Abstract
Objective
The aim was to assess the influence of the presence of biosimilar adalimumab on adalimumab budget savings in 14 high- and upper-middle-income countries.
Methods
This study analyzed Multinational Integrated Data Analysis System (MIDAS)-IQVIA data from the fourth quarter (Q4) of 2018 to the Q4 of 2019, comparing adalimumab expenditure (in United States dollars) and consumption (in standard units [SU]) across 14 countries (Australia, Austria, Brazil, Canada, France, Germany, Italy, Japan, Korea, Singapore, South Africa, Spain, Sweden, and Taiwan). The countries were divided into two groups based on the availability of adalimumab biosimilars during the study period. A difference-in-difference design was employed to analyze the groups, focusing on changes from Q4 2018 to Q4 2019. Additionally, changes in adalimumab expenditure were decomposed into price, quantity, and drug mix during the study period.
Results
Among countries with adalimumab biosimilars, there was a significant decrease in expenditure (− $371.0 per gross domestic product per capita; p = 0.03) over four quarters, while the consumption significantly increased (1.0 SU per 1000 population; p = 0.02). This was consistent with visual observations and differed from countries without adalimumab biosimilar. Sensitivity analysis with a narrowed list of countries (12 high-income countries) showed a consistent trend. Adalimumab expenditure decreased by 14% during the study period in countries where adalimumab biosimilars were available, mainly due to the price changes (Pt = 0.85; − 15%) and the drug-mix effect (εt = 0.88; − 12%). Yet, adalimumab expenditure (Et = 1.04; +4%) changed in a quantity-dependent manner (Qt = 1.06; +6%) in countries where adalimumab biosimilars were absent.
Conclusion
The availability of biosimilars was associated with a decrease in adalimumab expenditure without compromising the consumption of adalimumab.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
The uptake of biosimilars varies considerably across countries, yet few studies have explored whether the introduction of adalimumab biosimilars is associated with decreased expenditure of adalimumab, and whether it was achieved through changes in drug price, quantity (consumption), or the increased utilization of biosimilars (drug mix). |
Through a comparative analysis of 14 countries, we found out that the availability of adalimumab biosimilars is associated with reduced adalimumab expenditure, while maintaining or increasing adalimumab consumption levels. |
The price and drug-mix effect were the major contributing factors for the decreased adalimumab spending. Of particular significance is the drug-mix effect, which emerged as a major contributor to the observed changes in drug expenditure following the introduction of biosimilars. Our findings underscore the importance of introducing biosimilars as a strategy to optimize healthcare expenditure while ensuring patient access to essential treatments. |
1 Introduction
The advent of biological medicines (biologics) has revolutionized the treatment of cancer and autoimmune diseases, yet their high costs have placed a significant financial burden on healthcare budgets [1,2,3,4,5]. In 2018 alone, global sales of tumor necrosis factor-alpha (TNF-α) inhibitors, including adalimumab, reached a considerable $40 billion (United States dollars [USD]), with Humira® (originator adalimumab) accounting for half of that amount, generating nearly $20 billion (United States dollars [USD]) [6].
Humira® was approved by the US Food and Drug Administration (FDA) in 2002 and the European Medicines Agency (EMA) in 2003, quickly becoming the highest-selling biologic in the global pharmaceutical market by 2018. It has various indications, including rheumatoid arthritis (RA), skin diseases (such as psoriasis and hidradenitis suppurativa), and gastrointestinal diseases (such as irritable bowel syndrome, Crohn's diseases, and ulcerative colitis), as it acts on the immune system [7,8,9,10,11].
However, the cost landscape began to shift following the patent expiry of Humira® in October 2018 in the European market, with the introduction of five biosimilars, Amgevita®, Hyrimoz®, Imraldi®, Hulio®, and Idacio® [12,13,14]. Following Europe, adalimumab biosimilars were launched in Brazil and South Africa in 2020, Australia, Japan, and Korea in 2021, and Canada in 2022 [15,16,17,18,19,20]. There have been no reported launch plans for adalimumab biosimilars in Taiwan and Singapore.
A biosimilar is a biologic that is highly similar to an already approved originator biologic, known as the reference medicine, and is released following the expiration of the reference medicine’s patent [21, 22]. In general, biosimilars have lower acquisition costs than the reference product [23]. Therefore, they have demonstrated cost savings in the healthcare systems of high-income countries where the use of biologics is widespread [24,25,26,27]. Also, biosimilars are expected to improve access to biologic therapies in low-income countries, where access has been limited due to high costs [28, 29]. Previous studies have shown that most biosimilars were introduced at significantly lower prices compared to their originators, with discounts of up to 80% observed in a number of European countries [30,31,32,33]. Additionally, the price competition between biosimilars and their originators has, in certain instances, driven down the prices of originators by as much as 89% [30, 32, 34, 35].
Biosimilars offer cost savings through price competition or improving cost-effectiveness by switching to lower-priced products with similar effectiveness. Also, these cost savings could be extended to other patient groups, or used to hire more healthcare professionals, which could in turn improve patients’ access to care [32, 33, 36]. Yet, these potential benefits of biosimilars are realized differently across various jurisdictions due to diverse healthcare systems and government policies, such as demand-side and supply-side measures. Previous studies have explored the impact of the biosimilar entry on the market dynamics and the factors that contribute to variations in biosimilar utilization and extended access to treatments across different countries. Kim and colleagues reported that, unlike Japan, the UK, or France, the entry of biosimilars of infliximab (one of the TNF-α inhibitors) resulted in significant market expansion in Korea, which could be attributable to the absence of the demand-side measures [37]. Rémuzat et al. reported that the penetration of biosimilars for seven biologics varied considerably across countries and therapeutic classes in ten European Union (EU) member states, which could be explained by incentive policies and the timing of the introduction of the first biosimilar [38]. Barcina Lacosta et al., identified that the introduction of TNF-α inhibitor biosimilars (those for infliximab, etanercept, and adalimumab) resulted in cost savings despite similar or increased consumption in Southern European countries like Italy, Portugal, and Spain. They also observed heterogeneous utilization of biosimilars in Italy and Spain, which could be associated with the decentralized healthcare systems [31]. Vogler and colleagues highlighted that the policies to encourage the use of biosimilars in European countries have clearly demonstrated potential savings [39]. Barszczewska and Piechota reported that the introduction of more biosimilars could lead to sales competition, resulting in further price reductions and potential budget savings in Poland [40]. It has been reported that Austria’s strong pricing policy for biosimilars has discouraged biosimilar competition [41]. Namely, the uptake of biosimilars varies considerably by government policies and activities regarding biosimilars and the number of available biosimilars. Therefore, gaining a better understanding of the market dynamics following the introduction of biosimilars is important to fully leverage the benefits they offer beyond cost reduction for healthcare system.
Budget savings can be attributed to changes in the components of drug expenditures, namely price, quantity, and drug mix; these factors reflect the market penetration of more affordable alternatives [42,43,44,45,46]. Thus, by substituting cheaper biosimilars, we expect savings to the healthcare system, which relate to the drug-mix effect.
This study investigated the impact of introducing adalimumab biosimilars on the expenditure on adalimumab and identified drug cost components that contributed to the reduced spending on adalimumab.
2 Methods
2.1 Data Source
We obtained quarterly sales data for both the originator and biosimilar versions of adalimumab from October 2018 to October 2019 (four quarters) from the Multinational Integrated Data Analysis System (MIDAS)-IQVIA. The MIDAS-IQVIA database offers global sales information on medicines sold to retail and hospital pharmacies from manufacturers [47]. MIDAS-IQVIA data are based on collected sales volumes and generate the estimated sales values by multiplying the unit sold by prices from a variety of sources, including list prices, wholesaler transactions, and others [48, 49]. Previous studies have successfully utilized the MIDAS-IQVIA data for conducting cross-national and national studies, further validating its reliability and usefulness [37, 50,51,52,53].
We used the MIDAS-IQVIA database to obtain sales values in USD (converted from local currencies) and sales volumes measured using a standard unit (SU) of 40 mg per syringe, pen, or vial for adalimumab. The SU is defined as the number of standard ‘dose’ units sold by IQVIA. Multiple studies have been reported using MIDAS-IQVIA pertaining to SU to analyze medicine sales trends, including biologics [37, 50, 51, 53, 54]. Adalimumab 40 mg is considered the defined daily dose (DDD) for this medication, as established by the World Health Organization (WHO) [55]. Adalimumab is available in different dosage forms, such as 20 mg, 40 mg, and 80 mg. Among these options, adalimumab 40 mg accounted for approximately 97% of utilization in terms of SU in the fourth quarter (Q4) of 2018 across all the included countries. This percentage ranged from 91% in Japan to 100% in eight other countries. Also, adalimumab 40 mg has been used in previous studies to examine the dynamics of drug expenditure [42, 56, 57], suggesting the predominant use of the 40 mg dose of adalimumab and highlighting the consistency of its utilization across all included countries (Supplementary Table S1; see the ‘Supplementary Information’ in the electronic supplementary material).
2.2 Selection of the Biologics and the Countries
To conduct a cross-country comparison of adalimumab market dynamics, we identified biologics whose biosimilar had been launched, with varying availability across jurisdictions. Based on global sales values, we referred to TNF-α inhibitors (adalimumab, etanercept, and infliximab) and the launch dates of their respective biosimilars. The international launch dates for biosimilar etanercept and infliximab were relatively close, thus making it challenging to select a study period in which countries with and without biosimilars were evenly distributed. Consequently, adalimumab was the only biologic study drug whose originator (Humira®) ranked first in terms of the global biologics sales in 2018 [6].
We sought to include countries that encompassed geographical, economic, and demographic diversity: six European countries (Austria, France, Germany, Italy, Spain, and Sweden), five Asian Pacific countries (Australia, Japan, Korea, Singapore, and Taiwan), one North American (Canada), one Latin American (Brazil), and one African (South Africa) country. All of these countries are members of major international economic organizations, such as the Organisation for Economic Co-operation and Development (OECD), Asia-Pacific Economic Cooperation (APEC), and the Group of Twenty (G20). All included countries were classified based on the World Bank’s classification of economic level in 2019: (1) upper-middle-income economies (UMIEs) (Brazil and South Africa) and (2) high-income economies (HIEs) (Australia, Austria, Canada, France, Germany, Italy, Spain, Sweden, Japan, Korea, Singapore, and Taiwan) [58]. All included countries had already launched the adalimumab originator before the study period and maintained availability throughout the study period (from October [Q4] 2018 to October [Q4] 2019). If any biosimilar adalimumab was available throughout the study period for the specific country, it was classified as ‘yes’ for that country and ‘no’ otherwise. In conclusion, we included Australia, Brazil, Canada, Japan, Korea, Singapore, Taiwan, and South Africa for the control group.
Since a major indication for adalimumab is RA and RA activity can be influenced by seasonal changes [59, 60], we analyzed a minimum of four quarters for equal seasonal comparisons (Q4 2018 vs. Q4 2019). Although it would be ideal to analyze a longer time frame, our data source limited us to the available quarters. Fortunately, we were able to easily analyze seasonality due to the simultaneous launch of adalimumab biosimilars in all countries where they were available, which occurred on October 16, 2018 (Supplementary Table S2; see the ‘Supplementary Information’ in the electronic supplementary material) [12].
2.3 Descriptive Analysis
2.3.1 Time Series Analysis
To examine whether the cost savings in the healthcare system were associated with the launch of adalimumab biosimilars, we compared the adalimumab expenditure and consumption by each country in Q4 2018 and Q4 2019. The financial impact of the biosimilar adalimumab was described by (1) the sales values (in USD) and (2) the sales volumes (in SU) of the adalimumab originator and its biosimilar using the MIDAS-IQVIA database.
However, due to significant variations in the absolute values of sales values and volumes among all included countries, direct comparisons were challenging. To address this issue, we adjusted for economic differences and population size. Namely, the quarterly sales value (representing adalimumab expenditure) per the gross domestic product (GDP) per capita was calculated to adjust for the economic differences of all included countries. Also, to account for the difference in population size, we calculated the quarterly sales volume per a 1000 people, as previously conducted in cross-country comparison studies [50, 61,62,63,64,65]. GDP per capita data and population figures of all countries, except Taiwan, were obtained from the World Bank and OECD, respectively [66, 67]. For Taiwan, National Statistics open data and websites that released global countries’ populations were referred to [68, 69]. Using these adjusted measures, we compared the expenditure and volume of adalimumab among countries where the biosimilars were available versus those where they were not.
2.3.2 Decomposition of Adalimumab Expenditure
To quantify the impact of adalimumab biosimilars on adalimumab spending, we compared price, quantity, and drug mix between the countries where adalimumab biosimilars were available and those where they were not, which are the components of changes in drug expenditures. The changes in adalimumab expenditure from Q4 2018 to Q4 2019 can be expressed as in Eq. (1), which was developed by Gerdtham et al. [43] and Gerdtham and Lundin [44, 70].
In this Eq. (1), Q0 and Q1 represent the quantities of adalimumab (in SU) at Q4 2018 and after four quarters (Q4 2019), respectively. P0 and P1 represent the prices of adalimumab (in USD) at Q4 2018 and after four quarters (Q4 2019), respectively. The prices were calculated by dividing the expenditure of adalimumab (in USD) by the quantity of adalimumab (in SU), which are the ex-factory prices. Pt represents the change in the price of adalimumab, which is calculated using the Laspeyres index. Qt is the change in the quantity of adalimumab, which captures the treatment expansion effect. εt is the drug-mix effect, which captures a shift in prescription patterns towards cheaper alternatives.
If any of these indices are less than 1 among countries where biosimilars are available, it indicates that the presence of adalimumab biosimilars contributed positively to the decrease in drug expenditure by reducing prices through competition, decreasing the demand for adalimumab, or the switch to more affordable alternatives.
2.4 Statistical Analysis
To examine the changes in adalimumab expenditure and utilization, we employed the difference-in-difference (DID) method, one of the most widely used study designs for evaluating the impact in various fields, including healthcare, by comparing treatment–control group and before–after difference [71,72,73,74]. We compared the two groups, one with adalimumab biosimilars present and the other with biosimilars absent, from Q4 2018 and after four quarters (Q4 2019).
We defined countries without adalimumab biosimilars as the control group and countries with adalimumab biosimilars as the treatment group, at the beginning of the study period (Q4 2018) and after four quarters (Q4 2019).
Our DID outcomes Y were modelled using the following regression framework:
where Y represents the absolute changes in adalimumab expenditure and utilization; ‘treatment’ is a dummy variable, which is equal to 1 for countries where adalimumab biosimilars were present and 0 otherwise; and ‘post’ is a dummy variable, which is equal to 1 for the period after four quarters (Q4 2019) and 0 otherwise.
In this Eq. (2), β0 captures the intercept. β1 captures the time trend between the entry of adalimumab biosimilars (Q4 2018) and after four quarters (Q4 2019) for those of the control group (countries without adalimumab biosimilars). β2 measures the treated group effect between the control group (countries without adalimumab biosimilars) and the treatment group (countries with adalimumab biosimilars) at the beginning of the study (Q4 2018). The coefficient of interest in our study is β3, which captures the changes in adalimumab expenditure and utilization for countries with adalimumab biosimilars compared to the control group after four quarters, as a result of adalimumab biosimilars’ benefit.
The outcomes with a p value of less than 0.05 were deemed statistically significant. Statistical analyses were done with SAS 9.4 (SAS Institute, Cary, NC) using PROC MIXED.
2.5 Sensitivity Analysis
It has been reported that drug consumption is associated with GDP [50], and we recognized the importance of controlling for economic differences. Therefore, in the sensitivity analysis, we narrowed our focus to HIEs only, excluding UMIEs (Brazil and South Africa), to reduce the potential confounding effects of GDP variations.
3 Results
3.1 Classification of Countries
During the study period, we identified that adalimumab biosimilars were available in six countries, all of which were HIEs and European countries (Austria, France, Germany, Italy, Spain, and Sweden). On the other hand, we observed eight countries where adalimumab biosimilars were not available during the study period, which were five Asia-Pacific countries (Australia, Japan, Korea, Singapore, and Taiwan), one North American country (Canada), one African country (South Africa), and one Latin American country (Brazil). Except for Brazil and South Africa, the remaining six countries were also HIEs.
3.2 Changes in Adalimumab Expenditure
Figure 1a and b show the adjusted quarterly sales trends of adalimumab (adalimumab sales value in USD per GDP per capita) among countries with and without adalimumab biosimilars, respectively, during the study period. In Fig. 1a, which represents countries with adalimumab biosimilars, there was a notable decrease in adalimumab sales value per GDP per capita after four quarters in all included countries except for Italy ($0.1 per GDP per capita; from $2525.9 to $2526.0, 0.003%), ranging from − $1113 per GDP per capita (from $3906 to $2793, − 29%) in Spain to − $57 per GDP per capita (from $544 to $486, − 11%) in Sweden. Conversely, Fig. 1b displays the opposite trend for countries without adalimumab biosimilars. Namely, the adalimumab sales value per GDP per capita increased after four quarters in all countries except for Brazil (− $162 per GDP per capita; from $476 to $315, − 34%), ranging from $0.7 per GDP per capita (from $13.6 to $14.3, 5%) in Singapore to $213 per GDP per capita (from $3506 to $3719, 6%) in Canada.
Changes in adalimumab expenditure (USD/GDP per capita) and adalimumab consumption (SU/1000 population) in 14 countries after 4 quarters (Q4 2018 [0Q] to Q4 2019 [+4Q]). A, C The countries where adalimumab biosimilars were available. B, D The countries where adalimumab biosimilars were not available. 0Q the quarter of entry of adalimumab biosimilar in each country, GDP gross domestic product, Q4 fourth quarter, SU standard unit, USD United States dollars
The regression analysis also suggested a consistent trend. Table 1 shows that the adjusted sales value of adalimumab significantly decreased in countries where adalimumab biosimilars were available, in comparison to countries where adalimumab biosimilars were not available (− $371.0 per GDP per capita; p = 0.03). In other words, the introduction of biosimilars is expected to result in a budget saving of $371.0 per GDP per capita within the first year.
3.3 Changes in Adalimumab Utilization
Figure 1c and d compared the adjusted quarterly sales volume trends of adalimumab among countries with and without adalimumab biosimilars, respectively, during the study period. In Fig. 1c, which represents countries with adalimumab biosimilars, the adalimumab sales volume increased after four quarters among all included countries, ranging from 0.2 SU per 1000 population (from 4.9 SU to 5.1 SU, 4%) in France to 3.2 SU per 1000 population (from 6.3 SU to 9.5 SU, 51%) in Sweden. Particularly noteworthy is the significant increase in adalimumab consumption observed in Sweden (3.2 SU per 1000 population, from 6.3 SU to 9.5 SU, 51%), Austria (1.8 SU per 1000 population, from 6.6 SU to 8.4 SU, 27%), and Spain (0.7 SU per 1000 population, from 4.3 SU to 5.1 SU, 17%) (Fig. 1c), while the adalimumab expenditure decreased by $57 per GDP per capita (from $544 to $486, − 11%) in Sweden, $284 per GDP per capita (from $583 to $299, − 49%) in Austria, and $1113 per GDP per capita (from $3906 to $2793, − 29%) in Spain, respectively, after four quarters (Fig. 1a). On the other hand, Fig. 1d demonstrates the opposite trend during the same period. Namely, adalimumab sales volume per 1000 population either decreased or showed minimal growth, ranging from − 0.01 SU per 1000 population (− 34%) in Brazil to 0.1 SU per 1000 population (10%) in Taiwan. Notably, in Brazil, where adalimumab biosimilars were not available, both adalimumab expenditure (− 34%) and utilization (− 34%) considerably decreased (Fig. 1b and d). In summary, the adalimumab expenditure notably decreased but the adalimumab consumption increased in most of the countries where adalimumab biosimilars were present, whereas the opposite trend was observed among countries where adalimumab biosimilars were absent.
The regression analysis supports these findings. Table 1 shows that the adjusted adalimumab sales volume significantly increased after four quarters in the countries where adalimumab biosimilars were available, compared to countries where adalimumab biosimilars were not available (1.0 SU per 1000 population; p = 0.02). Namely, the introduction of biosimilars is expected to result in an increase of 1.0 SU in treatment accessibility per 1000 population within the first year.
3.4 Major Components of Changes in Adalimumab Expenditure
Table 2 shows the quantified effect of adalimumab biosimilars on adalimumab expenditure during the study period (Q4 2018 to Q4 2019). Among countries where adalimumab biosimilars were available, adalimumab expenditure decreased by 14% after four quarters. In contrast, among countries without adalimumab biosimilars, adalimumab expenditure remained stable (Et = 1.04; +4%).
Specifically, among countries where adalimumab biosimilars were available, increased penetration of adalimumab biosimilars (εt = 0.88; − 12%) and decreased price (Pt = 0.85; − 15%) had positively contributed to the decreased adalimumab expenditure. In Austria, where the adalimumab expenditures decreased the most (Et = 0.50; − 50%) among countries with adalimumab biosimilars, the adalimumab price significantly decreased (Pt = 0.40; − 60%), while the adalimumab consumption significantly increased (Qt = 1.28; +28%). In Sweden, where the adalimumab consumption increased the most (Qt = 1.53; +53%) among countries with adalimumab biosimilars, both adalimumab expenditures and price significantly decreased (Et = 0.85, − 15%; Pt = 0.63, − 37%), and there was a shift in prescription patterns to cheaper alternatives (εt = 0.89; − 11%).
Conversely, in countries where biosimilars were not available, while there were marginal price variations over time (Pt = 0.98; − 2%), the primary driver for changes in expenditure was the increase in consumption (Qt = 1.06; +6%). Consequently, without the presence of biosimilars, these countries witness an escalation in expenditure primarily attributable to augmented consumption.
3.5 Sensitivity Analysis
The robustness of the results was assessed with sensitivity analysis by excluding two UMIEs (Brazil and South Africa) and focusing only on 12 HIEs (Table 3). The result shown in Table 3 were consistent with the base-case analysis. Namely, the adjusted adalimumab sales value statistically significantly decreased among countries where adalimumab biosimilars were present in the 12 HIEs (− $400.1 per GDP per capital; p = 0.04) after four quarters, compared with countries where adalimumab biosimilars were absent. However, for the adjusted adalimumab sales volume, we observed a marginally significant increase in the countries where adalimumab biosimilars were available, compared to those where adalimumab biosimilars were not available for 12 HIEs (1.0 SU per 1000 population; p = 0.06).
4 Discussion
Our study demonstrated that the availability of adalimumab biosimilars is associated with reduced adalimumab expenditure while maintaining or increasing adalimumab consumption. This finding is supported by our descriptive and regression analysis conducted across 14 countries, including six countries where adalimumab biosimilars were available.
Our findings suggested that countries with adalimumab biosimilars may achieve financial savings due to two factors. First, the availability of adalimumab biosimilars is associated with lower prices for adalimumab. Although the exact ex-factory prices of both the originator and biosimilar adalimumab were not disclosed due to confidential negotiations between hospitals and pharmaceutical companies, we observed a significant decrease in adalimumab prices among countries where adalimumab biosimilars were available, in comparison to countries where adalimumab biosimilars were not available. Second, the drug-mix effect played a role in reducing adalimumab expenditure, by substituting expensive adalimumab with cheaper alternatives. In previous studies, it has been reported that countries that implement supply-side policies aggressively, like Austria, tend to experience significant price reductions [41, 75], whereas countries that actively adopt demand-side policies, like Germany, are likely to achieve higher penetration of biosimilars and realize greater budget savings [24, 38, 76,77,78,79]. Our results were consistent with those previous studies; namely, we observed that Austria achieved the highest price reduction of 60%, while in Germany, the drug-mix effect was the highest (0.81), indicating a significant shift to cheaper alternatives.
In summary, we found that the presence of biosimilars is associated with reduced expenditure, which is consistent with what has been reported previously [25, 28, 29, 36, 80]. Of particular significance is the drug-mix effect, which emerged as a major contributor to the observed changes in drug expenditure following the introduction of biosimilars, which is consistent with previous studies [42,43,44,45,46, 81, 82]. Our research underscores the significant advantages of biosimilars, not only in reducing expenditure, but also in improving the availability of vital treatments to patients, demonstrating the substantial value they offer in the evolving healthcare landscape.
Our study has several limitations. First, we focused on only one biologic, adalimumab, and the study period was relatively short. Therefore, the generalizability of our findings to other biosimilars may be limited. While we attempted to include other TNF-α inhibitors (adalimumab, etanercept, and infliximab) that had biosimilars available by 2020, the launch times of etanercept and infliximab biosimilars were closely aligned across jurisdictions, making it challenging to evenly distribute countries with and without biosimilars within the study period. Although Humira® (adalimumab) is the best-selling biologic in the world as of 2020 [83], future studies encompassing larger numbers of molecules and longer study periods should be followed. Second, while our analysis encompassed countries with diverse geographic and demographic characteristics, it is important to note that only high-income European nations were included for those with adalimumab biosimilars. As a result, our study primarily emphasized budget savings as the key advantages of biosimilars, omitting other potential benefits of biosimilars. However, previous studies have highlighted access constraints to high-cost medications in middle-income countries [84, 85]. Therefore, it can be anticipated that the introduction of biosimilars and the consequent price reduction will enhance accessibility in these regions. Future research is needed to generalize our results to other UMIE countries. Third, we estimated the adalimumab consumption of each country by dividing the adalimumab sales volume by the population, rather than using the actual number of patients. This assumption was made due to the challenges of accurately estimating the exact number of patients receiving adalimumab, which has various indications, such as RA, skin diseases, and gastrointestinal diseases. Therefore, we relied on the population as a proxy for the number of patients. Despite its limitations, using population as a denominator allows for relative comparisons of adalimumab consumption between countries. In addition, previous cross-country comparison studies also divided quantity of pharmaceuticals by the population [50, 61]. Fourth, while the MIDAS-IQVIA data provided insights into utilization patterns across countries based on collected sales volume, there are inherent limitations regarding cost data, especially for hospital products with confidential discounts. Thus, we could not confirm the exact ex-factory prices of adalimumab, which is a clear limitation. However, a previous study showed that the list price of Humira® decreased after loss of exclusivity, which occurred with the entry of the biosimilars in all included countries in this study except Germany (price unchanged) and France (not included in the study), with −80% in Italy (in the Veneto region, list and ex-factory prices have been unchanged, but discounts have been reported in Italy), − 51% in Austria, − 42% in Spain, and − 37% in Sweden, respectively [30]. The list price of biosimilar adalimumab was reported to be significantly lower than that of the originator in all included countries, excluding Sweden (the list price of biosimilar adalimumab was not reported) and France (not included in the study), with − 88% in Italy (in the Veneto region), − 58% in Austria, − 42% in Spain, and − 40% in Germany, respectively [30]. Additionally, the price of the originator significantly decreased, by 89% in the Netherlands and by 80% in the EU tender market, to stave off the use of biosimilars [34, 35]. Biosimilar competition has also led to considerable price reductions in Denmark, England, and southern European countries, such as in Italy, Portugal, and Spain [31,32,33]. The more price reductions, the greater the potential cost savings. Moreover, it is worth noting that tenders are conducted in all included countries where adalimumab biosimilars were launched [39], so the cheapest adalimumab option is the most likely to be prescribed as the winner of the tender. This further supports the speculation that the lower price of adalimumab, coupled with the drug-mix effect resulting from adoption of cheaper biosimilars, is associated with the savings in adalimumab expenditure. Last, our study used the ex-factory prices calculated by dividing the expenditure of adalimumab (in USD) by the quantity of adalimumab (in SU) based on the MIDAS-IQVIA database. Therefore, the actual price reductions for adalimumab may be greater than the price reductions demonstrated in our study.
Despite the limitations mentioned, our study is the first to attempt to assess the changes in expenditure and consumption of a biologic (adalimumab) by comparing 14 countries based on the availability of adalimumab biosimilars, using a regression analysis and decomposing factors associated with adalimumab expenditure. This study highlights the need for biosimilars leading to budget savings and the importance of balancing demand-side and supply-side policies to promote biosimilars use and to achieve sustainable budget savings.
5 Conclusion
Based on our analysis using MIDAS-IQVIA data with the DID method, we found that adalimumab expenditure significantly decreased while consumption increased in the countries where adalimumab biosimilars were present. In contrast, adalimumab expenditure changed in a quantity-dependent manner in countries where adalimumab biosimilars were absent. The observed decrease in adalimumab expenditure can be attributed to the lower price of adalimumab, resulting from increased competition between adalimumab products, and the drug-mix effect encouraging the use of cheaper biosimilar alternatives. Austria, with strong supply-side policies, achieved the highest price reduction, while in Germany, with strong demand-side policies, the drug-mix effect was the highest, indicating a significant shift to cheaper alternatives. Our findings highlight the importance of introducing biosimilars and balancing demand-side and supply-side policies as a strategy to optimize healthcare expenditure and ensure patient access to essential treatments.
Change history
22 January 2024
A Correction to this paper has been published: https://doi.org/10.1007/s40259-024-00645-6
References
Henry D, Taylor C. Pharmacoeconomics of cancer therapies: considerations with the introduction of biosimilars. Semin Oncol. 2014;41(Suppl 3):S13-20.
Moorkens E, Jonker-Exler C, Huys I, Declerck P, Simoens S, Vulto AG. Overcoming barriers to the market access of biosimilars in the european union: the case of biosimilar monoclonal antibodies. Front Pharmacol. 2016;7:193.
Godman B, Bucsics A, Vella Bonanno P, Oortwijn W, Rothe CC, Ferrario A, et al. Barriers for access to new medicines: searching for the balance between rising costs and limited budgets. Front Public Health. 2018;6:328.
IQVIA. The global use of medicine in 2019 and outlook to 2023—forecasts and areas to watch. 2023. https://www.iqvia.com/insights/the-iqvia-institute/reports/the-global-use-of-medicines-2023. Accessed 18 Jan 2023.
Smolen JS, Landewe RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685–99.
Grand View Research. Tumor necrosis factor inhibitor drugs market industry report, 2026. Grand View Research. 2020. https://www.grandviewresearch.com/industry-analysis/tumor-necrosis-factor-tnf-inhibitor-drugs-market. Accessed 22 Sep 2020.
Coghlan J, He H, Schwendeman AS. Overview of Humira(R) biosimilars: current european landscape and future implications. J Pharm Sci. 2021;110(4):1572–82.
Mikulic M. AbbVie's revenue from top product Humira from 2011 to 2020. 2023. https://www.statista.com/statistics/318206/revenue-of-humira/. Accessed 21 Feb 2023.
US Food and Drug Administration. Highlights of prescribing information-Humiar. 2008. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125057s114lbl.pdf. Accessed 1 Feb 2008.
European Medicines Agency. Summary of product characteristics. Humira. 2020. https://www.ema.europa.eu/en/documents/product-information/humira-epar-product-information_en.pdf. Accessed 11 Sep 2020.
European Medicines Agency. Medicine overview. Humira. 2020. https://www.ema.europa.eu/en/documents/overview/humira-epar-medicine-overview_en.pdf. Accessed 11 Sep 2020.
Big Molecule Watch. Amgen, Sandoz, Samsung, and Mylan Launch Biosimilars in Europe (UPDATED). 2018. https://www.bigmoleculewatch.com/2018/11/02/amgen-sandoz-samsung-and-mylan-launch-biosimilars-in-europe-updated/. Accessed 2 Nov 2018.
GaBI Online. Adalimumab biosimilar Idacio launched in Germany. 2020. https://www.gabionline.net/biosimilars/news/Adalimumab-biosimilar-Idacio-launched-in-Germany. Accessed 30 Nov 2020.
GaBI Online. Biosimilars approved in Europe. 2021. https://www.gabionline.net/biosimilars/general/biosimilars-approved-in-europe. Accessed 12 May 2021.
Big Molecule Watch. Adalimumab Biosimilars Ready To Enter Australian, Korean, Japanese and European Markets. 2021. https://www.bigmoleculewatch.com/2021/03/31/adalimumab-biosimilars-ready-to-enter-australian-korean-japanese-and-european-markets/. Accessed 31 Mar 2021.
PharmaShots. Amgen Launches Amgevita (biosimilar- adalimumab) for the Treatment of Inflammatory Diseases in Brazil. 2017. https://pharmashots.com/2159/amgen-launches-amgevita-biosimilar-adalimumab-for-the-treatment-of-inflammatory-diseases-in-brazil-1849811805. Accessed 23 Aug 2017.
Jeremias S. Overseas Successes: Celltrion Launches in Canada, Wins Tender in Brazil. AJMC The center for Biosimilars. 2021. https://www.centerforbiosimilars.com/view/overseas-successes-celltrion-launches-in-canada-wins-tender-in-brazil. Accessed 20 Oct 2021.
GaBI Online. Adalimumab biosimilar launched in Japan. 2017. https://gabionline.net/biosimilars/news/adalimumab-biosimilar-launched-in-japan. Accessed 23 Jan 2017.
Pulse. Samsung Bioepis picks Yuhan to sell Humira biosimilar Adalloce in Korea. 2021. https://pulsenews.co.kr/view.php?year=2021&no=244921. Accessed 22 Feb 2021.
Medpharma. Amgen launches AMGEVITA™ a biosimilar to adalimumab, in South Africa. 2022. https://medpharm.co.za/home-featured/amgen-launches-amgevitatm-a-biosimilar-to-adalimumab-in-south-africa/. Accessed 1 Feb 2022.
European Medicines Agency. Biosimilar medicines: Overview (European Medicines Agency). 2022. https://www.ema.europa.eu/en/human%02regulatory/overview/biosimilar-medicines-overview. Accessed 11 Jan 2022.
US Food and Drug Administration. Information on biosimilars. US Food and Drug Administration. 2022. https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/biosimilars#:~:text=Biosimilars%20%7C%20FDA%20Biosimilars%20Biosimilars%20are%20safe%20and,access%20to%20lifesaving%20medications%20at%20potentially%20lower%20costs. Accessed 11 Jan 2022.
IQVIA. The Impact of Biosimilar Competition in Europe. 2016. https://www.medicinesforeurope.com/wp-content/uploads/2017/05/IMS-Biosimilar-2017_V9.pdf. Accessed Aug 2018
Moorkens E, Vulto AG, Huys I, Dylst P, Godman B, Keuerleber S, et al. Policies for biosimilar uptake in Europe: an overview. PLoS ONE. 2017;12(12):e0190147.
Jarrion Q, Azzouz B, Robinson J, Jolly D, Vallet C, Trenque T. Penetration rate of anti-TNF biosimilars and savings at 5 years after their introduction in French hospitals. Therapies. 2022;77(4):467–75.
Matusewicz W, Godman B, Pedersen HB, Fürst J, Gulbinovič J, Mack A, et al. Improving the managed introduction of new medicines: sharing experiences to aid authorities across Europe. Expert Rev Pharmacoecon Outcomes Res. 2015;15(5):755–8.
Aladul MI, Fitzpatrick RW, Chapman SR. Impact of infliximab and etanercept biosimilars on biological disease-modifying antirheumatic drugs utilisation and NHS budget in the UK. BioDrugs. 2017;31:533–44.
Putrik P, Ramiro S, Kvien TK, Sokka T, Pavlova M, Uhlig T, et al. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis. 2014;73(1):198–206.
Baumgart DC, Misery L, Naeyaert S, Taylor PC. Biological therapies in immune-mediated inflammatory diseases: can biosimilars reduce access inequities? Front Pharmacol. 2019;10:279.
Moorkens E, Godman B, Huys I, Hoxha I, Malaj A, Keuerleber S, et al. The expiry of Humira((R)) market exclusivity and the entry of adalimumab biosimilars in europe: an overview of pricing and national policy measures. Front Pharmacol. 2020;11:591134.
Barcina-Lacosta T, Vulto G, Huys I, Simoens S. Evaluating the benefits of TNF-alfa inhibitor biosimilar competition on off-patent and on-patent drug markets: A Southern European analysis. Front Pharmacol. 2022;2022:4666.
Jensen TB, Kim SC, Jimenez-Solem E, Bartels D, Christensen HR, Andersen JT. Shift from adalimumab originator to biosimilars in Denmark. JAMA Intern Med. 2020;180(6):902–3.
NHS England. NHS set to save record £300 million on the NHS’s highest drug spend. 2023. https://www.england.nhs.uk/2018/11/nhs-set-to-save-record-300-million-on-the-nhss-highest-drug-spend/. Accessed 6 Oct 2023.
FIERCE Pharma. AbbVie's massive Humira discounts are stifling Netherlands biosimilars: report. 2023. https://www.fiercepharma.com/pharma/abbvie-stifling-humira-biosim-competition-massive-discounting-dutch-report. Accessed 6 Oct 2023.
FIERCE Pharma. AbbVie offers up 80% Humira discount in EU tender market to hold off biosimilars: report. 2023. https://www.fiercepharma.com/pharma/abbvie-offers-up-80-humira-discount-eu-tender-market-to-hold-off-biosims-report. Accessed 6 Oct 2023.
Dutta B, Huys I, Vulto AG, Simoens S. Identifying key benefits in European off-patent biologics and biosimilar markets: it is not only about price! BioDrugs. 2020;34(2):159–70.
Kim Y, Kwon HY, Godman B, Moorkens E, Simoens S, Bae S. Uptake of biosimilar infliximab in the UK, France, Japan, and Korea: budget savings or market expansion across countries? Front Pharmacol. 2020;11:970.
Rémuzat C, Dorey J, Cristeau O, Ionescu D, Radière G, Toumi M. Key drivers for market penetration of biosimilars in Europe. J Market Access Health Policy. 2017;5(1):1272308.
Vogler S, Schneider P, Zuba M, Busse R, Panteli D. Policies to encourage the use of biosimilars in European countries and their potential impact on pharmaceutical expenditure. Front Pharmacol. 2021;12:625296.
Barszczewska O, Piechota A. The impact of introducing successive biosimilars on changes in prices of adalimumab, infliximab, and trastuzumab—polish experiences. Int J Environ Res Public Health. 2021;18(13):6952.
GfK. Factors supporting a sustainable European biosimilar medicines market. Melton Mowbray: GfK NOP Limited; 2014. 2023. https://www.medicinesforeurope.com/wp-content/uploads/2016/03/GfK_Final_Report-_Factors_Supporting_a_Sustainable_European_Biosimilar_Medicines_Market.pdf. Accessed 1 Oct 2023.
Hsieh C-R, Sloan FA. Adoption of pharmaceutical innovation and the growth of drug expenditure in Taiwan: is it cost effective? Value Health. 2008;11(2):334–44.
Gerdtham U-G, Johannesson M, Gunnarsson B, Marcusson M, Henriksson F. The effect of changes in treatment patterns on drug expenditure. Pharmacoeconomics. 1998;13(1):127–34.
Gerdtham U-G, Lundin D. Why did drug spending increase during the 1990s? Pharmacoeconomics. 2004;22(1):29–42.
Addis A, Magrini N. New approaches to analysing prescription data and to transfer pharmacoepidemiological and evidence-based reports to prescribers. Pharmacoepidemiol Drug Saf. 2002;11(8):721–6.
Kwon H-Y, Yang B, Godman B. Key components of increased drug expenditure in South Korea: implications for the future. Value Health Reg Issues. 2015;6:14–21.
IQVIA. 2021 ACTS Annual Report. 2022. https://www.iqvia.com/-/media/iqvia/pdfs/library/publications/2021-acts-annual-report.pdf. Accessed 14 Feb 2022.
IQVIA. IMS MIDAS user guide: IMS MIDAS quantum help. Accessed 22 Jul 2019.
Troein P, Newton M, Patel J, Scott K. The impact of biosimilar competition in Europe: IQVIA. 2019.
Tong X, Li X, Pratt NL, Hillen JB, Stanford T, Ward M, et al. Monoclonal antibodies and Fc-fusion protein biologic medicines: A multinational cross-sectional investigation of accessibility and affordability in Asia Pacific regions between 2010 and 2020. Lancet Reg Health-Western Pac. 2022;26:100506.
Greiner W, Patel K, Crossman-Barnes C-J, Rye-Andersen TV, Hvid C, Vandebrouck T. High-expenditure disease in the EU-28: does drug spend correspond to clinical and economic burden in oncology, autoimmune disease and diabetes? PharmacoEconomics-open. 2021;5(3):385–96.
Ye X, Shami JJ, Yan VK, Kang W, Blais JE, Zhao J, et al. Global antiplatelet sales trend: A focus on P2Y12 inhibitors from 2008 to 2018. Am Heart J Plus: Cardiol Res Pract. 2021;4:100020.
Peng K, Blais JE, Pratt NL, Guo JJ, Hillen JB, Stanford T, et al. Impact of introducing infliximab biosimilars on total infliximab consumption and originator infliximab prices in eight regions: an interrupted time-series analysis. BioDrugs. 2023;37(3):409–20.
Li G, Jackson C, Bielicki J, Ellis S, Hsia Y, Sharland M. Global sales of oral antibiotics formulated for children. Bull World Health Organ. 2020;98(7):458.
WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment. Oslo, Norway: World Health Organization. 2022. https://www.whocc.no/atc_ddd_index_and_guidelines/guidelines/. Accessed 19 Dec 2022.
Yoo K-B, Lee SG, Park S, Kim TH, Ahn J, Cho M-H, et al. Effects of drug price reduction and prescribing restrictions on expenditures and utilisation of antihypertensive drugs in Korea. BMJ Open. 2015;5(7):e006940.
Pattanaprateep O, Pongcharoensuk P, Suvanakoot P, Kaojarern S. Pattern of statins’ utilization at Ramathobodi Hospital, 2005 to 2007. J Med Assoc Thai. 2011;93(10):1223.
World Bank. World Bank Open Data. 2021. https://www.ilae.org/files/dmfile/World-Bank-list-of-economies-2020_09-1.pdf, https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups. Accessed 1 Jul 2021.
Abasolo L, Tobías A, Leon L, Carmona L, Fernandez-Rueda JL, Rodriguez AB, et al. Weather conditions may worsen symptoms in rheumatoid arthritis patients: the possible effect of temperature. Reumatol Clín (Engl Ed). 2013;9(4):226–8.
Azzouzi H, Ichchou L. Seasonal and weather effects on rheumatoid arthritis: myth or reality? Pain Res Manage. 2020;2020:1–9.
Crosby M, von den Baumen TR, Chu C, Gomes T, Schwartz KL, Tadrous M. Interprovincial variation in antibiotic use in Canada, 2019: a retrospective cross-sectional study. Can Med Assoc Open Access J. 2022;10(1):E262–8.
Martin AB, Hartman M, Benson J, Catlin A, Team NHEA. National health spending in 2014: faster growth driven by coverage expansion and prescription drug spending. Health Aff. 2016;35(1):150–60.
Csákvári T, Ágoston I. Health insurance pharmaceutical expenditures in Hungary. Orv Hetil. 2019;160(Suppl 1):49–54.
Voda AI, Bostan I. Public health care financing and the costs of cancer care: a cross-national analysis. Cancers. 2018;10(4):117.
Mah JS. R&D policies and development of technology-intensive industries of Taiwan. Prog Dev Stud. 2015;15(2):125–38.
World Bank. World Bank Open Data. 2022. https://data.worldbank.org/indicator/NY.GDP.PCAP.CD?most_recent_year_desc=true. Accessed 5 Jan 2022.
OECD Data. Population. 2023. https://data.oecd.org/pop/population.htm. Accessed 2 Jun 2023.
Worldometers. Taiwan Population. 2020. https://www.worldometers.info/world-population/taiwan-population/. Accessed 1 Jul 2020.
National Statistics. National Statistics Open Data. 2020. https://eng.stat.gov.tw/Point.aspx?sid=t.1&n=4200&sms=11713. Accessed 1 Jul 2020.
Gerdtham U, Lundin D. How did drug expenditure change for different age groups during the 90’s?-Evidence from Sweden. Expert Rev Pharmacoecon Outcomes Res. 2004;4:343–51.
Marushka L, Hu X, Batal M, Sadik T, Schwartz H, Ing A, et al. The relationship between persistent organic pollutants exposure and type 2 diabetes among First Nations in Ontario and Manitoba, Canada: a difference in difference Analysis. Int J Environ Res Public Health. 2018;15(3):539.
Stuart EA, Huskamp HA, Duckworth K, Simmons J, Song Z, Chernew ME, et al. Using propensity scores in difference-in-differences models to estimate the effects of a policy change. Health Serv Outcomes Res Method. 2014;14(4):166–82.
Inoue K, Figueroa JF, Kondo N, Tsugawa Y. Changes in industry marketing payments to physicians during the covid-19 pandemic: quasi experimental, difference-in-difference study. BMJ Med. 2022;1:1.
Kim S, Kwon S. Impact of the policy of expanding benefit coverage for cancer patients on catastrophic health expenditure across different income groups in South Korea. Soc Sci Med. 2015;138:241–7.
Mestre-Ferrandiz J, Towse A, Berdud M. Biosimilars: how can payers get long-term savings? Pharmacoeconomics. 2016;34(6):609–16.
Davio K. After biosimilar deals, UK spending on adalimumab will drop by 75%. 2018. The Center for Biosimilars. 2020.
O’Callaghan J, Barry SP, Bermingham M, Morris JM, Griffin BT. Regulation of biosimilar medicines and current perspectives on interchangeability and policy. Eur J Clin Pharmacol. 2019;75(1):1–11.
Flume M. Regional management of biosimilars in Germany. Gener Biosimilars Initiat J. 2016;5(3):125–8.
Moorkens E, Barcina-Lacosta T, Vulto AG, Schulz M, Gradl G, Enners S, et al. Learnings from regional market dynamics of originator and biosimilar infliximab and etanercept in Germany. Pharmaceut (Basel). 2020;13:10.
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(4):348.
Mousnad MA, Shafie AA, Ibrahim MI. Systematic review of factors affecting pharmaceutical expenditures. Health Policy. 2014;116(2–3):137–46.
Alves JDC, Osorio-de-Castro CGS, Wettermark B, Luz TCB. Immunosuppressants in Brazil: underlying drivers of spending trends, 2010–2015. Expert Rev Pharmacoeconom Outcomes Res. 2018;18(5):565–72.
Urquhart L. Top companies and drugs by sales in 2020. Nat Rev Drug Discov. 2021;20(4):253.
Morin S, Segafredo G, Piccolis M, Das A, Das M, Loffredi N, et al. Expanding access to biotherapeutics in low-income and middle-income countries through public health non-exclusive voluntary intellectual property licensing: considerations, requirements, and opportunities. Lancet Glob Health. 2023;11:145.
Ocran-Mattila P, Ahmad R, Hasan SS, Babar ZUD. Availability, affordability, access, and pricing of anti-cancer medicines in low-and middle-income countries: a systematic review of literature. Front Public Health. 2021;9:462.
Acknowledgements
We thank Ms. Younghyun Song for her contribution to the primary data collection.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Funding
This work was supported by the National Research Foundation (NRF-2021R1F1A1050281).
Conflict of interest
All authors have no conflicts of interest to declare.
Availability of data
The datasets generated for this study will not be made publicly available; IMS-MIDAS can be purchased and accessed at IQVIA.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Code availability
Not applicable.
Authors’ Contributions
Concept and design: HK, SB. Acquisition of data: SB. Analysis and interpretation of data: HW, GS, DL, HK, SB. Drafting of the manuscript: HW, SB, HK. Critical revision of the paper for important intellectual content: DL, GS. Statistical analysis: HW, DL, GS. Administrative, technical, or logistic support: HW. Supervision: HK, SB. All authors approved the final version of the manuscript.
Additional information
The original article has been updated: Due to Funding note update.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Woo, H., Shin, G., Lee, D. et al. Is the Availability of Biosimilar Adalimumab Associated with Budget Savings? A Difference-in-Difference Analysis of 14 Countries. BioDrugs 38, 133–144 (2024). https://doi.org/10.1007/s40259-023-00636-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40259-023-00636-z