This study is, to the best of our knowledge, the first to investigate the market diffusion of a large number of different premium-priced biopharmaceuticals across Europe using health authority data. By incorporating real-world drug utilization data from 17 European countries and two regions, it reveals variability in the early diffusion of biopharmaceuticals across these nations and regions. The highest rate of biopharmaceuticals diffusion was observed in Germany and Austria, followed by several Northern European countries. The slowest uptake was seen among Central and Eastern European countries including Lithuania, Romania, and Latvia. Additionally, the study highlighted substantial challenges in acquiring data from health authorities, and the considerable differences in the data that was provided for monitoring drug utilization across the included countries/regions.

4.1 Determinants of Early Biopharmaceutical Diffusion

Previous literature has consistently found differences across European countries in the use and uptake patterns of novel and premium priced medicines, including biopharmaceutical products, orphan medicines, and oncology products. The differences are likely attributed to several interlinking and interacting reasons. Countries with a large market size and strong economies tend to exhibit rapid uptake and high utilization patterns [6, 48,49,50,51,52]. Countries with a lower gross domestic product and a smaller market size may in turn heavily restrict access through coverage decisions or reimbursement criteria because of budgetary reasons; alternatively, other barriers to access may limit their uptake [52,53,54]. Small markets may also lack attractiveness because of low profits in relation to entry costs attributed to regulatory processes and labeling requirements, and in the case of rare diseases, differences may be related to prevalence rates with smaller countries either having a rapid or a slow uptake [48, 55].

Restrained markets can also set lower pharmaceutical prices and thus experience delays in pricing applications to avoid price erosion in markets where reference pricing is based on the lowest available price [56, 57]. In such restrained settings, the use of biosimilars following loss of market exclusivity offers an increasing potential to improve access to biopharmaceuticals and promote more equitable use in countries with limited healthcare budgets [6, 58]. Cross-national comparisons are limited in this field. However, they are increasingly being undertaken and show similar results as for branded biopharmaceuticals, i.e., that there is a large variation between countries in their utilization [24, 58, 59]. This is attributable to a large variation in factors including specific measures taken to stimulate the utilization of biosimilars [59, 60].

Other important determinants for differences in early diffusion across countries that have similar macroeconomic features include regulatory and health technology assessment processes, payment models, distribution channels as well as pricing and reimbursement [56, 61]. The duration and outcomes of pricing and reimbursement processes vary significantly across countries [61, 62]. For example, some countries seem to place a higher emphasis on budget control, whereas others prioritize the potential benefits of new medicine [48, 50, 51, 63, 64]. As all new products are not equal in their value, a medicine’s therapeutic importance is a likely contributor [50]. Furthermore, some health systems may approve new treatments rapidly but impose strict usage conditions, such as limiting access to patients unresponsive to conventional therapies or to subgroups with demonstrated higher benefits. Others may delay decisions because of prolonged evaluations, yet ultimately provide broader access [57, 65, 66]. These divergent approaches influence both the timing of reimbursement decisions and the inclusiveness of access to novel therapies across populations [49, 54, 64, 67,68,69].

Furthermore, differences in interpretations of evidence and cultural factors are also among the hypothesized explanations for variation in uptake. The perceived clinical value and necessity of new therapies among key medical specialists, who frequently influence the development of clinical guidelines and prescribing norms, can play a crucial role [70, 71]. Variability in key specialist perspectives, both between and within countries, shaped by national and local diagnostic practices, clinical traditions, the influence of pharmaceutical companies, and differing levels of experience with specific patient populations, may contribute to divergent patterns in the adoption and use of biopharmaceuticals [72,73,74].

While the current study was not designed to formally assess associations between diffusion rates and macro-level determinants, the observed patterns broadly align with previous findings indicating a higher uptake of biopharmaceuticals in countries with greater economic resources. In particular, countries such as Germany, Austria, Norway, Denmark, Sweden, Belgium, and Iceland, characterized by higher gross domestic product and health expenditure per capita, as reported in the World Development Indicators database, appear at the top of the ranking. In contrast, countries with comparatively lower economic resources, including Romania, Latvia, Slovakia, Lithuania, and Croatia, tend to show a more limited uptake. These observations support the concept that a macroeconomic context plays a role in facilitating an earlier or broader adoption of biopharmaceutical therapies. One notable outlier is Scotland, which ranks comparatively low in this study despite being part of the UK, a country with a relatively high gross domestic product. As the data reflect only the Scottish context with a potentially more constrained health budget or different policy environment relative to the rest of the UK, this may still align with the broader interpretation.

Regardless of the countries or health system circumstances, collective efforts are essential within the European context to address the rising costs and associated of novel biopharmaceuticals [75]. Ongoing initiatives include the European Pharmaceutical Strategy [76] and European Network for Health Technology Assessment [77]. They aim to tackle challenges by establishing effective and sustainable structures, providing timely and transparent information to help reduce inequities and harmonize market access timelines across countries [76, 77]. Studies such as this one help in this process by highlighting appreciable differences in utilization rates of new biopharmaceutical medicines between European countries, which need to be explored further to provide future guidance.

4.2 Diffusion of Biologics Across European Healthcare Systems

The early diffusion rankings revealed considerable disparities among countries and regions in their adoption of new biopharmaceuticals. The highest-ranking countries displayed nearly three times the diffusion rate versus the lowest-ranking countries, indicating a substantial variation in early biopharmaceutical access and usage across the study population. The comparatively lower utilization of new biopharmaceuticals among Central and Eastern European countries is similar to previous studies including the tumor necrosis factor-α inhibitors for rheumatoid arthritis and Crohn’s disease [78, 79] as well as the lipid-lowering PCSK9 inhibitors [26].

While the overall ranking provided a concise summary of total diffusion, further analysis of the accumulated diffusion graphs revealed that the observed patterns of high or low uptake were not consistent across all therapeutic areas. Instead, several countries and regions exhibited high adoption in certain therapeutic areas while showing a low uptake in others. This finding aligns with previous cross-national comparisons [56, 80], and reflects the complex range of determinants influencing the uptake of new medicines [81,82,83,84].

For the FDC of insulin, as well as follitropin and tildrakizumab, only a limited number of countries demonstrated a substantial uptake, whereas most healthcare systems showed relatively modest diffusion. In contrast, IL-5 targeting therapies and immunosuppressive antibodies displayed a more uniformly distributed uptake across countries, with fewer instances of significantly elevated use and a more gradual tapering pattern. Dupilumab and the PCSK-9 inhibitors displayed similar diffusion patterns to the evenly distributed substances. However, uptake was observed in fewer countries and among those with higher usage, there was a steeper decline in diffusion compared with other therapies. Finally, for the CGRP receptor antagonists, two countries stood out with notably greater use, while the remainder exhibited lower and relatively constant levels of diffusion. It is important to note that these graphs are not presented on a uniform numerical scale, hence, absolute levels of use should be interpreted with caution.

Overall, high or low rates of diffusion do not necessarily reflect the performance of a healthcare system. Some medicines may fail to meet patients’ needs effectively, particularly when their cost outweighs their clinical efficacy and demand side measures, along with pressure from patient populations, which appreciably vary between European countries affecting their uptake [85]. Increased use of such medicines can place substantial burdens on healthcare systems without delivering proportional benefits, thereby undermining overall healthcare performance [19]. In addition, they may counteract existing priority areas for investment in new and established medicines. The analytical framework of “pharmaceuticalization” conceptualizes the growing economic, societal, and political importance of medicines and the pharmaceutical industry. It is often associated with negative connotations, such as media mediation and the use of medicines for enhancement rather than treatment [86]. This highlights the need for critical assessment of whether all new treatments are necessary, advocating for caution in the adoption of new medications.

4.3 Barriers and Opportunities in Accessing Utilization Data

The lack of harmonized data on pharmaceutical utilization across countries and regions has hindered comparisons of the diffusion and uptake of novel pharmaceuticals. Previous cross-national studies have relied on comprehensive commercial data, reporting both hospital and out-of-hospital diffusion [26, 30, 78]. However, commercial data are costly to obtain, making it inaccessible for many researchers. To transparently conduct research on drug utilization, data that are readily available without significant costs must be accessible, which is why commercial data were excluded from this study. The development of the new European Health Data Space Regulation represents an important initiative to facilitate access to key health data. The European Health Data Space Regulation aims to assist individuals in accessing, controlling, and sharing their health data, while also enabling the secondary use of such health data across borders within EU member states. The European Health Data Space Regulation therefore has the potential to support more equitable and transparent research on pharmaceutical utilization by improving access for non-commercial and academic researchers [87].

Aggregated health authority data on drug utilization were available from many European countries and regions. However, consistent with previous research [28, 30], the greatest challenge in accessing data was observed in the hospital setting. This is particularly concerning as many biopharmaceuticals are administered parenterally and are often introduced in hospital settings before potentially transitioning to out-of-hospital settings. Thus, the absence of hospital data severely limited the full scope of biopharmaceutical utilization in certain healthcare systems including France, Hungary, Republic of Ireland, and the Netherlands, to the extent that they could not be included in the analysis because of the uncertainty. However, Germany and Austria, which had only out-of-hospital data for this study, still provided valuable insights into utilization patterns within their healthcare systems, as implied by their rankings.

The ongoing global digital transformation, characterized by rapid technological advancements, has significantly expanded the capacity to collect and utilize healthcare data [88,89,90]. It is anticipated that this trend will continue, enhancing data collection and reporting for biopharmaceuticals. This would enable future studies to incorporate both out-of-hospital and hospital data, offering a more comprehensive view of biopharmaceutical utilization across healthcare settings. Consistent with the crucial need to obtain readily available and transparent data without the significant costs associated with commercial sources, this would enable more inclusive and equitable research, promoting a better understanding of drug utilization across diverse healthcare systems.

4.4 Distribution Preferences for Biopharmaceuticals

In recent years, many countries and regions have introduced funding models aimed at bridging the gap between hospital and outpatient sectors. These models are designed to prevent cost shifting of high-cost medications between sectors or payers, while also enabling countries and regions to benefit from public procurement arrangements [91, 92]. As such countries and regions differ widely in how they structure their systems, policies, and procedures regarding hospital versus out-of-hospital pharmaceuticals [43].

In our study, major variation in the distribution of pharmaceutical utilization between hospital and out-of-hospital pathways were observed across both medication classes and countries/regions. Countries and regions such as Catalonia, Denmark, Italy, and Scotland demonstrated a preference for hospital-based utilization, which aligns with earlier data on sales distribution [93]. In contrast, countries including Belgium, Finland, Iceland, and Sweden, which exhibited a majority of out-of-hospital utilization for three of the therapy classes, showed a shift toward hospital utilization for the severe asthma therapies. By contrast, Croatia, Estonia, and Lithuania exhibited a varied assortment of different pathways, revealing diverse distribution preferences of therapies.

The differences in distribution between out-of-hospital and hospital settings should be interpreted with caution, as they are often shaped by country-specific financing arrangements and reimbursement policies. It is also intensified by inconsistent classification systems and overlapping categories. Accurately understanding pathways patterns thus requires detailed national knowledge to uncover underlying factors and provide a reliable basis for interpretation.

4.5 Strengths and Limitations

The significance of this project lies in its extensive reach, including data from most European countries, a noteworthy achievement given the complexities of establishing large-scale cross-national comparisons. Through a descriptive approach, the study shed light on specific challenges and their implications for conducting comparisons of the early introduction of biopharmaceuticals. Additionally, the findings highlighted variations in early diffusion rates between different therapeutic areas. Other strengths relate to the use of the ATC-DDD system, recommended by the WHO for drug utilization studies [31], and the active participation of researchers and data holders from all countries/regions, enabling validation of findings.

We acknowledge, however, that there are some limitations. The main challenge was related to obtaining comparable data and identifying relevant collaborators in each country. As such, the data availability for this study may not fully reflect clinical practice across all countries. For instance, differences exist between European countries in how they define, fund, and organize in-hospital and out-of-hospital use within their healthcare systems, which can lead to inconsistencies and confusion. This motivated us to categorize the data accordingly, to reduce country-specific variation and enhance comparability. However, this approach may itself introduce some degree of misclassification or oversimplification.

Another issue was related to the available data provided and capturing the full extent of biopharmaceutical utilization, especially in countries/regions that could only provide out-of-hospital data. A further challenge of the study is attributed to its focus on the initial 4 years after market approval. Focusing solely on this period might not capture the entire picture, as diffusion patterns may change over time. Visualizing data with annual trends could offer more nuanced insights, revealing variations and potential changes over time. This is particularly relevant considering the dynamic nature and constant changes occurring within the European countries or regions.

We also acknowledge a challenge associated with using DDDs as a measure of utilization, as it resulted in the exclusion of some rapidly growing therapeutic areas for biopharmaceutical drugs, including orphan drugs and oncology. It is important to recognize the significance of these areas, as they may exhibit greater variation in access and use across European countries or regions than the therapies included in this study [94, 95]. Conducting further research in these areas could offer valuable insights into the equity of biopharmaceutical introduction in less explored but increasingly important therapeutic domains. The continued development of DDD measures for therapies in areas where they are currently lacking would help improve comparability and facilitate future research on biopharmaceutical utilization in these fields. Additionally, using DDDs per 1000 inhabitants over a 4-year period, allowed us to focus on longer term uptake patterns without being influenced by short-term fluctuations or cross-national inconsistencies in introductory approaches and utilization reporting. However, it may limit comparability to other studies and obscure shorter-term variations.