘Orange Book’ is a reference that identifies drug products approved on the basis of safety and effectiveness by FDA. One third (29%) of pharmacists refer to this at least weekly, 24% monthly, 6% daily, with the rest referring to it less frequently. In contrast, 28% of respondents had never heard of the FDA ‘Purple Book’ [17], that is, the resource for Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations, and almost 80% of respondents never or infrequently used or referred to it. Information contained in the Purple Book is designed to help enable a user to see whether a particular biological product has been determined by FDA to be biosimilar to or interchangeable with a reference biological product. The results from the survey are outlined below and presented in Tables 1 and 2. Only 2% of pharmacists used the Purple Book daily, 7% of pharmacists used it weekly, 12% of pharmacists used it monthly, 30% of pharmacists used it rarely, and 49% of pharmacists never used the Purple Book at all.

Table 1

Table 2

Knowledge of biosimilars
Survey participants were asked how familiar they were with biosimilar medicines with the following question:

‘Biosimilar medicines are intended to be copies of already approved biological medicines. They are referred to as “biosimilar” rather than “generic” because they will be similar, but not identical to the product they copy. How familiar are you with biosimilar medicines?’

Of the pharmacists who completed the survey, 57% of respondents said that they were familiar with biosimilars having a basic understanding and 35% said they had a complete understanding. Hospital pharmacists included in the survey reported being the most familiar with biosimilars, with 44% saying they had a complete understanding, while only 23% of retail pharmacists reported having a complete understanding.

Pharmacists were asked about their knowledge of the approval process for biosimilars using the following question:

‘Originator medicines are approved by the US Food and Drug Administration based on an evaluation of clinical data that demonstrates a medicine is safe and effective for the specified indication and data must be provided for every indication. The approval pathway for biosimilars is different than for originator medicines. Are you aware a biosimilar medicine may be approved for several or all indications of the reference product on the basis of clinical trials in only one of those indications?’

The responses suggest that overall knowledge among respondents was good with 86% answering yes (91% hospital pharmacists are more likely to respond ‘Yes’ versus 78% retail pharmacists). When asked if they thought that their understanding of the biosimilar approvals process was acceptable, there was a consensus that this was ‘acceptable’ (27%) or at least ‘somewhat acceptable’ (51%).

Naming knowledge
The survey participants were asked questions about their knowledge of the naming of biosimilars and what this meant about how these products could be used. Most respondents (63%) indicated that if biological medicines have the same non-proprietary scientific name, this would imply that the products are identical, with 68% hospital pharmacists are more likely to answer ‘Yes’ versus 57% retail pharmacists. Those respondents would expect the same results from biological medicines with the same non-proprietary scientific name. The majority of respondents (58%) believed that products sharing non-proprietary scientific names could be safely switched from a reference biological medicine to its biosimilar during a course of treatment and the same result would be expected with either of the products. When the same non-proprietary scientific name is used in two biological medicines, 55% of respondents would also assume that the medicines had both been approved for the same indications.

Naming requirements
When questioned about how biological naming should be regulated, the majority (68%) of the respondents thought that each product – originator or biosimilar – should have a distinct/unique non-proprietary scientific name. Furthermore, 77% of respondents thought the suffix on a biological medicine name should indicate its manufacturer, rather than a random suffix in future product approvals.

Biosimilar labelling
A total of 58% of respondents thought that it was very important that a product label for a biosimilar clearly indicates that it is a biosimilar. They also agreed that labels should include an explanation as to what a biosimilar is. Analytical information resulting from biosimilarity studies should be included, as should any clinical data submitted to FDA and any post-marketing data. There was also a consensus that the label should include reference to the brand name of the originator product.

Participants felt strongly that it should be clear and explicit on the label if a biosimilar product has not been approved for all indications approved for use of the reference product. The label should clearly distinguish data generated from the use of the biosimilar sponsor and that generated by the originator sponsor, and that it is clear which indications were studied with the biosimilar sponsor and which indications were approved based on extrapolation from studies of the reference product. Respondents also felt that labels should clearly include all relevant data used to establish similarity and clearly indicate if the biosimilar is interchangeable with a reference product.

Discussion

The results of this survey of pharmacists are consistent with the results from a survey of physicians in Europe [3]. In both surveys, respondents believed that products sharing a non-proprietary name could be considered identical, could be expected to produce the same results, could be used interchangeably and would be approved for all the indications of the reference product.

Many of the findings in this study support a recent survey sponsored by the Academy of Managed Care Pharmacy (AMCP) [18]. In the AMCP study, more than 60% of participants (62.3%) reported preferring a biosimilar naming convention that uses either a designated suffix (48.1% of all participants) or prefix (14.2% of all participants). Of the 48.1% who would prefer a designated suffix, the vast majority (83.4%) wanted a suffix that was based on the name of the manufacturer. In this survey, 77% of pharmacists expressed a preference for a suffix based on the manufacturer.

To date, FDA is yet to finalize its guidance for the naming of biologicals and labelling of biosimilars. This is a fast-evolving area – following publication of its draft guidance in 2015 and 2016 [11, 12], FDA issued a request for comments on expanding the number of suffixes that biosimilars makers could propose. The request was swiftly withdrawn; following what FDA said was an administrative error [19]. Some have speculated that the agency wanted to extend the comment period, which was originally in July 2016.

The results from surveys like the one described here will aid in the development of a clear and comprehensive system to promote the safe and effective use of biologicals and biosimilars, and as a result facilitate consumer confidence and market uptake in the US.

Conclusion

The pharmacists responding to this survey reported having a good overall knowledge of biosimilars and their approval process. The results suggest that when a biosimilar and the reference product share the same non-proprietary scientific name, it could lead to confusion among pharmacists. This is because two products sharing a non-proprietary name could be considered identical, be expected to produce the same results from both drugs, be used interchangeably, and be approved for all of indications of the reference product. As these are assumptions that cannot be made with biosimilars, pharmacist respondents agreed that all biological products should have unique names and that clear and explanatory labelling of these products should be required.

In general, all issues raised with regards to labelling were considered by pharmacist respondents to be very important for label inclusion. This means that they are supportive of biosimilar products being labelled specifically as such, with the clear inclusion of what a biosimilar product is. There should also be clear information about the analytical studies and clinical studies used for the approval of the product. In cases where the biosimilar is not approved for all indications of the reference product, this should be clearly indicated where these indications are based on extrapolation of the indications approved for the reference product, and whether the biosimilar is interchangeable.

Key points of the 2015 pharmacists naming and labelling survey

  • All items queried in the labelling survey were considered very important for label inclusion
    • The fact that a drug was a biosimilar was considered the most important; whether or not it was interchangeable was slightly less important.
  • 68% of pharmacist respondents thought FDA should require a distinct non-proprietary scientific name for every biological product – whether originator or biosimilar – that FDA had approved. 23% of pharmacists did not, and 8% had no opinion.
  • 77% of pharmacist respondents would prefer a suffix on the non-proprietary name, which is indicative of the product’s manufacturer; only 8% of pharmacists had no opinion. 15% of pharmacists thought a random suffix that does not indicate the manufacturer – as recently proposed by FDA – would be best.

Funding sources

The Alliance for Safe Biologic Medicines (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.

Disclosure of financial and competing interests: Mr Michael S Reilly, Esq, Executive Director, is employed by ASBM.

Professor Philip J Schneider is a member of the International Advisory Board of ASBM since 2012 without compensation. From September 2014, Professor Schneider has been the Chair of the International Advisory Board and is paid a small stipend for that role.

This paper is funded by ASBM and represents the policies of the organization.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Professor Philip J Schneider, MS, FASHP
Associate Dean, College of Pharmacy, University of Arizona, Phoenix Biomedical Campus 3384, 1295 N Martin, PO Box 210202, Tucson, AZ 85721, USA

Michael S Reilly, Esq
Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

References
1. Cohen JP, Felix AE, Riggs K, Gupta A. Barriers to market uptake of biosimilars in the US. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):108-15. doi:10.5639/gabij.2014.0303.028
2. Fuhr JP, Chandra A, Romley J, et al. Product naming, pricing, and market uptake of biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(2):64-71. doi:10.5639/gabij.2015.0402.015
3. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi:10.5639/gabij.2014.0302.018
4. Robertson JS. The challenges of nomenclature – INN, biosimilars and biological qualifiers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):110-2. doi:10.5639/gabij.2015.0403.025
5. Declerck PJ. Common or distinct INN for biosimilars? Only characteristics of the active substance prior to formulation should be considered. Generics and Biosimilars Initiative Journal (GaBI Journal).2014;3(1):8. doi:10.5639/gabij.2014.0301.003
6. Alexander EA. The biosimilar name debate: what’s at stake for public health. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(1):10-2. doi:10.5639/gabij.2014.0301.005
7. Maggio ET. Critical immunogenicity differences will be obscured by a common INN for biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):166. doi:10.5639/gabij.2013.0204.046
8. Feijó Azevedo V, Mysler E, Aceituno Álvarez A, et al. Recommendations for the regulation of biosimilars and their implementation in Latin America. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):143-8. doi:10.5639/gabij.2014.0303.032
9. Gewanter HL, Reilly MS. Prescribing practices for biosimilars: questionnaire survey findings from physicians in Argentina, Brazil, Colombia and Mexico. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):161-6. doi:10.5639/gabij.2015.0404.036
10. Shaw B. Biosimilars naming and prescribing policy in Australia. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):168-9. doi:10.5639/gabij.2013.0204.048
11. U.S. Food and Drug Administration. Nonproprietary naming of biological products. August 2015 [homepage on the Internet]. [cited 2016 Oct 28]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf
12. GaBI Online – Generics and Biosimilars Initiative. FDA issues draft guidance on biosimilars labelling [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Oct 28]. Available from: http://www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-biosimilars-labelling
13. U.S. Food and Drug Administration. Labeling for biosimilar products. March 2016 [homepage on the Internet]. [cited 2016 Oct 28]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf
14. Tell me the whole story: the role of product labelling in building user confidence in biosimilars in Europe. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(4):188-92. doi:10.5639/gabij.2014.0304.043
15. Safe Biologics. Olson K. Biosimilars naming and labelling. A study of U.S. pharmacists. October 2015 [homepage on the Internet]. [cited 2016 Oct 28]. Available from: https://safebiologics.org/wp-content/uploads/2015/10/2015-US-Pharmacists-Survey.pdf
16. U.S. Food and Drug Administration. Orange Book: Approved drug products with therapeutic equivalence evaluations [homepage on the Internet]. [cited 2016 Oct 28]. Available from: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
17. U.S. Food and Drug Administration. Purple Book: Lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations [homepage on the Internet]. [cited 2016 Oct 28]. Available from: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Therapeutic
BiologicApplications/Biosimilars/ucm411418.htm
18. Tomaszewski D. Biosimilar naming conventions: pharmacist perceptions and impact on confidence in dispensing biologics. J Manag Care Spec Pharm. 2016;22(8):919-26.
19. GaBI Online – Generics and Biosimilars Initiative. FDA withdraws biosimilar suffix proposal aplasia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Oct 28]. Available from: www.gabionline.net/Guidelines/FDA-withdraws-biosimilar-suffix-proposal

Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Source URL: https://gabi-journal.net/naming-and-labelling-of-biologicals-the-perspective-of-hospital-and-retail-pharmacists.html


Prescribing practices for biosimilars: questionnaire survey findings from physicians in Argentina, Brazil, Colombia and Mexico

Author byline as per print journal: Michael S Reilly, Esq; Harry L Gewanter, MD, FAAP, FACR

Introduction: World Health Organization (WHO) recommendations for the regulation of biosimilars form the basis of guidelines used across most of Latin America. However, the pace at which the region moves toward reaching its potential of having safe and effective biosimilars has been slow. The Alliance for Safe Biologic Medicines used a questionnaire to survey a sample of Latin American prescribers in order to determine what they understood about biosimilars, how they use them, and their concerns for the future.
Methods: A 15-minute web-based survey in their native language was sent to a total of 6,650 prescribers in four countries in Latin America: Argentina, Brazil, Colombia and Mexico who were off ered US$75 to complete the survey. Responses obtained from a total of 399 (6%) of these physicians were translated into English for analysis and reporting purposes.
Results: A total of 88% of respondents from all the countries said that they prescribed biological medicines although 35% did not consider themselves familiar with biosimilars. Nearly a third (30%) of respondents across all the countries surveyed were not aware that a biosimilar may be approved for all the indications of the innovator product on the basis of clinical trials in only one of a limited number of those indications. This varied by country: 37% of respondents claimed to be aware in Argentina, whereas only 23% of respondents in Brazil. How medicines are identified, and how biologicals were identified when reporting adverse events (AEs), was found to vary between countries. Respondents were split evenly between those that believed switching between biologicals with the same non-proprietary name was safe and would achieve the same result, and those that did not. A total of 75% of respondents claimed to be aware that the WHO has proposed adding a four-letter suffix called a ‘Biological Qualifier’ to the non-proprietary or scientific name of a biological. A total of 94% of respondents thought such a suffix would help ensure that their patients received the right medicine.
Conclusion: A total of 399 respondents (6% of those who were sent the questionnaire) were recruited from four Latin American countries for the survey. Reported prescribing practices varied across the region, and reveal gaps in understanding and in the use of distinguishable names for biologicals. Nearly all the Latin American physicians who completed the survey supported the WHO’s Biological Qualifier proposal.

Submitted: 3 October 2015; Revised: 23 November 2015; Accepted: 1 December 2015; Published online first: 14 December 2015

Methodology and sample characteristics

A total of 399 prescribers from four countries in Latin America: Argentina (n = 99, 25%); Brazil (n = 101, 25%); Colombia (n = 100, 25%); and Mexico (n = 99, 25%) completed a 15- minute webbased questionnaire written in their native language (Spanish for prescribers in Argentina, Colombia and Mexico; Portuguese for prescribers in Brazil), for which they were paid a stipend of US$75. The questionnaire was sent to 6,650 members of a global market research panel. The source used to identify the prescribers for this study was the M3 Global Research, a physician research panel. The only criteria necessary for inclusion in the study were that prescribers had to be in one of the target therapeutic specialties, in one of the target countries, and have requisite experience prescribing biological medicines. The overall study response rate was 6% (399 respondents of 6,650 asked who qualified for, and completed, the survey). Open-ended responses were translated into English for analysis and reporting purposes.

The primary therapeutic areas for participating prescribers (respondents) across all countries were as follows: Dermatology (22%); Oncology (18%); Neurology (18%); Endocrinology (17%); Rheumatology (13%); Nephrology (7%); Haematology oncology (2%); Transplant (1%); Metabolism (1%); and Other, including endocrinology metabolism and psychiatry, (2%).

Respondents across all countries were based in a range of practices: Hospital (32%); University Teaching Hospital (21%); Private multi-specialty clinic (18%); Traditional, non- government, medical practice (13%); Private primary care clinic (11%); Government-run multi-specialty clinic (2%); Government-run primary care clinic (1%); and Other (3%).

Taking all the countries together, most respondents had been working in medical practice for between 11–20 years (mean = 14.3 years). This varied according to country, see Table 1. Nearly two thirds (59%) of prescribers in all countries conducted more than 50 appointments per week, 36% conducted between 20–50 appointments and 5% conducted fewer than 20 appointments per week.

Respondents experience with biologicals and biosimilars

A total of 88% of respondents from all the countries involved in the study said that they prescribed biological medicines, see Table 2. Despite this, more than a third (35%) overall said they did not consider themselves familiar with biosimilars, see Figure 1. Of the countries surveyed, Argentinian prescribers were the least familiar with biosimilars, with 40% of respondents reported having either never heard of biosimilars or being unable to define them. Brazilian prescribers were the most familiar, with 28% never having heard of or being unable to define biosimilars.

Latin American prescribers reported having learned about biosimilar medicines in a number of ways. A total of 260 prescribers were given five categories by which they might have learned, and asked to select all that applied. Overall: 71% claimed to have gained familiarity by attending seminars and conferences; 55% through self-study; 32% through education that had been sponsored by biosimilar companies; 18% through clinical trial participation; and the remaining 4% by other means.

How respondents reported having learned about biosimilar medicines varied by country. For instance, nearly a third of prescribers in Argentina (29%) claimed to have learned about biosimilars through clinical trial participation, whereas just over a tenth of prescribers in Brazil (12%) reported learning though clinical trial participation. A relatively high number of prescribers in Brazil (60%) reported learning by self-study, compared with only 39% in Argentina. Over half the prescribers in Argentina (53%) claimed they became familiar with biosimilars with the help of (potentially biased) information from the companies that make biosimilars.

All 399 respondents were asked about their levels of familiarity with biosimilars. 35% (139) reported either never having heard of biosimilars or having heard of them ‘but could not define them.’

This subset (subgroup) of 139 respondents answered questions about how they would prefer to learn about biosimilars. Of these, only 37% of prescribers across the region said that they wanted to learn through pharmaceutical companies. In Argentina, this percentage was slightly higher (43%), although this is lower than the percentage of prescribers in Argentina who reported actually having learned about biosimilars from pharmaceutical companies (53%).

The majority of respondents in all countries said they would prefer to learn about biosimilars during national medical conferences and symposia (80% in Argentina; 89% in Brazil; 69% in Colombia; 71% in Mexico). A similar proportion of respondents said they would prefer to learn about biosimilars during inter national medical conferences and symposia (71% overall).

The 399 respondents were asked how familiar they were with ‘non-comparable biologicals’ (‘bio-copies’). The term noncomparable biological refers to a copy of an approved biological drug but differs from the definition of a biosimilar in that it lacks a complete biocomparability study and/or clinical trials. Non-comparable biologicals are copies that do not present simi lar safety and efficacy to the innovative product [1]. Across the whole region, only 6% said they had a complete understanding, with 35% saying they had a basic understanding. Nearly half the respondents (47%) had heard of non-comparable biologicals but could not explain them, and 12% had never heard of them.

Only half (49%) of the 399 prescribers were aware of the difference between biologicals, biosimilars and non-comparable biologicals. This figure was only 41% in Argentina.

International Nonproprietary Names (INN) for biological and biotechnological substances

Over 50 years ago the World Health Organization (WHO) established an International Nonproprietary Name (INN) Expert Group/WHO Expert Committee on Specifications for Pharmaceutical Preparations in order to assign non-proprietary names to medicinal substances. This system has been in place ever since, and it currently covers naming of biological medicines.

Biological medicinal products are an increasingly important sector of therapeutic and prophylactic medicines. Biological active substances now comprise more than 40% [2] of applications to the INN Programme and the percentage is increasing. Because of their complexity, bioequivalence cannot be easily established for a product containing a biological substance.

WHO has therefore proposed a scheme, applicable prospectively and retrospectively to all biological substances assigned INNs, that could be adopted on a voluntary basis by any regulatory authority and would be recognized globally. This voluntary scheme is intended to provide a unique identification code (Biological Qualifier, BQ), distinct from the INN, for all biological substances that are assigned INNs.

The BQ is proposed to complement the INN for a biological substance and uniquely identify directly or indirectly the manufacturer of the active substance in a biological product.

Knowledge of biosimilar approval

Nearly a third (30%) of responding prescribers across all the countries surveyed reported that they were not aware that a biosimilar may be approved for all the indications of the innovator product on the basis of clinical trials in only one of a limited number of those indications. This percentage varied by country, with 33% of prescribers in Colombia and just over a third of respondents in Argentina (37%) claiming to be unaware. A total of 28% of respondents in Mexico and 23% in Brazil reported being unaware of this aspect of biosimilar approval.

Just over half of the respondents overall (54%) said that they assumed that all biosimilars go through the same regulatory process for approval as the original biological products.

74% reported assuming that two products sharing the same non-proprietary name, for example, infl iximab and trastuzumab, would be approved for all the same indications. Just over a quarter (26%) of respondents in all countries surveyed said that they did not make this assumption.

There was confusion among the respondents over whether an identical nonproprietary name suggests or implies an identical structure. Over half (54%) of the respondents in these countries said they believe that products that share the same non-proprietary name are structurally identical.

Most prescribers (75%) reported being aware that WHO has proposed adding a four-letter suffix, the BQ, to the nonproprietary or scientific name of a biological, in order to clearly distinguish similar biologicals from one another [3]. This figure was greatest in Argentina (82%) and lowest, although still the majority, in Colombia (67%).

Nearly all responding prescribers in the countries surveyed (94%) thought that the distinguishable naming proposal would be useful to help them ensure that their patients receive the medicine that had been prescribed for them. Only 3% of respondents from Brazil, and 3% from Mexico, thought that a BQ would not be useful, while a surprising 11% of prescribers in Colombia thought it would not be useful.

Recording biologicals

How medicines are identified by the respondents was found to vary between countries. Overall, nearly two thirds (57%) reported identifying drugs in patient records exclusively by their non- proprietary/generic name. According to the study results, respondents in Brazil were the least likely to do this, see Figure 2.

Reporting adverse events

How biologicals were identified when reporting adverse events (AEs) varied widely. Across all countries, 28% of the respondents claimed they would identify a product by its non-proprietary/generic name when reporting an AE. A total of 41% claimed they would identify a product by its product or brand name, and 32% said they identified products by non-proprietary or product name equally when reporting AEs.

Considerably less than half (38%) of respondents across the countries surveyed report every AE. As many as 9% of the respondents reported that they never reported AEs while 25% claimed they rarely reported AEs, and 28% said they reported only some AEs. This is despite the fact that, in the words of the survey question: ‘It is acknowledged that physicians play an important role in the identification and reporting of unexpected or serious adverse events to their national regulatory agencies and manufacturers’ [4].

Several reasons were offered by these physicians in order to explain their failure to report AEs. Across all countries included in the study, nearly half (48%) responded that they were not sure about the reporting process, e.g. who to send the report to, how to submit the report. An additional 15% said they did not have enough time to report AEs, 10% said they did not receive any feedback as to whether other events had been reported for the product, and 7% said they were not sure about the information required to submit an AE report. This last reason was given by between 2% and 7% of respondents, but by a surprising 17% of responding prescribers from Brazil. Finally, 4% said they did not know the outcomes of events that are reported, 3% said that they did not believe the reports would be useful, and 3% were concerned about professional liability if an AE was reported.

Only about half of responding prescribers (51%) said that they consistently used the batch number when reporting AEs, with 16% saying that they sometimes used it. It is widely recommended that all appropriate measures should be taken to identify clearly any biological medicinal product which is the subject of a suspected adverse reaction report, noting both its brand name and batch number [4]. A worrying 18% of respondents said they never used the batch number, with a further 16% saying they only rarely used it.

As before, the reasons given for not including batch numbers in AE reports varied between countries. Forgetting to include the number was cited by an alarming 42% of responding prescribers from Brazil and 35% from Argentina (but only 6% in Colombia and 8% in Mexico). Surprisingly, 16% of responding prescribers from Brazil and 17% from Mexico said they were not sure what the batch number was for. Perhaps one of the reasons that so few prescribers in Colombia reported neglecting to include the batch number was that three quarters (75%) of these respondents said they did not have it available at the time of reporting. In addition to these explanations, a small number (between 0% and 6%) said they were not sure where to find the batch number. A sizeable 42% of respondents from Mexico, and 23% of respondents from Argentina, gave other reasons not listed above.

Switching between biologicals and biosimilars

Half (50%) of responding prescribers across the countries surveyed said they believed that if two biological medicines had the same non-proprietary scientific name, a patient could receive either product and expect the same result. This percentage varied between countries. In Colombia, only just over a third (34%) of responding prescribers said they believed this.

Slightly fewer (44% of respondents) said they believed that two biologicals sharing the same non- proprietary name implied that patients could safely be switched between them during a course of treatment, and the same results expected. Again, this percentage differed between countries, with less than a third (27%) from Colombia thinking that patients could be safely switched between the two medicines during a course of treatment.

Most responding prescribers (64%) said that they would not be comfortable switching between biologicals for cost reasons rather than medical reasons. This was true for respondents from all countries, but most marked in Colombia where 88% of respondents said they would not switch during treatment.

Pharmacy substitution

The authority of prescriber versus pharmacist when selecting biologicals showed some variation between the countries surveyed. In all countries, over 80% of responding prescribers thought that sole authority was either critical or very important. Overall, the prescriber’s sole authority over deciding, with their patients, the most suitable biological medicine, was considered critically important by over half (55%) of responding prescribers. However, in Brazil only 35% thought sole authority was critical, with 53% reported thinking it was very important.

The questionnaire asked: ‘In a situation where substitution by a pharmacist were an option in your country, how important would it be to have the authority to prevent pharmacist substitution and ensure the patient receives the prescription you intended to prescribe?’

This ‘dispense as written’ (DAW) authority was considered critical or very important by 85% of responding prescribers, with 43% considering it critical, and 42% very important. This pattern was seen across most countries, although only 32% of responding prescribers from Brazil said it was critical and 53% said it was very important, while 39% of responding prescribers from Mexico said it was critical, 36% said it was very important, and a relatively high percentage (18%) thought it was only ‘somewhat important’. Very few prescribers (≤ 6%) in all countries combined found DAW only slightly important or not important at all.

In line with this, 87% of responding prescribers across all countries said they considered it was either critical or very important that they received notification if their patient had received a biological other than the one they had prescribed. Although most responding prescribers in all countries considered this either critical or very important, relatively high proportions of physicians in Colombia and Mexico (14% and 16%, respectively) thought it only ‘somewhat important’ to receive notification of a switch.

Limitations
It is important to remember that these data represent only a very small proportion of prescribers in each of these countries. Of the prescribers surveyed, i.e. 399 prescribers (6% response rate of the total sample size) from these four Latin American countries. This limits the ability to extrapolate results to the general population of physicians who prescribe biological products in these countries. Nevertheless, the results raise some important issues concerning the knowledge about and use of biological medicines.

Conclusion

The prescribing practices reported by the physicians who responded to this questionnaire survey varied across the region. It was clear that, among those who completed the questionnaire, there were important gaps in the understanding and use of distinguishable names for biologicals.

As many as 57% of respondents said they refer to a medicine exclusively by its non-proprietary name in their patients’ records, which could result in a patient receiving a different version of the medicine than the one prescribed. Additionally, few responding physicians said they report AEs associated with biological medicines and of these only 28% indicated that they use the non-proprietary name when reporting AEs, which could, in the absence of an identifying suffix, result in attribution to the wrong medicine, see Figure 2.

Those Latin American prescribers who completed this questionnaire overwhelmingly supported WHO’s BQ proposal, which would allow biosimilars to be clearly distinguishable from the reference products upon which they are based for purposes of clear prescribing, dispensing and long-term tracking of safety and efficacy [3].

Key points of the 2015 Latin American prescribers survey

  • More than half (54%) of the responding prescribers felt that an identical non-proprietary name implies identical structure – which is not the case for biosimilar medicines [5]. Likewise, half (50%) of responding prescribers said they believed that if two medicines had the same non-proprietary scientific name, a patient could receive either medicine and expect the same result.
  • A total of 57% of responding prescribers said that they identified drugs in patient records by their non- proprietary/generic name. Only half of responding prescribers (51%) said that they always use the batch number when reporting adverse events (AEs). Over a quarter (28%) said they rarely or never use the batch number when reporting AEs.
  • Three quarters of responding prescribers (75%) were aware that World Health Organization (WHO) is proposing to add a ‘biological qualifier’ to the non-proprietary scientific name of biologicals in order to distinguish similar biologicals from one another [3].
  • Nearly all (94%) of responding prescribers thought WHO’s proposal would help ensure that their patients received the right medicine.
  • 85% of responding prescribing physicians said that they consider it either critical or very important that they have the authority to prevent pharmacist substitution and ensure that the patient receives the prescription that was originally intended, and 87% said they considered it critical or very important that they be notified in the event a substitution was made.

Funding sources

The Alliance for Safe Biologic Medicines (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.

Disclosure of financial and competing interests: Harry L Gewanter, MD, FAAP, FACR, Chairman of the Alliance for Safe Biologic Medicines (ASBM), and Mr Michael S Reilly, Esq, Executive Director; are employed by ASBM.

This paper is funded by ASBM and represents the policies of the organization.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines
Harry L Gewanter, MD, FAAP, FACR, Chairman, Alliance for Safe Biologic Medicines

References
1. Azevedo VF, Galli N, Kleinfelder A, D’Ippolito J, Urbano PC. Etanercept biosimilars. Rheumatol Int. 2015;35(2):197-209.
2. Who Health Organization. Biological Qualifier. An INN proposal. June 2015 [homepage on the Internet]. 2015 Jun 4 [cited 2015 Nov 23]. Available from: http://www.who.int/medicines/services/inn/bq_innproposal201506.pdf.pdf?ua=1
3. GaBI Online – Generics and Biosimilars Initiative. WHO investigates use of a biological qualifier for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Nov 23]. Available from: http://www.gabionline.net/Biosimilars/General/WHO-investigates-use-of-a-biological-qualifier-for-biosimilars
4. Giezen TJ, Schneider CK. Safety assessment of biosimilars in Europe: a regulatory perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(4):180-3. doi:10.5639/gabij.2014.0304.041
5. Alexander EA. The biosimilar name debate: what’s at stake for public health. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(1):10-2. doi:10.5639/gabij.2014.0301.005

Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2015 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Source URL: https://gabi-journal.net/prescribing-practices-for-biosimilars-questionnaire-survey-findings-from-physicians-in-argentina-brazil-colombia-and-mexico.html


Biosimilars naming, label transparency and authority of choice – survey findings among European physicians

Introduction: A survey of the views of European physicians on familiarity of biosimilar medicines has demonstrated the need for distinguishable non-proprietary names to be given to all biologicals.
Methods: The Alliance for Safe Biologic Medicines recruited 470 prescribers with clinical experience of biologicals in France, Germany, Italy, Spain and the UK to answer questions relating to their experience with these medicines in a 15-minute web-based survey which was carried out in the last quarter of 2013.
Results: Of the physicians surveyed, 53% mistakenly felt that an identical non-proprietary name implies identical structure; 61% said that identical non-proprietary names imply that the medicines are approved for the same indications, which they may not be, and 24% said they recorded only the non-proprietary name of the biological product in the patient record.
Conclusion: The responses of the European physicians demonstrate the need for distinguishable non-proprietary names to be given for all biologicals. Biosimilars, in contrast to generic drugs, have different structures, may have a different therapeutic profile, and may not be approved for all the indications for which the reference product has been approved.

Submitted: 11 March 2014; Revised: 15 May 2014; Accepted: 19 May 2014; Published online first: 2 June 2014

Introduction

With the growing number of biosimilar medicines on the European market [1], the Alliance for Safe Biologic Medicines (ASBM) has completed a survey of European physicians to:

Responses from 470 prescribers located in France, Germany, Italy, Spain and the UK were collected and analysed. Respondents were all specialists who prescribe biologicals, including nephrologists, rheumatologists, dermatologists, neurologists, endocrinologists and oncologists. The perspective of European physicians reflects hands-on clinical experience with biologicals in a therapeutic setting and highlights the point that non-proprietary names matter to patient safety.

The findings point to some confusion among physicians in Europe in the area of biological and biosimilar medicines, which indicates the need of further education [2] with proper information such as the Consensus Information Paper 2013 published by the European Commission [3]. Physicians were not in agreement on where the authority lies over selecting the most suitable biological medicine for a patient – with the physician and patient or with the pharmacist.

The absence of a Europe-wide agreement on how biological and biosimilar medicines are recorded was also identified. This will need to be rectified in order to achieve effective pharmacovigilance, limiting possible adverse events in the future [4].

Methods

By the last quarter of 2013, a total of 4,324 survey invitations were sent to prescribers in France, Germany, Italy, Spain and the UK. Participants were selected from a large global market research panel of prescribers; 1,002 responded, giving a total response rate of 23.1%. 62 of the 1,002 screened out. 470 prescribers (20% from each of the five European countries) completed the survey. Oncologists were paid the US equivalent of $32.00 to complete the survey. All other participants were paid the US equivalent of US$25.00. All surveys were presented in the local language (English, French, German, Italian and Spanish). Prescribers answered questions in a 15-minute web-based survey.

Prescribers included nephrologists (18%), rheumatologists (17%), dermatologists (17%), neurologists (16%), endocrinologists (16%) and oncologists (16%). They were based in hospitals (58%); academic medical centres (24%); private, family practices (8%); community settings (8%); multi-specialty clinics (2%); or other settings (1%).

Most physicians (46%) had 11–20 years’ experience, while 18% had 6–10 years, 28% had 21–30 years, 7% had more than 30 years and only 1% had 5 years’ or less experience. Nearly three quarters (70%) conducted more than 50 patient appointments a week, while a third (29%) conducted 20–50 appointments, and 1% conducted fewer than 20. Of these, the vast majority (92%) prescribed biological medicines. Three quarters of physicians (76%) said they knew that their patients were treated with biological medicines by other healthcare providers; while 12% knew that their patients were not treated with biological medicines elsewhere and the remaining 12% were not sure.

Only 19% of the surveyed physicians said they always used the European Public Assessment Report (EPAR) to learn about the details of a medicine for prescribing and monitoring, while 43% used it occasionally and a similar proportion (38%) never used it at all. Over 80% of physicians used the summary of product characteristics (SmPC) and the label to learn about the medicine either all of the time (43%) or some of the time (43%). Transparent information in the SmPC and the label are relevant for appropriate physician information. Other sources of information used are shown in Table 1.

Results

Prescriber’s knowledge of biosimilars
The prescribers’ overall knowledge of biologicals and biosimilars was ascertained on the basis of questions related to their understanding of these medicines coupled with information on where they had gained this understanding (at meetings, in journals or from biological or biosimilar companies, etc).

Most physicians (46%) responded that they had only a basic understanding of biological medicines, while 43% said they had a complete understanding. Only 1% of all physicians surveyed had never heard of biological medicines, while 11% were not able to define them. These results varied by country, a relatively high proportion of physicians surveyed from Spain (62%) were ‘very familiar’ with biological medicines, while this figure was only 30% in France. Results from the remaining countries stood at around 40%: Germany (39%), Italy (42%) and the UK (40%).

Over half (54%) of those surveyed reported that they are ‘familiar’, but with only a basic understanding, with biosimilar medicines, while 20% were unable to define biosimilars and 4% had never heard of them. Only 22% of physicians surveyed were ‘very familiar’ with a complete understanding of biosimilar medicines. As before, this varied by country; a higher proportion of physicians in both Germany (59%) and the UK (59%) were ‘familiar with a basic understanding’ with biosimilar medicines compared with physicians in France (44%).

The findings highlight an urgent need for further education of physicians and others related to the prescribing of these medicines. Further dialogue and collaboration between physicians, authorities and the healthcare biotech industry continues to be a priority. With this in mind, it is important to ascertain where physicians currently find out information about biosimilars.

The question of how physicians had become familiar with biosimilars was answered by only 357 of the 470 recruits (76%). Most of these gained familiarity through attending conferences and seminars (47%), while 35% learnt through self-study, 11% through studies sponsored by biosimilar companies and the remaining 6% split equally between studies sponsored by innovator companies, clinical trial participation and other routes. Prescribers in Spain were relatively more likely to have learnt about biosimilars through biosimilar company-sponsored study (21%) and relatively less likely to have learnt through self-study (20%). Self-study was more likely among physicians in France (37%), Germany (44%), Italy (31%) and the UK (45%), where the importance of scientific publishing is apparent. On this note, although only 20% of physicians in Spain learnt about biosimilars through self-study, 38% said they would prefer to learn through scientific publications. The preference for learning through scientific publications was shared by physicians in Germany (37%), Italy (44%) and Spain (39%).

Biosimilar approval awareness
Asked whether they were aware that a biosimilar might be approved for several or all indications of the innovator product on the basis of clinical trials in only one of these indications, over a third (37%) of all 470 physicians in the study believed that all indications have been clinically tested. The finding highlights a worrying lack of understanding in this area, making the case for further education and improved, more informative, and transparent labelling. There was a higher level of awareness of indication extrapolation among physicians in Italy, where 78% responded that biosimilars could indeed be approved for several or all indications of the innovator product on the basis of clinical trials in only one indication. 63% of prescribers in France responded that biosimilars could be approved for several or all indications, alongside 52% of physicians in Germany, 65% in Spain, and 55% in the UK.

Recording biologicals
Accurate recording is the linchpin of effective pharmacovigilance. In this section of the survey, physicians were asked how biological medicines were prescribed and recorded, and how adverse events were reported.

The vast majority (95%) of all physicians surveyed would identify any prescribed medicine, including biologicals, in the patient record, although this was slightly less likely in Germany (87%) and Spain (92%). If a patient was receiving a biological medicine prescribed by another healthcare provider, this was not identified in the patient record in 11% of cases. Again, this varied by country: a higher proportion of physicians from the UK (12%) and Germany (33%) do not record this information.

The question of how biological medicines were identified for prescription or in a patient record illuminated a worrying lack of Europe-wide convention. Based on answers from 417 of the physicians questioned, there was a three-way split in the way that biological medicines for prescription or recording in a patient record were identified between: (i) brand name and non-proprietary name (32%); (ii) brand name (30%); and (iii) non-proprietary/generic name (24%). A sizeable proportion (14%) answered that identification varies by medicine. The brand name was used most widely in France (53%) and Germany (40%), while brand name and non-proprietary name were more likely to be used in Italy (42%). The non-proprietary name/generic name was most likely to be used in the UK (37%).

Reporting adverse events
Alongside questions on how biological medicines were identified, physicians were asked how medicines were identified when reporting an adverse event (AE). Medicines were identified by both brand name and non-proprietary name by 54% of the 470 physicians questioned, by brand name by 29% of physicians, and by non-proprietary/generic name by 17% of physicians. Products were most likely to be recorded by brand name by physicians in France (58%) and Germany (36%).

Batch number inclusion when reporting an AE varied widely: from always (40%); to sometimes (33%); to never (27%). Batch number was always included by 57% of physicians in Italy and 45% of physician in Germany, but never included by 38% of physicians in France and 43% of physicians in Spain.

Physicians who did not routinely include batch numbers when reporting AEs (answering ‘Sometimes’ or ‘Never‘ to this question) were questioned further, highlighting areas that will need to be addressed before this data, essential to successful pharmacovigilance, can be included routinely, see Table 2. Of 281 physicians (60% of all those questioned) who did not routinely include batch number, a relatively high proportion of physicians from Germany (62%) said they did not have the number available when they reported the AE. Nearly a third of physicians in France (29%) and a quarter of physicians in the UK (24%) did not know where to find the information.

Non-proprietary name implications
The fact that biosimilars, in contrast to generic drugs, can have different structures and therapeutic profiles, and can be approved for less than all indications of the reference product, may be lost if two distinct medicines have the same non-proprietary scientific name. Clearly, it is potentially unsafe to assume these products are identical and approved for the same indications.

Answers to the question ‘If two medicines have the same non-proprietary scientific name, does this suggest to you or imply that the medicines are structurally identical’ highlight considerable confusion among physicians. Over half (53%) of physicians questioned held the incorrect assumption that these products are structurally identical. A surprising 15% had no opinion either way, which could suggest that the respondents did not understand the question. Among those more likely to believe that these products are structurally identical were physicians from France (59%), Germany (68%) and the UK (59%).

In turn, this leads to confusion over whether different medicines with the same non-proprietary name can be safely switched (between treatments or during a treatment course) or substituted. Asked whether two medicines with the same non-proprietary scientific name could be given safely to a patient with the same result, 40% said no, 47% said yes, and the remaining 13% had no opinion. There is no clear pattern here, prescribers in France (57%) were slightly more likely to believe their products could be safely switched than those in Italy (40%) and Spain (38%), but there were sizeable proportions of ‘yes’ and ‘no’ answers in every country surveyed, see Table 3.

The complexity is further illustrated by answers to the question that ‘if two medicines have the same non-proprietary scientific name, does this suggest to you or imply that a patient could be safely switched between the products during a course of treatment and expect the same result as treatment with only one of the products’. Thirty-nine per cent of physicians believed patients could be safely and effectively switched during a course of treatment, 45% believed they could not, and 16% had no opinion. Nearly half (49%) of prescribers in France believed switching was safe, while only 34% of physicians in Spain believed this.

Similarly, the physicians questioned were unclear whether two medicines with the same non-proprietary scientific name are approved for the same indications: 61% said they were; 31% said they were not; and 9% had no opinion. In other words – and these findings did not vary between countries – two thirds of prescribers do not have an understanding of the complexity and sensitivities surrounding biosimilars.

Clear naming and labelling is paramount. If a patient has an adverse reaction, which can occur months after receiving a biological medicine, the medicine needs to have been properly identified from the start. A clear naming system is essential in order to make identification possible, thereby enhancing access to these life-changing therapies, while also protecting patient safety.

Pharmacy substitution
The question of authority over selecting the most suitable biological medicine for a patient was posed in this survey, and physicians’ responses revealed a range of opinions across Europe. Of 470 physicians questioned, 24% thought it was critically important to have the sole authority to decide, together with their patients, the most suitable biological medicine for their disease. 48% thought it was ‘very important’, 23% thought it was ‘somewhat important’, 4% thought it was ‘slightly important’ and 1% thought it was ‘not important’.

These responses varied by country, with the highest proportion of physicians in Italy (34%) and Spain (33%) considering sole authority ‘critical’. Sole authority was considered only ‘very important’ or ‘somewhat important’ by physicians in Germany (38% and 37% respectively).

The importance of ‘dispense as written’ (DAW) or ‘do not substitute’ showed a similar pattern. Overall, 27% considered it critical, 47% thought it was ‘very important’, 20% thought it was ‘somewhat important’, 5% thought it was ‘slightly important’ and 1% thought it was ‘not important’. In Spain, 41% of physicians considered DAW critical, while only 13% of physicians in Germany considered it critical.

Most physicians among the 470 questioned felt it was important that pharmacists provide notification that their patient had received a biological other than the one prescribed if the patient was receiving chronic (repeated) treatment: 30% considered notification critical, 47% considered it very important, 16% somewhat important, 6% slightly important and 1% considered it not important.

Similarly, 62% of all physicians considered it not acceptable if the pharmacist decided which biological (innovator or biosimilar) to dispense, 35% considered it acceptable and 3% considered it totally acceptable. Unilateral decision making at the pharmacy was not considered acceptable by most prescribers, particularly in Italy where 77% of physicians considered it unacceptable.

Asked to define ‘bio-naïve’, 76% of physicians in the survey believed that this meant ‘a patient who has never received any biological treatment of this class.’ This was equally accepted across the countries studied, although slightly less likely in Germany, where only 66% of physicians agreed with this definition, see Table 4.

Conclusion

Biological medicines have had a profound effect in many medical fields, from oncology to neurology and across a host of other debilitating diseases, but the complexity of the molecule and its manufacturing process result in significantly higher cost than that of the small-molecule medicine. As the patents on biologicals begin to expire, it is hoped that the arrival of biosimilars – drugs that are similar, but not identical, to these innovator biologicals – will reduce the financial burden on healthcare systems [5]. But to benefit from these medicines it is crucial that prescribing physicians understand what these medicines are, and what these medicines are not.

The responses of European physicians recorded in this study reflect serious gaps in what is known about biological drugs in general and biosimilars in particular. There are several misconceptions regarding biologicals, and considerable education is needed in the area of differences between generic products and biosimilar products.

Unlike generic drugs, biosimilars are not identical to the innovator biological on which they are based; they have different structures, may have a different therapeutic profile, and may not be approved for all the indications for which the reference product was approved.

There is a clear need for distinguishable non-proprietary names to be given to all biological medicines to ensure intended prescribing as well as to support product identification when reporting and tracing adverse events [68].

Increasing numbers of biological medicines, both originator and biosimilar, are being approved around the world. According to the findings in this study, most physicians use the SmPC and the label to learn about a medicine, illustrating how important it is that clear information, and informative labelling, is provided for every biological and biosimilar.

With the co-existence of different biosimilars from different manufacturers, an effective pharmacovigilance system is urgently needed in order to allow accurate adverse events reporting. How these products are named will clearly play a central role in facilitating pharmacovigilance worldwide, supporting the safe use of these medicines [4, 8].

Alongside the prescribing physician, the pharmacist also plays a key role in effective pharmacovigilance. Switching between brand name pharmaceutical drugs and their generics presents little or no threat to patient safety since they should be identical, but switching between a biological drug and its biosimilar, or between different biosimilars, is not the same. Across Europe, this study revealed a range of opinions among prescribing physicians as to where the authority should lie when deciding on the most appropriate biological or biosimilar, with most insisting that physicians and their patients – not pharmacists – should have sole authority when making these decisions. It is important for most physicians to retain the authority to use ‘do not substitute’ to ensure the patient receives the correct medicine.

In addition to a clear need for further education for physicians who prescribe these medicines, distinguishable non-proprietary names are important to practising physicians, and we hope this system will be used by the World Health Organization in crafting a global standard that will improve patient safety worldwide [1].

The findings of this study echo, and reinforce, concerns already raised by the medical community. Effective Europe-wide, and by extrapolation worldwide, pharmacovigilance is urgently needed in order to benefit fully from the considerable advances offered by biological drugs and biosimilars, while limiting future adverse events.

Key points of the 2014 European prescribers’ survey

  • 53% of physicians surveyed felt that an identical non-proprietary name implies identical structure – which is not the case for biosimilar medicines. 15% of physicians had no idea whether this was the case or not, highlighting further confusion or lack of understanding
  • 61% of physicians said that identical non-proprietary names imply that the medicines are approved for the same indications, 9% had no idea if this was the case or not.
  • 17% of physicians record only the non-proprietary name/generic name of the biological product when recording an adverse event. 27% of physicians never include the batch number when reporting an adverse event and 33% do so only sometimes.
  • 86% of physicians used the SmPC/label to learn about the medicine either all of the time (43%) or some of the time (43%). Only 19% of physicians said they always use the European Public Assessment Report (EPAR) to learn about the details of a medicine for prescribing and monitoring, with 43% using it occasionally and 38% never using it at all.
  • 70% of physicians consider it either critical or very important that they together with their patients have the sole authority to decide on the most suitable biological medicine.

Acknowledgement

The authors wish to thank the medical writing and editorial support by Dr Bea Perks, GaBI Journal Editor.

Funding sources

The Alliance for Safe Biologic Medicines (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.

Disclosure of financial and competing interests: Dr Richard O Dolinar, Chairman of the Alliance for Safe Biologic Medicines (ASBM), and Mr Michael S Reilly, Executive Director; are employed by ASBM.

This paper is funded by ASBM and represents the policies of the organization.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Richard O Dolinar, MD, Chairman
Michael S Reilly, Executive Director
Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

References
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Author for correspondence: Michael S Reilly, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

Disclosure of Conflict of Interest Statement is available upon request.

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