### **Biosimilars in Europe**

Edited by Arnold G. Vulto, Steven Simoens and Isabelle Huys Printed Edition of the Special Issue Published in *Pharmaceuticals*

www.mdpi.com/journal/pharmaceuticals

**Biosimilars in Europe**

### **Biosimilars in Europe**

Editors

**Arnold G. Vulto Steven Simoens Isabelle Huys**

MDPI Basel Beijing Wuhan Barcelona Belgrade Manchester Tokyo Cluj Tianjin

*Editors* Arnold G. Vulto Hospital Pharmacy Erasmus University Medical Centre Rotterdam Netherlands

Steven Simoens Department of Pharmaceutical and Pharmacological Sciences KU Leuven Leuven Belgium

Isabelle Huys Department of Pharmaceutical and Pharmacological Sciences KU Leuven Leuven Belgium

*Editorial Office* MDPI St. Alban-Anlage 66 4052 Basel, Switzerland

This is a reprint of articles from the Special Issue published online in the open access journal *Pharmaceuticals* (ISSN 1424-8247) (available at: www.mdpi.com/journal/pharmaceuticals/special issues/biosimilars Europe).

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© 2023 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications.

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### **Contents**


Reprinted from: *Pharmaceuticals* **2021**, *14*, 306, doi:10.3390/ph14040306 . . . . . . . . . . . . . . . **127**

### **Ali M. Alsamil, Thijs J. Giezen, Toine C. Egberts, Hubert G. Leufkens and Helga Gardarsdottir**

Type and Extent of Information on (Potentially Critical) Quality Attributes Described in European Public Assessment Reports for Adalimumab Biosimilars Reprinted from: *Pharmaceuticals* **2021**, *14*, 189, doi:10.3390/ph14030189 . . . . . . . . . . . . . . . **143**

### **Yannick Vandenplas, Steven Simoens, Philippe Van Wilder, Arnold G. Vulto and Isabelle Huys**

Informing Patients about Biosimilar Medicines: The Role of European Patient Associations Reprinted from: *Pharmaceuticals* **2021**, *14*, 117, doi:10.3390/ph14020117 . . . . . . . . . . . . . . . **157**

### **About the Editors**

### **Arnold G. Vulto**

Arnold Vulto is Emeritus Professor at the Erasmus Medical Center in Rotterdam and Visiting Professor at KU Leuven. He is a hospital pharmacist and pharmacologist. In 2008, he was one of the co-founders of the Generics & Biosimilar Initiative and the GaBI Journal. In 2013, he was one of the founders of the Dutch Initiative Group on Biosimilars.

### **Steven Simoens**

Steven Simoens is a senior full professor of health economics at KU Leuven. His research interests focus on health economic aspects of medicinal products. Steven has carried out numerous cost(-of-illness) analyses, economic evaluations and budget impact analyses of medicinal products. He has also worked extensively in the area of policy relating to market access of medicinal products, with a particular interest in oncology medicinal products, orphan medicinal products, advanced therapy medicinal products, antibiotics, vaccines, generics and biosimilars.

### **Isabelle Huys**

Isabelle Huys is full professor at KU Leuven and specialises in intellectual property rights and regulatory sciences. Her research interests focus on legal and regulatory strategies for medicine development, with the aim to promote access to medicines, (human) biological samples and related therapies/diagnostics, as certain therapies remain underdeveloped and, hence, unavailable for patients due to legal or regulatory barriers.

### *Editorial* **Emerging Insights into European Markets of Biologics, Including Biosimilars**

**Steven Simoens \* and Isabelle Huys**

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; isabelle.huys@kuleuven.be

**\*** Correspondence: steven.simoens@kuleuven.be; Tel.: +32-16-323465

Biological medicinal products have revolutionised the treatment of many diseases, e.g., autoimmune diseases and cancer, by targeting key disease mediators with high specificity. As patents and other exclusivity rights on many high-selling and expensive biologics are expiring or have expired, biosimilars may enter the market. The market entry of biosimilars (the first of which was approved in the European Union in 2006) has raised questions about legal, regulatory, pricing and reimbursement procedures for these products, as well as regarding policies and incentive structures related to, for example, tendering mechanisms, gainsharing practices, physician quotas, prescribing and switching frameworks, substitutions and the education of stakeholders.

In response to this, KU Leuven (Leuven, Belgium), in collaboration with the Erasmus University Medical Center (Rotterdam, the Netherlands), established the MABEL research programme in 2016, with the aim of exploring the market environment of biologics, including biosimilars, in Europe. On the programme's fifth anniversary, we launched a Special Issue on "Biosimilars in Europe" to share some emerging insights derived from our research programme and from articles published in the Special Issue, as well as to identify unresolved questions and set out a research agenda for the future.

The Need to Reap the Rewards of Biosimilar Competition

The introduction of biosimilars may create competition, possibly resulting in lowered prices, altered market dynamics and the revision of company strategies; it might also attract new players to the biopharmaceutical market. As a result, some health care systems have embraced biosimilars as a tool to control increasing health care expenses or expand patient access to treatments. Competition between off-patent biologics and biosimilars may also induce incremental innovation and the development of next-generation biologics with, for example, a novel formulation or route of administration.

Three articles in this Special Issue provide empirical evidence concerning some of these rewards of biosimilar competition. A Spanish budget impact analysis estimated that biosimilar competition yielded a total saving of EUR 2.3 billion from 2009 to 2019, with approximately one-half of the savings originating from a reduction in list prices and the other half originating from hospital tender discounts [1]. Although total savings over this period were impressive in absolute terms, savings in relative terms amounted to less than 4% of pharmaceutical expenditures in 2019. In an analysis of the Bulgarian market for biologic disease-modifying antirheumatic medicines, Tachkov et al. showed that biosimilar market entry not only reduced prices, but also increased utilization (thus, widening patient access to treatment) and generated competition in a therapeutic class [2]. Finally, a Belgian study examined the introduction of an intravenous biosimilar in the presence of a subcutaneous reference biologic, and indicated that a cost comparison between such products needs to consider multiple factors, such as patient's body weight, discounts and intravenous vial sharing [3].

The Special Issue also confirms that not all European countries are currently reaping the full rewards of biosimilar market entry and competition. On the one hand,

**Citation:** Simoens, S.; Huys, I. Emerging Insights into European Markets of Biologics, Including Biosimilars. *Pharmaceuticals* **2022**, *15*, 615. https://doi.org/10.3390/ ph15050615

Received: 11 May 2022 Accepted: 13 May 2022 Published: 17 May 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Moorkens et al. suggest that the relatively high market shares of infliximab and etanercept biosimilars in Germany were attained through the implementation of biosimilar prescription quotas, variable procurement contracts between sickness funds and manufacturers, and gainsharing arrangements [4]. On the other hand, Lobo and Río-Álvarez explain how biosimilar competition in Spain is impeded by a variety of barriers, including physician and patient lack of trust in biosimilars and diverging stakeholder interest [5].

### The Need to Prescribe Best-Value Biologics

There has been much debate regarding the appropriate use of off-patent reference biologics, biosimilars and next-generation biologics. Instead of promoting the use of one over the other, we believe that the focus needs to shift towards the prescription of best-value biologics. Although the latter term is not uniformly defined, countries such as Ireland and England have implemented programmes stimulating the use of best-value biologics, which may be the off-patent reference biologic, a biosimilar version or a next-generation biologic. By framing the debate in the broader context of best-value biologics, it is possible to align the interests of different stakeholders towards the common objective of maximizing population health with limited resources. However, the introduction of such a programme is not easy, as described in the article by Van Wilder concerning the 2019–2020 "Best-Value Biologics" programme in Belgium [6].

We see an important role for hospital tender procedures to achieve the selection of best-value biologics. Based on a review of tender procedures for off-patent biologics and biosimilars in Europe, Barbier et al. highlighted the importance of creating a level playing field, of timely launching tenders in accordance with public procurement laws, and of guaranteeing supply by creating room for several manufacturers to be active in the market [7]. In addition to the design of tender procedures, competition and incentives were perceived to be crucial in creating a sustainable market for best-value biologics by a panel of European experts [8]. This article makes an important contribution to the field by proposing a consensus definition and identifying some 'dos and don'ts' of a competitive, but sustainable, market for off-patent reference biologics, biosimilars and next-generation biologics. However, much more research needs to be carried out to build a comprehensive theoretical framework to understand how European competitive markets of biologics, including biosimilars, can also be sustainable.

When selecting a best-value biologic or in general terms a best-value medicine, there is a need to consider a whole therapeutic class of products. Let us take the example of rheumatoid arthritis. Although there are differences in indications and target populations, the therapeutic arsenal for rheumatoid arthritis consists of synthetic disease-modifying antirheumatic medicines (e.g., methotrexate and leflunomide), off-patent reference biologics and their biosimilars (adalimumab, infliximab and etanercept), other reference biologics (abatacept, golimumab, sarilumab, tocilizumab and certolizumab pegol) and the recent targeted synthetic Janus kinase inhibitors (tofacitinib and baricitinib). As the market entry of biosimilars and novel biologic or synthetic medicines is likely to influence the relative (cost-)effectiveness of products within a therapeutic class, treatment guidelines need to be regularly updated. However, this is not regularly performed, and, in relation to our example, there is a need for research which assesses the value of Janus kinase inhibitors versus all therapeutic alternatives for rheumatoid arthritis.

### The Need to Optimise and Harmonise Regulatory Procedures

The European Medicines Agency has been a worldwide frontrunner in developing and implementing a regulatory pathway supporting the marketing authorisation of biosimilars, with the United States, Canada and Japan adopting similar pathways. The article by Ingram et al. presents a unique insight into how the regulatory agencies from these four countries responded to virtually the same set of data on eight candidate biosimilars from one company [9]. Even though authorisation decisions were the same, the authors noted some differences in how the regulatory agencies tackled the data review and benefit–risk

assessment. This lack of uniformity may raise the cost of biosimilar development and may also hamper patient access.

At the time of marketing authorisation, the European Medicines Agency publishes an extensive and detailed scientific assessment report (the so-called European Public Assessment Report) concerning all aspects of a medicine. The article by Alsamil et al. evaluated the critical quality attributes in the European Public Assessment Reports of all adalimumab biosimilars, corroborating that these biosimilars have the same functions and clinical profiles, notwithstanding small variations in glycoforms and charge variants [10].

### The Need to Educate Patients

Despite all the efforts and existing programmes available, informing and educating patients regarding biosimilars, there remains scepticism towards their use. Indeed, the article by Vandenplas et al. showed that biosimilar information provided by European patient organisations themselves is not always correct or sufficiently detailed [11]. Hence, this paper sends forth a call for regulatory authorities, industry associations, health care professional associations and patient organisations to jointly produce and disseminate unbiased information concerning biosimilars in a language that is accessible for patients. An additional avenue is to develop a dedicated European Commission-driven website for patients (and health care professionals) on biosimilars.

The Need for Further Research

Taking inspiration from Hippocrates, market and policy research of biologics, including biosimilars, should strive to declare the past and diagnose the present, with the intention of foretelling the future. In respect to the latter, additional research is needed, moving beyond identifying hurdles to biosimilar market entry and competition, and analysing the impact of strategies to overcome these hurdles. Furthermore, questions remain concerning the long-term sustainability of European markets of biologics, including biosimilars: how do we create a policy environment that not only promotes competition, but also safeguards economic viability and prevents shortages?

**Author Contributions:** Conceptualisation, S.S.; writing—review and editing: S.S. and I.H. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors are grateful to Arnold Vulto and to our PhD researchers Liese Barbier, Teresa Barcina-Lacosta, Evelien Moorkens and Yannick Vandenplas for their valuable insights.

**Conflicts of Interest:** S.S. and I.H. are among the founders of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL). S.S. was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD; he participated in advisory board meetings for Pfizer and Amgen; he contributed to studies on biologics and biosimilars for Hospira, Celltrion, Organon and Pfizer; and he had speaking engagements for Amgen, Celltrion and Sandoz. I.H. declares no competing interests.

### **References**


### *Article* **Budget Impact Analysis of Biosimilar Products in Spain in the Period 2009–2019**

**Manuel García-Goñi 1,\* , Isabel Río-Álvarez <sup>2</sup> , David Carcedo <sup>3</sup> and Alba Villacampa <sup>3</sup>**


**Abstract:** Since the first biosimilar medicine, Omnitrope® (active substance somatropin) was approved in 2006, 53 biosimilars have been authorized in Spain. We estimate the budget impact of biosimilars in Spain from the perspective of the National Health System (NHS) over the period between 2009 and 2019. Drug acquisition costs considering commercial discounts at public procurement procedures (hospital tenders) and uptake data for both originator and biosimilar as actual units consumed by the NHS were the two variables considered. Two scenarios were compared: a scenario where no biosimilars are available and the biosimilar scenario where biosimilars are effectively marketed. All molecules exposed to biosimilar competition during this period were included in the analysis. The robustness of the model was tested by conducting multiple sensitivity analyses. From the payer perspective, it is estimated that the savings produced by the adoption of biosimilars would reach EUR 2306 million over 11 years corresponding to the cumulative savings from all biosimilars. Three molecules (infliximab, somatropin and epoetin) account for 60% of the savings. This study provides the first estimation of the financial impact of biosimilars in Spain, considering both the effect of discounts that manufacturers give to hospitals and the growing market share of biosimilars. We estimate that in our last year of data, 2019, the savings derived from the use of biosimilars relative total pharmaceutical spending in Spain is 3.92%. Although more research is needed, our evidence supports the case that biosimilars represent a great opportunity to the sustainability of the NHS through rationalizing pharmaceutical spending and that the full potential of biosimilar-savings has not been achieved yet, as there is a high variability in biosimilar uptake across autonomous regions.

**Keywords:** biologics; biosimilars; budget impact analysis; savings; pharmaceutical spending; cost containment; Spain

### **1. Introduction**

Drug research and development has led to market access for many important therapeutic innovations, and undoubtedly is one of the multiple factors that influence population aging [1]. Powrie-Smith [2] points out how new therapies and vaccines have contributed to the fight against communicable diseases, resulting in a significant reduction in the incidence of viruses such as hepatitis B, as well as in infant mortality. Litchenberg [3,4] shows how those innovations have significantly improved the way health systems treat and care for the sick, increasing life expectancy and quality of life. However, those advances have come with an increase in health spending. In fact, Newhouse et al. [5] and Willeme and Dumont [6] have pointed to the advances in health technology and the therapeutic innovations developed as the most important determinants of such increases in health expenditures, and among those, pharmaceutical spending.

Trends in pharmaceutical markets have raised some concerns about the sustainability of pharmaceutical expenditure [7]. Thus, the focus should be placed on spending efficiency

**Citation:** García-Goñi, M.; Río-Álvarez, I.; Carcedo, D.; Villacampa, A. Budget Impact Analysis of Biosimilar Products in Spain in the Period 2009–2019. *Pharmaceuticals* **2021**, *14*, 348. https://doi.org/10.3390/ ph14040348

Academic Editors: Arnold G. Vulto, Steven Simoens and Isabelle Huys

Received: 31 December 2020 Accepted: 7 April 2021 Published: 9 April 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

rather on cutting spending, to ensure the maximum return on investment in pharmaceutical products. The global pharmaceutical market will exceed USD 1.5 trillion by 2023, as it is expected to grow at a rate of between 3 and 6% per year. However, this growth will be different in different areas of the world, and in fact, in the five main markets of Europe, this growth is expected to be lower, between 1 and 4% [8]. Those expectations are based on list prices that are exclusive of discounts and rebates paid to governments. This is relevant as a divergence of 1.4 percentage points between expenditure measured at list and net prices was found in a forecast of the pharmaceutical expenditure for the EU5 countries from 2017 to 2021 [9]. Thus, considering the net prices seems critical when estimating the economic impact of any health technology, either in-patent or offpatent medicines, in pharmaceutical expenditure. In any case, a significant part of this increase in pharmaceutical spending is related to the appearance and consolidated use in clinical practice of biological medicines [10], especially for the treatment of chronic and life-threatening diseases such as cancer, multiple sclerosis or rheumatoid arthritis [11]. Many biologic products can actually slow the progress of or even prevent disease [10], but normally present a higher price than that of chemical drugs. In 2018, over 30% of all European drug spending was on biological medicines and this percentage is expected to continue to grow [12].

As in the case of generics with chemical medicines, the loss of exclusivity and the expiry of a patent on innovative biological products, hereinafter referred to as the originator, allows the entry into the market of biosimilar products. The major difference between a generic and a biosimilar is that the natural variability and more complex manufacturing of biological medicines do not allow an exact replication, as is the case with generics. Consequently, biosimilars are subjected to a more comprehensive regulatory pathway to ensure that minor differences do not affect safety or efficacy [13].

As stated by the European Medicines Agency, "a biosimilar is a biological medicine highly similar to another already approved biological medicine" and "biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines" [13]. The European Medicines Agency (EMA) is responsible for evaluating the majority of applications to market biosimilars in the European Union. After the first biosimilar (the recombinant human growth hormone or somatropin) was approved in 2006, 62 biosimilar drugs corresponding to 17 active substances received marketing authorization by EMA as of 31 December 2020 [14]. In Spain, 53 biosimilar drugs for 16 active substances have been authorized for marketing to the same date [15]. However, it is worth noting that the design and implementation of pharmaceutical policies on biosimilars fall within the remit of EU Member States.

Biosimilars are lower cost alternatives of originator biologicals and are expected to bring meaningful budgetary savings to health systems. However, the spending on biosimilars is still very low, at around 1.5% of pharmaceutical expenditure in Europe in 2018 [12]. Unfortunately, there are still not many studies that estimate the savings derived from their use. Simoens et al. [16] published a review of budget impact analyses (BIA) of the use of biosimilars, although only focused mainly on two molecules, infliximab and etanercept. Furthermore, several recent studies have tried to estimate the budget impact of the introduction of recent biosimilars for either one or several molecules, at national or local levels in Italy [17–19], the UK [20,21] and Canada [22], including also in Canada a simulation exercise in which different penetration scenarios similar to the OECD average were considered [23]. In Spain, to date, the work by González Domínguez et al. [24] is the only previous study that estimated the savings due to biosimilars. They reported realized savings of EUR 478 million retrospectively from 2009 to 2016 and potential savings of EUR 1965 million in the period 2017 to 2020.

In order to understand the role of commercial discounts in price competition, it is convenient to first look at the regulation of prices for medicines in Spain (Figure 1).

hereinafter referred to as "commercial discount".

After marketing authorization has been granted, the price for a biosimilar medicine is set by the Interministerial Committee on Pricing of Medicines (ICPM). In general, the ex-factory price (EFP) for the first biosimilar of a given molecule is set at around 20–30% less than the originator price [25]. The same EFP is applied to any other biosimilar of the same molecule that is authorised afterwards. Thus, the originator and biosimilar(s) have different prices for a period of time, not more than one year, since in Spain the price of off-patent medicines is regulated by the Reference Price System (RPS) [26] in the same way as in other European countries [27]. Thus, annually a Reference Price Order (RPO), published in the Official State Gazette (Spanish: Boletín Oficial del Estado, BOE), establishes the reference groups (the reference group is the basic unit of the RPS and it is constituted by at least one presentation of a biosimilar medicinal product that has the same active pharmaceutical ingredient and identical administration route) and fixes the reference price (RP) or the maximum amount of public reimbursement of the presentations of medicinal products included in the reference groups established. After the publication of the corresponding RPO, the biosimilar and originator of a particular molecule share the same RP. EFP, or RP where applicable, is a fixed price in retail pharmacies (to which pharmacy and distributor margins and VAT are added). However, in Spain most originators and their biosimilars are dispensed at hospital pharmacies (11 of the 16 molecules with biosimilars on the Spanish market). In fact, the percentage of pharmaceutical spending on biosimilars within hospital pharmacy spending has grown continuously, from 1% in 2014 to 3% in 2018 [28]. This fact is relevant because these medicines are mainly purchased via public tenders (currently according to Law 9/2017, of 8 November, on Public Sector Contracts [29]; although previously according to Royal Legislative Decree 3/2011 [30] and before that, accordingly to Law 30/2007, of 30 October, on Public Sector Contracts [31]). Under public procurement, hospitals (or other health providers) tender a contract for the acquisition of medicines (originator and biosimilar) for a determined period and an estimated volume. Then, drug manufactures submit their bids (with a price lower or equal to the price tendered by the entity). The award of the contract depends on the economic offer, although other technical criteria are also taken into consideration. Hence, there is a

**Figure 1.** Price regulation of biosimilar medicines in Spain. 1According to Royal Decree 177/2014, of 21 March, regulating the reference price system and the system of homogeneous groups of medicinal products in the National Health System. 2According to Law 9/2017 of 8 November on public **Figure 1.** Price regulation of biosimilar medicines in Spain. <sup>1</sup> According to Royal Decree 177/2014, of 21 March, regulating the reference price system and the system of homogeneous groups of medicinal products in the National Health System. <sup>2</sup> According to Law 9/2017 of 8 November on public sector contracts.

sector contracts. After marketing authorization has been granted, the price for a biosimilar medicine is set by the Interministerial Committee on Pricing of Medicines (ICPM). In general, the ex-factory price (EFP) for the first biosimilar of a given molecule is set at around 20–30% less than the originator price [25]. The same EFP is applied to any other biosimilar of the same molecule that is authorised afterwards. Thus, the originator and biosimilar(s) have different prices for a period of time, not more than one year, since in Spain the price of off-patent medicines is regulated by the Reference Price System (RPS) [26] in the same way as in other European countries [27]. Thus, annually a Reference Price Order (RPO), published in the Official State Gazette (Spanish: Boletín Oficial del Estado, BOE), establishes the reference groups (the reference group is the basic unit of the RPS and it is constituted by at least one presentation of a biosimilar medicinal product that has the same active pharmaceutical ingredient and identical administration route) and fixes the reference price (RP) or the maximum amount of public reimbursement of the presentations of medicinal products included in the reference groups established. After the publication of the corresponding RPO, the biosimilar and originator of a particular molecule share the same RP.

> EFP, or RP where applicable, is a fixed price in retail pharmacies (to which pharmacy and distributor margins and VAT are added). However, in Spain most originators and their biosimilars are dispensed at hospital pharmacies (11 of the 16 molecules with biosimilars on the Spanish market). In fact, the percentage of pharmaceutical spending on biosimilars within hospital pharmacy spending has grown continuously, from 1% in 2014 to 3% in 2018 [28]. This fact is relevant because these medicines are mainly purchased via public tenders (currently according to Law 9/2017, of 8 November, on Public Sector Contracts [29]; although previously according to Royal Legislative Decree 3/2011 [30] and before that, accordingly to Law 30/2007, of 30 October, on Public Sector Contracts [31]). Under public procurement, hospitals (or other health providers) tender a contract for the acquisition of medicines (originator and biosimilar) for a determined period and an estimated volume. Then, drug manufactures submit their bids (with a price lower or equal to the price tendered by the entity). The award of the contract depends on the economic offer, although other technical criteria are also taken into consideration. Hence, there is a variable difference between purchase price and EFP price or RP, where applicable, hereinafter referred to as "commercial discount".

> This paper provides a new estimate of the budget impact generated by biosimilars in the National Health System for the years 2009 to 2019. It differs from a previous study

in Spain [24] because we take into account the real acquisition scenario, that is, EFP and commercial discounts. This work is part of a wider research project analyzing the budget impact of biosimilars in the Spanish NHS, which published a report (grey literature, not indexed) in Spanish on 27th November 2020 [32].

### **2. Results**

According to our results, the budget impact derived from the introduction of biosimilar medicines in the Spanish NHS would reach more than EUR 2306.48 million of cumulative savings in the 11-year period from 2009 to 2019 (Table 1). Somatropin (EUR 375 million), epoetin (EUR 589 million) and infliximab (EUR 450 million) biosimilars provide the greatest contribution to the aggregate savings up to 2019, which is attributable to their long presence on European pharmaceutical market (10, 10 and 5 years, respectively) and the combination of their uptake and price volumes.


**Table 1.** Results of the BIA (€ million savings).

<sup>1</sup> SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim.

Figure 2a shows the aggregated savings over time and the annual mean savings per effectively marketed biosimilar molecule. The temporal evolution analysis showed a growing trend as more biosimilar medicines enter the market. The breakdown of the contribution by molecule (see Figure 2b) revealed that epoetin is in first position with savings of EUR 589 million, followed by infliximab (EUR 450 million) and somatropin (EUR 375 million). Taken together, these three molecules account for more than 60% of total savings in the entire period. However, the entry of biosimilars of different molecules significantly changes the market and the estimation of savings. For instance, adalimumab ranks fifth (EUR 183.77 million) in just two years in the market and a biosimilar uptake of only 18% in 2019. It is not surprising as it is the most consumed drug in the Spanish NHS in terms of hospital pharmaceutical expenditure [33]. It is also worth noting that the savings derived from the use of biosimilars are starting to account for a significant percentage of pharmaceutical spending in Spain. Figure 2c shows the percentage of annual savings caused by the use of biosimilars with respect to total pharmaceutical spending published by the Ministry of Finance in Spain [34] since 2014, calculated at ex-factory prices (EFP),

### without discounts. Annual savings increase from 0.67% in 2014 to 3.92% in 2019. In total, from 2014 to 2019, the savings account for 2.11% of total pharmaceutical spending. Annual savings increase from 0.67% in 2014 to 3.92% in 2019. In total, from 2014 to 2019, the savings account for 2.11% of total pharmaceutical spending.

**Figure 2***.* Distribution of aggregate savings. (**a**) Aggregate savings over time. All molecules exposed to biosimilar competition each year were included in the analysis.; (**b**) Specific contribution of each of the molecules to the total amount of savings. SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim. **\*** Biosimilars marketed before 2009: somatropin, 2006; filgrastim and epoetin, 2008 (2009 is the first year with available consumption data). (**c**) Annual savings derived from the use of biosimilars, in percentages, since 2014 with respect to total pharmaceutical spending in Spain. Total pharmaceutical spending calculated by adding hospital pharmaceutical spending and spending on pharmaceuticals and medical devices per prescription, all calculated at ex-factory prices [34]. **Figure 2.** Distribution of aggregate savings. (**a**) Aggregate savings over time. All molecules exposed to biosimilar competition each year were included in the analysis.; (**b**) Specific contribution of each of the molecules to the total amount of savings. SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim. **\*** Biosimilars marketed before 2009: somatropin, 2006; filgrastim and epoetin, 2008 (2009 is the first year with available consumption data). (**c**) Annual savings derived from the use of biosimilars, in percentages, since 2014 with respect to total pharmaceutical spending in Spain. Total pharmaceutical spending calculated by adding hospital pharmaceutical spending and spending on pharmaceuticals and medical devices per prescription, all calculated at ex-factory prices [34].

### *Sensitivity Analysis Sensitivity Analysis*

The results from the analysis of alternative scenarios (see Figure 3a) show the great influence of commercial discounts at the hospital tendering on total savings. Significantly, when commercial discounts are excluded, savings realized would be reduced to EUR 1064 million from 2009 to 2019, which means about 50% reduction over the base case results. This The results from the analysis of alternative scenarios (see Figure 3a) show the great influence of commercial discounts at the hospital tendering on total savings. Significantly, when commercial discounts are excluded, savings realized would be reduced to EUR 1064 million from 2009 to 2019, which means about 50% reduction over the base case

in Table 2.

results. This scenario would represent the minimum savings due to biosimilar competition (application of the same PR to originator and biosimilar). The other scenario analyzed shows no significant differences from the base case estimate. The same goes for the one-way sensitivity analyses (see Figure 3b). Only the assumptions made in the absence of data (epoetin) show some relevant impact on the savings obtained in the base case, as they affect the data series of two active ingredients whose biosimilars have been on the market for a long time. scenario would represent the minimum savings due to biosimilar competition (application of the same PR to originator and biosimilar). The other scenario analyzed shows no significant differences from the base case estimate. The same goes for the one-way sensitivity analyses (see Figure 3b). Only the assumptions made in the absence of data (epoetin) show some relevant impact on the savings obtained in the base case, as they affect the data series of two active ingredients whose biosimilars have been on the market for a long time.

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 6 of 16

**Figure 3.** Results of the scenario and sensitivity analyses. (**a**) Scenario analysis. (**b**) One-way sensitivity analysis. The dotted line represents the base case value. **Figure 3.** Results of the scenario and sensitivity analyses. (**a**) Scenario analysis. (**b**) One-way sensitivity analysis. The dotted line represents the base case value.

**EPO** 589.15 590.26 546.85 - 634.32 **FOL** 54.92 54.92 53.71 - 56.07 **INF** 450.30 450.25 448.59 - 452.03 **INS** 110.54 110.40 106.08 - 115.03 **ETA** 90.48 90.60 83.26 - 99.25 **CHO** 9.32 9.32 8.99 - 9.68

Finally, probabilistic sensitivity analysis provides 11-year (2009–2019) cumulative savings with an average of EUR 2310 million (95% IC: EUR 2170–EUR 2461 million) for the NHS. Overall, these results are in line with those obtained for the base case as shown Finally, probabilistic sensitivity analysis provides 11-year (2009–2019) cumulative savings with an average of EUR 2310 million (95% IC: EUR 2170–EUR 2461 million) for the NHS. Overall, these results are in line with those obtained for the base case as shown in Table 2.

**Table 2.** Results of the probabilistic sensitivity analysis (€ million). **Molecule 1 Base Case Probabilistic Sensitivity Analysis Mean 95% CI SOM** 375.18 377.96 348.25 - 415.67 **FIL** 289.40 289.27 274.55 - 303.17 Figure 4 shows the 1000 Monte Carlo simulations performed in the probabilistic analysis. Each of the points represents one of the 1000 simulations carried out. Thus, a greater dispersion of the points along the axes represents a greater uncertainty of the results. As observed, a higher consumption of DDD does not always translate into higher savings, as seen with enoxaparin, chondroitin sulfate and insulin glargine. On the other hand, we see how rituximab achieves considerable savings without reaching high consumption values (in DDD).

10


**Table 2.** Results of the probabilistic sensitivity analysis (€ million).

<sup>1</sup> SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim. savings, as seen with enoxaparin, chondroitin sulfate and insulin glargine. On the other hand, we see how rituximab achieves considerable savings without reaching high consumption values (in DDD).

**Figure 4.** Scatter plot of 1000 Monte Carlo simulations. Vertical axis represents aggregated saving (€ million) for each molecule in the period 2009–2019. Horizontal axis represents the total amount of DDD (million) consumed in this period for each molecule. White dots represent the base case values. SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim. **Figure 4.** Scatter plot of 1000 Monte Carlo simulations. Vertical axis represents aggregated saving (€ million) for each molecule in the period 2009–2019. Horizontal axis represents the total amount of DDD (million) consumed in this period for each molecule. White dots represent the base case values. SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim.

### **3. Discussion 3. Discussion**

To our knowledge, ours is the first study that uses a BIA to estimate the retrospective savings in a European health system for the total of biosimilar molecules marketed and taking into account the real net price (EFP and commercial discounts in the hospital tenders). The only precedent for Spain is González-Domínguez et al. [24]. They estimated the savings derived from biosimilars in the NHS for the retrospective period 2009–2016 and for the prospective period 2017–2020. In order to compare our results to theirs, we To our knowledge, ours is the first study that uses a BIA to estimate the retrospective savings in a European health system for the total of biosimilar molecules marketed and taking into account the real net price (EFP and commercial discounts in the hospital tenders). The only precedent for Spain is González-Domínguez et al. [24]. They estimated the savings derived from biosimilars in the NHS for the retrospective period 2009–2016 and for the prospective period 2017–2020. In order to compare our results to theirs, we have

have estimated the savings through the budget impact analysis according to our model for the same seven active substances (somatropin, filgrastim, epoetin, follitropin, insulin

savings of EUR 343 million compared to EUR 478 million reported by [24]. This difference may be due to different assumptions on the price erosion, the application date of the estimated the savings through the budget impact analysis according to our model for the same seven active substances (somatropin, filgrastim, epoetin, follitropin, insulin glargine, infliximab and etanercept) and in the same period (2009–2016). We estimate savings of EUR 343 million compared to EUR 478 million reported by [24]. This difference may be due to different assumptions on the price erosion, the application date of the RPO, or the estimated uptake of each molecule used and merely reflects the complexity inherent to any estimation of savings.

Few studies have calculated the real retrospective savings derived from the introduction of biosimilars in the European context. Simoens et al. [16] reviewed full publications and posters focusing on BIA of biosimilar medicines. Their work revealed the lack of peer-reviewed information on the budget impact of biosimilar products. Only three studies were considered full budget impact models according to ISPOR good practice guidelines. They all aimed to estimate the budget impact of the introduction of an infliximab biosimilar over a prospective time horizon between 1 and 3 years, also considering some type of substitution or combination.

Since then, additional BIAs of biosimilar medicines in Europe have been published. They mainly aimed to analyze the budget impact of one molecule (antiTNF class is the wider class analyzed) in a time horizon between 3 and 5 years. For instance, in Italy, Rognoni et al. [17] estimates the impact of the use of a rituximab biosimilar in the Italian National Health System in a 3- and 5-year horizon that accounts for EUR 79.2 and EUR 153.6 million, respectively. Likewise, the introduction of an adalimumab biosimilar would generate savings of EUR 260 million in 5 years [19]. In the United Kingdom, Aladul et al. [20] updated their previous study [35] including the introduction of a new antiTNF biosimilar in the areas of rheumatology and gastroenterology. According to their calculations the impact would amount, in a 3-year horizon, to GBP 285 million. Other studies expand the focus to EU5 (infliximab) [36] or a greater pool of European countries (rituximab) [37]. In a very recent study, Agirrezabal et al. [21] estimated the impact of biosimilar insulin glargine in primary care in the NHS with, specifically, savings of GBP 900,000 between October 2015 and December 2018. They also provide an estimate of the savings lost due to reduced use of biosimilars, which could have reached GBP 25.6 million, indicating that only 3.42% of the potential savings have been achieved.

Of note, most studies cited used ex-factory prices excluding discounts as cost-input. This does not reflect reality, as hospitals usually negotiate individual discounts through public tenders. By contrast, our study uses purchase prices paid by hospitals. We believe this allows for a more accurate estimation of savings due to biosimilar competition in Spain since 2009. At the same time, the large period of time we analyze, from 2009 to 2019, allows us to observe how, in general and per molecule, savings are increasing in time.

In any case, our results are broadly consistent with the observed financial impacts from other countries in that biosimilar uptake translates into significant savings and that when longer periods are considered, higher savings are realized, as expected.

It is important to note that the estimated savings are affected by the variation and level of both quantities and prices. Consequently, a higher consumption of DDD does not always translate into higher savings, as observed with enoxaparin, chondroitin sulfate and insulin glargine, due to a lower price with respect to complex biosimilar molecules such as antiTNF or monoclonal antibodies. For the same reason, rituximab achieves considerable savings without reaching high consumption values.

It is worthwhile to highlight that adalimumab (the first biosimilar launched at the end of 2018) accounts for almost 8% of the 11-year (2009–2019) cumulative savings. This figure corresponds to realized savings of EUR 187 million in scarcely one year. It is not surprising as adalimumab is responsible for the highest drug spending in Spain [33]. This suggests that higher savings in the short term may be expected. In fact, we have estimated that the percentage of annual savings caused by the use of biosimilars with respect to total pharmaceutical spending is increasing and by 2019 it was 3.92%.

An additional finding of this work is that potential savings in Spain due to biosimilars are not yet fully exploited, as the biosimilar uptake is still lower than that in other countries, at least for some active substances. For example, antiTNF biosimilar uptake in Spain was 49% in 2019 vs. Denmark (96%), Germany (61%), Italy (64%) or Norway (74%). The same pattern is observed for biosimilar monoclonal antibodies in oncology. The penetration in Spanish market barely exceeds 35% vs. Denmark (74%), Germany (49%), Italy (52%) or Norway (70%). This lower utilization proves that there is a room for improvement in the Spanish NHS [38].

In any case, it is important to note that different molecules behave differently and not all contribute equally to savings in each country, or in different countries, because of the different price and reimbursement policies, procurement procedures, and other pharmaceutical policies, which vary greatly among European countries.

In the case of Spain, a comprehensive report by the Independent Authority for Fiscal Responsibility [39] confirmed the high variability across autonomous communities in terms of uptake levels and promotion policies. This may have been a driver for the Ministry of Health's attempt to establish a national policy on biosimilars [40]. This plan, still under revision, makes recommendations to revisit those supply and demand policies put in place in Spain with the further aim of promoting the utilization of biosimilar medicines in Spain. This aim is also supported by the Advisory Committee for the Funding of the Pharmaceutical Benefit of the National Health System, a collegiate body attached to the Ministry of Health. In its analysis of this plan, the committee is of the opinion that promoting the use of biosimilars will lead to more competition and reduction of the burden of pharmaceutical spending [41]. We consider that more research is needed on the role of biosimilar competition in pharmaceutical cost containment. Given the increasing concern regarding the sustainability of healthcare systems, and the contribution biosimilars can play towards that end, in line with our findings, more ambitious or fine-tuned policies for promoting biosimilars (in general or some biosimilars specifically) may be expected.

### *Limitations*

As in any other study, this retrospective BIA has certain limitations, mainly due to the non-availability of data, specifically among the first three biosimilar classes on the market (EPO, G-CSF, and hGH). Additional sources [42–44] were used to complete information gaps on the uptake of these biosimilars. When the price of the biosimilar prior the RPO launch was unknown, we assumed that it was a 10% higher than the price after RPO. We believe this assumption is a conservative position, as the RPO can lead to price reductions of up to 30%, as in the case of adalimumab.

Regarding the estimation of commercial discounts, as mentioned, a sample of 143 public procurement tenders (the most recent in each autonomous community) was used. Although the sample was considered to be representative, it does not include all the public procurement procedures in the country for the entire period of analysis. This is because sharing transparent information on purchase prices (tenders) is a very recent trend motivated by the EU directives on public procurement. In addition, we acknowledge that an unequal distribution of tender procedures per region might influence the estimation of actual savings in Spain. The degree of variability in the level of discounts awarded via public tenders for the same molecule within the regions is out of the scope of this research and merits itself further exploration. In addition, to overcome the lack of data on the public tenders prior to 2016, a linear regression was performed with 0% as the lower limit of discount matching the time of biosimilar launch. This would represent the evolution of price discounts derived from competition between an originator and biosimilars over the years.

The results of this BIA should be interpreted with these limitations in mind.

### **4. Materials and Methods** To estimate the budget impact, two scenarios are compared. First, the hypothetical scenario in which biosimilar drugs are not available on the market and therefore, an

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 10 of 16

evaluations and analyses previously developed in Spain [45,46].

### *4.1. Model Design* originator's price would keep constant throughout the period examined. This assump-

We perform a retrospective BIA of the introduction of biosimilars from the Spanish Health System perspective covering the period from 2009 to 2019. All the molecules exposed to biosimilar competition in this period were included in the analysis (Figure 5). We adopt the third-party payer perspective and thus, we only account for direct medical costs, in particular pharmacological costs prior to and after the market introduction of biosimilars. The calculation was conducted in a Microsoft Excel-based spreadsheet model. The model was constructed in compliance with methodology guidelines for economic evaluations and analyses previously developed in Spain [45,46]. tion is based on a review of the price evolution of originators (anti-TNFs, trastuzumab and rituximab). We found that these originator medicines did not undergo major price changes before biosimilar entry. This could be interpreted to mean that even if other molecules generate competition in the same indication, the originator's price is rarely modified. Second, the actual scenario with biosimilars available on the market after an originator's patent expiration is examined. In this scenario, competition leads to a price reduction for originator medicines. The difference in terms of costs between the two scenarios provides the savings generated by the introduction of biosimilars.


**Figure 5.** Biosimilar medicines effectively marketed in Spain as of December 2019. 1 Biosimilars marketed before 2009 (2009 is the first year with available consumption data). 2 For the purpose of this study, epoetin zeta and alfa are considered as a single molecule. Bevacizumab and teriparatide biosimilars have been recently marketed in Spain (September 2019 and June 2020, respectively) but they are not included in this analysis. **Figure 5.** Biosimilar medicines effectively marketed in Spain as of December 2019. <sup>1</sup> Biosimilars marketed before 2009 (2009 is the first year with available consumption data). <sup>2</sup> For the purpose of this study, epoetin zeta and alfa are considered as a single molecule. Bevacizumab and teriparatide biosimilars have been recently marketed in Spain (September 2019 and June 2020, respectively) but they are not included in this analysis.

The two main variables of the analysis are uptake (consumption data) and price for each molecule, both originator and biosimilar. To provide clarity on some specific terminology a glossary table (see Table 3) with English terms used in this manuscript and their Spanish equivalents is provided. **Table 3.** Glossary of English/Spanish terms and their abbreviations. **English Term Spanish Term Abbreviation in Spanish**  National Health System (abbreviated in text as NHS) Sistema Nacional de Salud SNS To estimate the budget impact, two scenarios are compared. First, the hypothetical scenario in which biosimilar drugs are not available on the market and therefore, an originator's price would keep constant throughout the period examined. This assumption is based on a review of the price evolution of originators (anti-TNFs, trastuzumab and rituximab). We found that these originator medicines did not undergo major price changes before biosimilar entry. This could be interpreted to mean that even if other molecules generate competition in the same indication, the originator's price is rarely modified. Second, the actual scenario with biosimilars available on the market after an originator's patent expiration is examined. In this scenario, competition leads to a price reduction for originator medicines. The difference in terms of costs between the two scenarios provides the savings generated by the introduction of biosimilars.

Interministerial Committee on Pricing of Medicines (abbreviated in text as ICPM) Comisión Interministerial de Precios de Medicamentos CIPM The two main variables of the analysis are uptake (consumption data) and price for each molecule, both originator and biosimilar. To provide clarity on some specific terminology a glossary table (see Table 3) with English terms used in this manuscript and their Spanish equivalents is provided.

(abbreviated in text as EFP) Precio de venta del laboratorio PVL

Ex-factory price


**Table 3.** Glossary of English/Spanish terms and their abbreviations.

### *4.2. Uptake Estimation*

We use two sources of data on the uptake of biosimilars. For the period between 2009 and 2015, we use data provided by all manufacturers, representing the number of units effectively consumed by the NHS (BioSim, data on file) and for the period between 2016 and 2019, we use data provided by the Ministry of Health (Ministry of Health, data on file). In both scenarios (with and without biosimilars) the volumes have been converted to daily doses using the published World Health Organization (WHO) defined daily doses (DDD) [47] as previously used by Haustein et al. [48] to estimate the impact of the introduction of biosimilars in several European countries. Figure 6 shows the evolution over time of biosimilar uptake in the Spanish pharmaceutical market. In the bottom of the figure, the estimated average uptake after launch of the first biosimilar (that means, mean uptake of first year of commercialization, mean uptake of second year of commercialization, and so on) are shown.

### *4.3. Price Estimation*

For each molecule, drug acquisition costs (EFP) for the year 2019 have been obtained from BotPlus, the Health Information database of the General Council of the Association of Official Pharmacists that provides harmonized information on medicines [49]. For the previous years, price evolution was also obtained from BotPlus, and when not available, these prices were provided by BioSim (BioSim, data on file). RPO published in the OSG from 2014 to 2019 were consulted to provide RP. RP is assumed to affect price calculations in the same month of the publication of the RPO when it is prior to the 15th day of the month, otherwise RP will apply the following month. When a biosimilar price between its commercialization and its regulation by the reference pricing system is unknown, we assume an increase of 10% over the RP, following the observation of other biosimilars for which full price data are available.

Purchase prices in hospital tenders were used to calculate discounted prices per DDD compared to the EFP for infliximab, etanercept, adalimumab, trastuzumab and rituximab (data from 143 public tenders collected by Acobur S.L. (https://www.acobur.es, accessed on 15 April 2020). This reduced price was weighted by the total volume (in units) of each award (of originator and biosimilars) to obtain the commercial discount for each molecule and year. In the case of somatropin, epoetin, filgrastim and pegfilgrastim, internal BioSim data for years 2018 and 2019 were used and a linear regression was conducted assuming

a discount of 0% the year before the marketing of the first biosimilar. No discount is considered for follitropin alfa, insulin glargine, chondroitin sulfate and enoxaparin, as they are mostly dispensed by retail pharmacies, where commercial discounts do not apply. Table 4 shows the number of tenders analyzed and the level of discount for each molecule. *Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 11 of 16


**Table 4.** Level of discount on price per molecule. Reference price

Level of discount on price (either EFP or RP): + (low) 0–25%; ++ (medium) 25–50%; +++ (high) >50%. <sup>1</sup> SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim; <sup>2</sup> Biosimilars marketed before 2009: somatropin, 2006; filgrastim and epoetin, 2008 (2009 is the first year with available consumption data). <sup>3</sup> The amount of public tender analyzed exceed 143 as some of them were tendered for several molecules. evolution over time of biosimilar uptake in the Spanish pharmaceutical market. In the bottom of the figure, the estimated average uptake after launch of the first biosimilar (that means, mean uptake of first year of commercialization, mean uptake of second year of commercialization, and so on) are shown.

**Figure 6.** Biosimilar penetration in Spain over time (adapted from [29]). Biosimilar uptake (%) is calculated as volume of biosimilars over volume of biosimilars plus the originator product (DDDs). \* Chondroitin sulfate and the three biosimilars marketed before 2009 (somatropin, filgrastim and epoetin) were excluded to avoid distorting the mean. SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chon-**Figure 6.** Biosimilar penetration in Spain over time (adapted from [29]). Biosimilar uptake (%) is calculated as volume of biosimilars over volume of biosimilars plus the originator product (DDDs). \* Chondroitin sulfate and the three biosimilars marketed before 2009 (somatropin, filgrastim and epoetin) were excluded to avoid distorting the mean. SOM: somatropin; FIL: filgrastim; EPO: epoetin; FOL: follitropin alfa; INF: infliximab; INS: insuline glargine; ETA: etanercept; CHO: chondroitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab; PEG: pegfilgrastim.

droitin sulfate; RIT: rituximab; TRA: trastuzumab; ENO: sodium enoxaparin; ADA: adalimumab;

PEG: pegfilgrastim.

*4.3. Price Estimation* 

of Official Pharmacists that provides harmonized information on medicines [49]. For the

### *4.4. Molecule-Specific Assumptions*

In addition to the general assumptions mentioned above, it was necessary to adopt other specific assumptions given the lack of specific information about both uptake and price variables (Table S1).

### *4.5. Sensitivity Analsyses*

In order to evaluate the uncertainty associated with the variables used in the budget impact model and determine the robustness of the results obtained, we carried out both deterministic and probabilistic sensitivity analyses.

In the scenario analysis, some of the assumptions are modified with respect to the base case (non-additively) (Table 5). The new alternatives (non-additive) propose different ways to calculate the price variable. Scenario 1 estimates the impact on price of ignoring the discounts that manufacturers give to hospitals. Scenario 2 ignores the volume-weighting, that is to say, the purchase price only applies to the year in which the tender is awarded regardless of the duration of the contract.


**Table 5.** Scenario and one-way sensitivity analyses.

One-way sensitivity analysis was performed by changing, one by one, some parameters of the model: the price of some biosimilars prior the application of the RPO, the month of application of the RPO, and the market share of biosimilar epoetin in 2011–2015 (data from [42]) (Table 5).

We also performed a probabilistic sensitivity analysis using the Monte Carlo method with 1000 simulations, simultaneously modifying all parameters from base-case values following a normal distribution, in line with the recommendations of the literature [50].

### **5. Conclusions**

The increase of health expenditures, and in particular, of pharmaceutical expenditures in Spain highlights the need for effective strategies to contain and rationalize pharmaceutical spending.

This is the first study carried out which jointly analyzes the savings for the Spanish NHS in terms of pharmaceutical expenditure derived from both the uptake of biosimilar products and the downward effect on prices resulting from competition (RPS and public tenders, with commercial discounts).

Our results show how the introduction of biosimilar drugs in the Spanish pharmaceutical market has brought competition in the market of biological products, and unquestionable, increasing and significant savings, especially at the hospital level, where the majority prescriptions for the molecules herein analyzed are issued. Thus, biosimilar medicines represent a great opportunity to promote the sustainability of the NHS through rationalization and efficiency in pharmaceutical expenditure. Our study also shows that the

full potential of biosimilar savings has not been achieved yet, as there is a high variability in biosimilar uptake across autonomous regions.

This is a first approach to the impact of biosimilar medicines on the pharmaceutical market in terms of price competition, uptake and savings. However, a further research might address other issues such as level of competition, variability across molecules and within regions, relationships, if any, between market size and number of competitors or price discounts.

In any case, any pharmaceutical policy to be adopted should not only analyze its expected impact in the short-term, but also in the medium- and long-term, to promote healthy competition in the market for biological pharmaceutical products, whether originator or biosimilar. After all, the ultimate goal is the sustainability of the healthcare system with rapid access to innovative products, but also a healthy competition from biosimilars when the patent from the originators expires, resulting in better access for patients to obtain the clinical benefits derived from the treatments.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/ph14040348/s1, Table S1: Assumptions adopted for each molecule.

**Author Contributions:** Conceptualization, M.G.-G.; methodology, D.C. and A.V.; validation, M.G.- G.; formal analysis D.C.; investigation, D.C., M.G.-G., and I.R.-Á.; resources, I.R.-Á.; data curation, D.C.; original draft preparation, I.R.-Á., D.C., and M.G.-G.; review and editing, M.G.-G. and A.V.; supervision, M.G.-G.; project administration, I.R.-Á. All authors have read and agreed to the published version of the manuscript.

**Funding:** The authors thank financial support for the development of this research by The Spanish Biosimilar Medicines Association, BioSim.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data is contained within the article.

**Acknowledgments:** The authors would like to thank Maria Lores (Hygeia Consulting S.L.) for her contribution to data processing. The authors also thank Marta Trapero-Bertrán (Universitat Internacional de Catalunya) her advice in the early stages of this research.

**Conflicts of Interest:** M.G.-G., D.C. and A.V. declare no conflicts of interest. I.R.-Á is employee of the Spanish Biosimilar Medicines Association who funded this research.

### **References**


### *Article* **Did the Introduction of Biosimilars Influence Their Prices and Utilization? The Case of Biologic Disease Modifying Antirheumatic Drugs (bDMARD) in Bulgaria**

**Konstantin Tachkov <sup>1</sup> , Zornitsa Mitkova <sup>1</sup> , Vladimira Boyadzieva <sup>2</sup> and Guenka Petrova 1,\***


**Abstract:** The aim of this study is to evaluate the effect of the introduction of biosimilars in Bulgaria on the prices and utilization of biologic disease modifying antirheumatic drugs (bDMARD). It is a combined qualitative and quantitative analysis of time of entry of biosimilars on the national market and the respective changes in the prices and utilization during 2015–2020. We found 58 biosimilars for 16 reference products authorized for sale on the European market by the end of 2019, but for 2 of the reference products biosimilars were not found on the national market. Only inflammatory joint disease had more than one biosimilar molecule indicated for therapy. Prices of the observed bDMARD decreased by 17% down to 48%. We noted significant price decreases upon biosimilar entrance onto the market. In total, the reimbursed expenditures for the whole therapeutic group steadily increased from 72 to 99 million BGN. Utilization changed from to 0.5868 to 2.7215 defined daily dose (DDD)/1000inh/day. Our study shows that the entrance of biosimilars in the country is relatively slow because only half of the biosimilars authorized in Europe are reimbursed nationally. Introduction of biosimilars decreases the prices and changes the utilization significantly but other factors might also contribute to this.

**Keywords:** biosimilars; pricing; reimbursement; utilization

### **1. Introduction**

It is largely well-established, as supported by evidence, that after the introduction of generic medicines the price of originals decreases, allowing for an increase in medicines utilization [1–4]. This is mostly valid for the synthetic medicines where the criteria for essential similarity between the originator and off-patented versions are scientifically and regulatory established [5]. Generic medicines benefit the market by offering equally high-quality treatment as originator medicines but at much lower prices [6,7]. Based on the essential similarity of medicines, countries introduce a variety of measures to stimulate generic medicines manufacturing, prescribing, dispensing, and utilization in the society [8,9]. Those measures are described as generic medicines policy [10,11]. Generic medicines policy has been promoted by the World Health Organization for many years with the main goal of encouraging governments to introduce it as part of their national drug policy [12,13]. A core element of the generic medicines policy is a list of essential drugs comprising the most widely used by the majority of people and medicines for a large number of diseases [14]. The aim of introducing generic incentives is to foster competition, decrease prices, and enlarge the utilization of essential medicines, thus, covering the needs of the majority of the population [15–17].

Biological medicines encompass a wide group of therapeutic agents that are manufactured through living organisms and include monoclonal antibodies, peptides (e.g., insulin),

**Citation:** Tachkov, K.; Mitkova, Z.; Boyadzieva, V.; Petrova, G. Did the Introduction of Biosimilars Influence Their Prices and Utilization? The Case of Biologic Disease Modifying Antirheumatic Drugs (bDMARD) in Bulgaria. *Pharmaceuticals* **2021**, *14*, 64. https://doi.org/10.3390/ph14010064

Received: 20 November 2020 Accepted: 11 January 2021 Published: 14 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

vaccines, blood products, RNA targeting therapies, and gene and cellular therapies [18]. A biosimilar medicine is a biological medicine that is similar to another biological medicine that has already been authorized for use [19–21]. Biosimilars have a number of important differences from generic small-molecule drugs, including manufacturing processes that are unique from their reference products (i.e., originators) [20]. There is considerable debate, still, in the scientific community about the safety and interchangeability of biological products [21]. Authors consider that the availability of biosimilars might provide an opportunity to lower health care expenditures as a result of the inherent price competition with their reference product [22]. This is due to the fact that biological products are rising as a proportion of drug expenditures globally [23]. There are estimates that over 30% of all drug spending in Europe is on biological medicines and out of them 1.5% are for biosimilars. There has been an increase by 3.4% over the last five years for all biologic medicines, and by 1.2% since 2014 for biosimilars. By the end of 2018, 16 biological molecules have had biosimilar products introduced in Europe, meaning that there is a possibility to enhance biosimilars competition with reference biological products. In countries where there is no officially introduced generic medicines policy, we can expect obstacles towards the market penetration, prescribing, and competition in the field of biological products [24,25]. This stimulated our interest towards the topic.

The aim of this study is to evaluate the effect of the introduction of biosimilars in Bulgaria on the prices and utilization of biologic disease modifying antirheumatic drugs (bDMARD) for inflammatory joint diseases therapy.

### **2. Results**

### *2.1. Availability of Biosimilars in the Reimbursement Drug List*

We found 58 biosimilars for 16 reference products authorised for sale on the European market by the end of 2019, but for 2 of the reference products (insulin lispro and enoxaparin) biosimilars were not found on the national market. The national market included 14 reference products for which 29 biosimilars are reimbursed (Table 1).

Fifteen biosimilars are reimbursed for the outpatient practice. Adalimumab, infliximab, etanercept, and rituximab are biologic disease modifying antirheumatic drugs (bD-MARD) indicated for inflammatory joint diseases therapy for which nine biosimilars were found. The rest of the INNs for outpatient practice possess only one biosimilar reimbursed in the country, except epoetin alfa with two biosimilar (Table 1).

Trastuzumab, bevacizumab, filgrastim, pegfilgrastim, and follitropin alfa are reimbursed for inpatient practice but for different therapeutic areas and we could not compare them at a therapeutic level. Fourteen biosimilars are authorized for those INNs (Table 1).

From Table 1, it is also evident that the time period for biosimilar entry on the national reimbursed market after its marketing authorization in Europe varies from two months (infliximab first biosimilar) to nine years (bevacizumab biosimilar). It is also evident that a total six biosimilars were present in the reimbursed practice for a limited time period which were later excluded from the Positive Drug List probably due to marketing authorization holder request.

Reviewing the changes in the authorized for sale and reimbursed indications of inflammatory joint disease therapy, we found the following. Infliximab was the first reimbursed by the National Health Insurance Fund bDMARD for the indication of RA therapy, subsequently AS was added, as well as PSA as an indication. All of the indications were approved by the NCPR prior to the observed period 2015–2019. During the observed period, entrance of an infliximab biosimilar to the reimbursement practice allowed for reimbursement of all aforementioned indications immediately upon receiving approval. This was the case for other biosimilars for inflammatory joint diseases therapy as well.


**Table 1.** Available biosimilar in the reimbursement practice and date of entrance.

### *2.2. Changes in Prices and Utilization of Anti-Inflammatory Joint Diseases Medicines*

During 2015–2020, a total of nine biosimilar products for four INNs were found available on the reimbursement drug list within the group of anti-inflammatory joint diseases (Table 2).


**Table 2.** Reference price per define daily dose (DDD) for anti-inflammatory joint diseases medicines (BGN).

**Legend:** \* biosimilar included; ↓ biosimilar excluded.

In 2015, infliximab had only two biosimilar alternatives available, with a third being introduced in 2019; however, this inclusion was of the originator of infliximab. Its price was influenced by the already established reference price per DDD of the corresponding biosimilars as per the active legislation requiring the reimbursing of the lowest price per DDD. The price of infliximab dropped down by nearly 41% during the period and the highest decrease was observed when the third product was included in the list. One biosimilar for etanercept entered the reimbursement practice leading to almost a 75% decrease in the reference price per DDD at the moment of entrance and total 49% price decrease during the whole period observed. Adalimumab appears to be the most competitive INN with four biosimilars introduced during the period and nearly double the decrease in the price. Originator for tocilizumab added one new dosage form leading to a small decrease in reference price per DDD. For rituximab, we found one included biosimilar and the price dropped down by 1.3 BGN per DDD. This dosage form was subsequently excluded, leading to an increase in reference price with 0.27BGN (Table 2).

Regarding the changes in prices, we observed a decrease by nearly 50% for INNs where biosimilars were introduced and with 5–21% for INNs where there was no biosimilar competitor available prior to introduction (Table 2). The decrease in the prices of the other INNs where there is no biosimilars could be explained with the regular price revision. If there is a price decrease in the reference countries it immediately affects the prices on the national market. For the period 2015–2020, all changes in prices were found to be statistically significant (*p* < 0.001). The inclusion of baricitinib resulted in a nonsignificant change in prices for the period 2019–2020 (*p* = 0.1326).

Reimbursed expenditures increased for almost all INNs in 2019 in comparison with 2015 (Table 3). Only for infliximab we noted a decrease in expenditures by 49%, which could be attributed both partly to the decreasing prices, and partly due to the entrance of new therapeutic and biosimilar competitors. Similar is the situation with adalimumab, whereby until 2018 reimbursed expenditures increased and upon the introduction of biosimilars it started to decrease. We can assume that the price decrease leads also to decrease in the reimbursed expenditures.

In total, the reimbursed expenditures for the whole therapeutic group steadily increased from 72 to 99 million BGN by the end of the observed period (nearly 36–45.9 million Euro)—Figure 1. Variations in the percent change of total reimbursed expenditures was noted between 2017 in comparison to 2016 (*p* < 0.05) when the increase is less than between 2016 and 2015 (*p* > 0.05). In 2019, we observed a decrease in total expenditures with 2.83%, which was nonsignificant. However, the change in expenditures between 2017 and 2018 were significant (*p* < 0.05), and seem to be largely influenced by the increased expenditures for secukinimab and rituximab.

1.4


**Figure 1.** Total reimbursed expenditures and % change every year. **Figure 1.** Total reimbursed expenditures and % change every year.

Utilization in DDD/1000inh/day is stable for most INNs, with a smooth increase except for rituximab and adalimumab (Figure 2) for which a significant increase is observed. 111,597,027.2. Please confirm. **Commented [gp24R23]:** Yes it is correct Utilization in DDD/1000inh/day is stable for most INNs, with a smooth increase except for rituximab and adalimumab (Figure 2) for which a significant increase is observed.

**Commented [M23]:** Plus commas in five-digit numbers to indicate thousand in the figure, e.g.,

increase in utilization in 2018 when the first biosimilar entered the market.

As a whole, during 2015–2019 the utilization in DDD/1000inh/day increased from 0.657 to 2.395. The increase in utilization was found to be significant (*p* < 0.001). Adalimumab is definitely a leader in utilization in DDD/1000inh/day accounting for 32% to 21% of total utilization during the period (Table 4). For rituximab we noted a tremendous increase in utilization in 2018 when the first biosimilar entered the market.


**Table 4.** Share of utilization in DDD/1000inh/day.

What is worth noting, however, is that all changes in utilization were found to be significant, even those between 2018 and 2019 (*p* < 0.05), despite the changes in total NHIF expenditures for the same time period being nonsignificant. This seems to indicate that introduction of biosimilars and the implementation of cost-containment measures is able to control for an increase in expenditures, and allow for increase in utilization of these medicines.

### **3. Discussion**

To the best of our knowledge, this is the first national study exploring the entrance of biosimilars on the national market and their influence on the reimbursed prices and utilization of a particular therapeutic group in DDD/1000inh/day. There are two other national studies focusing on biosimilars [26,27]. The first one compared the prices of biological products for rheumatoid arthritis therapy, and found that manufacturer prices of reference biological product and biosimilars shows 36% difference for etanercept, 39% for rituximab, and 31% for infliximab, while at retail level the differences are 11%, 86%, and 143%, respectively [28]. It does not explore their reimbursement prices and utilization, but only officially published manufacturer and retail prices. Authors noted this as a limitation of the study. The second article explores the access to biotechnological drugs for rare diseases and found that they comprise a high proportion of pharmaceutical expenditures in the reimbursed biotechnological medicinal products market [29].

Similar international comparisons reviewed the requirements for reimbursement of biosimilars and compared the reimbursement status, market share, and reimbursement costs of biosimilars in Bulgaria, the Czech Republic, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, and Romania during 2016–2017, using a questionnaire, focusing mostly on the regulatory requirements for the pricing and reimbursement of biosimilars for each country [30]. Authors pointed out that the total expenditure on the reimbursement of biologic drugs in the CEE countries was 397,097,152 EUR in 2014 and 411,433,628 EUR in 2015, but the data for Bulgaria was scarce.

None of the national studies explore the entrance of all biosimilars. Our research found that almost half of all authorized by EMA biosimilars are available on the market but only in one therapeutic group could we establish price competition. There are still many biosimilars that are not available. In addition to this slow penetration, the time for entrance is also variable. For the earlier biosimilars it was extremely long (nine years for the epoetin alfa) but in recent years, the time of inclusion has become faster; in some cases, as quickly as two months, which indicated progress in marketing penetration. This might be also due to the fact that in the area of bDMARD for inflammatory joint diseases therapy not only is biosimilar competition increasing, but also therapeutic competition, and the range of improved indications has expanded to cover other forms of arthritis. The first bDMARD (infliximab) for joint diseases therapy were positioned for rheumatoid arthritis in 2000, subsequently the indications increased to allow for other types of inflammatory joint diseases (RA, PSA, AS). In 2003, the indication AS was added, and in 2004 the indication of psoriatic arthritis (PSA) was approved. Despite the approval received by EMA for the treatment of RA in 2000 for etanercept and 2003 for adalimumab, the NHIF added both bDMARDS with a significant delay at the end of 2009, but for the three inflammatory joint diseases (RA, PSA, AS). In 2010, the NHIF included in the list two new molecules: anti-IL-6-tocilizumab and anti-CD20-rituximab with indication RA (rituximab received approval also for Wegener's disease in 2015). One year later, certolizumab pegol was included in the therapeutic arsenal, approved by the NHIF, for the indication RA, and in 2015 for the other two inflammatory joint diseases. In 2012, golimumab received approval for the three diagnoses and ustekinumab a year later, but only for the indication of psoriatic arthritis. The last two bDMARDs received approval in 2017 for secukinumab and in 2019 for ixekizumab. A new group of medicines-target synthetic DMARDS has entered widely in the practice of rheumatologists in 2018. Tofacitinib was the first approved by the NHIF in March 2018, followed by baricitinib in 2019. To date, no biosimilar products of these have been presented but we found that their entrance changes the utilization in the group as a whole.

It is also important to note that biosimilars entrance is delayed also by the market exclusivity practices of the pharmaceutical companies [31].

A limitation of our study is that we focused only on the therapeutic group for outpatient practice, because the reimbursed prices of medicines for hospitals are an object of tenders and all of them are also subject of confidential rebate negotiation so the real market price could not be established.

Regarding the prices, we confirmed the hypothesis that the biosimilars decrease the prices of biological product even at the moment of their entrance in the reimbursement system. The prices are highly competitive and in comparison with the INNs, where there is no biosimilars, prices are falling down at twice the rate [27]. The pricing policy in Bulgaria is oriented towards lower costs and lower prices. External reference pricing is applied for price approval and lowest ex-manufacturing price is used out of 10 reference countries. After the reimbursement approval, the lowest price per DDD is used as a reference price for reimbursement within the INN. The fact that the years with the most included biosimilars (2018–2019) had a nonsignificant change in total expenditures indicates that these costcontainment measures are effective.

We also confirm that the entrance of biosimilars influences the utilization in a positive direction, except for infliximab, with significant changes being observed for all INNs. The decrease in utilization of infliximab could be attributed to the constantly lowering prices and entrance of new bDMARDS within the group. This is probably influenced by adalimumab who is the leader in the group. Adalimumab is one of the most commonly prescribed blockers of TNFa due to its well-established long-term safety profile [28], tolerability, and effectiveness compared to other bDMARDS [32]. It is one of the first three bDMARDS approved for treatment by the NHIF with 18 indications to date. Recent studies reveal that adalimumab is one of the most prescribed biologics in the United States after an analysis of the treatment of 40,373 RA patients [33].

A study of the utilization of biosimilars was conducted in Korea, where authors found an increasing market share for infliximab biosimilars at over 30%, while rituximab and trastuzumab had a share of 12.89% and 13.93%, respectively [34]. They also found savings over six years after the biosimilar entry to the market. A similar study explores the utilization of infliximab and filgrastim on the US market and it was one of the first matching the importance of biosimilar products [35]. The cost savings are considered as benefits from the introduction of biosimilars [36]. Other authors also prove that biosimilars not only decrease the prices but also increase the utilization but still there are concerns for their interchangeability [37,38].

The other study discussed the market drivers for biosimilars [39]. The authors confirm that there is a correlation between the biosimilar penetration and price decrease. They consider that incentive policies to enhance uptake remain an important driver of biosimilar penetration. The only incentive that is available at the moment in Bulgaria is that the price of biosimilar should be no more than 80% of the price of originator, but it was introduced in the legislation just in 2018 so it does not affect the whole period studied [40]. Therefore, we could not consider that this change in regulation is influencing the price decrease during the whole period.

### **4. Materials and Methods**

The study utilized a combined quantitative and qualitative analysis of time of entry of biosimilars on the national market and the respective changes in the prices and utilization of biologic disease modifying antirheumatic drugs (bDMARD).

### *4.1. Qualitative Analysis*

The qualitative analysis included comparisons of market entry of biosimilars—their time of approval and entry onto the Bulgarian market. Information regarding all authorized biosimilars and approval of their new indications till the end of 2019 was taken from the EMA webpage [41]. Subsequently, the Internet page of the National Council of Prices and Reimbursement (NCPR) [42] was searched for reimbursed biosimilars up until the end of 2020.

The availability was presented as the number of biosimilars per international nonproprietary name (INN), authorized by EMA and available on the European market, which was then compared to the date of product entry into the reimbursement list on the national market.

### *4.2. Quantitative Analysis*

After the qualitative analysis, we selected a single therapeutic group-biologic disease modifying antirheumatic drugs (bDMARs) for further analysis. The choice was based upon the fact that this therapeutic group had the largest number of reimbursed biological and biosimilar products for the longest duration of time. Under inflammatory joint diseases we encompass rheumatoid arthritis (RA), psoriatic arthritis (PSA), and ankylosing spondylitis (AS) because those are the most often reimbursed diagnoses.

Two data sources were accessed for the quantitative analysis—the National Health Insurance Fund (NHIF) and the NCPR. From the NHIF we extracted data on the reimbursed expenditures for the period 2015–2019 of bDMARD for inflammatory joint disease medicines. The changes in expenditures for every year are presented in national currency (BGN) at the exchange rate of 1 BGN = 0.95 Euro. The exchange rate of BGN to Euro in Bulgaria has been fixed since 1997.

The NCPR database was accessed retrospectively to follow changes in medicine reference prices per defined daily dose (DDD) and per INN throughout the period 2015–2020. The reference price per DDD is the lowest reimbursed price per DDD.

Utilization of the medicines for inflammatory joint diseases was analyzed in monetary units and in DDD/1000inh/day by using the WHO formula ((Sales data/DDD/number of inhabitants/365) × 1000) [43].

### *4.3. Statistical Analysis*

Friedman's variant of ANOVA was applied for all years for which data was available to follow the changes in prices and utilization. Where a new medicine was introduced, and data was available only for two years, a Wilcoxon nonparametric analysis was applied to analyze the changes in therapy for all biologics. *p*-values of less than 0.05 were considered statistically significant. The software package MedCalc version 19.6 was used.

### **5. Conclusions**

Our study shows that the entrance of biosimilars in the country is relatively slow because only half of the authorized biosimilars in Europe are reimbursed. Introduction of biosimilars decreases the prices and changes the utilization significantly but other factors might also contribute to this.

**Author Contributions:** Conceptualization, G.P. and K.T.; methodology, Z.M., K.T.; formal analysis, K.T., Z.M., V.B., G.P., data curation G.P., Z.M.; statistical analysis, K.T.; writing, K.T., Z.M., V.B., G.P.; supervision, G.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data sharing not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**


### *Article* **Simulating Costs of Intravenous Biosimilar Trastuzumab vs. Subcutaneous Reference Trastuzumab in Adjuvant HER2-Positive Breast Cancer: A Belgian Case Study**

**Steven Simoens 1,\* , Arnold G. Vulto 1,2 and Pieter Dylst <sup>3</sup>**


**Abstract:** This study aimed to compare drug costs and healthcare costs of a 1 year adjuvant course with intravenous biosimilar trastuzumab vs. subcutaneous reference trastuzumab in HER2-positive breast cancer from the Belgian hospital perspective. Our simulation is based on the methodology used by Tjalma and colleagues, and considered costs of drugs, healthcare professional time and consumables. We calculated intravenous drug costs for different body weights, and computed drug costs and healthcare costs to treat 100 patients with either trastuzumab formulation, assuming a binomial body weight distribution in this sample. Scenarios were run to account for drug discounts and intravenous vial sharing. Drug costs amounted to €1,431,282 with intravenous biosimilar trastuzumab and €1,522,809 with subcutaneous reference trastuzumab for a sample of 100 patients in the base case analysis. When healthcare professional time and consumables were also considered, healthcare costs with intravenous biosimilar trastuzumab were similar to those with subcutaneous reference trastuzumab. Differences in healthcare costs between intravenous biosimilar trastuzumab and subcutaneous reference trastuzumab depended on the level of discounts on these formulations and on intravenous vial sharing. Our case study demonstrates that comparing costs of intravenous vs. subcutaneous formulations is complex and multifactorial, and entails more than a simple cost comparison of products.

**Keywords:** trastuzumab; biosimilar; intravenous; subcutaneous; HER2-positive breast cancer; drug costs; healthcare costs; cost simulation

### **1. Introduction**

Trastuzumab has played, and continues to play, a pivotal role in the standard firstline treatment of HER2-positive breast cancer for approximately two decades. Initial approval was based on the significant overall survival advantage demonstrated in key clinical trials in both the metastatic [1–3] and adjuvant [4,5] breast cancer settings. Until relatively recently, trastuzumab was administered using intravenous (IV) regimens either as monotherapy or, more usually, in combination with chemotherapy or biologic therapy. A subcutaneous (SC) formulation of trastuzumab was subsequently developed and was approved for use in Europe. The IV and SC formulations of trastuzumab show comparable pharmacokinetics [6–8], and have been reported to have equivalent (non-inferior) efficacy and tolerability in the HannaH, PrefHer and MetaspHer clinical studies [9–11]. In 2020, the global ex-factory turnover of reference trastuzumab accounted for more than US\$4 billion [12].

A drug cost comparison at 2017 ex-factory prices in Belgium has been performed for the IV and SC formulations of reference trastuzumab for patients in different weight categories [13]. The calculation for a total of 18 cycles of adjuvant trastuzumab showed

**Citation:** Simoens, S.; Vulto, A.G.; Dylst, P. Simulating Costs of Intravenous Biosimilar Trastuzumab vs. Subcutaneous Reference Trastuzumab in Adjuvant HER2-Positive Breast Cancer: A Belgian Case Study. *Pharmaceuticals* **2021**, *14*, 450. https://doi.org/ 10.3390/ph14050450

Academic Editor: Jean Jacques Vanden Eynde

Received: 16 April 2021 Accepted: 7 May 2021 Published: 11 May 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

higher drug costs with the SC formulation for patients weighing >75 kg and with the IV formulation for those weighing <75 kg. The main reason for this was the single fixed available dose for the SC formulation (600 mg). formulation for those weighing <75 kg. The main reason for this was the single fixed available dose for the SC formulation (600 mg). A biosimilar is a biological medicine that is highly similar to another already ap-

higher drug costs with the SC formulation for patients weighing >75 kg and with the IV

*Pharmaceuticals* **2021**, *14*, x FOR PEER REVIEW 2 of 7

A biosimilar is a biological medicine that is highly similar to another already approved biological medicine (the "reference medicine") and does not show clinically meaningful differences from the reference medicine with respect to pharmaceutical quality, efficacy, and safety [14]. Several IV trastuzumab biosimilars have reached advanced stages of clinical development globally [15], some of which are available in Europe. proved biological medicine (the "reference medicine") and does not show clinically meaningful differences from the reference medicine with respect to pharmaceutical quality, efficacy, and safety [14]. Several IV trastuzumab biosimilars have reached advanced stages of clinical development globally [15], some of which are available in Europe. The aim of this case study was to compare drug costs and healthcare costs of IV bio-

The aim of this case study was to compare drug costs and healthcare costs of IV biosimilar trastuzumab vs. SC reference trastuzumab (Herceptin®, Roche) as adjuvant treatment for one year in women with HER2-positive breast cancer from the hospital perspective in Belgium as an example to show the multifactorial character of an at-first-sight simple comparison. Our study is based on the methodology used by Tjalma and colleagues [13,16]. similar trastuzumab vs. SC reference trastuzumab (Herceptin®, Roche) as adjuvant treatment for one year in women with HER2-positive breast cancer from the hospital perspective in Belgium as an example to show the multifactorial character of an at-first-sight simple comparison. Our study is based on the methodology used by Tjalma and colleagues [13,16].

### **2. Results 2. Results**

Drug costs for a 1 year course of adjuvant treatment with IV biosimilar trastuzumab (at 2020 Belgian list prices) ranged from €17,858 for a patient weighing 87.5 kg to €10,244 for a patient weighing 50 kg (see Figure 1). In the case of a 1 year course with SC reference trastuzumab, drug costs amounted to €15,228, irrespective of patient body weight. Thus, treatment with IV biosimilar trastuzumab was less expensive in terms of drug costs than with SC reference trastuzumab for patients weighing up to 75 kg (see Figure 1). Drug costs for a 1 year course of adjuvant treatment with IV biosimilar trastuzumab (at 2020 Belgian list prices) ranged from €17,858 for a patient weighing 87.5 kg to €10,244 for a patient weighing 50 kg (see Figure 1). In the case of a 1 year course with SC reference trastuzumab, drug costs amounted to €15,228, irrespective of patient body weight. Thus, treatment with IV biosimilar trastuzumab was less expensive in terms of drug costs than with SC reference trastuzumab for patients weighing up to 75 kg (see Figure 1).

**Figure 1.** Drug costs for 1 year course of adjuvant treatment with IV biosimilar trastuzumab or with SC reference trastuzumab. **Figure 1.** Drug costs for 1 year course of adjuvant treatment with IV biosimilar trastuzumab or with SC reference trastuzumab.

We next determined the difference in healthcare costs (i.e., drug costs, healthcare professional time costs and consumables costs) between the IV and SC formulations. This calculation took into account that the IV trastuzumab administration was previously estimated to cost €907.20 per course more than SC administration in terms of healthcare professional time costs and consumables costs [16]. Figure 2 shows that healthcare costs for a 1 year course of adjuvant treatment with IV biosimilar trastuzumab were lower than costs with SC reference trastuzumab for a patient weighing 50 kg, for a patient weighing 56.25 kg and for a patient weighing 62.5 kg. Healthcare costs with IV biosimilar trastuzumab exceeded those with SC reference trastuzumab for a patient weighing 75 kg, for a patient weighing 84 kg and for a patient weighing 87.5 kg; the reason being that IV trastuzumab is dosed on a mg/kg basis and the SC formulation has a fixed dose for all body weights. We next determined the difference in healthcare costs (i.e., drug costs, healthcare professional time costs and consumables costs) between the IV and SC formulations. This calculation took into account that the IV trastuzumab administration was previously estimated to cost €907.20 per course more than SC administration in terms of healthcare professional time costs and consumables costs [16]. Figure 2 shows that healthcare costs for a 1 year course of adjuvant treatment with IV biosimilar trastuzumab were lower than costs with SC reference trastuzumab for a patient weighing 50 kg, for a patient weighing 56.25 kg and for a patient weighing 62.5 kg. Healthcare costs with IV biosimilar trastuzumab exceeded those with SC reference trastuzumab for a patient weighing 75 kg, for a patient weighing 84 kg and for a patient weighing 87.5 kg; the reason being that IV trastuzumab is dosed on a mg/kg basis and the SC formulation has a fixed dose for all body weights.

**Figure 2.** Difference in healthcare costs of 1 year course of adjuvant treatment with IV biosimilar trastuzumab as compared with SC reference trastuzumab. **Figure 2.** Difference in healthcare costs of 1 year course of adjuvant treatment with IV biosimilar trastuzumab as compared with SC reference trastuzumab.

When calculated for a sample of 100 patients, the difference in drug costs between the IV and SC formulations amounted to €91,527 (see Table 1). When also considering healthcare professional time and consumables, healthcare costs for a 1 year course of adjuvant treatment with IV biosimilar trastuzumab were similar to those with SC reference trastuzumab (i.e., savings of €807 with IV biosimilar trastuzumab). Furthermore, Table 1 shows that differences in healthcare costs between IV biosimilar trastuzumab and SC reference trastuzumab depended on the level of discounts on these formulations. In a scenario assuming a discount of 50% on IV biosimilar trastuzumab and 20% on SC reference trastuzumab, savings in healthcare costs of €411,886 were generated by treating 100 patients with IV biosimilar trastuzumab as compared to SC reference trastuzumab. These savings increased to €430,192 when IV vial sharing is considered. When calculated for a sample of 100 patients, the difference in drug costs between the IV and SC formulations amounted to €91,527 (see Table 1). When also considering healthcare professional time and consumables, healthcare costs for a 1 year course of adjuvant treatment with IV biosimilar trastuzumab were similar to those with SC reference trastuzumab (i.e., savings of €807 with IV biosimilar trastuzumab). Furthermore, Table 1 shows that differences in healthcare costs between IV biosimilar trastuzumab and SC reference trastuzumab depended on the level of discounts on these formulations. In a scenario assuming a discount of 50% on IV biosimilar trastuzumab and 20% on SC reference trastuzumab, savings in healthcare costs of €411,886 were generated by treating 100 patients with IV biosimilar trastuzumab as compared to SC reference trastuzumab. These savings increased to €430,192 when IV vial sharing is considered.


**Table 1.** Drug costs and healthcare costs of treating 100 patients with IV biosimilar trastuzumab vs. SC reference **Table 1.** Drug costs and healthcare costs of treating 100 patients with IV biosimilar trastuzumab vs. SC reference trastuzumab.

### IV-SC −€807 €17,498 −€197,194 €31,227 −€411,886 **3. Discussion**

and IV vial sharing.

**3. Discussion**  This study has simulated drug costs and healthcare costs for a 1 year course of adjuvant treatment with either IV biosimilar trastuzumab or SC reference trastuzumab in HER2-positive breast cancer patients in Belgium. Our results indicated that the cost difference between IV and SC formulations depends on patient body weight, drug discounts This study has simulated drug costs and healthcare costs for a 1 year course of adjuvant treatment with either IV biosimilar trastuzumab or SC reference trastuzumab in HER2 positive breast cancer patients in Belgium. Our results indicated that the cost difference between IV and SC formulations depends on patient body weight, drug discounts and IV vial sharing.

In our base case analysis, drug costs were less for IV biosimilar trastuzumab for a patients weighing less than 75 kg. The median weight of women with breast cancer is invariably <75 kg and has ranged from 64 to 72 kg in European studies comparing IV and SC reference trastuzumab administration [17–20]. Therefore, it can be expected that drug costs of IV biosimilar trastuzumab would be lower than for SC reference trastuzumab for the majority of patients.

When considering healthcare costs, our base case analysis took into account that IV administration is associated with more costs related to healthcare professional time and consumables than SC administration, in addition to differences in drug costs. However, savings in healthcare professional time and consumables with SC administration might not be as high when trastuzumab is given in combination with chemotherapy. When trastuzumab is administered in combination with chemotherapy, this is usually for the first 6–8 cycles of 18 cycles during adjuvant therapy. During these 6–8 cycles, there are potential cost savings with respect to healthcare professional time and consumables with IV trastuzumab administration by piggy backing on the costs that must be applied for IV chemotherapy administration during concurrent or sequential administration. The combination of trastuzumab with chemotherapy is usual practice (94%) during adjuvant therapy across German hospitals [21], whereas trastuzumab monotherapy is the norm in the Southeast Netherlands (100%) [22] and most common in Southeast Wales (83%) [23].

Multiple studies have reported that SC reference trastuzumab administration is associated with less indirect costs related to productivity loss than IV administration [16,19,20]. Our analysis did not consider productivity loss and, hence, underestimated savings of SC vs. IV trastuzumab administration. However, such indirect costs associated with trastuzumab administration (irrespective of administration route) are relatively low (1–4%) when compared to total costs [24].

When we applied healthcare cost estimates to a sample of 100 patients, lower drug costs with IV biosimilar trastuzumab as compared to SC reference trastuzumab offset higher costs of healthcare professional time and consumables in our base case analysis. Also, we ran scenario analyses accounting for drug discounts and for the re-use of IV vial leftovers. We believe that these scenarios more accurately reflect market and clinical practices in Belgium, even though the related input parameters are associated with more uncertainty and resulting cost difference estimates are illustrative rather than exact. In terms of generalizability to other healthcare systems, healthcare cost differences between these trastuzumab formulations of course depend on the difference between the drug procurement cost and reimbursement rate, on local healthcare professional and consumable costs, and on the hospital or retail setting in which IV and SC formulations are typically provided.

Our results are in line with those of an Italian study [25], which found that treatment with IV biosimilar trastuzumab was less expensive than with SC reference trastuzumab in patients weighing less than a specific threshold. Also, this study corroborated our finding that, when vial leftovers are used for other patients, savings with IV biosimilar trastuzumab grew.

We hope that our case study contributes to a more differentiated view on the difference between IV and SC formulations beyond the bare price of the products alone. Indeed, we acknowledge that other factors may also play important roles like the business models of hospitals and the earning system of physicians. A hospital that is short in IV administration capacity, and gains limited earnings from IV administrations, may like to avoid investments to expand such (expensive) capacity. On the other hand, if physician reimbursement for IV administration is higher than for SC administration, then it will be attractive for physicians to favor the former. In a number of countries, parenteral drugs are increasingly being administered outside the hospital, closer to where patients are living. Such initiatives are more dependent on the availability of SC formulations.

There are a number of limitations in our study. The estimate of cost savings related to healthcare professional time and consumables with SC trastuzumab administration related to 2017 [16], while drug prices related to 2020. Although the former are likely to have increased since then, this is unlikely to change our result that healthcare cost differences between IV and SC trastuzumab formulations depend on patient body weight. Also, any analysis is dependent on the potential for changing prices and discounts that might be offered in particular situations for both IV biosimilar trastuzumab and SC reference trastuzumab, as underlined by our sensitivity analysis.

Few studies have explored cost differences between IV biosimilar trastuzumab and SC reference trastuzumab [26]. More research is required that replicates our cost estimates in healthcare systems that are organized and financed differently than in Belgium and that takes into account market dynamics and shifts in prescribing practices between different trastuzumab formulations.

### **4. Materials and Methods**

Calculations of drug costs for IV biosimilar trastuzumab vs. SC reference trastuzumab were conducted in the same manner and following the same methods as reported for the comparison of IV vs. SC reference trastuzumab in the study by Tjalma and colleagues [13]. Drug costs were compared for a 1 year trastuzumab course in the adjuvant HER2-positive breast cancer setting in Belgium. For IV biosimilar trastuzumab, there is an initial loading dose of 8 mg/kg infused over 90 min, followed by maintenance doses of 6 mg/kg infused over 30 min every 3 weeks for a total of 18 cycles. For SC reference trastuzumab, the equivalent schedule of 600 mg SC is administered by slow injection over 2–5 min every 3 weeks for 18 cycles. For each treatment (IV biosimilar vs. SC reference), the number of vials required per patient was determined for different patient body weights (87.5, 84, 75, 62.5, 56.25 and 50 kg) and was rounded to the next highest half vial (as is usual practice). The number of vials was then multiplied by the ex-factory list price in 2020 to calculate drug costs. List prices were reduced by 15% given that Belgian hospitals can only invoice 85% of a drug's list price to the National Institute for Health and Disability Insurance once a biosimilar is available [27]. All prices were exclusive of tax. The 85% list price of IV biosimilar trastuzumab (Herzuma®) was €276.87 per 150 mg vial and that for SC reference trastuzumab (Herceptin®) was €846.01 per 600 mg vial [28].

Next, we compared healthcare costs for IV biosimilar trastuzumab vs. SC reference trastuzumab at the previously defined different patient body weights (see above) by taking into consideration potential savings through SC use that have been previously estimated by Tjalma and colleagues [16]. They estimated savings at 2017 prices of SC vs. IV administration of €907.20 per course related to healthcare professional (i.e., nurse, pharmacist and assistant) and consumables (e.g., syringes, needles, alcohol, swabs, etc.) costs. Oncologist time was not included as a healthcare professional cost as this consultation visit was assumed to be the same for both the IV and SC reference formulations.

Drug costs and healthcare costs to treat 100 patients with either trastuzumab formulation were then calculated assuming the following numbers of patients in each body weight category: 87.5 kg (*n* = 7); 84.0 kg (*n* = 16); 75.0 kg (*n* = 25); 62.5 kg (*n* = 25); 56.25 kg (*n* = 20); and 50.0 kg (*n* = 7). This distribution of patients by body weight category was based on the binomial distribution normally found among patients with early-stage HER2-positive breast cancer [17–20].

In addition to the base case analysis, we conducted a sensitivity analysis that accounts for discounts offered by the manufacturer to the hospital. As discounts are confidential, we ran multiple scenarios, but the scenario assuming a discount of 50% on the IV biosimilar formulation and 20% on the SC reference formulation was deemed most realistic after consultation with an industry expert.

The base case analysis used an IV vial (or half a vial for IV trastuzumab in Belgium) as the unit of measurement. Hence, costs associated with the total number of vials administered over 18 cycles were calculated, even if some of the last vial's contents had to be discarded. However, in clinical practice, any drug not used may not necessarily be wasted but rather used for other patients scheduled for treatment in parallel on the same day [20]. This practice is common in many countries [24] and also appears to be the practice in

Belgian hospitals. If hospitals use the potentially wasted drug in other patients, it will generate savings from the hospital perspective. Therefore, we ran a second scenario in which cost estimates accounted for discounts and reflected actual use of the IV biosimilar formulation (i.e., not rounded to the next half vial).

All calculations were performed in Microsoft Excel 2016.

**Author Contributions:** Conceptualization and methodology, P.D.; formal analysis: P.D. and S.S.; writing—review and editing: S.S., A.G.V. and P.D. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Access to data supporting reported results can be requested from the corresponding author.

**Acknowledgments:** Medical writing support was provided by Peter Todd of Tajut Ltd. (Kaiapoi, New Zealand) and was funded by Mundipharma Comm. VA (Mechelen, Belgium).

**Conflicts of Interest:** S.S. and A.G.V. are among the founders of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL). S.S. was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD; he has participated in advisory board meetings for Pfizer and Amgen; he has contributed to studies on biologics and biosimilars for Hospira, Celltrion and Pfizer; and he had speaking engagements for Amgen, Celltrion and Sandoz. P.D. was an employee of Mundipharma at the time of conceptualizing and conducting the analysis.

### **References**


### *Article*

### **Learnings from Regional Market Dynamics of Originator and Biosimilar Infliximab and Etanercept in Germany**

**Evelien Moorkens 1,**† **, Teresa Barcina Lacosta 1,**† **, Arnold G. Vulto 1,2,\* , Martin Schulz 3,4,5 , Gabriele Gradl <sup>5</sup> , Salka Enners <sup>5</sup> , Gisbert Selke <sup>6</sup> , Isabelle Huys 1,**‡ **and Steven Simoens 1,**‡


Received: 7 August 2020; Accepted: 17 October 2020; Published: 21 October 2020

**Abstract:** Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the influence of biosimilar policies on these dynamics. This study is based on: (1) a literature review in which German biosimilar policies are identified, (2) the analysis of dispensing data (2010–2018) for the class of TNFα inhibitors, and (3) ten semi-structured interviews investigating prescribers' and insurers' views on factors potentially influencing biosimilar uptake. The analysis of biosimilar market shares of infliximab and etanercept revealed wide variations across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions). Quantitative analyses indicated that biosimilar market shares for infliximab and etanercept were significantly lower in former East Germany when compared to former West Germany regions. Through qualitative interview analyses, this study showed that the use of infliximab and etanercept biosimilars across Germany is primarily influenced by (1) the regional-level implementation of biosimilar quotas and the presence of monitoring/sanctioning mechanisms to ensure adherence to these quotas, (2) the different insurer-manufacturer discount contracts, and (3) gainsharing arrangements established at the insurer-prescriber level.

**Keywords:** infliximab; etanercept; TNFα inhibitors; biologics; biosimilars; Germany; policies; incentives; uptake; market dynamics

### **1. Introduction**

The incorporation of biologic therapies into clinical practice has positively transformed health outcomes for many patients diagnosed with severe and highly debilitating chronic conditions [1–3]. As a result, these therapies have represented a growing market in recent decades (accumulated global sales of USD 312 billion in 2018) [4]. Being approved for an increasing number of disease areas, high-cost biologic therapies constitute an important budget impact to be managed by healthcare systems across Europe [5]. However, with the expiration of patents and other exclusivity rights for biologics, non-innovator and therapeutically equivalent versions, i.e., biosimilars, enter the market with the potential to create competition within the therapeutic classes [6]. This leads to altered market dynamics and potentially to decreasing treatment costs and increasing patient access to biologic therapies [7].

Germany, with 83 million inhabitants [8], is the most populous country of the European Union and is an important market for biologics and biosimilars [9,10]. Here, sales of biologics amounted to EUR 11 billion in 2017 [11]. An important class of biologics that has been subject to competition by biosimilars is that of TNFα inhibitors (sales of EUR 2.2 billion in 2017 for Germany) [4]. Five active substances with a TNFα neutralizing activity (infliximab, etanercept, adalimumab, golimumab and certolizumab pegol) are available for the treatment of immune-mediated inflammatory diseases [12]. The originator products—Remicade® (infliximab), Enbrel® (etanercept) and Humira® (adalimumab)—have been present in the German pharmaceuticals market for more than 15 years now. In 2013, infliximab biosimilars under the names Inflectra® and Remsima® received marketing authorization by the European Medicines Agency (EMA) and accessed different European markets. Consequently, in 2015, Inflectra® and Remsima® were launched in Germany. They were followed by the market entry of infliximab biosimilars Flixabi® (2016) and Zessly® (2018). In the case of etanercept, biosimilar products Benepali® and Erelzi® were brought to the German market in 2016 and 2017, respectively [11]. The offer of TNFα inhibitors has been expanded with the incorporation of adalimumab biosimilars Imraldi®, Hyrimoz®, Amgevita®, Hulio® in the last quarter of 2018 and the posterior market launch of Idacio ® (2019) and awaits further developments, once exclusivity rights for Cimzia® (certolizumab pegol) and Simponi® (golimumab) have expired in 2021 and 2024, respectively [13,14].

The German law for more safety in the supply of pharmaceuticals (German: Gesetz für mehr Sicherheit in der Arzneimittelversorgung, GSAV June 2019) has been recently amended to optimize the use of biosimilar products as a cost-containment tool [15]. The introduced changes would provide a more favorable environment for the close monitoring of biosimilar regional market dynamics at the federal level. This is of relevance based on the decentralized organization of the German healthcare system, where the German regions are responsible for managing prescription and drug budget control activities. Regional differences in biosimilar policies and practices have been associated with the heterogeneous uptake of biosimilars between product classes and across regions [15–18]. In Germany, differences in biosimilar market shares were described for TNFα inhibitors at the end of 2018: in Westphalia-Lippe and Lower Saxony, biosimilar uptake was two times higher than in Baden-Württemberg. However, reasons behind the variable uptake of biosimilars across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions; German: Kassenärztliche Vereinigungen (KV)) have not been examined in detail [19].

In this study, we analyze the regional market dynamics of TNFα inhibitors following the entry of biosimilars for infliximab and etanercept, and investigate the influence of diverse factors, especially biosimilar policies and practices, on biosimilar uptake. This study builds on previous research analyzing regional market dynamics of infliximab and etanercept originators and biosimilars in Sweden (see Box 1) [17,18].

### **Box 1.** Summary of what is already known about this topic and the added value of the study.

### **What is already known about this topic**


### **What this study adds**


### **2. Results**

### *2.1. Overview of TNF*α *Inhibitor Dynamics in the German Healthcare System*

### 2.1.1. The German Market for TNFα Inhibitors

In Germany, the federal and regional governments delegate certain healthcare responsibilities to self-regulated organizations of payers and providers that can operate within the Statutory Health Insurance (SHI; German: Gesetzliche Krankenversicherung (GKV)) scheme or the substitutive Private Health Insurance (PHI; German: Private Krankenversicherung (PKV)) scheme. Within SHI, the main payers are multiple membership-based not-for-profit insurance companies (sickness funds; German: Krankenkassen), which may function nationwide or at the regional level [20]. According to SHI data, originator products Humira®, Enbrel® and Simponi® and a biosimilar version of Enbrel® (Benepali®) still ranked in 2018 among the top 30 contributors to pharmaceutical expenditure [19]. Due to the scheme for care delivery in Germany, most of this expenditure is managed by the ambulatory sector, through which the majority of prescriptions for TNFα inhibitors are issued. In Germany, there is a clear distinction in the provision of outpatient and hospital care. Outpatient care is delivered by individual doctor practices and specialized medical centers, where services are provided that are usually a hospital competence across Europe [21,22]. In this sense, most prescriptions for intravenous infliximab (70% issued by gastroenterologists) and subcutaneous etanercept (87% issued by rheumatologists) go through the German ambulatory sector [11]. Within this sector, sickness funds negotiate overall prescription budgets with the Federal Association of Statutory Health Insurance Physicians (German: Kassenärztliche Bundesvereinigung (KBV)). They also contract prescription budgets for the regions through negotiations with the 17 German PA regions. Although Germany is divided into 16 federal states (German: Bundesländer), the areas Northrhine and Westphalia-Lippe within the state of Northrhine-Westphalia are represented by two independent PA regions [19].

### 2.1.2. Regulations of the German Market for TNFα Inhibitors

TNFα inhibitor therapies entered the German market under a free-pricing and full reimbursement scheme (up to a patient co-payment of at most EUR 10 per pack dispensed). However, lower list prices are expected for biosimilars when compared to the originator. While price setting for pharmaceuticals in the hospital market is unregulated and established through direct hospital-manufacturer negotiations, some instruments for regulation are applicable to the retail market [19]. For example, reference price groups were established for infliximab and etanercept in accordance with §35 German Social Code Book V (German: Sozialgesetzbuch V (SGB V)) [23]; the reference price acts as a reimbursement limit, with any overshooting cost borne by the patient. The inclusion of all infliximab-containing products into a reference price group resulted in a 22% reduction in Remicade®'s selling price at the end of

2018 [19]. Until recently, the German Legislation (§129 SBG V) only allowed automatic substitution for bioidenticals (i.e., biosimilars made by the same production site and process, as is the case for Inflectra® and Remsima®) [19]. Modifications of the law for more safety in the supply of pharmaceuticals (GSAV) have extended these regulations to non-bioidentical biosimilars, provided that the Federal Joint Committee (German: Gemeinsamer Bundesausschuss (G-BA)) recognizes interchangeability [15]. Based on the restrictions for automatic substitution of biologics, the type of procurement contract (§130a SGB V) usually applied to generics has been deemed inadequate for biosimilars. Despite the various alternative procurement mechanisms possible (e.g., tendering), insurance companies mostly rely on the organization of "open-house rebate contracts" (German: Open-House-Rabattverträge) in which all suppliers of originator biologics and biosimilars can participate. Participants in "open-house rebate contracts" qualify to sign a supply contract if they adhere to certain pre-defined contractual conditions, including mandatory discounts on list prices. These conditions are freely set by the insurer and cannot depend on individual negotiations with certain suppliers [19].

The market for TNFα inhibitors is indirectly regulated through the establishment of prescribing targets. Every year, the National Association of Statutory Health Insurance Funds (German: Gesetzliche Krankenversicherung-Spitzenverband (GKV-SV) and KBV agree on target areas for prescribing control (biosimilars included). For these areas, they use the previous year's prescription rates to set recommendations. The output of this negotiation is reflected in a non-binding contract (German: Bundesrahmenvorgaben für die Arzneimittelvereinbarungen) that serves as a guideline for regional agreements. Insurer companies and regional physician associations look at the national advisory agreement and define implementation details for contracts which are binding at the regional level (German: Arzneimittelvereinbarungen). Minor deviations are allowed, as long as the overall cost-containment effect is achieved. This means that regional physician associations are not forced to rely on biosimilar prescription quotas. Instead, they can give more importance to alternative cost-containment mechanisms that still meet the general objective [19].

### *2.2. Analysis of Dispensing Data for TNF*α *Inhibitors*

### 2.2.1. TNFα Inhibitor Products: Evolution in Sales Volume

Overall, in Germany, the sales volume of TNFα inhibitor products has increased over time (from 17.68M defined daily doses (DDDs) in 2010 to 42.06M DDDs in 2018). From 2010 to 2018, sales volume for infliximab and adalimumab increased over two-fold, and 1.8-fold for etanercept (see Figure 1). The rise in the sales volume of TNFα inhibitors has been attributed to several factors (e.g., the lower threshold at which treatment with biologics is initiated, changes in the dosing regimen) [24,25]. In the case of infliximab and etanercept, the data in this study showed that year-over-year increases (%) in use occurred shortly after biosimilar entry (13.4% increase for infliximab and 13.7% increase for etanercept).

The compound annual growth rate (CAGR) of sales volume (DDDs) indicated different growth trends for infliximab and etanercept (see Figure 1). While growth intensified for etanercept in the last few years, it decreased in the case of infliximab. This suggests a saturation of the market for infliximab, which has been subject to the competitive pressure of TNFα inhibitor therapies with a different administration profile and approval for an extended range of indications [7].

Figure 2 shows the composition of the market for TNFα inhibitors in terms of individual products from 2010 until 2018. In 2010, the greatest volume share corresponded to adalimumab (40%), while the shares for infliximab and etanercept were 21% and 34%, respectively. The volume share for the innovative products Cimzia® and Simponi® amounted to 5%. During a nine-year time period, the volume share for adalimumab remained stable, while the shares for infliximab and etanercept decreased in favor of the originator therapies Cimzia® and Simponi®. The data represented in Figure 2 indicate that the market entry of infliximab biosimilars (2015) has not induced a shift in prescribing trends from other TNFα inhibitor originator products (Enbrel®, Humira®, Cimzia®, Simponi®) towards

German Regions

volume of TNFα inhibitors.

Figure 3).

infliximab-containing products. This observation also applies to the entry of etanercept biosimilars in 2016. *Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 5 of 21

**Figure 1.** Sales volume evolution (2010–2018) expressed as a percentage of 2010 volume and measured as defined daily doses (DDDs) for originator and biosimilar products containing infliximab, etanercept and adalimumab (primary axis). Year-over-year (YoY) growth (%) is represented on the secondary axis. Compound annual growth rate (CAGR) is calculated before and after biosimilar launch. The graphical representation of the data is based on a figure published by IQVIA [26]. **Figure 1.** Sales volume evolution (2010–2018) expressed as a percentage of 2010 volume and measured as defined daily doses (DDDs) for originator and biosimilar products containing infliximab, etanercept and adalimumab (primary axis). Year-over-year (YoY) growth (%) is represented on the secondary axis. Compound annual growth rate (CAGR) is calculated before and after biosimilar launch. The graphical *Pharmaceuticals*  representation of the data is based on a figure published by IQVIA [ **2020**, *13*, x FOR PEER REVIEW 6 of 21 26].

**Figure 2.** Composition of the market for TNFα inhibitors in terms of individual products from 2010 to 2018. The sales volume (DDDs) for infliximab (originator + biosimilars), etanercept (originator + biosimilars), adalimumab (originator + biosimilars), certolizumab pegol and golimumab is expressed as a share of the total volume of TNFα inhibitors. **Figure 2.** Composition of the market for TNFα inhibitors in terms of individual products from 2010 to 2018. The sales volume (DDDs) for infliximab (originator + biosimilars), etanercept (originator + biosimilars), adalimumab (originator + biosimilars), certolizumab pegol and golimumab is expressed as a share of the total volume of TNFα inhibitors.

**Figure 3.** Composition of the market for TNF α inhibitors in terms of biosimilar products (2015–2018). Biosimilar market shares (%) for infliximab and etanercept are calculated in relation to the total

2.2.2. Infliximab and Etanercept Biosimilars and Originators: Evolution in Market Shares for the

0

10

20

30

40

50

**Percent volume share (DDD)**

60

70

80

90

100

2.2.2. Infliximab and Etanercept Biosimilars and Originators: Evolution in Market Shares for the German Regions 2.2.2. Infliximab and Etanercept Biosimilars and Originators: Evolution in Market Shares for the German Regions

At the end of 2018, the combination of biosimilar products for infliximab and etanercept represented, in terms of sales volume (DDDs), 25% of the German market for TNFα inhibitors (see Figure 3). At the end of 2018, the combination of biosimilar products for infliximab and etanercept represented, in terms of sales volume (DDDs), 25% of the German market for TNFα inhibitors (see Figure 3).

**Figure 2.** Composition of the market for TNFα inhibitors in terms of individual products from 2010 to 2018. The sales volume (DDDs) for infliximab (originator + biosimilars), etanercept (originator + biosimilars), adalimumab (originator + biosimilars), certolizumab pegol and golimumab is expressed

**Infliximab Etanercept Adalimumab Certolizumab pegol + golimumab**

2010 2011 2012 2013 2014 2015 2016 2017 2018

**21% 20% 21% 20% 20% 19% 18% 20% 20%**

**34% 32% 27% 30% 26% 24% 24% 25% 25%**

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 6 of 21

**5% 7% 8% 9% 12% 15% 17% 17% 17%**

**40% 42% 43% 42% 40% 40% 41% 40% 40%**

**Figure 3.** Composition of the market for TNF α inhibitors in terms of biosimilar products (2015–2018). Biosimilar market shares (%) for infliximab and etanercept are calculated in relation to the total **Figure 3.** Composition of the market for TNF α inhibitors in terms of biosimilar products (2015–2018). Biosimilar market shares (%) for infliximab and etanercept are calculated in relation to the total volume of TNFα inhibitors.

volume of TNFα inhibitors. The level of biosimilar penetration for infliximab and etanercept was comparable (56% and 61%, respectively) in Germany at the end of the third year after biosimilar market entry (see Figure 4). However, regional data on the uptake of infliximab and etanercept biosimilars (Q4 2018) pointed to a wide variation in biosimilar market shares between the 17 German PA regions (see Table 1). In the case of infliximab, the lowest biosimilar market share was observed for Brandenburg (33%), while the largest value was observed for Lower Saxony (87%). In a similar way, there was large variance of market shares for etanercept, with Brandenburg being the region with the lowest biosimilar uptake (33%) and Westphalia-Lippe being the highest (77%). The time evolution analysis of market shares showed that in general, regions with an early adoption of biosimilars (e.g., Northrhine, Westphalia-Lippe) also reached high biosimilar uptake levels (Q4 2018). Exceptions to this trend were identified (e.g., Brandenburg). While Brandenburg behaved as an early adopter of infliximab biosimilars, uptake levels at the end of 2018 were low.

*Pharmaceuticals* **2020**, *13*, 324

**Table 1.** Market shares (%) of biosimilar infliximab and etanercept in Germany's 17 PA regions. Colors gradually change from red to green with increasing biosimilar market shares.


uptake levels at the end of 2018 were low.

The level of biosimilar penetration for infliximab and etanercept was comparable (56% and 61%, respectively) in Germany at the end of the third year after biosimilar market entry (see Figure 4). However, regional data on the uptake of infliximab and etanercept biosimilars (Q4 2018) pointed to a wide variation in biosimilar market shares between the 17 German PA regions (see Table 1). In the case of infliximab, the lowest biosimilar market share was observed for Brandenburg (33%), while the largest value was observed for Lower Saxony (87%). In a similar way, there was large variance of market shares for etanercept, with Brandenburg being the region with the lowest biosimilar uptake (33%) and Westphalia-Lippe being the highest (77%). The time evolution analysis of market shares showed that in general, regions with an early adoption of biosimilars (e.g., Northrhine, Westphalia-Lippe) also reached high biosimilar uptake levels (Q4 2018). Exceptions to this trend were identified

**Figure 4.** Biosimilar penetration for infliximab and etanercept in Germany over time. Biosimilar market shares (%) are calculated as volume of biosimilars over volume of biosimilars plus the originator product (DDDs). **Figure 4.** Biosimilar penetration for infliximab and etanercept in Germany over time. Biosimilar market shares (%) are calculated as volume of biosimilars over volume of biosimilars plus the originator product (DDDs).

**Table 1.** Market shares (%) of biosimilar infliximab and etanercept in Germany's 17 PA regions. Colors gradually change from red to green with increasing biosimilar market shares. **Q1 2015 Q2 2015 Q3 2015 Q4 2015 Q1 2016 Q2 2016 Q3 2016 Q4 2016 Q1 2017 Q2 2017 Q3 2017 Q4 2017 Q1 2018 Q2 2018 Q3 2018 Q4 2018 INFLIXIMAB**  Lower Saxony 2% 11% 17% 24% 26% 34% 40% 48% 74% 76% 83% 84% 88% 88% 87% 87% Biosimilar uptake patterns for infliximab and etanercept were similar across Germany in Q4 2018 (see Figure 5). Indeed, regional biosimilar market shares for infliximab and etanercept were positively correlated (adjusted R<sup>2</sup> = 0.64). This allowed us to identify common low- and high-biosimilar uptake regions. Saxony, Saxony-Anhalt, Brandenburg, Berlin and Baden-Württemberg showed low uptake for both infliximab and etanercept biosimilars. On the contrary, Lower Saxony, Westphalia-Lippe, Bavaria and Northrhine showed high uptake for both infliximab and etanercept biosimilars (see Figure 5c).

Westphalia-Lippe 3% 20% 25% 33% 40% 49% 57% 64% 68% 73% 77% 79% 83% 84% 86% 86% Bavaria 2% 12% 18% 25% 30% 37% 38% 42% 55% 66% 70% 72% 75% 77% 78% 78% Bremen 0% 3% 14% 21% 24% 10% 22% 38% 37% 48% 53% 58% 61% 71% 74% 77% Schleswig Holstein 2% 9% 12% 13% 20% 21% 25% 27% 33% 40% 38% 47% 55% 63% 73% 76% Rhineland Palatinate 1% 11% 17% 25% 25% 37% 41% 47% 55% 59% 60% 69% 69% 70% 62% 70% Northrhine 1% 13% 27% 32% 40% 46% 50% 53% 57% 57% 61% 62% 63% 67% 69% 70% Saarland 3% 24% 22% 24% 31% 33% 44% 49% 61% 57% 61% 63% 65% 67% 67% 69% Hesse 6% 19% 28% 38% 44% 42% 43% 45% 47% 52% 51% 55% 55% 56% 58% 60% Mecklenburg Western Pomerania 0% 0% 7% 8% 11% 12% 12% 25% 22% 28% 46% 43% 42% 43% 48% 58% Thuringia 1% 3% 8% 15% 22% 26% 24% 23% 27% 36% 39% 50% 54% 56% 59% 53% Hamburg 0% 1% 6% 11% 17% 14% 16% 21% 22% 25% 31% 34% 39% 43% 49% 52% Baden-Württemberg 1% 3% 8% 12% 14% 14% 16% 21% 27% 30% 34% 41% 42% 48% 47% 49% Berlin 0% 2% 5% 10% 15% 26% 29% 31% 36% 36% 38% 40% 43% 45% 44% 49% Figure 5 shows a predominant location of low-uptake regions within the regions formerly forming East Germany (Brandenburg, Mecklenburg Western Pomerania, Saxony, Saxony-Anhalt and Thuringia). The statistical analysis conducted (see Section 4) indicated that biosimilar market shares were significantly lower in former East Germany when compared to former West Germany. The dichotomous variable East/West location has been considered a potential co-founder in this study. In order to identify underlying predictor variables behind variable biosimilar uptake, multiple bivariate regression models were conducted to study the statistical association between a number of determinants of socio-economic welfare and regional biosimilar market shares. This is further detailed in Section 4. None of the chosen socio-economic predictor variables were found to be significantly correlated to regional biosimilar market shares.

Saxony-Anhalt 8% 29% 35% 31% 27% 27% 27% 25% 31% 42% 43% 46% 51% 53% 53% 48%

Brandenburg 7% 21% 25% 25% 27% 30% 29% 31% 30% 29% 28% 29% 30% 33% 34% 33%

### Saxony 0% 3% 4% 9% 10% 14% 14% 16% 18% 20% 22% 29% 33% 36% 40% 45% *2.3. The Role of Biosimilar Policies and Practices on Biosimilar Uptake: Interview Results*

**ETANERCEPT**  Physician associations regard biosimilars as a tool for economic prescribing and recommend that physicians initiate eligible patients on biosimilars and switch from the reference product to the biosimilar when possible. The view of physician associations has been generally consistent across Germany, with some discrepancies on the importance given to maintaining the prescriber's choice over an argument of prescribing more economically. Relatively high price differences between the biosimilar and the originator product after discounting were regarded by interviewees as a driver for increased biosimilar use (see Table 2). Sickness fund representatives from the Saxony/Thuringia area signaled that physicians may prefer to prescribe discounted originators over biosimilars when price differences are small. This may explain the comparatively low biosimilar infliximab and etanercept market shares in this area and, in general, in regions formerly forming East Germany. When asked for reasons behind the lower biosimilar uptake in former East Germany regions, interviewees pointed to the past reliance of eastern Germany physicians on the strategies applied by originator companies to

increase customer fidelity. This may have created stronger historical bonds between physicians and originator manufacturers that are still present today. It was also signaled that low biosimilar market shares do not necessarily reflect inefficiency regarding economic prescribing, but reliance on alternative cost-containment mechanisms. *Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 9 of 21

**Figure 5.** (**a**) Market shares (%) of biosimilar infliximab in Q4 2018. (**b**) Market shares (%) of biosimilar etanercept in Q4 2018. (**c**) Low- and high-uptake PA regions which are common for infliximab and etanercept biosimilars in Q4 2018. The dotted pattern refers to regions with high biosimilar uptake for both infliximab and etanercept. The crossed pattern refers to regions with low biosimilar uptake for both infliximab and etanercept. The map templates were extracted from mapchart.net. **Figure 5.** (**a**) Market shares (%) of biosimilar infliximab in Q4 2018. (**b**) Market shares (%) of biosimilar etanercept in Q4 2018. (**c**) Low- and high-uptake PA regions which are common for infliximab and etanercept biosimilars in Q4 2018. The dotted pattern refers to regions with high biosimilar uptake for both infliximab and etanercept. The crossed pattern refers to regions with low biosimilar uptake for both infliximab and etanercept. The map templates were extracted from mapchart.net.

Physician associations regard biosimilars as a tool for economic prescribing and recommend that physicians initiate eligible patients on biosimilars and switch from the reference product to the biosimilar when possible. The view of physician associations has been generally consistent across Germany, with some discrepancies on the importance given to maintaining the prescriber's choice over an argument of prescribing more economically. Relatively high price differences between the biosimilar and the originator product after discounting were regarded by interviewees as a driver for increased biosimilar use (see Table 2). Sickness fund representatives from the Saxony/Thuringia area

*2.3. The Role of Biosimilar Policies and Practices on Biosimilar Uptake: Interview Results* 

market shares in this area and, in general, in regions formerly forming East Germany. When asked for reasons behind the lower biosimilar uptake in former East Germany regions, interviewees pointed **Table 2.** Summary of factors identified to drive biosimilar use and facilitate biosimilar acceptance in Germany. These factors have been identified through the qualitative analysis of interview data.


In contrast, physician and sickness fund representatives from Westphalia-Lippe supported the prescription of biosimilars over originators, regardless of the real price difference realized after discount agreements. Here, the strategic long-term perspective relied on viewing biosimilars as a tool to reduce the increasing economic pressure that threatens the sustainability of the German Healthcare System.

### Incentives for Increased Biosimilar Use

As stated by interviewees, certain policies/practices may affect the market penetration of biosimilars. These can differ between regions and be associated with regional variations in biosimilar market shares. Table 2 summarizes the identified drivers and facilitators for increased biosimilar use in Germany.

The establishment of biosimilar quotas was consistently identified as an important control instrument to drive biosimilar use. Interviewees indicated that the success of quotas depends on the effectiveness of the mechanisms put in place to monitor adherence to these quotas, as well as on the presence of mechanisms to sanction non-adherence. Interviewees agreed on the importance of setting out effective communication strategies to inform physicians about their accomplished prescribing rates and to facilitate biosimilar acceptance. The effectiveness of these strategies would depend to a certain extent on the robustness of the reporting capability of the regional physician associations. Interviewees also indicated that the preferential use of biosimilars over originator products has been driven by the organization of gainsharing contracts between groups of physicians and insurers. An example is the BioLike initiative, launched by the insurer company Barmer GEK for gastroenterologists and rheumatologists in different PA regions (e.g., Hamburg, Saarland, Saxony, Schleswig-Holstein, Thuringia, Westphalia-Lippe). This initiative has led to an increased use of TNFα inhibitor biosimilars and has allowed sharing the realized savings through biosimilar prescriptions between groups of prescribers and the insurer companies [27]. One of the interviewed experts signaled the positive experience of physicians with this initiative in Westphalia-Lippe.

Several German organizations, including the Drug Commission of the German Medical Association (German: Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ)), the Federal Association of German Hospital Pharmacists (German: ADKA - Bundesverband Deutscher Krankenhausapotheker) and the Paul Ehrlich Institute (German: Paul Ehrlich Institut (PEI)), have published favorable statements on the safety of switching between a reference product and its corresponding biosimilars, as well as between biosimilars [28–30]. Interviewees mentioned that the publication of these statements may especially drive biosimilar acceptance in regions where biosimilar uptake has historically been low (e.g., Baden-Württemberg). The views of stakeholders with respect to the benefits of allowing the pharmacy-level automatic substitution of biologics (GSAV) are more divided. While physician representatives have mostly expressed doubts about the added benefit of implementing this policy, insurers have regarded it as an instrument for increased biosimilar use.

Interviewees participating in this study were also asked to identify factors primarily associated to regional variations in biosimilar uptake. Both the differing regional-level implementation of biosimilar quotas and the varying characteristics of procurement contracts appeared as important contributors. Through a comparative analysis of regional agreements for biosimilar prescription quotas, the current

study showed variability in the way the national recommendations have been implemented regionally (see Table 3). Most regions have established binding biosimilar quotas. However, other regions have defined prescribing targets to be interpreted as recommendations. While biosimilar quotas for Westphalia-Lippe and Northrhine have historically been more ambitious than the national reference, Baden-Württemberg has only established non-binding recommendations for specialists known to be more familiar with TNFα inhibitor biosimilars (gastroenterologists and rheumatologists).

**Table 3.** Comparative analysis of regional quota agreements for TNFα inhibitors, based on information available on the websites of the 17 German PA regions [31–47]. Quotas were set either generally for biosimilars or more specifically for the therapeutic group or for each of the active substances within the therapeutic group. Quotas may apply to all prescribers or to specific medical specialties.


A certain flexibility has been allowed as well in the design and implementation of "open-house rebate contracts" established at the insurer-manufacturer level. Interviewees indicated that this may lead to intra- and inter-regional variability in biosimilar uptake. Interviewees in Westphalia-Lippe, Saxony and Thuringia reported the possibility of sickness funds to follow more or less aggressive strategies, depending on the magnitude of the pre-specified discount set as an entry requirement. Contract participants may be asked to offer the maximum level of discount possible and entry requirements may be set in a way that the differences in prices between the contract participants are minimized. These strategies may discourage the participation of originator manufacturers, leading to no discounts being negotiated for the originator. This limits the cost-savings potential that insurers could have attained through lower net prices for originator products. Therefore, insurers may adopt a less aggressive strategy where they ask for the maximum discount that the originator company is willing to provide. This strategy, although it may meet the insurer's cost-containment objectives, results in lower than expected reductions of prices after biosimilar market entry.

### **3. Discussion**

Across Europe, the level of market penetration for biosimilars has been described to be countryand product-class-specific [7,48]. In Germany, we have found similar levels of market penetration for

infliximab and etanercept biosimilars at the end of 2018. However, we had expected higher biosimilar market penetration for etanercept due to the experience already gained by the market presence of infliximab biosimilars. The lower than expected market penetration of etanercept biosimilars could be partly explained by the different competition strategies followed by originator companies, which were reported to be more aggressive in the case of etanercept. Interviewees also indicated that the different administration routes for infliximab (intravenous) and etanercept (subcutaneous) may have played a role. The switch from Enbrel® to etanercept biosimilars implies changes in the administration device used by patients when self-administering the drug, while this is not the case for the switch from Remicade® to infliximab biosimilars.

Previous biosimilar uptake studies in Sweden [17,18] and the current study for Germany have shown that biosimilar market penetration is also region-specific and that there are wide regional variations in biosimilar market shares for TNFα inhibitors [19]. Our study of biosimilar market shares across the German regions showed common high and low uptake regions for infliximab and etanercept biosimilars. The data on market shares for adalimumab biosimilars (up to 2020) [49] indicate that regions where the uptake of infliximab and etanercept biosimilars has been high, also behaved as early adopters for adalimumab biosimilars. Therefore, we presume that biosimilar incentive policies applied regionally have had a consistent effect on the incorporation of biosimilars for the whole class of TNFα inhibitors. This observation might not be applicable to other biologic therapies (e.g., filgrastim, follitropin α) for which biosimilar uptake patterns differ from the patterns described along this study [49]. Several studies have investigated biosimilar policies implemented across Europe to qualitatively assess their impact on biosimilar uptake [50,51]. Instead, the current study examined regional variations in biosimilar uptake in order to derive practices/incentives influencing biosimilar use. Studies published by Moorkens et al. [17,18] followed this approach and were among the first to identify factors driving biosimilar use through quantitative analysis [52–54]. According to Moorkens et al., the absolute/relative difference in discounted price between originator and biosimilars influence decision-making regarding biosimilar use in Sweden [17]. We have not quantitatively evaluated price effects on biosimilar uptake, as information on discounted/rebated prices was not available. However, as described in the following section, we have been able to identify a set of incentive measures driving the use of infliximab and etanercept biosimilars in Germany.

### *3.1. Incentives for Increased Biosimilar Use*

This study described different approaches taken by the German regions to implement a system of biosimilar prescription quotas. More active (e.g., Westphalia-Lippe) and less active (e.g., Baden-Württemberg) approaches were identified. Baden-Württemberg constituted an example of a region where the implementation of biosimilar quotas was lenient and biosimilar uptake levels were low. The role of lenient approaches on lack of adherence to biosimilar quotas has been commonly reported [27,48]. The current study, however, indicates the importance of setting instruments to support adherence with biosimilar quotas. Interviewees identified that these instruments are an effective monitoring and sanctioning system and an effective communication strategy to bridge the objectives of insurers, physician associations and individual prescribers. The capacity of regional physician associations to actively communicate with physicians and to regularly report on achieved uptake levels has been suggested as a factor driving biosimilar use in Westphalia-Lippe [55].

In Germany, the discounts realized through the establishment of "open-house rebate contracts" are confidential. The real price difference between biosimilars and the respective originator product is usually not known by prescribers. However, sickness funds are aware of the magnitude of the discounted price difference between the originator and the biosimilar alternatives. Interviewees indicated that this may define the commitment of insurers to incentivize biosimilar use over the use of discounted originator products. Based on this, the investment in educational and other resources needed to encourage biosimilar use may vary for the different sickness funds and for the different regions. Gainsharing initiatives established across Germany are an example of the active involvement

of sickness funds with the promotion of biosimilars. Some of these initiatives have opted to inform participating physicians on net prices realized through discounting. It has been suggested that this approach might increase the interest of physicians on the principles of cost-effective prescribing [27]. The publication of favorable statements on the safety of switching between reference products and biosimilars is also an example of the active involvement of scientific expert committees. We hypothesize that these committees operate as opinion leaders in Germany, having an influence on prescriber's decision-making regarding biosimilars.

Finally, the proposal to implement a policy for the automatic substitution of biologics at the pharmacy level (GSAV) has elicited conflicting views among stakeholders in healthcare [19]. We hypothesize that this measure may have a considerable impact on biosimilar uptake, potentially equalizing differences in biosimilar market shares across Germany. Further research would be needed to evaluate whether the implementation of this measure substantially changes the situation described in this study.

### *3.2. Study Limitations*

The analysis of market dynamics for the class of TNFα inhibitors was based on the availability of data from ambulatory prescriptions covered by the SHI funds. The lack of information on prescriptions issued by the PHI system or at the hospital level was not expected to affect the comprehensiveness of the analysis, as most sales volume for TNFα inhibitors has been generated within the ambulatory care sector and the SHI scheme is covering 87% of Germany's population [8,56].

We conducted a regression analysis to assess the statistical relationship between several variables chosen as predictors and the outcome variable (biosimilar market shares). We could only include descriptors of socio-economic welfare and performance indicators for the different regional healthcare systems as explanatory variables. Due to the lack of publicly available data, we could not study the association between procurement contract conditions/real differences in discounted prices between originators and biosimilars and regional biosimilar market shares. According to the view of the experts interviewed for this study, we hypothesize that these factors may better explain regional-level variability in biosimilar market shares. The availability of a limited number of observations (N = 16; we combined the data from Northrhine and Westphalia-Lippe) also conditioned the analysis: only the association between two predictor variables and market shares could be modelled simultaneously.

The qualitative analysis of interview data supplemented findings from the quantitative analysis and identified regional predictors of biosimilar uptake that could not have been easily quantified or proxied. However, it must be noted that these interviews were carried out only in nine of the 17 German PA regions. The lack of representation of every region is expected to have only a moderate impact on the generalizability of the study findings, as the interviewed regions represent > 50% of the sales volume for TNFα inhibitors in Germany.

### *3.3. Future Research*

The current study provides an overview of market dynamics for the class of TNFα inhibitors in Germany and especially evaluates the evolution in sales volume for all TNF α inhibitors after the market entry of infliximab and etanercept biosimilars. To accurately evaluate the impact of biosimilar entry within the class of TNFα inhibitors, we would have needed to study the evolution in costs per molecule and per patient before and after the market launch of TNFα inhibitor biosimilars. This analysis could not be conducted due to the lack of publicly available data, but it constitutes an interesting starting point for future studies.

As part of this study, we have stressed the influence of biosimilar policies/practices for prescription and budget control on biosimilar uptake. However, the implementation success for these policies has varied across the German regions. It might be useful for future analyses to evaluate the cumulative effect of implementing multiple incentive policies/practices and to see how this effect relates to observed biosimilar market shares for the regions.

### **4. Materials and Methods**

The methodology chosen for this study is based on previous studies that investigated factors influencing biosimilar uptake in Sweden [17,18]. We first conducted a literature review to describe the main characteristics of the German market for TNFα inhibitors. For reasons of international comparability, we refer to German-specific terminology identified through the literature search by using the English equivalent term. A glossary table (see Table 4) with English terms used in this manuscript and their German equivalent is provided below. Then, we examined dispensing data on sales volume and biosimilar market shares for this drug class. In order to investigate potential factors behind the variable regional uptake of infliximab and etanercept biosimilars, we relied on quantitative and qualitative analyses conducted in parallel, as detailed in the following subsections.


**Table 4.** Glossary of English/German terms and abbreviations.

### *4.1. Literature Review*

The main characteristics of the German healthcare system in dealing with biologics, including biosimilars, were extracted from a literature review. PubMed, Embase and Scopus were searched up to December 2019 to yield information on combined searches including the terms: policies, practices, measures, biosimilars and Germany. Studies in English and German were accepted. The website of the Federal Ministry of Justice and Consumer Protection (German: Bundesministerium der Justiz und für Verbraucherschutz (BMJV)) was accessed to retrieve relevant articles from the German Social Code Book (SGB) V [57]. Additionally, the websites of the KBV [58], the different KVs [31–47], and the GKV-SV were consulted [59].

### *4.2. Analysis of Dispensing Data for TNF*α *Inhibitors*

Regional data on sales volume and uptake of TNFα inhibitor originators and biosimilars were provided by the database of the German Institute for Drug Use Evaluation (German: Deutsches Arzneiprüfungsinstitut e.V. (DAPI)). This database contains anonymous claims data of drugs prescribed and subsequently dispensed by community pharmacies at the expense of the SHI Funds. Nearly 87% of Germany's population is insured by the SHI system [8,56]. The DAPI database covers all claims data from a representative sample of more than 80% of the community pharmacies throughout all regions. Dispensing data were linked to the database of the ABDA – Federal Union of German Associations of Pharmacists (German: ABDA—Bundesvereinigung Deutscher Apothekerverbände e.V.) containing information about the (brand) name, composition, active ingredient, strength, package size, dosage form, and route of administration of German medicinal products [60]. Defined daily doses (DDDs) [61] were calculated from dispensing data and extrapolated by regional factors to 100% of all community pharmacies, and thus 100% of the SHI insured population.

For this analysis, drug use data were examined from the first quarter (Q1) of 2010 to the last quarter (Q4) of 2018. The study of the evolution of sales volume (DDDs) for all marketed TNFα inhibitors allowed us to visualize the effect of the market entry of infliximab and etanercept biosimilars. In addition, shifts in drug utilization trends across the class of TNFα inhibitors were described following biosimilar incorporation, as well as after the market entry of the innovator therapies Cimzia® and Simponi®. Biosimilar market shares were calculated from volume data (DDDs) and represented the volume of biosimilars over the volume of biosimilars plus the respective originator product. The evolution of biosimilar market shares for infliximab and etanercept was studied at the national level and across the 17 PA regions from the quarter in which the biosimilar entered the market (Q1 2015 for infliximab; Q1 2016 for etanercept) to the last quarter of 2018. The regional analysis of market shares allowed the identification of high- and low-biosimilar uptake regions. Uptake was considered to be high in regions where biosimilar market shares were ≥69% for infliximab and ≥63% for etanercept, and low in regions where market shares were ≤51% for infliximab and ≤48% for etanercept. (These thresholds correspond to the lower and upper third of the maximum difference in market shares observed for Q4 2018).

The predominant location of low-uptake regions within the former East Germany, i.e., Brandenburg, Mecklenburg Western Pomerania, Saxony, Saxony-Anhalt and Thuringia, led us to evaluate the statistical relationship between regional biosimilar market shares (dependent variable; N = 16) and the East/West location of the regions at a level of significance of 0.05. This univariate regression analysis was conducted with SPSS (IBM SPSS Statistics 26). Two regression models, one accounting for infliximab data and another for etanercept were built and used as a baseline for a more exhaustive statistical analysis. As the East/West location of the regions was considered to be a co-founding variable, the objective of conducting a more exhaustive analysis was to identify underlying predictor variables (socio-economic factors) behind variable biosimilar uptake. We built various bivariate regression models to examine the statistical relationship between biosimilar market shares and a set of predictors describing: (1) the variable level of socio-economic welfare across the 16 German federal states (e.g., gross domestic product (GDP) per capita, human development index) and (2) the

performance of the different regional healthcare systems (e.g., number of healthcare workers employed per 1000 inhabitants, total healthcare expenditure and healthcare expenditure calculated as a share of GDP) [62]. Furthermore, we studied the correlation between regional biosimilar market shares for infliximab and etanercept to evaluate whether biosimilar uptake patterns were similar within the class of TNFα inhibitors.

### *4.3. Interviews*

A total of ten semi-structured interviews (12 participants) were organized from October 2018 to February 2020 with a view to gain insight into factors potentially influencing biosimilar uptake. The conduction of interviews allowed us to complement the findings from the quantitative analysis and to investigate determinants of biosimilar uptake that could not have be evaluated quantitatively.

A selective sampling methodology was followed to achieve representation from physician associations and health insurance companies operating at the national and regional level. The interviewed representatives from these two stakeholder groups have been involved in decision-making regarding drug budget and prescription control activities and have expertise in the field of biosimilars. Participation from representatives in Baden-Württemberg, Bremen, Hamburg, Mecklenburg Western Pomerania, Lower Saxony, Saxony, Schleswig-Holstein, Thuringia and Westphalia-Lippe was achieved.

For data collection, an interview guide was drafted, validated and approved (August 2018) by the UZ/KU Leuven ethics committee (reference number: MP006423). The interview guide followed the structure of a guide previously developed by the department to study regional management of biosimilars in Sweden [17,18]. The topics were adapted for Germany through a literature search conducted as part of a master's thesis [63]. Interview questions were organized into questions on dispensing data for TNFα inhibitors and questions on national and regional-level biosimilar policies. All interviewees received an email with an attached informed consent form and were asked for permission to record the interviews. All interviews were conducted in English via telephone calls. The recorded interviews were transcribed ad verbatim and processed using the software QSS NVivo 12. For content analysis, we built a thematic framework based on previous knowledge and findings emerging from the interviews. The results of the qualitative study were shared with the contacted interviewees for a validation exercise.

### **5. Conclusions**

Variation in market penetration of TNFα inhibitor biosimilars between German regions depends on a complex interplay of multiple factors.

Experts interviewed for this study have highlighted the influence of prescription and budget control activities (organized at the regional and insurer level) on the variable uptake of infliximab and etanercept biosimilars across Germany. The use of biosimilars has been found to depend on: the regional-level implementation of biosimilar quotas, the presence of an effective monitoring and sanctioning system to regulate adherence to biosimilar quotas, the effectiveness of the communication between regional physician associations and individual prescribers, the different conditions for discount contracts established at the insurer-manufacturer level and the organization of initiatives for gainsharing. The allowance of pharmacy-level automatic substitution for biologics is expected to play a decisive role in the evolution of biosimilar consumption patterns across Germany.

**Availability of Data and Materials:** The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

**Ethics Approval:** The interview guide and methodology for this study was approved by the Research Ethics Committee UZ/KU Leuven on 28 August 2018 (MP006423).

**Consent to Participate:** Informed consent was obtained from all individual participants included in the study.

**Author Contributions:** I.H., S.S., A.G.V. and E.M. were involved in the conceptualization of this study. G.G. and M.S. took part in data provision and analysis. E.M. and T.B.L. were involved in data collection and analysis. E.M. and T.B.L. drafted the initial version of the manuscript. I.H., S.S., A.G.V., M.S., G.G., S.E. and G.S. critically reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported by KU Leuven and by the Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL).

**Acknowledgments:** The authors would like to thank Irene Langner for her insights into the German healthcare system and into the quota system for biosimilars in Germany. The authors also thank the participating interviewees for their contribution to this study and for their feedback on the manuscript. In addition, the authors acknowledge the Leuven Biostatistics and Statistical Bioinformatics Centre for statistical advice during the project and Yannick Mouha for his help with data collection in the context of his master's thesis.

**Conflicts of Interest:** S.S., I.H. and A.G.V. have founded the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL). S.S. was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD; he has participated in advisory board meetings for Pfizer and Amgen; he has contributed to studies on biologics and biosimilars for Hospira (together with A.G.V. and I.H.), Celltrion, Mundipharma and Pfizer, and he has had speaking engagements for Amgen and Sandoz. A.G.V. is involved in consulting, advisory work and speaking engagements for a number of companies, a.o. AbbVie, Accord, Amgen, Biogen, EGA, Pfizer/Hospira, Mundipharma, Roche, Sandoz. E.M., T.B.L., G.G., S.E., M.S. and G.S. declare no conflict of interest.

### **References**


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### *Review* **Barriers to Biosimilar Prescribing Incentives in the Context of Clinical Governance in Spain**

**Félix Lobo 1,\* and Isabel Río-Álvarez <sup>2</sup>**


**Abstract:** Incentives contribute to the proper functioning of the broader contracts that regulate the relationships between health systems and professionals. Likewise, incentives are an important element of clinical governance understood as health services' management at the micro-level, aimed at achieving better health outcomes for patients. In Spain, monetary and non-monetary incentives are sometimes used in the health services, but not as frequently as in other countries. There are already several examples in European countries of initiatives searching the promotion of biosimilars through different sorts of incentives, but not in Spain. Hence, this paper is aimed at identifying the barriers that incentives to prescribe biosimilars might encounter in Spain, with particular interest in incentives in the framework of clinical governance. Both questions are intertwined. Barriers are presented from two perspectives. Firstly, based on the nature of the barrier: (i) the payment system for health professionals, (ii) budget rigidity and excessive bureaucracy, (iii) little autonomy in the management of human resources (iv) lack of clinical integration, (v) absence of a legal framework for clinical governance, and (vi) other governance-related barriers. The second perspective is based on the stakeholders involved: (i) gaps in knowledge among physicians, (ii) misinformation and distrust among patients, (iii) trade unions opposition to productivity-related payments, (iv) lack of a clear position by professional associations, and (v) misalignment of the goals pursued by some healthcare professionals and the goals of the public system. Finally, the authors advance several recommendations to overcome these barriers at the national level.

**Keywords:** incentives; clinical governance; biosimilars; Spain; barriers

### **1. Introduction**

This paper is aimed at identifying the barriers that incentives to prescribe biosimilars might encounter in Spain. Incentives were chosen as one of the main policy actions to stimulate biosimilar use in Spain because they have an important potential leverage, they are relatively underdeveloped in Spain, and they may be controversial in promoting prescription patterns.

We particularly focus on incentives in the framework of clinical governance as they are intertwined concepts. Clinical governance would be impossible to implement without incentives, and incentives, if not impossible, would be difficult to establish in different frameworks.

Biosimilar medicines significantly help to improve patient access to biological therapies that have revolutionised the prognosis of multiple serious diseases, while contributing to price competition in the market and the sustainability of healthcare systems. If one of the main current problems in health policy is to make access to new medicines compatible with sustainability, biosimilars are part of the solution by freeing up very considerable resources [1] (p. 7).

Biosimilar medicines have a long history in the Spanish pharmaceutical market. Since the approval of the first biosimilar medicine in 2006, within the European regulatory

**Citation:** Lobo, F.; Río-Álvarez, I. Barriers to Biosimilar Prescribing Incentives in the Context of Clinical Governance in Spain. *Pharmaceuticals* **2021**, *14*, 283. https://doi.org/ 10.3390/ph14030283

Academic Editors: Arnold G. Vulto, Steven Simoens and Isabelle Huys

Received: 22 January 2021 Accepted: 19 March 2021 Published: 22 March 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

framework [2–6], there are currently 54 authorised medicines (42 effectively marketed) for 17 active ingredients [7]. Biosimilar uptake varies greatly between Autonomous Communities, hospitals, and clinical services. There is also high variability in uptake between molecules regardless of their time on the market [8]. Even so, a budget impact analysis published by the end of 2020 quantifies the savings generated by biosimilars in the National Health System (NHS) at over €2300 million over the 2009–2019 period: "This shows how the entry of biosimilars into the Spanish pharmaceutical market has led to unquestionable and significant savings, especially in hospital pharmacy" [9] (p. 11). The same study estimates that unless major changes occur in market behaviour, the expected savings for 2020–2022 would exceed €2800 million.

However, the uptake of biosimilars in Spain is below the European neighbouring countries' average. This is observed in the antiTNF group, epoetin and human growth hormone, three of the six active ingredients for which there are data available, which means that there is room for improvement in their use [8]. Thus, the aforementioned budgetary impact analysis estimates that if biosimilar uptake reached 80% in 2022, the €2800 million would be increased by an additional €430 million. The French government set a similar objective in its National Health Strategy for 2018–2022 [10].

The promotion of biosimilars is part of most Pharmaceutical policy strategies. The Independent Authority for Fiscal Responsibility (Autoridad Independiente de Responsabilidad Fiscal, AIReF), which is responsible for ensuring the sustainability of public finances, considers the promotion of biosimilars the most relevant tool for controlling hospital pharmaceutical expenditure [8]. This institution suggests the establishment of biosimilar prescribing incentives to maximise this savings opportunity.

The "Action Plan to promote the use of market regulating medicines in the National Health System: biosimilar medicines and generic medicines" of the Ministry of Health states that "In the Autonomous Communities [ . . . ] actions will be carried out to link financial or other incentives" [11] (p. 38). This two-level (national and regional) approach is because the Spanish NHS is a decentralised system since health competences are transferred to the 17 Autonomous Communities. Coordination, strategy for pharmaceutical policy and medicine pricing and financing decisions, among others, lie essentially with the Ministry of Health, and with Autonomous Communities when it comes to budgeting, purchasing and provision [12].

Further, the Commission for Social and Economic Reconstruction of the *Congreso de los Diputados* (the lower Parliament chamber) dealing with the reform of the NHS to tackle with the Covid-19 pandemic included in its report the need to "significantly increase the proportion of biosimilars" [13] (p. 25).

In short, the promotion of biosimilars in general, and the establishment of prescribing incentives in particular, seem to be unavoidable tasks according to decision-makers and policy makers in the short-term.

Therefore, this paper is aimed at identifying the barriers that a model of incentives to prescribe biosimilars might encounter in the context of clinical governance in Spain. Both concepts are intertwined as incentives are the instrument and clinical governance the organisational form.

This is a pioneering approach, as the research literature on this topic is very scarce.

This work is based on a broader study of the incentives that, in the context of clinical governance, can lead to greater use of biosimilar medicines in healthcare [14]. This study reviews and presents the most outstanding experiences of this sort developed in high income countries and examines the possible barriers to their implementation in Spain.

### **2. Incentives and Clinical Governance**

Incentivising health professionals, especially prescribing physicians, is a crucial issue for the organisation and reform of the NHS and for policies to promote biosimilars. Payment systems, including pay for performance, and competition, including benchmarking and yardstick competition, are typical financial incentives [15,16]. However,

the incentives that move people are not only financial, nor, of course, only monetary. In the health sector there are other very powerful motivations such as: dedication to service, altruism, professional satisfaction, and reputation; scientific curiosity, the feeling of belonging to a group, etc. [17].

Before moving on, it should be noted that in this study we refer to a very narrow definition of incentive. Specifically, financial incentives that are not necessarily monetary or exclusive to the prescriber. This is critical since many studies about European biosimilar landscape refer to "incentive policies" that are not necessarily financial incentives. For instance, educational campaigns, quotas, or tendering practices are considered incentive tools to increase the uptake of biosimilars and financial incentive would be just another mechanism for that purpose [18–21]. An important study carried out by the European Commission considers that one of the challenges for the Spanish NHS in the future is "to align the incentives of the different service providers with the system's quality and efficiency goals. For example, staff incentives could be improved." [22] (p. 253).

The use of incentives to influence physicians' prescribing patterns and encourage their alignment with organisational goals is a policy that has been embodied in various experiences over time and across countries. In Spain, towards the end of the 1990s, financial incentives related to prescription were already applied in several Autonomous Communities. By 2018, there were at least seven autonomous communities applying them. The AIReF, in its 2018 review of public expenditure on medication dispensed through prescription, recommends establishing prescription incentives [23]. The same recommendation is made in its recent evaluation of the pharmaceutical spending in the public hospital setting in Spain, but now directly linked to biosimilar prescription: "in view of the success of international experiences, it is proposed to implement a gain-sharing incentive system for hospitals, care services and health professionals" [8] (p. 89). A gain-sharing incentive system (also called gainshare agreement) is based on sharing savings associated with more efficient use of medicines at the same time as any efficiencies made will be invested back into patient care to improve their health outcomes [24].

However, when it comes to promoting biosimilars, there are doubts about the most appropriate type of incentives. Some voices are in favour of financial incentives and argue in their support, for example, their contribution to the progress of biosimilars in Germany. "Prescribers need confidence in outcomes, and they and/or the health system need to benefit financially from using biosimilars" [25]. Other opinions consider that it is better to motivate physicians through schemes that avoid direct financial incentives [26].

Incentives are easier to implement in well-organised broader contexts such as health services following the lines of what is known as "clinical governance". We acknowledge that there is no consensus definition for clinical governance. Our vision of the concept is as follows: This is an organisational form of health services at the micro-level, aimed at achieving better outcomes in terms of patient health, characterised by the following elements:


Some biosimilar prescribing incentives have been put in place in Europe. Although it is not the scope of this research, we summarise in Table 1 the more relevant initiatives to our view, the British experiences being those closer to our approach of clinical governance.


**Table 1.** European initiatives on biosimilar prescribing incentives.

The gainshare agreements reached with regional or local leadership in the United Kingdom [32–34], mostly between 2015 and 2017, under a well-established framework [35] are examples of what we mean by biosimilar prescribing incentives in the context of clinical governance. However, in 2018, NHS England began to link the concept of best-value drug to drug procurement as part of a wider strategy to increase savings [36,37]. While this measure might be effective, it does not fall under our definition.

In Spain, a good example of combining incentives and clinical governance is the "Área del Corazón" (Heart area) of the University Hospital of La Coruña, coordinated by Dr Alfonso Castro Beiras in the 1990s [38]. The project was based on the willingness to cooperate from the cardiology and cardiac surgery services. This clinical management model was based on four elements: (i) Process standardisation; (ii) Strengthening of information systems; (iii) Use of diagnosis-related groups as patient classification systems and (iv) Self-evaluation. The management of the human and material resources and the control over the budget appear to be decisive for the development of this autonomy-based model. The results were very positive. Activity and care indicators improved, and savings were invested back in human resources, making it possible to staff the new intermediate care unit.

Although this initiative is no longer running, there is no doubt that clinical governance offers good possibilities for the efficient use of effective and good quality biosimilars by prioritizing health outcomes, motivation, quality of care processes and efficient use of resources. Actually, we might be talking about one of the first gainshare agreements in Spain. This precedent seems significant enough to support a pilot gainshare agreement in Spain like those successfully implemented in the United Kingdom [34].

It is now time to ask what are the barriers and difficulties that incentives to prescribe biosimilars encounter in Spain.

### **3. Barriers According to Their Nature**

As we are particularly interested in barriers to incentives in the framework of a model of clinical governance and both questions are strongly related, we present here different barriers encountered in Spain that we have been found relevant for both concepts.

### *3.1. Payment System*

The current payment system is also a barrier primarily for incentives but also for clinical governance. Its regulation, tradition, and the culture it has generated are very much in opposition to the incentives and flexibility required by efficient organisations. The 2006 report on Spain by the European Observatory on Health Systems and Policies noted that after having completed the healthcare transfer process to the Autonomous Communities in 2002 "the most concerning issue was that most of the pay increases affected the fixed components . . . compared with income related with performance" [39] (p. 110). Several sources suggest that remuneration based on results and effort is motivating and that a variable remuneration based on targets should be increased in relation to fixed payments [40–42].

### *3.2. Rigid and Bureaucratic Budgetary and Economic Management Legislation and Procedures*

In Spain, bureaucratic control has traditionally prevailed over the evaluation of outcomes, at all governmental levels. "The budgetary system has long suffered from being excessive rigid" [43] (p. 278). These rigid legislation and budgetary and financial management procedures involve major difficulties and delays and are a significant impediment when implementing incentives and clinical governance. The production of health services requires agility and flexibility to manage personnel and material resources to improve health outcomes. Furthermore, as suggested by Zornoza Pérez [43] (p. 295), "flexibility and control must be properly combined with accountability to induce managers to behave in accordance with the principles of efficiency and economy in the management of public expenditure." This need remains outstanding. In 2016, Esteban and Arias [44] (p. 98) state that "one of the main challenges for the NHS is to progress towards the de-bureaucratisation of the system by leaving the current public law regime in the field of human resources."

### *3.3. Spanish NHS Labour Relations Model*

The employment relationship of physicians and other health professionals with the services that make up the Spanish NHS (so called "statutory personnel") follows the civil service model. The rigidity and the difficulties it entails to achieve efficient management have often been criticised [45]. One of its main problems is the inflexibility in adapting to care needs and the limitations in differentiating individual and collective merit [46]. It hinders decisively the introduction of incentives and clinical governance. The elimination of this model and the establishment of a modern, flexible, and efficient labour relations system, particularly for physicians, is considered one of the basic structural reforms to be addressed in the NHS. That would mean to eliminate civil-service-like regulations and reintroduce professionalism and evolve towards forms of market labour relations [40,46,47].

### *3.4. Clinical and Health Service Disintegration*

The disintegration of health care in the NHS is an especially important barrier to implementing clinical governance and promoting biosimilars through incentives. Disintegration implies gaps and borderlines, multiplicity of providers, uncoordinated services, neglect of patient preferences, poor measurement of relevant outcomes, and lack of incentives oriented towards the provision of comprehensive care [48]. Clinical integration is the basic goal of reform plans for the health services to respond to current needs, mainly determined by chronic and degenerative diseases [45,48]. Sometimes integration is accompanied by financing schemes that cover all health services and generate incentives for efficiency. Excessively rigid boundaries between specialties also prevent cross-sectional and team work, organisation of services according to care processes and patient orientation [47]. This is a key difficulty that opposes the development of incentives for individual and collective merit within the framework of clinical governance.

### *3.5. Absence of General Legislation on Clinical Governance*

In Spain, clinical governance is not regulated by law. The draft Royal Decree RD /2015 laying down the basis for the implementation of Clinical Management Units in the Health Services [49] was an interesting initiative. In the interests of a high-quality, safe, and integrated healthcare, the draft suggested providing professionals in the NHS with greater levels of autonomy and responsibility in their clinical decision-making. It included governance-related terms such as planning, incorporation of new technologies and knowledge management, all from a perspective of "decentralisation of the organisation" as well as continuous evaluation of results. Although promising in terms of progress, it was finally rejected by the Council of State because it had to be passed as a law by Parliament. The opposition from trade unions and certain professional spheres, the lack of sufficient support from the Autonomous Communities and the political instability of the past years made it difficult for the draft Royal Decree to become a Law. However, in view of the impact of Covid-19 pandemic, some proposals of the Commission for Social and Economic Reconstruction of the Congress of Deputies suggest that progress could be expected in this regard. "The professionalisation of the governance of health services must be guaranteed and health professionals must be encouraged to perform managerial roles. The executive directors of health services should follow epidemiological, public health and clinical governance approaches" [13] (pp. 3–4).

### *3.6. Governance-Related Barriers: Lack of Professionalisation of Health Services Managers and Absence of Governing Boards*

In Spain, healthcare managers, such as hospital general managers and others, do not always have the appropriate professional profile and appointments are generally based on discretionary decisions. Open and competitive recruitment and selection processes and periodic performance evaluations are not always the rule. Collective and independent boards of directors controlling the micro-management of elementary organisations such as hospitals and health areas in a decentralised and transparent manner [47] are scarce. Only some Autonomous Communities, such as the Comunidad de Madrid [50], have adopted legislation that reflects these principles. In this scenario, major organisational reforms, such as clinical governance and the establishment of incentives, seem unlikely.

The second Amphos Report [51], prepared with the contribution of 80 managers and clinicians, provides an interesting overview of the barriers that delay the implementation of clinical governance units. Fifteen were identified and classified according to their nature into: political, economic, legal, technological, and human or cultural (Table 2). Some of them match those highlighted above. We also find it interesting to highlight the difficulty in making an organisational change that generates medium-term results when policies are focused on the short term and lack of evidence on objective and reliable results that show the benefits of clinical governance units. These barriers were also classified according to priority. To this end a group of 72 health professionals and managers with previous experience in clinical governance was asked to grade each of the barriers on a scale of 0 to 5 (being 5 the highest) not in absolute values but in comparison with others. The highest barrier was the labour framework, followed by the lack of political will and the regulatory framework.

The potential savings due to biosimilar competition expected in Spain for the period 2020–2022 (€2800 million) [9] may become the pretext to put in place mechanisms to overcome these barriers, provided, of course, that all parties benefit from these savings. Again, gainshare agreements emerge as a powerful tool for that.


**Table 2.** Barriers to clinical governance and score according to priority [51,52].

### **4. Barriers According to Stakeholders**

*4.1. Physicians with Limited Information and Distrust of Biosimilars*

As biosimilars are biological medicines, they must be prescribed by their brand name [53]. In addition, in Spain the pharmacist cannot dispense a brand other than that prescribed, without authorisation of the prescribing physician according to Order SCO/2874/2007 [54]. Therefore, the physician is the key actor for the market entry of biosimilars. The physician's trust and preference for prescribing biosimilars is critical.

However, as previously pointed out by Acha and Mestre-Ferrándiz (2017) [55] (p. 263) the biosimilar market faces "the second translational gap" once concerns about the guarantees of the regulatory framework have been dispelled. The authors recognise that "Despite many efforts by regulators to reach out to clinicians, there remains a translational gap for biosimilars which need to be incorporated in healthcare pathways and understood by clinicians and patients. Only by bridging this gap will biosimilars fully play their role in healthcare for Europe".

Weise et al. (2012) [56] listed the main uncertainties of physicians about biosimilar medicines: (i) doubts about their quality and manufacturing process; (ii) the "similar but not identical" paradigm; (iii) immunogenicity; (iv) possible gaps in post-marketing pharmacovigilance; and (v) extrapolation of efficacy and safety data without clinical trials in certain indications. A recent systematic review conducted on physicians' perceptions about the uptake of biosimilars suggests that little has changed since then [57]. Physicians

still have doubts related to the safety, efficacy, and immunogenicity of biosimilars and consider that cost savings is the main advantages of biosimilars. In addition, most of the physicians had negative perceptions of pharmacist-led substitution of biological medicines.

Another review aimed at identifying the barriers to the use of biosimilar medicines in Europe medicines points out that physicians act as a barrier to biosimilars in several ways [58]. Firstly, their concerns about true similarity between originator and biosimilars. Second, the absence of incentives or benefits for prescribing lower-cost medicines that would compensate the effort they make when explaining to the patient the switch to a biosimilar medicine. Finally, the strong ties between physicians and the originator pharmaceutical companies, which often support clinical research and continuous education (opposite incentive). Given these scenarios, national policies on biosimilars have focused on improving physicians' trust in biosimilars through a variety of training programs, which are sometimes local and generally relying on prescription guidelines [18].

In Spain, Agustí y Rodriguez (2015) [59] predicted that the success in biosimilar adoption would depend largely on the trust of health professionals and pointed out that the accumulated experience with biosimilars would help overcome reluctant attitudes.

As biosimilar medicines are mainly used into the hospital setting, hospital physicians have been the focus of many educational programmes (funded by the industry, scientific societies, professional associations, and regional governments). This is also observed in the constant review of position papers on biosimilars by scientific societies in most relevant specialties, such as Oncology, Rheumatology, Haematology, or Digestive Pathology [60–64]. Although one might expect that these statements build trust and shape prescription patterns equally among physicians, a high variability is found when comparing biosimilar uptake between hospitals within a single region. For instance, in 2014, several hospitals in the Community of Madrid rarely used biosimilars, while others showed uptake rates between 60% and 70% [65]. This suggests that despite sharing guidelines from the same regional health service or scientific society, the influence of opinion leaders or heads of departments can accelerate or slow the biosimilar access to hospitals. Nor can we overlook the effect of some sort of incentive set internally at the hospital level, although there is no evidence in this respect.

In the case of primary care setting, the arrival of new biosimilars is a new challenge. From a survey with over 700 respondents, it appears that 58% of the respondents do not know the definition of biosimilars and 73% do not know that the handling of biosimilars is not comparable to that of generics, for which in Spain prescription by active ingredient is applied [66]. Moreover, in the primary care setting, a strategy based on education/information, and constant communication with health professionals, succeeds in improving knowledge about biosimilars and changing prescription patterns [67]. By contrast, any initiative to promote biosimilars not agreed upon with physicians is doomed to failure [26].

In short, physicians that are informed through official and reliable sources tend to consider biosimilars as alternatives that are efficient for the health system and effective and safe for their patients and are able to convey the trust needed for preventing the nocebo effect (nocebo effect refers to negative expectations of the patient regarding a treatment that translate into negative side effects or outcomes) and ensuring treatment compliance. However, improving the knowledge about biosimilars and afterwards communicating the information to patients require big efforts by physicians. Therefore, it cannot be overlooked that recognising physicians' efforts through incentives or other formulas aimed at sharing benefits will guarantee their commitment in the medium term.

### *4.2. Misinformed Patients and Mistrust towards Biosimilars*

A major barrier to the spread of biosimilar medicines is misinformation and mistrust from the part of patients. The complexity of the world of medicines and their names, especially if they are biological products, makes it difficult for patients to have timely information and knowledge of their characteristics and guarantees [19]. It may be particu-

larly difficult to know and be aware that all medicines that are authorised for marketing, whether they are original products or biosimilars, offer the same safety, efficacy, and quality guarantees. This limited knowledge impacts on their willingness to accept the prescription of biosimilar treatments [68]. In addition, patient organisations often have close links with the originator industry, which sometimes finances their meetings and educational activities [18].

The difficulty often arises, not for the naïve patients, but for those whose treatment was initiated with the original product and are encouraged to change it for a biosimilar product (switch). There may be differences in the brand name or appearance [69]. In addition, sometimes the inherent variability in the manufacturing processes of biological products can lead to certain characteristics not being totally identical to those of the originator, but this variability is strongly controlled within acceptable limits to ensure there is no relevant clinical impact [70]. Despite that, biosimilars are not well understood by many healthcare professionals and patients, and such a mistrust is exacerbated by negatively biased information disseminated by some parties [71].

A study on policies to promote biosimilars in 24 European countries found that educational initiatives aimed at patients were rare. Patients are informed mainly through their organisations, through brochures and letters to explain the switch from originator to biosimilar. It recognises that biosimilar policies should include all stakeholders, including patients, and recommends strengthening educational initiatives through instruments such as question and answer (Q&A) documents [18].

However, a very recent study by Vandenplas and collaborators (2021) [72] emphasised that over the past few years several surveys among European patients have shown a lack of knowledge and trust in biosimilars. In addition, they performed a web-based screening of European Patients' Forum and International Alliance of Patients' Organisations on publicly available information about biosimilars and found a high variability among correctness, the level of detail, and the tone when providing information.

The physician–patient relationship is absolutely crucial to overcome these information or mistrust issues. There is no doubt that as long as the physician is properly informed and trusts biosimilars, the patient will follow his or her guidelines.

It should be borne in mind that having accurate information and access to medicines are rights that are widely recognised in different jurisdictions. According to the Spanish legislation the physician must inform the patient. Indeed, according to Article 10 of the General Health Services Law 14/1986 [73], patients have the right to be informed on the health services they have access to and the requirements for their use. According to Law 41/2002, Article 4, on patient autonomy and rights and obligations regarding clinical information and documentation [74] patients have the right to know all available information on any action touching their health, including, at least, "the purpose and nature of each intervention, its risks and consequences". In addition, the physician must guarantee the fulfilment of this right to information from the part of patients. Article 10 of the General Health Law (LGS) also states that patients have the right "to obtain medicines and medical devices that are considered necessary to promote, preserve or restore their health".

In Spain, Calleja et al. (2020) [75] identify patient education and involvement in the decision-making process as key points to increase acceptance of biosimilars and counteract the nocebo effect. This is the view of at least eleven patient associations in Spain as embodied in the "Joint statement by physicians and patients on treatments with originator biologics and biosimilars" [76]. Thus, some requests read as follows "Health administrations often lack biosimilars training programmes for physicians", "The debate on originator biological and biosimilar medicines should be open to the participation of physicians and patients", "Policies that would make the cost/efficiency principle a systematic argument would not be acceptable", or "Some administrative decisions could seriously interfere with the normal functioning of the physician-patient relationship". The last two could be an obstacle to the establishment of biosimilar prescribing incentives from the patients' perspective.

### *4.3. Unions Opposition to Productivity-Based Variable Remuneration*

One of the barriers to the establishment of biosimilar prescribing incentives is the opposition of trade unions to variable remuneration based on outcomes, targets, or productivity. This exists not only in Spain but also in other countries, and in any sector, not only in health. The study by García-Olaverri y Huerta (2011) [77] shows that trade unions defend salary standardisation and oppose differentiation according to the different abilities or skills of workers. These objections are found also in the governmental and health sectors.

The disagreement clearly appears in the 2014 document of the State Confederation of Medical Trade Unions (CESM, in its Spanish acronym) on clinical governance: "Under no circumstance may incentives be linked to savings over the agreed budget, but rather to the level of compliance with it, and with the care and quality targets established in accordance with the provisions laid down in the management contract." "This implies that the health service that decides to promote clinical governance must allocate additional funds to pay for these incentives" [78] (p. 10). This position is clearly contrary to the establishment of, for example, gain-sharing programmes which have been successfully established in other countries [34] where part of the savings from increased use of biosimilar medicines revert to the healthcare system itself.

### *4.4. Professional Corporate Bodies, Clinical Governance and Incentives*

Professional corporate bodies, especially those of physicians, react positively to clinical governance insofar as it increases their autonomy, responsibility, and decision-making capacity. Other features such as performance assessment, performance-related incentives and transparency and accountability do not generate the same enthusiasm [79,80]. These corporations may defend based on professionalism and technical criteria organisational and management changes that promote their professional practice and the health of patients. However, they also experience the pressure of electoral cycles. Then, they usually oppose structural reforms advocating the interests of less committed colleagues (as if this behaviour were the rule) to get the most votes in their corporation's elections.

### *4.5. Physicians and Other Health Professionals Not Aligned with the Objectives of the System*

Although it is a very limited group, health professionals not aligned with the goals of the system, poorly committed to the public system, can be a barrier to clinical governance and incentives for good performance in general, and for biosimilar prescribing incentives in particular. Attitudes such as opposition to transparency or to performance assessment leading to differentiated remuneration must be corrected, as they have a very negative effect on the morale of the vast majority of those who are compliant. When it comes to biosimilars, the strong ties that originator companies have with physicians through supporting clinical research or training may influence prescription choices [55]. Additionally, guidelines with an economic rationale intended to deliver benefits at societal level may be badly received by some physicians, who may consider that their professional decisions are challenged [81]. Thus, it seems reasonable that a greater alignment between the medical community and the regulators would help build trust on biosimilar medicines [82].

### **5. Recommendations for Spain to Overcome the Barriers to Implement Incentives for Biosimilars**

According to our review we recommend the following actions to overcome the barriers to implement incentives for biosimilars:


based on gain-sharing programmes) can bring about for the NHS, patients, and professional practice.


**Author Contributions:** Conceptualization, F.L. and I.R.-Á.; methodology, F.L. and I.R.-Á.; investigation, F.L. and I.R.-Á.; resources, F.L. and I.R.-Á.; writing—original draft preparation, F.L. and I.R.-Á.; writing—review and editing, F.L. and I.R.-Á.; supervision, F.L. and I.R.-Á.; project administration, F.L. and I.R.-Á. Both authors have read and agreed to the published version of the manuscript.

**Funding:** The broader study from which this article is extracted was funded by The Spanish Biosimilar Medicines Association, BioSim.

**Conflicts of Interest:** I.R.-Á. is employee of the Spanish Biosimilar Medicines Association. F.L. has no conflict of interest.

### **References**


### *Commentary* **The Off-Patent Biological Market in Belgium: Is the Health System Creating a Hurdle to Fair Market Competition?**

**Philippe Van Wilder**

Ecole de Santé Publique, Université Libre de Bruxelles (ULB), Brussels 1050, Belgium; philippe.van.wilder@ulb.be

**Abstract:** We investigated the off-patent biological market in Belgium from a policy maker's perspective, in light of the Belgian pharmaceutical health system. The main barriers relate to a short-term budgetary focus, to the overwhelming innovator's reach and to a concertation model with assessment and appraisal being mixed which results in poorly effective policy measures.

**Keywords:** biosimilar; reference biological; competitive market; Belgium

### **1. Introduction**

Biosimilar products have been authorised in the European union in areas such as oncology, inflammatory diseases, diabetes and haematology. As these products are authorised as having no clinically meaningful differences [1] compared to the originator products, the major benefits relate to lower prices for the payer (health insurance), following lower development costs, and in enhanced price competition in theory. The savings may serve as a healthcare budget control tool or may be invested in widening the eligible patient group or in providing access to other innovative but expensive treatments.

Many EU member states have experienced a gradual uptake [2] of biosimilar products with uptake figures [3] in 2019, easily exceeding 30% in big EU-countries while in Belgium [4,5] the uptake is incredibly low with market shares of biosimilar products being three-times lower or less.

Different authors have analysed the limited uptake of biosimilar products in Belgium and identified several factors responsible for this phenomenon. Recently, Moorkens et al. [6] provided a critical overview of these hurdles which include a lack of trust among some stakeholders, a lack of clear, persistent and consistent communication channels, a tremendous innovator's reach and the disturbing impact of a hospital financing system with incentives for high priced medicines.

In this commentary, we aim to consider the impact of the organisation of the pharmaceutical healthcare system. We believe the cumulative impact of distinct policy measures within the Belgian healthcare system is creating a strong hurdle to the access of biosimilar products.

### **2. Belgian Policy Initiatives to Favour Access to Biosimilar Products**

Because of the low use of biosimilar products in Belgium, various policy measures aiming to impact the biosimilar uptake have been implemented. First, there is a simplified and facilitated administrative reimbursement track [7] for biosimilar products if the formal indications and conditions of use are nearly identical between biosimilar and reference biological product. In 2015, a Convention was signed by the competent authority and the main stakeholders [8], to enhance the biosimilar product uptake. This initiative included a regular monitoring of the use of biosimilar products to check this objective. In 2019, financial incentives [9] (between € 750 and € 1500) were provided towards individual prescribers of the biosimilar products of etanercept and adalimumab in the retail market. Finally, a 'best value biological' program management [10] was initiated in 2019, aiming to bring a broader perspective to the use of biological medicinal products [11].

**Citation:** Wilder, P.V. The Off-Patent Biological Market in Belgium: Is the Health System Creating a Hurdle to Fair Market Competition? *Pharmaceuticals* **2021**, *14*, 352. https://doi.org/ 10.3390/ph14040352

Academic Editors: Jean Jacques Vanden Eynde, Arnold G. Vulto, Steven Simoens and Isabelle Huys

Received: 2 February 2021 Accepted: 6 April 2021 Published: 10 April 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

After all of these ad hoc initiatives, the Belgian biosimilar market share evolution illustrates the lack of competition between biosimilar and biological reference product. Clearly, the biosimilar product uptake objectives are not reached at all despite these ad hoc measures.

The relationship between competent authority and pharmaceutical industry is complex and particular. In the BE Healthcare system, decision-making is based on extensive concertation with stakeholders. This allows to capture thoughts from the field and enables the decision-making to hold a balanced view of the expressed legitimate opinions, but it may lack strength because of the weighting of the impact across the stakeholders.

In my opinion, the biosimilar market uptake in Belgium suffers from a short-term narrow budgetary focus, the limits of a concertation model with mixed expert and stakeholder input which (in this field) result in poorly effective policy measures and from the overwhelming innovator's reach.

### **3. Some Characteristics of the Pharmaceutical Healthcare System**

### *3.1. Short-Term Budgetary Focus*

The Belgian healthcare system emphasises the short-term (pharmaceutical) healthcare budget instead of considering the healthcare budget and the longer-term efficiency. To illustrate this, I would refer to the mandatory price decreases that are applicable 12 years after the reimbursement of the reference product or at entrance of the biosimilar product, whichever comes first. These price reductions are applicable to both the reference product and the biosimilar product. The consequence of this policy measure is that there is no or limited additional saving potential between a biosimilar or biological reference product for the healthcare payer. This effect is strengthened by the hospital financing mechanism in which a lower (biosimilar) price would result in less earnings for the hospital, because the discounts offered by a manufacturer are lower if the National Institute of Health and Disability Insurance (NIHDI) list price is lower.

In some cases, the potential for price competition is even further hampered by repeated managed entry agreements (MEAs) for the reference biological product. If such a confidential MEA is still effective at the entrance of the biosimilar product, the type of agreement and the extent of the price–volume compensation is unknown to the applicant of the biosimilar product, making the biosimilar reimbursement submission a blind spot.

Price decreases go beyond 50% resulting in much desired short-term cost savings but without incentives to increase the market share of biosimilar products with the aim to facilitate longer-term competition once biosimilar products achieve substantial market volumes. A mix of off-patent reference biologics, biosimilars, and follow-up treatment alternatives, is considered critical [12] to obtain a competitive and sustainable market for long term access to biological therapy at the lowest cost. The actual regulation is applicable even if the NIHDI is aware of the risks linked to a lack of competition. On its website [13], it expresses the concern of missing future biosimilar products on the Belgian market, which may be a threat to the sustainability and control of the healthcare budget.

The already mentioned simplified reimbursement track for biosimilar products is limited to 90 days (which is half the duration of other reimbursement procedures). It builds on the similarity in the clinical and therapeutic characteristics between biological reference and biosimilar product and will mainly address the budget impact estimates, without any pharmaco-economic assessment. Cost-effectiveness analyses may be of little value in some cases but they are indicated [14] if cost differences exist between these products (administration route and costs, dosing interval, limited price differences, etc.) and if therapeutic alternatives exist on a different anatomic-therapeutic-chemical (ATC)-level, a pharmaco-economic assessment will probably result in a different relative positioning of the available products. The focus should be more directed towards disease strategy and look beyond individual medicinal products.

### *3.2. Mixing Assessment and Appraisal*

The biosimilar market uptake is also affected by the unclear split between assessment and appraisal in the healthcare decision-making. This also affects other medicinal products. The Belgian reimbursement procedure reflects the Transparency Directive [15] requirements and starts with an internal assessment report to be delivered by day 60, followed by appraisal and proposition from the reimbursement commission by day 120 and day 150, prior to the decision of the Minister. However, in my opinion, despite the tremendous support of a dedicated team of NIHDI-experts and pharmacists, assessment and appraisal are sometimes mixed [16] instead of these being clear and distinct activities. This is mainly the consequence of having a commission of stakeholders [17] all along the procedure instead of having distinct expert assessors and stakeholder appraisers. This approach is hampering the scope of the performed assessments, resulting, too often, in limited pharmaco-economic assessments. It is limited because it is not going beyond the individual submitted dossier and because it merely criticises the applicant's submission without making own assumptions and performing own economic analyses. Until now, the impact of the economic assessment as a significant reimbursement factor, could not be demonstrated as opposed to the significant effect of the medical need and the extent of therapeutic value.

The biosimilar conundrum is a topic in which the pharmaco-economic assessment, even from a direct healthcare perspective, should go beyond the individual dossier and include elements of (lack of) future competition (especially if a lifelong time horizon is relevant). A proposal might be to strengthen the possible collaboration between the NIHDI and the formal health technology assessment (HTA) Agency which is the Federal Knowledge Centre for health (KCE). KCE has the expertise for making full HTA-reports. Assessment reports should be 'validated' by expert assessors from NIHDI and KCE and remain unchanged by the reimbursement commission of stakeholders. The Commission members should focus on the appraisal of the assessment report and discuss criteria and weights to provide a documented and informed advice to the competent Minister. Such collaboration would facilitate assessments that go 'beyond the dossier' and include longer-term considerations. Such collaboration may enable the reimbursement commission to prepare for future challenges and develop an adapted framework for oncology biological products.

### *3.3. Far Reaching Innovator's Reach*

The biosimilar market uptake is also affected by the originator's extensive reach [6] and creative off-patent strategy. The innovative pharmaceutical industry is strongly represented in Belgium with R&D centers and/or production facilities of companies such as Glaxo-Smith Kline (GSK), Johnson & Johnson, or Pfizer. GSK's site in Rixensart produces various vaccines for world-wide distribution. Pfizer manufactures in Puurs the COVID-19 vaccine Comirnaty® which is distributed across the EU and abroad. The innovative industry [18] represents an export volume of more than € 42 billion in 2018 and invested € 3.6 billion in the development of medicinal products in 2018 (R&D is facilitated by fiscal incentives).

The COVID-19 pandemic offers a marketing opportunity, certainly for the vaccine producing pharma, but also for the whole pharmaceutical sector, if the sector delivers highly valued medicinal products protecting individuals from disease and excessive mortality and making it possible for societies to reopen economic and societal activities.

This innovative industry is particularly creative to manage the off-patent hurdle. Follow-up compounds with claims of added value enter the market prior to the patent expiry and are being promoted to facilitate a shift from the biological product to the followup product (e.g., Janus kinase (JAK) inhibitors versus tumor necrosis factor (TNF) blockers).

The biosimilar product manufacturers should consider their own strengths and weaknesses in this 'originator' landscape. They should not only be reactive to the activities of the originator but also develop proactively own strategies, expressing their commitment towards local authorities and stakeholders (including patients), reflecting on product differentiation and investing in a tangible roadmap to achieve the objectives.

The originator is also rapidly reactive to the changing market situation. Initially, as the analysis of Dutch market data [19] illustrates, substantial price differences existed between adalimumab reference product and biosimilar products, which resulted in decreasing market shares for the adalimumab reference product. For etanercept, no or limited price differences exist and market shares of the biological reference product did not dramatically decrease.

A collateral 'benefit' of this tactical approach, is that originator and biosimilar products provide a similar amount of savings, which allows the originator industry to make the (legitimate) claim of facilitating the pharmaceutical healthcare budget control (which budget had an excessive double-digit growth in 2020).

### **4. The 'Best Value Biologicals' Program 2019–2020**

With a less than desirable interest in longer term efficiency in the Belgian healthcare system, the claim by the originator that savings are equally resulting from reference and biosimilar products, yields a considerable threat to any future incentive for biosimilar products.

To illustrate this, the example of the 2019 'best value biologicals' program management is appealing.

The 'best value biologicals' program management, sponsored by the NIHDI and which may be considered as the initiation of a broader and sustained approach towards biological products, ended in April 2020. The program delivered to the competent authority NIHDI, a documented report including recommendations with suggested follow-up measures aiming to create a level playing field for biosimilar and biological reference products in Belgium. Briefly, the report's recommendations referred, among others, to extensive and repeated communication and education channels on biological products to healthcare providers and patients, to smoothen the lengthy and complex tendering process in hospitals, to consider gain sharing mechanisms (sharing the healthcare savings with those enabling them) and a specific recommendation on setting market share quota for biosimilar products.

However, the coronavirus pandemic interfered strongly and obviously modified healthcare priorities.

Still, the report's recommendations were endorsed later, in October 2020, by the General Council of the NIHDI [20] in their approval of the 2021 federal healthcare budget. However, the wording used by the General Council was particular: when it comes to the intention to stimulate the use of biosimilar products, a condition is set and the wording ends with 'with non-discriminatory incentives'.

The General Council inserted the 'no discrimination' condition, prior to any concrete policy measure being written. For initiatives relating to biosimilar product uptake, an a priori condition is already 'adopted', prior to making clear how the policy measure should be conceived and implemented. No other healthcare initiative in the text of the General Council is linked to a non-discriminatory criterion.

Maybe, the proposal to use quota for uptake of biosimilar products is perceived as 'discriminatory' by some General Council members. However, quota is used by other EU Member States. At the EC-workshop of October 2019 on biosimilar products [21], various Member States shared their experience on the effectiveness of local policy measures. France [22] explained their positive pilot experience with quota for biosimilar products which resulted in increased biosimilar market shares. This enabled them to reach a competitive level playing field between original and biosimilar biological products. The French experience was acceptable for the EC, because the economic rationale was clear and unambiguous and the quota policy was limited in time under strict conditions.

### **5. Conclusions**

By having the 'with no discriminatory incentives' written in the General Council document, any forthcoming policy measure creating incentives for the uptake of biosimilar products will be challenged on this condition. The perception of discrimination is made and

any initiative having a purpose to enhance uptake of biosimilar products will not only need to be valid for that purpose, but also reverse the created perception. The formulation of the various recommendations and the implementation of concrete measures will probably be an uphill battle, with opportunity for the originators to have lengthy discussions on the compliance of each measure with the non-discrimination condition. In my understanding, some of the proposed recommendations giving incentives to biosimilar products may be differential but not discriminatory, because they are limited in time and are proposed to create a level playing field for both type of biological products, which is hardly the case at patent expiry of the reference biological product. It will be important to refer to the international examples to reverse the perception of discrimination already linked to upcoming incentives.

At stake are the availability of the next biosimilar products in Belgium and the shift towards a real competitive market. The expected future savings in oncology and rare diseases, to be triggered by the local availability of biosimilar products, may be reduced and/or delayed. Non-differential mandatory price decreases do and will not resolve the conundrum of the biosimilar market uptake. Policy makers in Belgium should focus on the longer-term health economic assessment and strengthen the economic assessment capacity and scope (i.e., going broader and beyond the individual dossier). This is much needed to achieve a level playing field for biosimilar products in Belgium, 15 years after the first introduction in the EU.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The thoughts and opinions expressed in this article reflect the personal work experience of the author as healthcare consultant for private pharmaceutical companies and for public institutions. The expressed thoughts, opinions and policy proposals are given at personal title, with no responsibility for the private companies and the public institutions, nor for the actual or former employers of the author.

### **References**


gezondheidsproduct/geneesmiddel-voorschrijven/Paginas/biosimilaire-geneesmiddelen-buiten-ziekenhuis.aspx (accessed on 25 March 2021).


### *Article* **Off-Patent Biologicals and Biosimilars Tendering in Europe—A Proposal towards More Sustainable Practices**

**Liese Barbier 1,\* , Steven Simoens <sup>1</sup> , Caroline Soontjens <sup>1</sup> , Barbara Claus <sup>2</sup> , Arnold G. Vulto 1,3 and Isabelle Huys <sup>1</sup>**


**Abstract:** Background: In Europe, off-patent biologicals and biosimilars are largely procured by means of tender procedures. The organization and design of tenders may play a key role in the evolving biosimilar market, and currently, it is not fully elucidated how tenders for off-patent biologicals and biosimilars are designed and if approaches are aligned with sustaining market competition and societal savings for healthcare systems over the long term. This study aims to (i) explore the design and implementation of tender procedures for off-patent biologicals and biosimilars in Europe, (ii) identify learnings for sustainable tender approaches from purchasers and suppliers, and (iii) formulate recommendations in support of competitive and sustainable tender practices in the off-patent biologicals market. Methods: A mixed methods design was applied. A quantitative web-survey was conducted with hospital pharmacists and purchasers (N = 60, of which 47 completed the survey in full), and qualitative expert-interviews with purchasers and suppliers (N = 28) were carried out. Results: The web survey results showed that the organization and design of tenders for off-patent biologicals and biosimilars, and the experience of hospital pharmacists and purchasers with this, considerably varies on several elements across European countries. From the qualitative interviews, signals emerged across the board that some of the current tender approaches might negatively affect market dynamics for off-patent biologicals and biosimilars. The focus on generating short-term savings and existence of originator favouring tender practices were identified as elements that may limit timely competition from and market opportunity for biosimilar suppliers. The need to optimize tender processes, considering a more long-term strategic and sustainable view, was expressed. In addition, challenges appear to exist with differentiating between products beyond price, showing the need and opportunity to guide stakeholders with the (appropriate) inclusion of award criteria beyond price. Due to the variety in tender organization in Europe, a 'one size fits all' tendering framework is not possible. However, on an overarching level, it was argued that tender procedures must aim to (i) ensure market plurality and (ii) include award criteria beyond price (warranted that criteria are objectively and transparently defined, scored and competitively rewarded). Depending on the market (maturity), additional actions may be needed. Conclusions: Findings suggest the need to adjust tender procedures for off-patent biologicals and biosimilars, considering a more long-term strategic and market sustainable view. Five main avenues for optimization were identified: (i) safeguarding a transparent, equal opportunity setting for all suppliers with an appropriate use of award criteria; (ii) fostering a timely opening of tender procedures, ensuring on-set competition; (iii) ensuring and stimulating adherence to laws on public procurement; (iv) securing an efficient process, improving plannability and ensuring timely product supply and (v) safeguarding long-term sustainable competition by stimulating market plurality.

**Citation:** Barbier, L.; Simoens, S.; Soontjens, C.; Claus, B.; Vulto, A.G.; Huys, I. Off-Patent Biologicals and Biosimilars Tendering in Europe—A Proposal towards More Sustainable Practices. *Pharmaceuticals* **2021**, *14*, 499. https://doi.org/10.3390/ ph14060499

Academic Editor: Jean Jacques Vanden Eynde

Received: 19 March 2021 Accepted: 14 May 2021 Published: 24 May 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Keywords:** tender; procurement; off-patent; biological; biosimilar; award criteria; switching; interchangeability; sustainability; competition

### **1. Introduction**

Biological medicines represent a growing share of the total pharmaceutical spend, primarily driven by their high prices and increasing use and as such place a growing pressure on healthcare budgets [1]. In Europe, in 2018, over 30% of pharmaceutical expenditure was on biological medicines, totalling approximately EUR 53 billion [2].

With the expiration of patents and other exclusivity rights for numerous block-buster biological medicines, interest in the development and commercialization of biosimilars rose [3]. Biosimilars are products that are similar to an already authorized biological product, the originator product, with regards to quality, safety and efficacy [4]. The EU has the most mature biosimilar market at present, with 57 biosimilars approved for 16 distinct molecules across various therapeutic areas such as rheumatology, gastroenterology and oncology [5]. The biosimilar market is rapidly evolving and the number of approved biosimilars is expected to grow over the following years [6]. Biosimilars pose an opportunity for healthcare systems to foster competition following the originator's loss of market exclusivity and lower spending on biological medicines while safeguarding safe and effective treatment. Of the total spend on biological medicines in the EU, 21% is now exposed to biosimilar competition (EUR 12 billion yearly) [2]. Biosimilar market entry has shown to lead to significant price reductions and increased patient access to biological therapies [3,7]. The 2020 IQVIA *The Impact of Biosimilar Competition in Europe* report showed that, based on list-price changes, biosimilar market entry has led to an overall 5% reduction in the total EU drug budget spending since 2014 [8].

On a pan-European level, moderate biosimilar uptake and considerable price reductions have been achieved. The experience of individual countries, regions and hospitals with biosimilars differs however considerably, which might be partly explained by the differences in biosimilar policies between and within countries [3,9].

To face budgetary pressures, cost-containment measures have been introduced by European payers to reduce pharmaceutical spending [10]. Tender practices are of specific interest as cost-containment measure in the context of off-patent biological and biosimilar procurement as they make use of supplier competition. Tendering is defined as a formal and predefined procedure in which multiple suppliers enter a contract competition, with the aim to select a best value for money medicine or medicines [10–12]. A tender procedure is generally applied to procure medicines when alternatives or equivalents for a specific medicine are available, which is the case for off-patent (originator) biological medicines and biosimilars. Hospital medicines, including most biologicals, should generally be procured by means of tenders in Europe. Public hospitals or non-public hospitals that are considered as bodies governed by public law should in principle organise tenders according to the harmonised EU rules on public procurement [13]. The EU rules are transposed into national legislation and apply to tenders whose monetary value exceeds a certain amount [14,15]. In tender procedures, price reductions beyond (mandatory) decreases at list-price level can be achieved. Together, these allow healthcare systems to optimize spending on off-patent biologicals and biosimilars. In addition to stimulating price competition, tenders may incentivize suppliers to compete on product or service differentiation, creating additional value for the patient and/or the care process.

When organized and applied in an appropriate way, tendering can be an efficient procurement mechanism, providing equal access to the different suppliers on the market and fostering competition between them, creating an opportunity for healthcare systems to contain expenditure and/or achieve savings that can be invested in other areas of care while possibly creating additional value for patients and care processes [12]. However, questions exist around the effective organization and application of tender procedures and

significant variation exists in the organization of such tenders across European Member States, regions and purchasing groups [10,16–19]. The way how tender procedures are designed may have important implications on pharmaceutical market competition over the longer term [12,20–22]. Tender design elements such as the level on which tenders are organized, the number of winners, the tender duration and selection-and award criteria are important in this.

The importance of effective biosimilar competition for healthcare systems, together with emerging questions regarding the sustainability of tender approaches, the application of award criteria beyond price and the long-term viability of biosimilar commercialization [2,23], poses a timely opportunity to assess current tender practices for off-patent biologics and biosimilars and considerations regarding its possible influence on dynamics in the off-patent biologics market in Europe.

This study aims to (i) explore the design and implementation of tender procedures by contracting authorities for off-patent biologicals and biosimilars and (ii) identify stakeholders' learnings and components for sustainable tender approaches, to in the end (iii) formulate proposals in support of competitive and sustainable tendering practices, supporting long-term presence of different competitors and accompanying benefits for healthcare systems. Table 1 provides manuscript highlights.

**Table 1.** Highlights.

### **What is already known about the topic?**


### **What does the paper add to existing knowledge?**


### **What insights does the paper provide for informing health care-related decision-making**


In this manuscript, the term "off-patent biologicals" refers to reference biologicals that lost patent protection and are exposed to competition from biosimilar alternatives.

### **2. Results**

### *2.1. Survey Results—Organization and Design of Tenders for Off-Patent Biologicals and Biosimilars*

In total, 60 hospital pharmacists and purchasers participated in the web-survey. The number of participants varied throughout the survey due to survey logic and participant drop-out. Forty-seven respondents completed the survey in full. Survey participants' characteristics are shown in Table S1 in Supplementary Materials. In general, survey results showed that the implementation and design of tenders for off-patent biologicals varied on several elements.

### 2.1.1. Perceptions about the Tender Organization

The majority of participants (61%) indicated their organisation to have moderate to extensive *experience* with tendering for biological medicines. Hospital pharmacists (88%), physicians (68%) and a procurement office (67%) were indicated to generally participate in formulating the tender conditions and subsequent product selection. A similar proportion of participants mentioned that differences (44%) and no differences (46%) exist between tender procedures applied for biologicals and small molecule medicines.

When tendering for biological medicines, 60% of participants identified *questions* about interchangeability and switching between biological reference products and biosimilars as challenging. Participants also identified the formulation of appropriate award criteria (25%), supply chain reliability (23%) and the formulation of criteria to select viable suppliers (19%) as challenges when tendering for biologicals. About one fifth of participants indicated to not identify specific challenges with tendering for biological medicines, different from those experienced with tendering for medicines in general. Full survey results are shown in Table S2 in Supplementary Materials.

### 2.1.2. The Tender Design

The reported *average tender duration* varied substantially. Over one quarter of participants (27%) indicated that tender agreements are made for one up to two years. Approximately 20% of participants indicated that tender agreements last between six months and one year, and a similar number indicated tenders to last between two and three years. Tenders shorter than 6 months (12.5%) or longer, between 3 and 4 years (12.5%) appear less common. Approximately half of participants (55%) indicated that contracts can be *reopened after loss of exclusivity* of the tendered originator product.

Almost half of participants (46%) indicated that tenders are generally awarded to a single *winner*. The same proportion of participants indicated that both single and multiple winner constructs are possible. Only 9% indicated to organize tenders with multiple winning suppliers.

Over half of participants (56%) indicated that the *physician's voice* is incorporated in the tender procedure as being part of the tendering committee. According to 68% of participants, physicians can request a motivated exception to prescribe a different product than the tendered product. Only 10.5% indicated that physicians *maintain therapeutic freedom* to prescribe a different product than the tendered product. Full survey results are shown in Table S3 in Supplementary Materials.

### 2.1.3. Application of Selection and Award Criteria

According to 68% of participants, no meaningful *differences* exist in the selection criteria applied in tender procedures for small molecule and biological medicines. Similarly, 60% of participants indicated that there are no differences in the award criteria for biological medicines and those for small molecule medicines while 33% made a distinction.

In terms of applied *selection criteria* (when applicable), 27% indicated to consider the financial viability of the supplier. One fifth of participants indicated to consider the supplier's reputation and the supplier's production capacity. To a lesser extent, participants indicated to consider the supplier's track record of previous tenders (16%), previous collaboration (12%), the duration that the supplier already markets the product (8%), the market share of the product (6%) and the supplier's investment in academic research (4%).

In terms of applied *award criteria besides price*, the product's registered indications (49%), the product's stability/shelf life (45%), the product's delivery device (35%) and the packaging (35%) were indicated to be generally considered. In terms of award criteria related to supply, 41% of participants indicated to consider the supply conditions and 29% the emergency delivery and 24/7 reachability of the supplier. Almost a quarter (22%) of participants indicated to award on additional efficacy and/or safety data (in addition to the data required for regulatory approval, such as clinical data in an additional patient population, or switching data). Value added services (e.g., supporting educational activities, product training programs, information brochures for HCPs or patients about the product, support with switching from the medicinal product previously used) (18%), customer

support (14%) and expenses incurred from switching from the previous winner (6%) were considered to a lesser extent.

The *relative weight given to price* when awarding the tender varied among participants. The majority of participants indicated that a certain weight was given to award criteria besides price (predominately awarded on price (38%), a 50/50 distribution between price and other criteria (19%), predominately on other criteria besides price (19%)). Approximately 20% of participants indicated tenders to be awarded entirely on price.

When formulating *award criteria*, a large number of participants indicated to do so in collaboration with or advice from experts within their own organization (70%). Over half of participants indicated to base themselves on previous experience and almost half to base themselves on national or European guidelines. Thirteen percent of participants indicated to formulate award criteria in collaboration with or advice from (one of) the suppliers. Full survey results are shown in Table S4 in Supplementary Materials.

### 2.1.4. Interchangeability and Switching Considerations in the Context of Tenders

For the formulation of the tender, over half of participants deemed biosimilars interchangeable with their reference product, while 28% believed this depends on the product class and 13% indicated that biosimilars and their reference product are not interchangeable. The majority of participants (68%) indicated that biosimilars and the reference product are grouped in the same lot. According to 43% of participants, no *difference* is made between bio-naïve patients and patients already under treatment with the biological medicine when tendering for biological medicines, with 36% indicating that a difference is made. When the patient already undergoes treatment with the previous winner, approximately half of participants indicated that the option is foreseen to keep patients on therapy with the previous winner. This was indicated to be realized via a multiple winner tender, i.e., there are multiple winners, and one of them is the previous winner (29%), direct procurement of the previous winner (42%) or via an existing contract with the previous winner (21%). Full survey results are shown in Table S5 in Supplementary Materials.

### *2.2. Interview Results—Considerations Regarding the Design and Organisation of Tender Procedures*

In total, 28 expert-interviews were conducted. Tables S6 and S7 in Supplementary Materials provide an overview of interview participants' characteristics.

### 2.2.1. Considerations Regarding Tender Design Elements

### Dividing Product Volume among Suppliers—Ensuring Market Plurality

Presently, tenders are often organised on a single-winner basis, in which the total tendered volume is awarded to one supplier. A *single-winner tender design* generally leads to significant discounts, certainly if the product volume is significant such as in national single-winner tenders. The generated initial price pressure has proven advantageous for healthcare systems to realize immediate large savings. However, awarding total market volume to a single winner excludes non-winning competitors from the market for the duration of the tender contract. While price-driven, single winner tenders generally translate in welcomed large initial savings for healthcare systems, these might decrease supplier plurality in the market. A proliferation and continuation of the single winnertakes-all approach may as such lead to reduced levels of competition. In addition, relying on a single or limited number of suppliers may impact the continuity of patientcare in case of product shortages. Large volume, single-winner tenders may in addition imply a potentially large time and product write-off for contenders who did not win.

Dividing the market among multiple suppliers, providing a commercial opportunity for several suppliers and ensuring *plurality in the market*, was the single most recommended intervention by interviewees towards creating more sustainable tender practices. Some hesitations were expressed by purchasers, as the organization of multiple winner tenders increases the complexity of tenders and product management in the hospital. Healthcare

systems and purchaser authorities need to be equipped to accommodate and effectively organize such a multi-winner tender structure. Besides this remark, both purchasers and suppliers broadly voiced their support. Awarding tenders to multiple winners may also contribute to lower price pressure due to the smaller product volumes. In addition, it provides price reductions on all tendered products and may possibly increase the physician's therapeutic freedom to choose between different products, as such avoiding physicians using a higher-priced non-tendered product. The availability of multiple commercial products on the market may further help to mitigate supply chain issues.

*Various scenarios* could be explored and applied to ensure market plurality, depending on the market size and product volume. Multi-winner tenders (i.e., the tender is awarded to multiple bidders) can be organized or markets can be divided into multiple commercial single-winner opportunities (e.g., on hospital network or regional level).

To effectively organize a multi-winner tender, interviewees argued that some *conditions* need to be fulfilled. First, the tendered volume on purchaser level needs be large enough to be divided among multiple bidders. Second, from the perspective of the purchaser, purchasing capacity would need to be consolidated to increase the feasibility of organizing multi-winner tenders, as this may add to complexity and workload. Third, suppliers should be provided with a guarantee regarding the allocation of volume per supplier. A clear volume estimation per winner is needed to allow them to manage their supply chain and formulate a competitive bid. Multi-winner scenarios in which the first winner is the utilized product and other winners serve as back-up in case supply issues would occur with the first-ranked winner are to be avoided.

In countries where tendering takes place on hospital (group) level (typified by small volumes and generally small procurement teams), single-winner tender structures may be a more efficient route while still stimulating competition as multiple opportunities to win volume exist across the market.

Dividing the market volume among multiple winners on a central or regional purchasing level should not necessarily translate in the availability of multiple products on an individual hospital level. The different winners may be allocated to certain regions or hospitals, which is for example the case in England.

The advantages and conditions related to the organization of multi-winner tenders are outlined in Table 2.


**Table 2.** Organizing multi-winner tenders—considerations.

Tender Award Criteria—Ensuring a Fair Design and Application

Purchasers are encouraged to award a tender based on the Economically Most Advantageous Tender (MEAT) principle, including qualitative elements linked to the tendersubject beyond price, as outlined in the EU Procurement Directive 2014/24/EU [13,24,25]. Tender procedures that solely or mainly focus on price, while delivering savings in the short term, may lead to price erosion and lower the number of competitors over the longer term. Interviewees cautioned that this could ultimately result in de novo market consolidation and increased prices in a given market.

Lowest bid procedures should be avoided, and suppliers should aim to compete sustainably *on additional elements*. Multiple European trade organizations (both originator and biosimilar oriented associations) and also the European Association of Hospital Pharmacists (EAHP) underwrite the practice to include criteria beyond price in tender procedures [20,21,26–28], as such awarding the best-value biological(s). An overview of position statements of these organizations is made available in Table S8 in Supplementary Materials. The inclusion of award criteria beyond price can lead to benefits for the patient (e.g., less painful injection) or the broader organization of care (e.g., facilitating efficient handling by means of ready-to-use preparation or pre-filled syringes). Including additional criteria besides price can furthermore contribute to countering steep price erosion identified in price-only tenders, as this would stimulate to suppliers to innovate and sustainably compete on value-adding criteria.

Four main *challenges* related to including additional award criteria emerged from the interviews. First, the inclusion of award criteria besides price appears not to be routinely included in tenders for off-patent biologicals and biosimilars. According to interviewees, price remains often the sole or dominant differentiator in tender decisions.

Second, stakeholders appear to have questions on how to exactly formulate and apply these criteria. Both purchasers and suppliers mentioned difficulties with translating the MEAT principle to applicable award criteria for off-patent biologicals and biosimilars. As stipulated in the EU Public Procurement Directive, criteria should be compliant with the principles of transparency, non-discrimination and equal treatment to allow an objective comparative assessment [13]. Any criteria that could be perceived as anti-competitive or introduce bias should be excluded from inclusion. Further, only criteria that are related and proportionate to the subject matter of the tender should be included. Caution should be exerted regarding requesting or offering additional services or benefits. In case these are not directly related to the subject matter, these should be strictly avoided. Some interviewees mentioned for example the offering or requesting of research funding. This leads to the third identified challenge related to the application of award criteria.

It appears that in some cases where additional criteria are included; these may *a priori* favour the reference product or disadvantage the biosimilar. For example, including an award criterion on the length of product market presence would structurally disadvantage recently launched products, i.e., biosimilar alternatives, compared to the reference product. Including such an award criterion could therefore be considered as an unreasonable expulsion of competition. Moreover, criteria that are not directly related to the subjectmatter can steer the decision-making on non-product related factors and especially when these are disproportionally weighted in the decision. Additional product-related services are mentioned to be interpreted broadly in some instances. Requesting or offering bonuses or benefits beyond the scope of the product, such as research grants and conference support, should be strictly excluded. In Table 3, an overview of the types of criteria that should be avoided is shown. In Belgium, it was mentioned by stakeholders that the possibility to provide free goods via medical need programs might also disadvantage biosimilars, as these cannot be applied for if already been granted for the reference product.

**Table 3.** A selection of criteria to consider and avoid in tender procedures.

### **A Selection of Possible Criteria to Consider beyond Price**

### **1. Quality and technical related criteria**


### **2. Service-related criteria**


### **3. Patient related criteria**


### **A Selection of Less Desirable Criteria to Consider**

*Only criteria that drive actual benefits (meaningful product differentiation, advantage for purchaser and/or patient) and are related to the subject matter should be included. The below criteria may be considered to impact the level playing field between products, to be misaligned with the biosimilarity principle and/or to be of limited value.*

**1.** Criteria that require the product **to be already on the market for a certain period of time**, as these would naturally advantage products with longer market presence, i.e., the originator product, and disadvantage recently launched biosimilars


EMA: European Medicines Agency, HCPs: healthcare professionals, IV: intravenous, SC: subcutaneous. Consulted reference materials, besides interview transcripts: tender contracts, [29,30].

> Fourth, suppliers expressed difficulty in terms of determining award criteria that would allow to truly differentiate and compete on. It was mentioned that the applied award criteria beyond price often can be relatively easily fulfilled by all suppliers. In such case, including additional criteria increases the effort and cost for the supplier, without playing a differentiating role in the allotment. Interviewees also mentioned that most criteria only temporarily offer a certain differentiation. With the increasing experience with biosimilars, the need for services in terms of educational switch support may for example wane. Moreover, competitors will prepare to meet differentiating additional award criteria in the subsequent tender rounds. Due to the comparable nature of reference biologicals and biosimilars, it may prove challenging to develop criteria on a product level that could offer differentiation over a longer term. Purchasers also alluded to the fact that the inclusion of additional award criteria should serve to drive actual added value rather

than complicating interchangeability of products. To allow for appropriate evaluation of possible differentiating elements such as injection pain of the product, appropriate supporting data are needed.

From both the supplier and purchaser perspective, there is a strong request for a *framework* with general principles regarding the structuring and application of award criteria. In order to stimulate the inclusion of criteria besides price and ensure a correct application, guidance should be drafted to support involved stakeholders, especially purchasers with formulating their tenders. The EU Public Procurement Directive has set out a frame in which Member States and purchasers can operate. Further action may be needed to ensure proper translation and application of MEAT in practice on Member State and purchaser level. Relevant experts should be integrated to identify appropriate award criteria. In countries where procurement is organized on a local or individual hospital level, it may be useful for governments to provide such guidance to purchasers. Here, a flexible or semi-structured tender template could be designed to guide purchasers. Room for flexibility should be foreseen, to allow tailoring based on product-specific considerations and strategic differentiation. Such an award criteria template could be piloted with collaboration from tender authorities and governments.

Only additional criteria that drive *meaningful product differentiation*, leading to an advantage for the organization of care and/or the patient should be included. Criteria could include considerations related to various elements such as supply, packaging, product presentation, storage, reconstitution and easiness of use, licensing and product-related services. To give an example, several purchasers deemed data from stability studies a possible important differentiator for products that require reconstitution. An overview of criteria that can be taken into account is shown in Table 3. Award criteria besides price should also be *proportionally rewarded* based on the additional value created. This should enable criteria besides price to truly play a role in the allotment. Suppliers mentioned that actions are needed to include these additional criteria in the tender, otherwise potential differentiation strategies could be done in vain from the supplier perspective.

Finally, award criteria need to be *transparently formulated*, and it must be clear to participants how these will be evaluated, i.e., which weight will be given to the criteria in the decision-making, and how will they be scored.

Arguments were made that a shift to the inclusion of additional decision-making criteria may gain more attention in future tenders. As first tenders focussed on steep discounts, further discounting opportunities are finite. Including other award criteria may increasingly help differentiate between products.

### Tender Frequency and (Re-)Opening of Contracts—Ensuring Timely Competition

The time between the first possible use of a biosimilar after loss of exclusivity of the corresponding originator product and its actual use should be minimized. In addition to streamlining pricing and reimbursement procedures, a *timely opening* of tender procedures is essential to avoid delays in competition and ensure swift market opportunity for biosimilar alternatives. In addition to ensuring commercial opportunity, a timely opening of tenders should be stimulated to generate savings for healthcare systems as soon as possible.

Several interviewees mentioned that in some cases tenders are opened with a *significant and unnecessary delay*. Contracts with the supplier of the reference product that still apply at the time of biosimilar market entry could possibly explain a delayed tender opening. It was hypothesized that in some cases these contracts were strategically agreed prior to biosimilar market entry to as such extend the originator's market exclusivity artificially. Another possible explanation, which was also mentioned by purchasers, links to the fact that an overview of upcoming loss of exclusivities of reference products and biosimilar market entry dates on governmental and/or purchasing level lacks.

To ensure timely competition, healthcare systems and purchasers should *anticipate and prepare* for biosimilar market entry well in advance. Horizon scanning should be performed

to identify the upcoming loss of exclusivity of reference products and anticipated biosimilar market entry dates. In addition to early preparation for the opening of tenders upon loss of exclusivity of the reference product, purchasers should coordinate contracts with the originator prior to its loss of exclusivity, taking the future entry of biosimilars into account. The length of the contract with the originator prior to biosimilar market entry should thus be set accordingly and preferably/compulsory include a clause that allows reopening if a biosimilar alternative enters the market, to avoid such blocking contracts at the time of biosimilar market entry.

In essence, competition should be realized as soon as possible, providing commercial opportunity, onset savings and possibly additional benefits. Below, different *approaches* are suggested that could be suitable to translate the timely opening of tenders into practice. First, healthcare systems and purchasers could set a certain term in which for existing public contracts a new tender procedure would need to be organised. This term could be included in legislation and made mandatory, such as is the case in Italy [31]. Here, regional authorities are obliged to re-open supply agreements within 60 days after entrance of the biosimilar medicine to the market [31]. A few interviewees mentioned that it should be made (more) clear if reopening is expected with every new entrant. Opening a tender upon market entry of the first biosimilar(s) could challenge market opportunity for subsequent biosimilar entrants for the same product. On the other hand, launching a new tender upon market entry of each subsequent biosimilar should be avoided as a reopening would increase workload, possibly involve repeated switching and increase uncertainty related to the product volume. The latter may prove especially challenging for suppliers. Installing a shorter-term tender (e.g., 6 months) immediately upon market entry of the first biosimilar competitor(s), combined with a longer subsequent tender duration agreement (12–24 months) once the market has further matured in the number of competitors, could be an appropriate alternative when multiple biosimilars are expected to arrive to market in a staggered way. The combination of an on-set short term tender with a subsequent longer one, would allow direct competition, leading to immediate savings for the payer and commercial opportunity for the first biosimilar supplier(s), while avoiding a closed market for subsequent suppliers for a considerable length of time. Once the market has further crystalized in terms of number of available products (e.g., in 6 months or a year depending on estimated market entry dates), tenders for existing public contracts could be reopened. Such a combined approach is for example applied by the central purchasing body Amgros in Denmark.

The appropriate approach in terms of tender timing and frequency could be determined based on the *market-specific circumstances of the product*, such as the expected number of competitors and their anticipated dates of market entry. Tenders that are organized on a quarterly basis might create a high administrative burden for both purchasers and suppliers in addition to being undesirable from the switch perspective. On the other hand, tenders with a duration beyond two years may restrict competition from other suppliers over the longer term. Generally, a tender duration between 12 and 24 months is considered desirable in terms of stimulating market dynamics, while considering feasibility and avoiding a regular switch of patients by interviewees.

In countries where tendering is organized on a regional, purchasing group or hospital level, tender procedures could open up at varying times throughout the year, to spread commercial opportunity for suppliers and accommodate manufacturing capacity. Such a *rolling system* is in place in England, with the Tranche frameworks opening every six months in another one of the four regions [32]. A *specialist procurement office* can play an important role in organizing and coordinating the timing and duration of tender procedures for products with biosimilar competition.

A *financial stimulus* (positive or negative) could also be considered to motivate purchasing bodies/hospitals to timely organize tenders, aligning the incentives of the purchaser with these of the overall healthcare system (savings for healthcare budgets, and/or premium payers/patients). For example, in Belgium the reimbursement agency lowered

the reimbursement for biologicals for which a biosimilar alternative exists with 15% to hospitals [33,34]. As margins on the negotiated price difference between the tendered price and reimbursement limit can be retained by hospitals, hospitals are motivated to organize competitive tenders to procure medicines at low net prices [35]. A similar construct exists in the Netherlands, where health insurers reimburse hospitals the list price of biologics with biosimilar competition only in part, anticipating savings based on discounts that hospitals negotiate in tender procedures [36].

Supply Conditions—Increasing Volume and Predictability to Ensure Continuity of Supply

Tender procedures need to be *efficiently managed*, to increase predictability and plannability for the supplier, which can in turn guarantee timely product supply for the purchaser. Special attention needs to be paid to the setting of product volume, lead time and supply agreements.

First, *increasing predictability* regarding the tendered volume is of benefit for both the purchaser and the supplier. It provides suppliers the ability to accurately assess the economies of scale in their bid, increase the ability of suppliers to participate in tender bidding and manage production. The latter may help to avoid undue pressures on the supply chain.

This includes *setting of reliable estimates of the volume* to be supplied, with guaranteeing a minimum volume and defining a maximum cap. Moreover, in the context of multiwinner tender structures, a clear and guaranteed (division of) volume was considered a prerequisite to allow participating bidders to plan accordingly. In addition, *clinical use guidelines* should be reviewed and revised, if needed in this context, following introduction of biosimilars to allow purchasers to correctly estimate (potentially increased) volumes for tenders. Covering an unexpected increase in demand may be difficult, as it is complex and lengthy to increase the production scale due to the complex manufacturing process of biologicals. In case no minimum volumes would be guaranteed, tenders could lead to a risk of unused stock and issues with scaling [37]. Suppliers with overstock may go for highly competitive offers in pending or subsequent tender procedures, which may lead to unsustainable market dynamics.

Second, the time between the announcement of the winner(s) and the start of the contract (first delivery), also called *lead time*, is in some instances (deemed too) short, making the first supply deadline challenging. Lead times between minimum three to six months should be respected to support the supplier's supply chain management (taking into account that decisions regarding for example packaging cannot be easily re-allocated to other markets), as such reducing the risk of delayed deliveries and shortages. In general, *early communication* regarding the timing of tender procedures and expected volumes should be promoted.

Third, although fortunately no interviewees reported supply inabilities having occurred (yet) in the context of off-patent biologicals and biosimilars, the *hedging agreements for possible supply problems* are a point of consideration. By contract, suppliers are generally obliged to compensate the difference between the tendered price and the price at which the alternative product is offered by a competing supplier, often the list price, to remediate the supply issue. Although the burden of securing and financing an alternative product should naturally not be placed on the purchaser, the supply conditions should be set in such a way that they are manageable for suppliers to achieve, i.e., based on early and accurate communication regarding timing and volume of tender. Moreover, penalties should be proportionate to the contract value and the cause of the inability to supply (force majeure/external reasons for which could not be controlled), ensuring a fair balance of risk and reward for the supplier. For example, in France, penalties are based on list price and not net price, which might lead to an unbalanced risk and reward [37]. Suppliers might decide not to participate in tenders where penalties are disproportionate, leading to reduced competition. *Dialogue* between purchasers and industry should be stimulated to establish manageable supply conditions and balanced penalties.

In the case of a supply issue in a single winner tender market, other manufacturers might not be able to cover the sudden demand and remedy a potential shortage as their production may be reduced or discontinued [37]. *Multi-winner tenders* might thus also be preferred in the context of mitigating the risk of possible medicine shortages, increasing the opportunity to source the product with another supplier. Purchasing strategies that result in steep and perhaps over the longer term unsustainable price reductions may also impact supply, as companies might economize on services such as the presence of strategic stocks. It was argued that focussing on price only may impact additional services and as such the quality of the supply chain.

A *joint tendering initiative* was set up between Norway, Iceland and Denmark in 2019 in response to the growing challenges with regard to supply security, especially for older medicines [38]. Such contracts with large volumes are likely to be prioritized by pharmaceutical companies because of the potential large gain. Such evolution may however be less advantageous on a broader level as it further consolidates the market. Cross border procurement should be reserved to situations where purchasing and supply of products can alternatively not be ensured.

### 2.2.2. Considerations Regarding the Organization of Tenders

Considerations Regarding Transparency about the Tender Procedure and Price

*Transparency* in tenders should be stimulated *throughout the procedure*. Prior to the start of the procedure, at the time of publishing, the tender format, including the eligibility and award criteria and the relative weight that is awarded to these, should be clearly communicated. Upon awarding the contract, feedback should be foreseen to the participating supplier regarding the allocation decision and their scoring. Moreover, the obligation to publish the contract award notice for contracts for which prior announcement is not needed, e.g., for exclusivity contracts (negotiated procedure without prior call for competition) with the incumbent/patent holder prior to biosimilar market entry, should be complied to increase transparency towards the biosimilar entrants. Managed entry agreements (MEAs) ask for specific attention in this regard. The confidential and opaque nature of MEAs, with also the concealment of the patent expiration date of the reference biological, hampers the market entry of biosimilar alternatives. Confidentiality provisions should be addressed to improve the design and transparency of such agreements [39].

A few interviewees argued that a *Best and Final Offer (BAFO) procedure*, which involves a negotiation or clarification on a first written offer, after which bidders are invited to submit a final offer, or any route that would provide a certain supplier to submit a second (informal) bid to surpass the offer of competitors, should be avoided. This practice may provide leeway for suppliers and purchasers to include offers or request elements that are outside the scope of the tender subject matter, as transparency lacks during the final offer made, and impact the equal opportunity setting.

The size of rebates in tender procedures is noted to vary considerably (depending on market maturity and tender volume), ranging between 10% and 90% of the list price [8]. In terms of *price transparency*, actual contract prices are seldom publicly available, hampering the insight in the size of actual rebates [8]. In Norway, where prices were made public from 1995 until 2017, prices from tender procedures are no longer made public [40]. Industry might be willing to provide larger discounts when tender prices remain confidential and list prices un-impacted. *Providing confidential discounts in tenders* is likely to be preferred over pricing strategies that lower the medicine's list price. List prices are often included in external reference pricing systems, acting as benchmark in terms of list price regulation in other European countries. Confidential tender discounts avoid such leverage in price negotiations in other jurisdictions.

Switching Considerations in the Context of Tenders—Clinical Data, Cost, Physician Freedom and Guidance

Increasingly, guidance statements from EU Member States support that prescribers can safely switch patients from a reference biological to its biosimilar [41]. Requesting *additional switching studies* could create an extra barrier for biosimilar developers and may advantage the incumbent, who does not need to gather such data, in tender procedures.

Similarly, determining and including *a switch fee per patient* in tender procedures would disadvantage the biosimilar competitor, as an additional price lowering of for example 5% would be needed to offset the switch fee. Most purchasers argue that the *cost of switching* is marginal compared to the savings that are generally generated in a tender and will as such not play a decisive role in tender decisions. Originator companies may have however some leverage in the broader procurement context, as the price of the originator product that may needed to be purchased to treat the rest population (patients that remain under treatment with the reference product) can be raised by the company in case they lose the tender contract. This could limit or offset the discount realized in the tender procedure, where the originator competes with its biosimilar (alternatives).

In addition to *guidance* regarding interchangeability and switching by authorities [41], purchasers and hospitals should receive *practical support* regarding the use of biosimilars and switching in clinical practice. Practical barriers associated with biosimilar use and uncertainty among stakeholders should be lowered. For example, in England, the NHS set-up different initiatives to educate stakeholders about biosimilars and provide guidance, with the aim of supporting safe, effective and consistent use of biologicals, including biosimilars [42,43]. In the Netherlands, some health insurers have applied a differential reimbursement, reimbursing hospitals at a premium for using biosimilars, as a benefit share between insurers and hospitals, with the aim of compensating hospitals for the time and cost investment associated with a switch [36].

### Collaboration and Communication in the Context of Tenders

Collaboration among stakeholders could be stimulated to ensure the development of more sustainable tender practices. First, early involvement and agreement between the internal stakeholders at the purchasing side (i.e., dialogue between purchasers, hospital pharmacists, physicians, nurses, etc.) regarding the modalities of the tender is believed to be essential. In hospitals, this is generally organized in a Drug and Therapeutics Committee. In countries with a centrally organized procurement such as Denmark and Norway, procurement bodies work together with specialist groups or expert committees. This approach is argued to result in good agreement of physicians to prescribe the tendered medicine.

Second, collaboration *among purchaser(s) (groups)* can increase negotiating strength and add to the consolidation of expertise, professionalism and capacity which is needed to conduct efficient and high-quality tenders. Third, *communication between industry and purchasers* should be stimulated. Increased dialogue could reduce supplier uncertainties and increase efficiency for the different stakeholders involved, establishing a balanced shared risk and reward between suppliers and purchasers. This could be pursued both on the supplier and purchaser level, in the context of specific procedures (preliminary market consultations, with the prerequisite that every supplier is treated equally and receives the same information) and by stimulating dialogue between umbrella industry and purchaser associations. Position statements on the organisation of tenders for off-patent biologicals and biosimilars have been published by these associations. Table S8 in Supplementary Materials provides an overview of the main viewpoints outlined in the position statements.

In terms of optimizing communication in the tender itself, multiple supplier interviewees mentioned that the information requested in a tender procedure should be streamlined. Only information that would be essential to the tender should be included. Continuing the digitalization of tender procedures will contribute towards increasing efficiency in this regard.

### Healthcare Professional Involvement and Motivation

*Involving physicians in the procurement process*, avoiding top-down organized tenders, may help to increase physician adherence to the tender outcome. In Norway, the high adherence among physicians to prescribe the recommended medicine may be explained by the voluntary nature of and the involvement of stakeholders throughout the tender process [44]. Informing and educating healthcare professionals about biosimilar medicines and related concepts can also help to increase acceptance of the tender outcome.

In some countries, *benefit sharing models*—in which savings generated by tender procedures and or biosimilar use are shared between purchasing bodies or payers and the hospital—are applied to incentivize stakeholders. In England, such benefit sharing is in place between the Clinical Commissioning Groups and the trust providers. The example of the University Hospital Southampton NHS, in which a 3-year benefit sharing model was applied, reported significant cost savings and investment in clinical services (such as increasing the capacity of the nurse-led service) while maintaining similar patient-reported outcomes as result of their managed switch programme from infliximab reference product to biosimilar in inflammatory bowel patients [45].

Instead of providing a positive benefit share incentive, other approaches have been reported such as the abovementioned lowering of the reimbursement level for biological medicines for which a biosimilar alternative is available in Belgian hospitals [35].

Interviewees were in favour of organizing stakeholder incentives to increase motivation among stakeholders and support them in their work but cautioned regarding implementing rewards or quota to drive biosimilar uptake in particular. Establishing quota and incentives for the *use of best-value biologicals*, which could be either the originator or one of its biosimilars, was generally deemed more appropriate in terms of establishing a level playing field.

2.2.3. Considerations Regarding the Sustainability of Tender Procedures and Their Impact on Market Dynamics

Several interviewees considered that current tender designs often focus on *maximizing short-term savings*, which they argued resulted in higher than originally anticipated price erosions. Several interviewees mentioned that the publicly reported discounts up to 70% in the Nordics established a certain precedent for subsequent price competition [23,40,46]. Although tender procedures should aim to obtain the most advantageous offer, a race to the bottom should be avoided. The majority of participants indicated that the *sustainability of current practices* should be reconsidered to ensure benefits to society and patients over the longer term.

The steep price erosion was in part attributed to the fact that companies appear to be willing to fiercely *compete on price* due to important advantages associated with winning first product volumes ("first in the market"). This would allow the supplier to gather real-world data and accustom stakeholders with their product. Early winners may also be successful in retaining the market, as the incentive to reopen soon could be low if subsequent additional savings are low and would for example not outweigh the costs (although estimated to be minimal by interviewees) and work associated with a second switch.

Moreover, originator companies appear to apply *strong defensive tactics* to maintain market share by significant price dropping. This was recognized to limit biosimilar market entry in several markets. Originator suppliers may have more leeway for pronounced discounts compared to their biosimilar counterparts due to the different stage in recuperation of development cost in the lifecycle of the product. Where biosimilar developers need to earn back biosimilar development investments upon market entry, investments are generally recouped at this stage for the originator product. Additionally, it was hypothesized that some companies lower prices to such an extent that other suppliers start to drop out. This was believed to have been the case with tender practices for adalimumab, where the originator company offered especially steep discounts in some markets. In cases where the

originator swiftly dropped originator prices, originators have mostly been able to maintain a significant portion of the market.

A balance between realizing short-term savings vs. avoiding possible unintended consequences in terms of decreased competition over the mid-long term should be considered. Some markets could be more at risk than others for reduced competition, depending on the commercial opportunity in terms of volume and expected prices in the given market. Multiple suppliers believed that action is essential to prevent this evolution and cautioned that hesitations exist among developers regarding the continuation of their biosimilar programs. As counterargument, it was reasoned that not all suppliers need to remain on the market for some products, as three to four suppliers would suffice for a sustainable market environment.

In markets with high price pressure, suppliers may economize by for example reducing their emergency stock available, which adds vulnerability to the product supply chain. A race to the bottom in terms of price should be avoided. Several interviewees argued that the shortage sensitive dynamics in the off-patent small molecule market should be avoided for off-patent biologicals and biosimilars.

The development of a longer-term vision is argued to be needed, to avoid competition loss and to ensure sustainable dynamics and benefits for the healthcare system over the longer term. It was mentioned that there is a need to act now, to ensure healthcare systems and tender practices are prepared for the anticipated next wave of biosimilars reaching European markets. Collaboration between the public sector and manufacturers (umbrella organizations) is believed needed to establish such common ground and exchange of perspective. Willingness appears to exist from different parties to work towards a more sustainable framework. As several manufacturers invest in both originator and biosimilars products, consideration for sustainable tender approaches may be increasingly supported.

### 2.2.4. Considerations Regarding Competition Dynamics—Ensuring a Level Playing Field

As noted earlier, some tender processes appear to advantage the reference product over its biosimilar (alternatives). Suppliers can attempt to steer the structuring of the tender in their favour. Competition-limiting elements (such as considering research financing) are also reported to be pro-actively requested by purchasers, which may be explained by loyalty to and (financial) ties with the incumbent. In addition to a possible deliberate steering of tender structures to favour a certain outcome/bidder, purchasers may in some cases introduce unintentional biases due to limited (procurement) expertise, questions around the structuring or hesitations regarding biosimilars.

Examples of dynamics that favour the originator product include the delayed opening of tenders due to ongoing contracts with the originator at the time of biosimilar market entry, the application of originator favouring award criteria or offering of conditional discounts. The latter could be for example linked to the length of the contract, the ranking of the product or the offering of services that are unrelated with the subject matter of the tender, such as research financing. In the Netherlands, 20–50% of contracts were reported to include such a conditional discount structure in 2018 by a sector enquiry of the anti-Tumour Necrosis Factor product market [36,47]. Clauses that stipulate that the discounts of the competitor will be matched or renegotiated, matching the lowest offer or guaranteeing lowest price, can impact biosimilar market entry and also distort price competition, as the originator is likely to match the offer. Adding a Best and Final Offer (BAFO) round may lead to similar distortions. Contract linkage, in which offers or requests are made to provide rebates for previously delivered or contracted medicines or on a related product, in case the tender contract is won, is also reported to occur.

In case the level of price reductions offered would force biosimilar developers to compete with a price below cost of goods due to a dominant position of the originator, these can also be considered anti-competitive.

The existence of anti-competitive procurement practices warrants action. Awareness should be raised about the public procurement integrity rules; a culture of integrity should

be promoted, and a better collection and analysis of data should be ensured to improve governance. Fostering the uptake of e-procurement and supporting procurers with the appropriate tools and exchange of best practice can contribute in this regard. The appropriate application of tenders should be monitored by the EU national Competition Authorities and the European Commission must support actions of EU countries in this regard [48].

### 2.2.5. Future Outlook of Interviewees: Possible Evolutions in Tender Organization

To contain costs, competition could be further opened up by *tendering beyond the international non-proprietary name (INN)* for biologicals, which is already applied in certain cases or settings, such as in some hospital groups in the Netherlands. Including products in a same therapeutic class, which may include in some cases branded medicines, will allow to further increase competition and could be considered as option to contain spending [49].

Tender procedures may also evolve from focussing exclusively on the product's price, to taking a more holistic approach, including the overall cost of treatment, which includes but is not limited to the medicine price. Procurement, which takes total cost of care delivery into account, also called *value-based procurement*, aims to focus on patient outcomes the product should have an impact on. Where traditional procurement may often focus on the technical specifications of the product, price and short-term benefits, value-based procurement focusses on getting a maximum patient outcome against total cost of care [50]. For instance, the total cost of the in-hospital infusion of an intravenous medicine could be compared to the cost of the patient's self-administering of an oral medicine, or to the home-administration of a subcutaneous alternative.

Another possible foreseen development in tender practices includes *subscription-model tendering*, where for well-defined patient profiles, medicine packages focussing on the broader therapeutic needs of the patient could be tendered. Some countries and regions (US, Australia, UK) are testing such subscription-based procurement models, also called the Netflix-model [51,52]. In this type of procurement model, purchasers pay a pre-agreed flat amount to the supplier, irrespective of the volume of medicines used [51]. Such approach could provide substantial benefits as it includes a capping of costs for the payer and 'derisked' revenue for the supplier. It however also increases volume uncertainty for the supplier, which could result in supply chain management challenges [53].

### **3. Discussion**

Tender procedures warrant a careful organization, design, execution, and evaluation and if needed readjustment, to ensure that they are aligned with sustainable outcomes for patients, industry and society at large over the longer term. It is a delicate balancing between ensuring the most efficient use of public financial resources and safeguarding market opportunity for multiple suppliers, as such stimulating competition over the longer term. In addition to optimizing the spending of public funds, public procurement and the effective use of tender criteria beyond price may achieve other benefits for society, healthcare systems and patients [15].

In this mixed methods study, we sought to assess the experience with tendering procedures for off-patent biologicals and biosimilars in Europe and identify learnings from current practices, drawing from a quantitative web-survey in European purchasers and qualitative expert-interviews with both purchasers and suppliers.

### *3.1. Challenges in the Organization of Tenders for Off-Patent Biologics and Biosimilars*

During the qualitative analysis, three main challenges arose with the organization of tenders for off-patent biological medicines and biosimilars. First, current tender practices appear to focus on realizing short-term savings. This may be explained in part by the design of the tender, which often considers only price and rewards to one single winner. Moreover, changing originator competition strategies may play a part. Whereas originator manufacturers originally appeared to protect market shares via the development of second generation or reformulated products (e.g., Humira®'s new formulation launch aimed for

less injection pain, or the subcutaneous versions of Herceptin® and MabThera®), strategies have shifted and include increased competition on price [2]. From the payer's perspective, one could argue that cost savings are realized in such a scenario, regardless of any biosimilar uptake. Considering biosimilar market entry as leverage to encourage a price cut from the incumbent (via a mandated list price decrease or discounts in tender procedures) may be a successful strategy in the short-term in terms of realizing savings. However, over the mid-long term, this is likely to lead to opposite effects due to market impoverishment.

The second main identified challenge pertains to the fact that tender processes were in some cases argued to advantage the reference product over its biosimilar (alternatives). This could be both deliberately or unintentionally driven, possibly because of stakeholder preference to continue with the reference product due to brand loyalty and/or additional benefits and/or issues with the design of the tender due to limited expertise with procurement of off-patent biologicals and biosimilars. While including additional award criteria provides the opportunity to compete more sustainably on value-adding elements besides price, it also gives room for possible steering.

Third, including award criteria beyond price appears to be challenging in practice. Purchasers expressed difficulties to find the right balance between award criteria which allow to differentiate and which are non-discriminatory. From both the survey and expertinterviews, guidance appears to be needed on how to design tenders for off-patent biologicals and biosimilars and especially how to formulate appropriate award criteria. Only when truly differentiating and value-adding criteria are identified, included, objectively assessed and proportionally rewarded in the tender, the concept of MEAT can be successfully implemented and play a role in the allotment.

### *3.2. Five Main Avenues for Optimization*

Based on the stakeholder insights from this study, we conclude with proposals on five identified main avenues for optimization of public procurement processes for offpatent biologicals and biosimilars: (i) safeguarding a transparent, equal opportunity setting for all suppliers; (ii) fostering a timely opening of tender procedures, ensuring on-set competition; (iii) ensuring and stimulating adherence to laws on public procurement; (iv) securing an efficient process, improving plannability and ensuring timely product supply and (v) safeguarding long-term sustainable competition. Table 4 outlines these avenues for tender optimization.

Generally, stimulating market plurality, enabling market opportunity for multiple products, is considered to be the cornerstone towards creating a more sustainable and competitive tender market by stakeholders. This is in line with the findings of the KPMG cross-country analysis into the delivery of healthcare in hospitals by optimized utilization of medicines [37] and is supported by position statements of various industry umbrella organizations (Table S8). To realize the objective of sustained product plurality, several Member States and regions have been actively pursuing new approaches from which best practices can be derived, such as the Commissioning Framework for biological medicines in England and the changes in the Italian legal framework related to biosimilars [31,54,55].

Overall, a combined action of all actors; suppliers, pharmaceutical industry associations, purchasers, payers, governments and competition authorities, is required to promote and strengthen the competition between off-patent biological medicines and biosimilars via tenders, and by extension establishing effective, healthy market dynamics. This requires a combination of practical and policy changes, involving alterations at purchaser level but also in the policy framework. Policymakers should set out a tender policy strategy, with appropriate organizational structures and stakeholder management to ensure adherence to public procurement rules. In addition to changes to the policy framework, any perverse incentives in the financing structure of purchaser bodies should be revised to ensure a level playing field. A combination of guidance (with initiatives such as horizon scanning, a tender template, award criteria framework and feedback systems), transparent reporting on the structuring and evaluation of tender procedures and monitoring and feedback

from governments or competition authorities will be necessary to sensitize stakeholders in this regard.

In general, monitoring the application of the tendering policy and subsequent changes in market dynamics is warranted, together with adapting its design if needed. National authorities should actively support purchasers with the appropriate application of tender procedures and introduction of award criteria, by providing the necessary guidance and feedback. Policy makers, purchasers and pharmaceutical industry associations should take action to collaboratively develop tender frameworks that include award criteria beyond price. For example, medical devices industry associations were successful in stimulating dialogue and collaborating with contracting authorities in order to develop a methodology to encourage the uptake of value-based procurement throughout the EU [56,57].

Moreover, guidelines for biosimilar use to increase confidence and lower hurdles with the use of biosimilars [58] and an active promotion of best-value biological use by developing proper stakeholder incentivization schemes are warranted [9,55,59,60].

As exemplified by both the survey and interview data, the design and execution of tenders for off-patent biologicals and biosimilars varies across European countries, regions and hospitals. As the tender landscape is variable across Europe, measures need to be adapted to country, region and setting specific needs. The results from the expert-interviews suggest that countries in which procurement is organized on a more local or hospital individual level, where there is more flexibility and individual purchaser freedom in the design and structuring of the tender, would especially benefit from increased guidance on tender and award criteria design. European regions, where tenders are organized with a central or regionally coordinated approach, such as for example England, were generally considered to have a well thought out procurement strategy and high level of tender expertise by interviewees. In addition to a consolidation of expertise, a more central or coordinated organization of tenders aggregates purchasing needs, as such freeing up resources and time while increasing buying power.

The diverse approaches and outcomes with relation to the market entry of adalimumab biosimilars in the European countries included in the study illustrates again the diversity in healthcare systems and procurement practices across Europe. For example, NHS England and Amgros (the Danish procurement body) sought strategies to ensure rapid biosimilar adoption and generate immediate savings [54,61]. In Norway and the Netherlands, the originator manufacturer was able to retain market share by offering steep discounts [62]. Although the biosimilar market entry of adalimumab biosimilars may have been a unique casus, as a multitude of competitors were lined up to enter simultaneously the market to compete with the number one blockbuster drug worldwide, lessons can be derived, such as the importance of well in advance preparing and planning for biosimilar market entry [54,55].

### *3.3. Strengths and Limitations*

The organisation of tenders for off-patent biologicals and biosimilars has been previously investigated in the context of a KPMG study on improving healthcare delivery in hospitals [37]. Here, authors identify the following elements to foster biosimilar utilization in the hospital environment: swiftly reopening of tenders, organizing multi-winner tenders, implementing benefit sharing methods and switching towards MEAT criteria. These elements are considered relatively easy to implement with a potential high impact on the system [37]. Also, the law firm Baker McKenzie performed a multi-jurisdictional European study, identifying key legal and practical aspects of the biosimilars market, in particular with regard to public tendering [63]. To the knowledge of the authors, this paper is the first scientific publication to assess in-depth stakeholder experiences with tender practices for off-patent biologicals and biosimilars and explore the sustainability of current practices.

The study presents both quantitative and qualitative data and is based on both purchaser and supplier experience. The qualitative survey data provide a snapshot of the heterogeneity of procurement practices and experiences of purchasers with the procure-

ment of off-patent biologicals and biosimilars, across European countries. Participants from 23 different European countries, with varying levels of procurement organization (central, regional, local level) were queried. Overall, the quantitative data exemplify varying experiences across countries and provide a general overview of attitudes and challenges towards procurement of off-patent biologicals and biosimilars.

For the qualitative study part, interviews were conducted with experts in a selection of European countries that represent different tender structures, which enabled gathering information from various European contexts. In addition, interviews on a pan-European level were conducted to strengthen both country-specific and European-broad insights. Interviews were conducted with both purchaser- and supply (industry)-side participants, reflecting the insights of the two principal stakeholder groups in the tender process. The choice of qualitative interviews permitted to gain detailed insight in current practices and gather proposals for improvement from experts in the field. Experts from a purposive sample of European countries were invited, to capture a broad range of insights from countries with varying practices. However, no interview insights were obtained from Eastern-European countries. It may be useful for future research to expand on in-depth country analyses, assess perspectives of policy makers on proposed measures and conduct a systematic analysis on tenders in the EU database on tenders.

The general set of principles and proposals as outlined in Table 4, based on pan-European and country specific expert insights, could be applied mutatis mutandis to specific countries and settings. It is important to note that not all findings are generalizable to the whole off-patent biologicals segment across Europe, as some are product, country, setting or time related. Depending on the tender organization and maturity of the respective country or setting, measures on different levels may be needed and these should be tailored to country context. Some of the proposed recommendations are based on existing best practices. Several countries, regions or hospitals implement at present one or multiple of the proposed practices as outlined in Table 4. Some learnings may not be limited to tender practices for originator biologicals and biosimilar and might apply to tender practices in general. The fact that discounts in tender procedures are generally confidential prevents to properly mirror the gathered qualitative insights on price competition with actual price data beyond list-price level. As estimated by IQVIA, confidential discounts range between 10% and 90% on list price and could offer a 5–10% saving to the overall drug budget [8].

**Table 4.** Proposals on how to optimize tender procedures for off-patent biologicals and biosimilars, ensuring sustainable competition and associated savings in the long-term in the off-patent biologicals segment—five main avenues for optimization.

Tender practices should abide with the European Union and Member State rules on tendering. The involved actors, suppliers, purchaser bodies, payers, government and competition authorities, have a role to fulfil to ensure efficient, fair and transparent tender procedures for off-patent biologics and biosimilars.


The proposals outlined below can be considered as a general set of principles that can inform the different actors involved on possible improvements. Depending on the tender organization and maturity of the respective country or setting, measures should be selected and tailored to the country's context. Some of the proposed recommendations are based on existing best practices. Several countries, regions or hospitals have implemented already one or multiple of the proposed practices as outlined here.

**Table 4.** *Cont.*

**1. Safeguarding a transparent, equal opportunity setting for all suppliers, with an appropriate use of award criteria**

The tender procedure needs to be **transparent** and **non-discriminatory** with **predefined rules and pathway**, which are **adhered to** throughout the process

	- # Selection and award criteria should be carefully formulated, to avoid that participants are excluded a priori or certain products are disadvantaged on improper grounds. **Criteria for which longer market presence is required or would be advantageous should be avoided,** as these could lead to unreasonable competition expulsion, disadvantaging recently launched products.
	- # Only criteria that are **related and proportionate** to the subject matter should be included. Any criteria that could unreasonably limit competition or introduce bias should be excluded. The link with the subject matter should be clear. Caution should be exerted regarding requesting or offering additional services or benefits, and this should be strictly avoided if not directly related to the subject matter.
	- # Only additional criteria that **drive actual benefits** (meaningful product differentiation, advantage for purchaser and/or patient) should be included.
	- # Award criteria besides price should be **proportionally rewarded** based on the additional value created, as the provision of additional services increases investment for suppliers. This will also enable these criteria to truly play a role in the allotment.
	- # **Relevant experts** should be integrated to identify appropriate award criteria. In countries where procurement is organized on a local or individual hospital level, **governments** should provide **guidance** to purchasers regarding the structuring of the tender and application of selection and award criteria. Here, a **flexible/semi-structured tender template** could be designed to guide purchasers but also allowing room for tailoring based on product—specific considerations and strategic differentiation.

### **2. Fostering a timely opening of tender procedures, ensuring on-set competition**

Tender procedures should be **opened as soon as possible**, to avoid delays in competition and market opportunity for biosimilar competitors:

	- # Systems should be prepared to organize tenders upon biosimilar market entry to reduce barriers to entry. A continuous re-opening of procedures with every new competitor entering the market should however be avoided, as this could introduce uncertainty in terms of volume and tender duration for the first tender winner(s) (lowering volume predictability) and also be burdensome for contracting authorities and industry.
	- # Installing a shorter-term tender (e.g., 6 months) immediately upon market entry of the first biosimilar competitor(s), combined with a longer subsequent tender agreement, would allow immediate competition and market opportunity for the different competitors once the market has further crystalized in terms of number of available products.
	- # Alternatively, a differentiated, product—specific approach in determining the appropriate term for opening a tender, taking into account the number of expected competitors, could be appropriate.

### **Table 4.** *Cont.*


### **3. Ensuring and stimulating adherence to laws on public procurement**

The rules on public procurement should be correctly applied:

	- # **Disincentives** to organize competitive tenders or **incentives that favour a specific product/preference for the originator/more expensive product** should be **removed.**
	- # **Financial incentives schemes or other policies** should be put in place:
		- Top-down: such as **lowering the reimbursement level** of products that are open to competition to stimulate purchasers to timely organize competitive tender procedures.
		- Stakeholder-involved: Savings from tender procedures could be allocated in part to remunerate HCPs for their time investment in switching, as part of a **gain-sharing model**. Such a gain-sharing model could motivate and involve stakeholders, increasing adherence to the tendered winner(s) and countering possible financial incentives and preferences to use the originator product.

### **4. Securing an efficient process, improving plannability and ensuring timely product supply**

The tender procedure needs to be efficiently managed, optimizing and reducing the administrative and time burden for both suppliers and purchasers, as well as increasing predictability and plannability for the supplier—supporting timely product supply.

	- # This includes setting of **reliable estimates of volume to be supplied** (with guaranteeing minimum volumes and a maximum cap), **timely communication regarding** the **timing** of tender procedures and making use of **acceptable lead times** to support suppliers to better forecast and anticipate on demand, as such reducing the risk of shortages.
	- # In case of supply issues, **penalties** should be **proportionate** to the contract value and the cause of the inability to supply (force majeure/external reasons for which could not be controlled), ensuring a fair balance of risk and reward. In case of inability to supply volumes that are higher than estimated (e.g., not specified in procurement contract), the supplier should bear no (disproportionate) financial risk.
	- # In some cases, a good strategy could be that tender procedures **open up throughout the year**, to spread commercial opportunity for suppliers and accommodate manufacturing capacity.

### **Table 4.** *Cont.*

	- # <sup>A</sup> **dedicated, expert procurement office** that consolidates knowledge, skill and experience with tender procedures should be available **to support purchasers/procurement bodies with the timely planning and efficient organization** of tender procedures.
	- # Such a specialized procurement office should **set out strategy**, **coordinate** purchasers and tender procedures, **perform horizon scanning** to inform stakeholders on the upcoming loss of exclusivity of reference products and anticipated biosimilar market entry dates, **prepare stakeholder guidance** documents and **monitor** the number of competitors on the market.
	- # Beyond coordinating the procurement strategy for products with anticipated biosimilar competition, the expert office should apply a long-term view and advice on contract length of new contracts, **considering future market entries**, **avoiding "blocking" contracts** at the time of biosimilar market entry, which would delay market competition.
	- # **Specific measures** or a **tailored approach** could be applied to prepare for biosimilar market entry of a specific product (or product category) (as was done in several countries to prepare for adalimumab biosimilar market entry) or could be adjusted based on specific market dynamics.
	- # Such an overarching expert office would also be beneficial in terms of **consolidating efforts, avoiding duplication**
	- and **professionalising** the processes, as required by the increasingly complex structure of tender procedures. # Depending on the country, such expert centre could be established **at national or regional level**.

### **5. Safeguarding long-term sustainable competition by stimulating market plurality**

The tender procedures and overall procurement strategy need to take a long-term view into account, tailored to supporting long-term sustainability, providing commercial opportunity for multiple suppliers

### - **Stimulating market plurality and multiple commercial opportunities for suppliers**

	- # Market dynamics such as the numbers of competitors and associated manufacturers should be reviewed on an annual basis and tendering policies should be reviewed in this context, avoiding market concentration and de novo monopolies

### *3.4. Balancing Short and Long Term Benefits*

It is clear from this study that it is a delicate balance between optimizing efficient spending of public funds, addressing patient needs and preserving competition over the longer term. When designed efficiently and conducted appropriately, tenders can stimulate competition and as such form a cornerstone for sustainable market dynamics. As ensuring the most efficient use of public resources and broad access to medicines is a common societal goal, actions to ensure that tender processes are effective and motivate suppliers to participate over the longer-term are essential. Starting in the next five years, the number of biologic loss of exclusivities will increase substantially [8]. Healthcare systems across

Europe need to be prepared to facilitate and optimize market access for and competition from the next wave of biosimilar market entries, drawing from earlier experiences. This will allow healthcare systems to maximize the benefit of biological competition efficiently over the long term.

### **4. Materials and Methods**

The study follows a mixed methods design, consisting of a survey and semi-structured interviews, gathering both quantitative and qualitative data. The study concentrates on tender procedures organised by contracting authorities. Tenders that are organized by private entities are not bound to organise public procurement procedures and are therefore out of scope. Ethics approval of the study was granted by the Research Ethics Committee UZ/KU Leuven (MP006498, Belgium).

### *4.1. Quantitative Web-Survey*

### 4.1.1. Recruitment

A quantitative, anonymous web-questionnaire was developed to survey purchasers and hospital pharmacists about the organisation of tenders for off-patent biologicals and biosimilars. The survey was disseminated to hospital pharmacists and purchasers across Europe, via professional associations such as the European Association of Hospital Pharmacists, by contacting procurement entities and the network of the research group.

### 4.1.2. Survey Development

The survey was developed based on a study of the literature and consisted of questions about (i) the experience of participants with tender procedures for off-patent biologicals and biosimilars and perceived challenges, (ii) the design of tender procedures (number of winners, average tender duration, reopening of tenders, physician involvement), (iii) the application of selection-and award criteria and (iv) considerations about interchangeability and switching, as tenders may result in an exchange of products. The survey questions were refined based on comments from both a hospital pharmacist and a supplier. The survey was developed online in the KU Leuven Websurvey-server and gathered anonymous data. The survey consisted of closed multiple choice, ranking or Likert-scale questions. Participants were given the possibility to add additional information in an open text field for certain questions and answer options such as "Other". The first window of the web survey provided participants with information about the study, the voluntary nature of participation and a statement regarding agreement to participate. The survey was anonymous, and no personal data were collected.

### 4.1.3. Analysis

Responses were gathered between October 2018 and February 2019. The survey answers were analysed descriptively on an overall group level.

### *4.2. Qualitative Semi-Structured Interviews*

### 4.2.1. Recruitment

To gather qualitative, in-depth expert insights regarding the organization of tenders for off-patent biologicals and biosimilars, semi-structured interviews were conducted with hospital pharmacists, purchasers and pharmaceutical industry employees. The sampling was purposeful to obtain a range of experiences and perspectives, reflecting both the purchaser and supply side perspective, from individuals that are knowledgeable about and experienced with tender processes for off-patent biologicals and biosimilars.

Eligible participants worked currently or formerly as (i) medicine purchaser or hospital pharmacist, (ii) in, or as consultant to, a pharmaceutical company with at least one EMAapproved originator biological or biosimilar (or having both originator and biosimilar products) or for a pharmaceutical industry trade organization. Employees from both legacy originator and legacy generic companies were recruited. Participants were selected for

their experience with and knowledge about tender practices for off-patent biologics and biosimilars [65].

To capture diverse and comprehensive insights, both participants with insights on a pan-European level (e.g., from European professional associations, European pharmaceutical company headquarters or trade organizations) and participants with country specific insights were invited. For the latter, participants were recruited from a purposive selection of seven European countries, representing different tender organizational systems (central purchasing: Denmark and Norway, regional purchasing: England and Italy, buying group/hospital individual purchasing: France, the Netherlands and Belgium). The choice to capture the insights of both purchaser- and supply (industry)-side participants was made to obtain views from the two principal stakeholder groups in the tender process.

Participant recruitment was carried out by screening relevant websites, scientific and professional stakeholder associations, relevant conferences and publications and the network of the research group for eligible participants.

While different sampling strategies were applied for the survey and the interviews (broad vs. purposeful sampling), a certain overlap in participants may theoretically have been possible. The impact of having a respondent possibly participating in the survey and a subsequent interview is considered negligible on interview results since the survey and interviews served distinct purposes.

### 4.2.2. Interview Guide and Interviews

Interviews were carried out in English, with the exception of a few interviews in Dutch, in person, via telephone or teleconference between March 2019 and February 2020. All participants provided written informed consent prior to the start of their interview. Consent was given by all participants for using the encoded and anonymized data from their interview for scientific publication. Interviews were conducted using an interview guide based on topics identified from scientific literature, policy documents, position statements related to the procurement of off-patent biologics and biosimilars and the quantitative survey results. Interviewees were asked to share their insights on challenges, best practices and learnings regarding tender practices for off-patent biologicals and biosimilars, as well as proposals towards long-term sustainable tender practices. An overview of discussed topics is shown in Supplementary Materials Table S9. All interviews were audio-recorded and transcribed verbatim. Interviews were carried out until saturation of the data [65].

### 4.2.3. Analysis

Interview transcripts were pseudonymised and analysed according to the thematic framework method, using Nvivo® data analysis software [66].

### **5. Conclusions**

This study found that opportunity exists to improve tender practices for off-patent biologicals and biosimilars in Europe. In order to realise the competition potential of biosimilars and benefits from appropriate tender procedures for healthcare systems and patients, concerted actions by policymakers and purchasers, in dialogue with industry associations, with a long-term strategic view are needed to optimize tender frameworks. Depending on the country's policy environment and the maturity of the procurement body, different sets of policy and practical measures are needed. In general, measures should aim to ensure supplier market plurality, establish a transparent and objective process, and include award criteria beyond price. This may contribute to creating a sustainable climate, with long-term competition in the off-patent biologicals market.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/ph14060499/s1, Table S1: Survey participants' characteristics, Table S2: Experience with and perceptions about tenders for off-patent biologicals and biosimilars, Table S3: Structuring of tenders for off-patent biologicals and biosimilars, Table S4: Application of selection and award criteria in tenders for off-patent biologicals and biosimilars, Table S5: Interchangeability and switching

considerations in tender design, Table S6: Interview participants' characteristics, Table S7: Interview participants' characteristics, Table S8: Recommendations extracted from position/white papers on tender procedures (for off-patent biological medicines and biosimilars) in Europe, Table S9: Main topics addressed during the interviews.

**Author Contributions:** A.G.V., I.H., S.S. and L.B. developed the idea of this study and were involved in its design. B.C. provided feedback at different stages of the study. L.B. and C.S. collected and analysed the survey data. L.B. collected and analysed the interview data. L.B. prepared the first draft of the manuscript. All authors critically reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work is supported by KU Leuven and the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL Fund).

**Institutional Review Board Statement:** Ethics approval was granted by the Research Ethics Committee UZ/KU Leuven (MP006498, Belgium).

**Informed Consent Statement:** Written informed consent was obtained from all interviewees involved in the study. All interviewees provided consent for using the encoded and anonymized data from their interview for publication in scientific journals.

**Data Availability Statement:** The survey data presented in this study are available on reasonable request from the corresponding author. The interview data are not available upon request as they contain information that could compromise interviewees' privacy and consent.

**Acknowledgments:** First, the authors thank all participants who shared their insights in the survey and/or in an interview. The authors thank T. De Rijdt (UZ Leuven) and A. Abouzid (IQVIA) for their review of the survey. The authors would like to thank A. Baeyens (DG GROW, European Commission), B. Boone (Apollegis) and F. Turk (University of Paderborn) for their valuable comments on the manuscript. The authors also express their thanks to the European Association of Hospital Pharmacists (EAHP) and the organizers of the Biosimilars Educational Masterclass for Pharmacists (BEAM) for disseminating the survey among hospital pharmacists.

**Conflicts of Interest:** I.H., S.S. and A.G.V. are founders of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL Fund). A.G.V. is involved in consulting, advisory work and speaking engagements for a number of companies, i.e., AbbVie, Accord, Amgen, Biogen, Medicines for Europe, Pfizer/Hospira, Mundipharma, Roche, Novartis, Sandoz, Boehringer Ingelheim. S.S. was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD; he has participated in advisory board meetings for Sandoz, Pfizer and Amgen; he has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma and Pfizer; and he has had speaking engagements for Amgen, Celltrion and Sandoz. L.B., I.H., C.S. and B.C. declare no conflicts of interest that are directly relevant to the content of this article. Authors declare that the research was conducted in the absence of any commercial or financial relationship that could be perceived as a potential conflict of interest.

### **References**


### **Sustainability of Biosimilars in Europe: A Delphi Panel Consensus with Systematic Literature Review**

**Arnold G. Vulto 1,2 , Jackie Vanderpuye-Orgle 3,\*, Martin van der Graa**ff **4 , Steven R. A. Simoens <sup>2</sup> , Lorenzo Dagna <sup>5</sup> , Richard Macaulay <sup>6</sup> , Beenish Majeed <sup>6</sup> , Je**ff**rey Lemay <sup>7</sup> , Jane Hippenmeyer <sup>8</sup> and Sebastian Gonzalez-McQuire <sup>8</sup>**


Received: 7 August 2020; Accepted: 31 October 2020; Published: 17 November 2020

**Abstract:** Introduction: Biosimilars have the potential to enhance the sustainability of evolving health care systems. A sustainable biosimilars market requires all stakeholders to balance competition and supply chain security. However, there is significant variation in the policies for pricing, procurement, and use of biosimilars in the European Union. A modified Delphi process was conducted to achieve expert consensus on biosimilar market sustainability in Europe. Methods: The priorities of 11 stakeholders were explored in three stages: a brainstorming stage supported by a systematic literature review (SLR) and key materials identified by the participants; development and review of statements derived during brainstorming; and a facilitated roundtable discussion. Results: Participants argued that a sustainable biosimilar market must deliver tangible and transparent benefits to the health care system, while meeting the needs of all stakeholders. Key drivers of biosimilar market sustainability included: (i) competition is more effective than regulation; (ii) there should be incentives to ensure industry investment in biosimilar development and innovation; (iii) procurement processes must avoid monopolies and minimize market disruption; and (iv) principles for procurement should be defined by all stakeholders. However, findings from the SLR were limited, with significant gaps on the impact of different tender models on supply risks, savings, and sustainability. Conclusions: A sustainable biosimilar market means that all stakeholders benefit from appropriate and reliable access to biological therapies. Failure to care for biosimilar market sustainability may impoverish biosimilar development and offerings, eventually leading to increased cost for health care systems and patients, with fewer resources for innovation.

**Keywords:** biosimilar market; biosimilar/supply and distribution; biosimilar sustainability; Delphi technique

### **1. Introduction**

The global biosimilars market was valued at \$4.5 billion in 2019 and is expected to reach \$23.6 billion by 2024; this is an estimated growth rate of 39.4%, with most of this growth occurring in Europe [1,2]. Such a rapid acceleration in the biosimilars market may result in numerous challenges, and it is important to support a thoughtful deployment of biosimilars. This will provide an opportunity for sustainability of global health care budgets and evolving health care systems [3,4].

At present, the European Medicines Agency (EMA) defines a "biosimilar" as "a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product (reference medicinal product)" for which "similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise needs to be established" [5,6]. Manufacturers in both the United States and Europe are required to demonstrate that the proposed biosimilar and its reference product are highly similar and have no clinically meaningful differences [5,7].

Thus, biosimilars are manufactured following the same strict standards of quality, safety, and efficacy observed for the reference product [5,7]; this is reflected in the development cost, which ranges from \$100 to 300 million [8]. Biosimilars can broaden product choice and have the potential to reduce prices, whilst continuing to support a high standard of patient care [9]. In the United States, potential cost saving from switching from originator biologics to biosimilars is projected to be between \$40 and 250 billion by 2025, and in Europe, cost savings are already estimated to be more than €10 billion [2,10–12].

Many organizations representing physicians, pharmacists, and patients across Europe support the use of biosimilars [3,4,13–15], and have issued position papers outlining best practices for their use. However, biosimilar markets are still evolving, and there are marked differences between policies and practices across European countries [16–18]. For example, some payer bodies have implemented single winner tender-based systems. While this can secure significant short-term payer savings, such systems risk locking out many biosimilar manufacturers, and may limit the number of competing manufacturers in the medium term. In addition, single-manufacturer tenders can place a lot of risk on the supply chain and, potentially, on patient access. Therefore, systems need to be set up to ensure that long-term savings are realized for payers and sufficient manufacturer incentives are in place to sustain multiplayer competition. Further, the notion of biosimilar sustainability is currently inconsistently and poorly defined, and there is a lack of awareness on the vulnerability of the current system. Previous analyses of the biosimilars market have concluded that there is a need to improve sustainability, and several areas have been identified for further research to develop a coherent long-term vision of sustainability. These include safeguarding the interests of patients, maintaining physician autonomy and patient choice, effective purchasing/pricing and reimbursement strategies, good pharmacovigilance practices, and healthy levels of competition to ensure consistent supply of a range of high-quality products [11,19,20].

To consider these issues and examine biosimilar market sustainability in more detail, we conducted a systematic literature review (SLR) and Delphi panel discussion to: (i) establish a multistakeholder definition of biosimilar market sustainability; (ii) further identify components of a sustainable biosimilar market; and (iii) identify drivers and risks of a sustainable biosimilar market.

### **2. Methods**

### *2.1. Design*

The modified Delphi process is a commonly published approach to generate discussion around topics without consensus and is an effective way to start dealing with complex multifactorial challenges [21]. A modified Delphi process, involving 11 key opinion leaders representing various sectors of the health care system in Europe, was conducted between September and November 2019. Participating stakeholders comprised one patient advocate, two physicians, two hospital pharmacists, two procurement pharmacists, one national payer, two policy advisors, and one manufacturer from

across Europe. The modified Delphi process was based on a published approach, [22] and consisted of brainstorming, structured feedback, and a facilitated roundtable discussion (Figure 1). [22] and consisted of brainstorming, structured feedback, and a facilitated roundtable discussion (Figure 1).

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 3 of 19

**Figure 1.** Modified Delphi process. **Figure 1.** Modified Delphi process.

### *2.2. Procedure 2.2. Procedure*

The Delphi process was initiated by multiple stages of brainstorming, in which participants contributed their initial views by email and telephone using the questionnaire shown in Appendix A. Participants were provided with stimulus materials identified by an SLR and they were also asked to identify any key papers to support their feedback. The SLR is briefly described in this paper, but it is published elsewhere [18]. The Delphi process was initiated by multiple stages of brainstorming, in which participants contributed their initial views by email and telephone using the questionnaire shown in Appendix A. Participants were provided with stimulus materials identified by an SLR and they were also asked to identify any key papers to support their feedback. The SLR is briefly described in this paper, but it is published elsewhere [18].

The SLR was conducted using EMBASE, MEDLINE, and grey literature searches. The searches were conducted using recent evidence (from 2008 to 2019) to capture all key biosimilar publications after their introduction in Europe in 2006. Only publications in English were included. Search methods were based on recommendations from the Cochrane Handbook [23] and the Centre for Reviews and Dissemination [24]. The SLR identified materials relating to major economies in Europe and answered three predefined key questions on the: (Q1) frequency, causes, and consequences of shortages of reference product biologics and biosimilars; (Q2) costs (direct and indirect costs, resource utilization, and external costs) and impacts resulting from switching patients between biosimilar products; and (Q3) causation between tendering, market concentration, drug shortages, and achievement of savings, and the implications of tender models for supply risk (reliability) and sustainability of competitive biosimilar markets. The SLR was conducted using EMBASE, MEDLINE, and grey literature searches. The searches were conducted using recent evidence (from 2008 to 2019) to capture all key biosimilar publications after their introduction in Europe in 2006. Only publications in English were included. Search methods were based on recommendations from the Cochrane Handbook [23] and the Centre for Reviews and Dissemination [24]. The SLR identified materials relating to major economies in Europe and answered three predefined key questions on the: (Q1) frequency, causes, and consequences of shortages of reference product biologics and biosimilars; (Q2) costs (direct and indirect costs, resource utilization, and external costs) and impacts resulting from switching patients between biosimilar products; and (Q3) causation between tendering, market concentration, drug shortages, and achievement of savings, and the implications of tender models for supply risk (reliability) and sustainability of competitive biosimilar markets.

In an initial screening phase, one reviewer identified relevant titles and abstracts from among all retrieved records; in a second screening stage, one reviewer re-evaluated each selected publication in a full-text review. In both stages, a second reviewer was consulted in cases of uncertainty, and consensus between the two was reached. Data extraction was performed by two reviewers, with one extracting the data and the second checking the data against the original publication. Any discrepancies were resolved through discussion or through the intervention of a third reviewer. The SLR flow chart is shown in Appendix B. The findings of the SLR were provided to the panel during the brainstorming stage; participants reviewed the material (amendments were allowed) and provided their ideas. The feedback was discussed with each participant via telephone to ensure that it was interpreted correctly, and the finalized brainstorming responses were collected via email. The amended stimulus material is shown in Appendix C [3,4,16–18,25–27]. These references and the brainstorming responses were used to develop the themes and statements for the second stage. In an initial screening phase, one reviewer identified relevant titles and abstracts from among all retrieved records; in a second screening stage, one reviewer re-evaluated each selected publication in a full-text review. In both stages, a second reviewer was consulted in cases of uncertainty, and consensus between the two was reached. Data extraction was performed by two reviewers, with one extracting the data and the second checking the data against the original publication. Any discrepancies were resolved through discussion or through the intervention of a third reviewer. The SLR flow chart is shown in Appendix B. The findings of the SLR were provided to the panel during the brainstorming stage; participants reviewed the material (amendments were allowed) and provided their ideas. The feedback was discussed with each participant via telephone to ensure that it was interpreted correctly, and the finalized brainstorming responses were collected via email. The amended stimulus material is shown in Appendix C [3,4,16–18,25–27]. These references and the brainstorming responses were used to develop the themes and statements for the second stage.

In the second stage of the Delphi process, the brainstorming responses and evidence extracted from the stimulus materials were converted into themes and statements (Appendix D), using In the second stage of the Delphi process, the brainstorming responses and evidence extracted from the stimulus materials were converted into themes and statements (Appendix D), using standard

standard primary research methodology. Feedback was sought on: (i) the components for a definition of biosimilar market sustainability and (ii) drivers and risks to achieving sustainability. Participants primary research methodology. Feedback was sought on: (i) the components for a definition of biosimilar market sustainability and (ii) drivers and risks to achieving sustainability. Participants were asked to indicate on a Likert scale (from "strongly disagree" to "strongly agree") their level of agreement with each theme and statement, and how strongly they felt the evidence supported each theme and statement. Each participant had 1 week to provide their responses.

Stage 3 was a facilitated roundtable discussion that aimed to derive a multistakeholder definition of sustainability and achieve consensus on the components of a sustainable biosimilar market. First, the participants were presented with a definition of sustainability (derived from feedback supplied in stage 2) and were then asked to provide feedback on the definition, stating their level of agreement ("strongly disagree" to "strongly agree"), and providing any revisions they wished to make in free text. Based on the responses, the initial definition was revised and presented to participants for comment and final agreement at the end of the roundtable discussion. Participants were then presented with eight statements on the components of a sustainable biosimilar market and on drivers and risks to sustainability (derived from feedback supplied in stage 2). Participants were asked to provide individual feedback regarding how much they agreed with each statement, how important each statement was to them, and free-text suggestions on how to rephrase each statement so that it would align better with their views. The purpose of the discussions on each statement was to explore areas of agreement and disagreement between stakeholder groups. Where groups agreed, consensus was noted; however, the process could cease if stakeholder views remained divergent.

### **3. Results**

### *3.1. Delphi Panel Consensus*

### 3.1.1. A Multistakeholder Definition of Biosimilar Market Sustainability

The multistakeholder consensus definition of a sustainable biosimilars market is provided in Box 1. After much deliberation, this definition was agreed upon by all participants; however, different stakeholder groups emphasized different priorities within this definition. Patients wanted to be well-informed, physicians wanted biosimilar-related savings reinvested, pharmacists/manufacturers emphasized quality, and payers/policy advisers focused on mechanisms (e.g., competition) to lower prices. These differing priorities were not considered to be mutually exclusive, and all participants considered it important to incorporate the perspectives of all stakeholders into the definition of a sustainable biosimilar market in Europe.

**Box 1.** A multistakeholder consensus definition of a sustainable biosimilar market.

• A sustainable biosimilar market means that . . . "All stakeholders, including patients, benefit from appropriate and reliable access to biological therapies. Competition leads to a long-term predictable price level, without compromising quality, while delivering savings that may be reinvested."

### 3.1.2. Components of a Sustainable Biosimilar Market

Participants agreed that a sustainable biosimilar market: (i) must deliver tangible and transparent benefits to the health care system; (ii) must address the needs of all stakeholders; and (iii) requires collaboration between stakeholders. The level of consensus achieved on these key points is summarized in Box 2 and Table 1.


**Table 1.** Consensus on components of a sustainable biosimilar market. **Table 1.** Consensus on components of a sustainable biosimilar market. **Table 1.** Consensus on components of a sustainable biosimilar market. **I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system**

**Table 1.** Consensus on components of a sustainable biosimilar market.

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 5 of 19

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 5 of 19

## **I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system** Biosimilars have the potential to reduce the cost of treatment; this, in turn, strengthens the sustainability of health care expenditure


and home care) settings; these differences may need to be considered

services. Unnecessary disruptions (i.e., frequent transitions and/or transitions that do not

**III. A sustainable biosimilar market requires collaboration between stakeholders**

**II. A sustainable biosimilar market must address the needs of all stakeholders**

and home care) settings; these differences may need to be considered

**PHARMACIST**

**PHARMACIST**

**PHYSICIAN**

**PHARMACIST**

**PHARMACIST**

**PHYSICIAN**

**PHARMACIST**

**PHYSICIAN**

**PATIENT**

**PHYSICIAN**

**PATIENT**

**CONSENSUS**

**PHARMACIST**

**PHARMACIST**

**PHYSICIAN**

**CONSENSUS**

**PHYSICIAN**

**PHYSICIAN**

**III. A sustainable biosimilar market requires collaboration between stakeholders**

Disruption caused by biosimilar transition may be unavoidable in some therapeutic areas (e.g., acute vs. chronic conditions); however, switch is not advisable if treatment duration

deliver tangible savings) should be minimized

Disruption and transition costs occur in both hospital and out-of-hospital (including retail

Disruption caused by biosimilar transition may be unavoidable in some therapeutic areas (e.g., acute vs. chronic conditions); however, switch is not advisable if treatment duration

and home care) settings; these differences may need to be considered

is short

**III. A sustainable biosimilar market requires collaboration between stakeholders**

**III. A sustainable biosimilar market requires collaboration between stakeholders**

and home care) settings; these differences may need to be considered

Disruption and transition costs occur in both hospital and out-of-hospital (including retail

is short

**III. A sustainable biosimilar market requires collaboration between stakeholders**

Transitioning between biosimilars causes disruption to patient care and health care services. Unnecessary disruptions (i.e., frequent transitions and/or transitions that do not

**III. A sustainable biosimilar market requires collaboration between stakeholders**

deliver tangible savings) should be minimized

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 5 of 19

**Table 1.** Consensus on components of a sustainable biosimilar market.

is short **PHARMACIST PHYSICIAN PATIENT** Disruption caused by biosimilar transition may be unavoidable in some therapeutic areas Note: icons shown on the right represent level of agreement between the stakeholders. The 'consensus' icon indicates that all stakeholders (physicians, payers, policy **PHARMACIST MANUFACTURER** Note: icons shown on the right represent level of agreement between the stakeholders. The 'consensus' icon indicates that all stakeholders (physicians, payers, policy advisors, manufacturers, pharmacists, and patients) agreed on that point. Benefits, such as expanded access, have also been noted in the literature [9]. Note: icons shown on the right represent level of agreement between the stakeholders. The 'consensus' icon indicates that all stakeholders (physicians, payers, policy advisors, manufacturers, pharmacists, and patients) agreed on that point. Benefits, such as expanded access, have also been noted in the literature [9]. Note: icons shown on the right represent level of agreement between the stakeholders. The 'consensus' icon indicates that all stakeholders (physicians, payers, policy advisors, manufacturers, pharmacists, and patients) agreed on that point. Benefits, such as expanded access, have also been noted in the literature [9].

**PHARMACIST**

**PHARMACIST**

**PHYSICIAN**

**PHYSICIAN**

**PHARMACIST**

**PHYSICIAN**

**PATIENT**

Disruption and transition costs occur in both hospital and out-of-hospital (including retail

advisors, manufacturers, pharmacists, and patients) agreed on that point. Benefits, such as expanded access, have also been noted in the literature [9].

(e.g., acute vs. chronic conditions); however, switch is not advisable if treatment duration

and home care) settings; these differences may need to be considered

is short

**III. A sustainable biosimilar market requires collaboration between stakeholders**

and home care) settings; these differences may need to be considered

**III. A sustainable biosimilar market requires collaboration between stakeholders**

Disruption and transition costs occur in both hospital and out-of-hospital (including retail

•

•

•

nationally

nationally

•

•

•




In brief, participants strongly agreed that biosimilars have the potential to promote competition among biologic options and reduce treatment costs. However, there was a need to identify and minimize transition and disruption costs when switching to a biosimilar or between biosimilars to improve savings associated with these products further. These savings should be tangible (i.e., measurable) and reinvested in health care or other public services where possible. This could include budget deficits and funding of innovative therapies; biosimilars have the potential to expand access [8]. Transparency regarding reinvestment was regarded as another important motivator for physicians and patients to use biosimilars. Minimizing transition costs could be achieved by identifying key differences between therapeutic areas and clinical settings. For example, oncology treatments usually follow a short, defined treatment course reducing the need for switch, whereas rheumatoid arthritis treatments may be chronic with multiple use of biosimilars and combinations. Clear guidance (policies and practices) from regulators and clinical organizations, such as the EMA, regarding biosimilar transition is warranted with the need for real-world evidence based on biosimilars that physicians can effectively communicate to patients to avoid any negative perceptions. Collaboration between stakeholders would help enable any guidance to be consistent, more comprehensive, and more easily communicated.

### 3.1.3. Drivers and Risks of a Sustainable Biosimilar Market (Competition and Incentives)

The consensus achieved by participants regarding drivers and risks of a sustainable biosimilar market is summarized in Box 3 and Table 2. Points of consensus were formulated as follows: (i) competition is a more effective mechanism to achieve a long-term predictable price level than regulation; (ii) there needs to be incentives for investment in future biosimilars; and (iii) government and pricing bodies need to drive incentives.

For key market drivers, participants agreed that competition generated by the introduction of biosimilars has been effective in reducing prices for biological therapies in Europe [28,29]. Participants also agreed that the price expectations of decision makers must reflect market opportunity. This was illustrated by the case of adalimumab biosimilars, the entry of which into the market in 2018 triggered almost immediate and substantial discounting. However, adalimumab was used in a large patient population and had achieved extremely high revenues prior to biosimilar entry, making it a very attractive target for biosimilar manufacturers. Consequently, the price levels achieved by adalimumab biosimilars might not be repeated in other biosimilar products, especially those with orphan status. Incentives driven by governments and pricing bodies (such as limits on tender) were also identified as key drivers for future market; these incentives could include procurement design, including contract length, a cap on the number of manufacturers selected, and introduction of geographical divisions (national vs. regional vs. local).

*Pharmaceuticals* **2020**, *13*, 400 *Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 5 of 19

**Table 2.** Consensus on drivers and risks to biosimilar market sustainability (competition and incentives). **Table 1.** Consensus on components of a sustainable biosimilar market. *Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 8 of 19 *Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 8 of 19

**Table 2.** Consensus on drivers and risks to biosimilar market sustainability (competition and incentives).

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 8 of 19

**I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system**

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 5 of 19

**Table 1.** Consensus on components of a sustainable biosimilar market.

## **I. Competition is a more e**ff**ective mechanism to achieve a long-term predictable price level than regulation** sustainability of health care expenditure **I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system Table 2.** Consensus on drivers and risks to biosimilar market sustainability (competition and incentives). **Table 2.** Consensus on drivers and risks to biosimilar market sustainability (competition and incentives).

Biosimilars have the potential to reduce the cost of treatment; this, in turn, strengthens the


**III. A sustainable biosimilar market requires collaboration between stakeholders**

and home care) settings; these differences may need to be considered

Continued investment in biosimilar development and market entry is important to generate competition for biological therapies for which no biosimilar is currently available and, to a lesser

Continued investment in biosimilar development and market entry is important to generate competition for biological therapies for which no biosimilar is currently available and, to a lesser

extent, therapies with biosimilars already available

extent, therapies with biosimilars already available

extent, therapies with biosimilars already available

**PHARMACIST**

**PHYSICIAN**

**CONSENSUS**

**CONSENSUS**

**CONSENSUS**

**III. A sustainable biosimilar market requires collaboration between stakeholders**

Disruption and transition costs occur in both hospital and out-of-hospital (including retail

Continued investment in biosimilar development and market entry is important to generate competition for biological therapies for which no biosimilar is currently available and, to a lesser

*Pharmaceuticals* **2020**, *13*, 400 *Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 8 of 19

**Table 2.** *Cont.* **Table 2.** Consensus on drivers and risks to biosimilar market sustainability (competition and incentives).

**I. A sustainable biosimilar market must deliver tangible and transparent benefits to the health care system**

*Pharmaceuticals* **2020**, *13*, x FOR PEER REVIEW 5 of 19

**Table 1.** Consensus on components of a sustainable biosimilar market.
