Volume and trends of adalimumab and pembrolizumab reimbursed market: the Bulgarian perspective

Abstract The global market of monoclonal antibodies (mAbs) is growing very fast. The aim of this study is to analyze the reimbursed market of adalimumab and pemborlizumab in Bulgaria. A retrospective cost analysis of the reimbursed mAbs adalimumab and pemborlizumab for ambulatory and hospital settings, respectively, paid by the National Health Insurance Fund (NHIF) was performed based on official NHIF data. The share of their costs from the total mAbs costs was calculated. The results showed that the most cost-consuming mAbs were adalimumab in ambulatory and pembrolizumab in hospital settings: 31% and 31.59% in 2020 out of the total reimbursed mAbs budget, respectively. Regardless of the extension of the reimbursed therapeutic indications, the costs for adalimumab decreased from 25,575,836.32 Euro in 2018 to 20,493,187.02 Euro in 2019 as a result of inclusion of 3 biosimilars and international price referencing. Despite the reduction of the registered price with 20%, the pembrolizumab costs have almost tripled probably because of reimbursement of five additional therapeutic indications. Overall, the reimbursed costs for pemborlizumab have been increased every year as a result of reimbursement of new therapeutic indications and increase in the number of patients treated with mAbs. The adalimumab trend is for a stable decline in the reimbursed costs because of entrance of biosimilars.


Introduction
Аntibodies (Abs) are protein components of the immune system related to cellular and humoral reactions to different substances [1]. Monoclonal antibodies (mAbs) are made by one type of immune cells, which makes them identical. Since 1975, when Kohler and Milstein created the first mAb by fusion of murine myeloma cells with murine-antibody-secreting lymphocytes, many more mAb have been developed and used for different purposes such as for diagnostic procedures and immunotherapy [2].
The number of approved mAbs as medicines reached almost 100 [1]. Their revolutionary potential in the treatment of various nonmanageable diseases with no existing or specific therapies such as cancers, autoimmune diseases, cardiovascular, respiratory, rare diseases, neurological diseases, infections including COVID-19 etc., has been revealed not only during clinical studies but in the real-world settings [3][4][5][6][7]. mAbs ensure better therapeutic outcomes, delay of progression and prolongation of overall survival, respectively, and improved quality of life of those affected [8][9][10][11][12][13].
Historically, human and humanized monoclonal antibodies (mAbs) were approved as the most suitable therapeutic antibodies [14]. By detecting novel biomarkers, identification of the intimate molecular mechanisms of different diseases, modifications in the structure and application of significant technological advances, scientists discover new mAbs with higher specificity which is associated with better efficacy [15]. Crucial issues is reaching high therapeutic effect parallel with overcoming the side effects and the significant ecnomic burden of mAbs [15]. The percentage of successfully marketed mAbs motivates hundreds of companies to engage themselves in mAbs development. Over 500 mAb names have been provided by World Health Organization till 2017. Clinical trials of more than 570 mAbs are currently ongoing and about 90% of them are in the early phase of safety and efficacy assessment in different patient populations. About 70% of the mAbs entering phase 1 clinical trials are targeted to cancer. The ratio of mAbs entering or located in Phase 2 and Phase 3 with onco-indication and those with another indication is almost equal [16]. In the last 10 years, the number of mAbs in the last phases of clinical trials has tripled to 79 compared to 2010, when it was 26. Fastly, mAbs became the most preferrable class of new medicines by the pharmaceutical companies as their market share has been growing every year: US$115.2 billion in 2018 and the expectations are to reach almost 300 billion dollars in 2025 [15]. The impact of mAbs on the budget is high with increasing trend leading to challenges for the reimbursement institutions [17]. The entrance of biosimilars is defined as an instrument "in reducing costs for medication and increasing patient access to treatment" [18]. They are shown to decrease the prices and to influence utilization of biologic medicines [19].
The aim of the study is to analyze the reimbursed market of the most cost consuming mAbs for the ambulatory and hospital practice in Bulgaria: adalimumab and pemborlizumab.

Methods
This is a cross-sectional top down cost study performed through the analysis of three data sets. A qualitative analysis was applied to identify the number and INNs of all marketing authorized mAbs in the European Union and reimbursed in Bulgaria.
Information about the authorized mAbs in the EU (by October 2020) was obtained from the European Medicines Agency website [20]. The availability of mAbs in Bulgaria was analyzed by crossing the medicines identified in the European list with those in the Bulgarian Positive Drug List (PDL) Annex 1 and in Annex 2, group B (medicinal products guaranteed by the National Health Insurance Fund (NHIF) budget, intended for treatment of malignant diseases paid in hospital care beyond the cost of medical services).
A retrospective 5-year cost analysis of mAbs paid by the National Health Insurance Fund (NHIF) in Bulgaria for ambulatory (group A, Annex 1 of the Positive Drug List (PDL)) settings (at community pharmacy level) and a 3-year analysis for hospital (group B, Annex 2 of PDL) settings were performed. Data for the reimbursed costs and the number of health insured patients treated with mAbs were received officially from the NHIF website; more detailed information was obtained through a dedicated application to the National Health Insurance Fund for access to public i n f o r m a t i o n i n 2 0 2 0 ( e n t r y N o . 24-03-381/12.11.2020).
The most cost-consuming mAbs for both settings were identified and the share of their costs in the total mAbs costs was calculated. A detailed costs reimbursed packages analysis for the most cost-consuming mAbs by NHIF code and ICD code was conducted.
The costs were extrapolated for the next 5-year period using the TREND function in Microsoft Excel.
The expenditures for every year were presented in euro at the fixed exchange rate of 1 BGN = 0.5113 Euro (European Central Bank/Euro foreign exchange reference rates).

Availability and affordabily of monoclonal antibodies in Bulgaria
There are 74 monoclonal antibodies authorized for sale in the European Union as of October 2020, the number of brand names in total being 104. Antineoplastic and immunomodulating agents (section L of the Anatomical Therapeutic Chemical Classification System) composed 76% of all brand names and 69% of all mAbs international nonproprietary names (Table 1).
We found that 30 out of 104 mAb-containing medicinal products are reimbursed by the National Health Insurance Fund of Bulgaria for ambulatory settings, 54 out of 104 are included in the PDL, Annex 2 for hospital use and 28 out of 104 are oncology products part of group B (Group B contains medicines for malignancies, life-threatening haemorrhages and emergency surgical and invasive interventions for congenital coagulopathies, paid by the NHIF beyond the cost of hospital medical services).
The percentages of reimbrused mAbs in Bulgaria from the total authorized mAbs in the EU are presented in Figure 1.
Most mAbs are reimbursed for the purposes of hospital use probably because of the 'restricted' medical prescription of some biologic medicines, reserved for use only in certain specialized areas. Twenty-six biosimilar mAbs are authorized by the European Commission, corresponding to 5 INNs (adalimumab, bevacizumab, infliximab, rituximab and trastuzumab). Health-insured Bulgarian patients have access to biosimilars containing adalimumab, bevacizumab, infliximab, rituximab and trastuzumab (Table 1).

Utilization analysis mAbs included in PDL, Annex 1: Adalimumab costs
The total number of mAbs in Annex 1 of PDL is 24. Of these, 6 (Figure 2). The total costs paid by the NHIF for mAbs for the period 2016 − 2020 have increased each year. This can be explained by the inclusion of new mAbs in the PDL, extension on eligible patient populations related to reimbursement of new therapeutic indications, and the overall increase in the number of patients treated with mAbs ( Figure 3). Tocilizumab cost followed an increasing trend, perhaps due to the lack of biosimilars and expansion of eligible patients' population. The cost for secukinumab increased sharply in accordance with the growing number of patients for the period 2019 − 2020.
When a new product is included in the PDL, a strident increase in the costs of the National Health Insurance Fund is observed in the second year, followed by a smoother one. For the products launching in the BG market after 2017 in the second year, NHIF paid an average of 7.6 times more than in the first year (min. 2.4 times more for alemtuzumab, and max. 15.9 times more for mepolizumab) ( Table 2).
Bisomilars for adalimumab have been available in the PDL since the end of 2018. Up to May 2021, NHIF has been covering the cost of adalimumab for 21 different therapeutic indications: Other disorders of the eye and adnexa (H20.1, H20.8, H30.0, H30.1, H30.2 (Figure 4). This is because of the introduction of new local legislation in April 2019, concerning the price of biosimilars on the one hand, and on the other -international price referencing every 6 months for origrinal product before biosimilars. When included in the PDL the registered price of biosimilars cannot be higher than 80% of the price of the original product. This requirement is in addition to the previous one that the price should be lower among the referent countries. The costs for the reference product have increased, but not as significantly as those for biosimilars ( Figure 5). The original product's market share has decreased in 2020 in constrast to biosimilars: 98.95% vs. 1.05% in 2019 and 94.77% vs. 5.23% in 2020.
The costs for the period 2016-2020 and the extrapolated costs and number of patients for the period of 2021-2022 are shown in Figure 6. The expectations are for a decrease in the total costs for adalimumab in the period of 2020-2022 and an increase in the     (Table 3; Figure 8). The reference price for pembrolizumab followed a tendency for lower values: 39.5617 Euro/mg in 2018 to 31.5530 Euro/mg in 2020. The costs for pembrolizumab have increased despite the reduction in the registered price by 20% (Figure 4), most likely due to the inclusion of 5 additional therapeutic indications which are paid by the NHIF.

Trends in the market of mAbs adalimumab and pembrolizumab
The trend for the analyzed period shows growing of pembrolizumab and decline in adalimumab reimbursed market. The extrapolated data for the next 5-year period illustrate the same trend for both mAbs without considering any other influencing factors (such as international price referencing and inclusion of other biosimilars with INN adalimumab) ( Figure 9).

Discussion
Our study revealed that more than half of the mAbs authorized in the EU are included in the reimbrusement medicines list for hospital use, more of them being for the oncology and antireumatic practice. In contrast, the number of mAbs for ambulatory practice  is far below 50% (around 32%) of all 74 mAbs accessible at the European market. We could conclude that Bulgarian patients have a good access to mAbs, as the health-insurance fund covers both ambulatory and hospital settings. A study conducted in Bosnia and Herzegovina also concluded that there appeared to be a relatively good availability of mAbs despite some limitations [21].
Similar to other studies, our study confirmed that biosimilars decrease the prices of mAbs at the moment of their entrance in the reimbursement list due to legislation reguirements, as the external and internal prices referencing. Further reduction can be expected as a rezult of relevant hospital tender procedures. By reducing the treatment costs, the opportunity for better access to effective biological medicines for the citizens grows [19,20,[22][23][24][25][26]. Despite this correlation, the trend is for expansion of mAbs reimbursed market for both ambulatory and hospital settings in Bulgaria as a result of treatment of more patients and reimbursment approval for additional therapeutic indications. Considering inclusion of bisoimilars for adalimumab and market protection period for pembrolizumab since 2015, the expectations are for lower total reimbursed costs for adalimumab and growing the volume of pembrolizumab market in the next years. Despite the negative trend for the adalimumab market, it is still the most cost-consuming mAb for the ambulatory practice in Bulgaria. It exceeds the cost for the next most consuming mAb, tocilizumab, almost 3 times in 2020 having more and more eligible patients. Adalimumab was the top-selling medicine of all times with sales of US$20 billion in 2018 generating 60% of AbbVie's revenue. In contrast, the market conditions (increased competition and expiring patents) for adalimumab are leading to a negative trend and a decline in the costs, pembrolizumab seems to be the next medicine number one in sales [19]. Approval of additional indications for pembrolizumab (melanoma, nonsmall cell lung cancer, small cell lung cancer, head and neck cancer, Classical Hodgkin Lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high (MSI-H) cancer, renal carcinoma etc.) affirms the hypothesis for the growth of its market [27,28]. A similar trend is shown in a study by Elias et al. (2016) -by 2016, pembrolizumab ranked first in the list, representing 64% of the total cost of lung cancer treatment in Lebanon [29]. According to a study from 2016, the costs of oncology drugs were expected to rise above $150 billion by 2020, and pembrolizumab and nivolumab are defined as "harbingers of the market for cancer immunotherapies" [30]. A Chinese report also predicts that the pembrolizumab sales revenue has increased significantly, as the Compound annual growth rate (CAGR) was 284.67% from 2018 to 2020 [31]. A study revealed that ipilimumab, nivolumab and pembrolizumab have substantial costs which have tripled for only a 1-year period (120 million euros in 2015 to >340 million Euro in 2016) [32]. Despite the expenses for pembrolizumab, many studies prove its cost-effectiveness and enough incremental clinical and economic benefits [33][34][35][36]. The other possible reason for the market share increase migth be the fact that the products for hospital use are less affected by the internal prices referencing.
The main limitation of our study is that we did not include data for hospital use on mAbs not indicated for oncology patients due to limited access to information for a previous period. Moreover, we have not considered additional factors which could also infuence the future costs and trends for the mAbs market in Bulgaria. This is not the first study focusing on the biotechnology medicines but it seems to be one of the few developing the trends in the mAbs reimbursed market in this country. At some level, it could be used as a basis for predicting and planning the health-insurance budget and developing strategies for the sustainability of the healthcare system.

Conclusions
The reimbursed costs for pemborlizumab have increased in recent years as a result of reimbursement of new therapeutic indications and increase in the number of treated patients. This increasing is difficult to optimize with now applicable cost-containment measures like international price referencing and compensated mechanism of NHIF expenditures. The adalimumab trend is for a stable decline in the reimbursed costs probably because of biosimilars entrance and reduction in the international price referencing. The nationally-based expectations are for a stable expansion of the total mABs reimbursed market as a result of more eligible patients for treatement with mAbs and approval of additional therapeutic indications subject to reimbursement.