This budget impact analysis employed a retrospective database to assess the economic impact of the introduction of epoetin alfa biosimilars in the German SHI market. It is based on real-world data collected from January 2008 to December 2023 (16 years), focusing on price trends and volume usage to determine cost-savings and market dynamics.

The primary data sources comprise price and product data from ABDATA and volume data from IQVIA Pharmascope, ensuring comprehensive coverage and reliability, as well as consistency in data collection and cost estimations. Price and product data from the ABDATA database provide detailed information on product identifiers (Pharmazentralnummer, PZN), strength, dosage, and pack size, along with official list prices of drugs sold in Germany. This dataset is updated on the 1st and 15th of each month. This analysis encompasses data from January 1st, 2007 to December 15th, 2023, with pricing data from 2007 used exclusively for the purpose of list price comparison with the originator product. Volume data, sourced from IQVIA Pharmascope, provides monthly sell-out units per individual PZN. For the current analysis, data from January 2008 until December 2023 were utilized. The ABDATA dataset represents the complete population of all available PZNs marketed in Germany during the study period. IQVIA Pharmascope data was matched to ABDATA data via the unique identifier PZN on monthly basis. If a PZN was missing in IQVIA Pharmascope data set for a specific period, the respective unit value was set to zero.

Neither ABDATA nor IQVIA’s Pharmascope are publicly accessible; they are subscription-based, professional databases and analytical services designed for the pharmaceutical industry.

The analysis included all listed Pharmaceutical Central Numbers (PZNs) for epoetin alfa products, encompassing both originator and biosimilar formulations. These were categorized according to their therapeutic indication and dosage strength, with nephrological strengths ranging from 1,000 IU to 10,000 IU and oncological strengths ranging from 20,000 IU to 40,000 IU. If a PZN was discontinued, it remained included as long as it appeared in the ABDATA dataset.

Products were excluded based on specific criteria. Epoetin variants such as epoetin beta, theta, and zeta were omitted from the cost-saving analysis due to regulatory or chemical differences. In addition, PZNs with an ex-factory price of zero were excluded, as these represented hospital-use or sample packages.

The pricing structure consists of two key components: Firstly, the ex-factory price (“Abgabepreis des pharmazeutischen Unternehmens,” APU), representing the official list price, is published and accessible for each pharmaceutical product (identified by its PZN) on two specific dates per month, namely the 1st and 15th. In order to compile a single data set per each month, an average APU (AVG APU) is calculated per PZN. The AVG APU is calculated as the mean of the APU values available on the 1st and 15th of the month, expressed as:

In case a PZN was launched on the 15th, the AVG APU for that respective month will be equal to the APU of the 15th.

The second component is a price baseline (APU_fixed), representing the price level before the introduction of epoetin alfa biosimilars to the pharmaceutical market. APU_fixed is an average of all PZNs (originator and importers) with identical strengths and pack sizes available on April 1st, 2007, thus yielding a single price per package category defined by strength and pack size. Prices from importers are included to account for price competition prior to market entry of biosimilars.

Calculation of APU_fixed package per dosage and pack size combination based on the available APU prior to epoetin alfa biosimilars (cut-off date, April 1st, 2007).

In addition to price calculations, market share analyses were performed. Market shares were calculated based on volume data obtained by IQVIA Pharmascope, which provides monthly data at the PZN level, expressed in units (packages). The basis for determining the market share of epoetin alfa among epoetin derivates was the accumulated volume data per year for epoetin alfa, epoetin beta, epoetin theta and epoetin zeta. Market share calculations of specific dosages were based on volume data per year for epoetin alfa exclusively.

When discussing costs relevant for the German SHI system, the pharmacy selling price would seem to constitute an appropriate basis for drug cost calculation basis, but only after deducting mandatory manufacturing rebates, pharmacy rebates and rebates from confidential contracts with state insurance companies. Mandatory pharmacy as well as manufacturing rebates are defined in social legislation (§130 und §130a SGB V), while rebate contracts are individually negotiated by insurance companies. Pharmaceutical companies participating in such contracts are obliged to grant refunds according to the defined rebate conditions. These conditions vary across contract frameworks of the insurance company and are not publicly disclosed. The pharmacy selling price itself is determined through formal calculation rules defined within the Pharmaceutical Price Regulation (“Arzneimittelpreisverordnung” (17)). Given that the pharmacy selling price is influenced by legal regulations, changes at this level may occur independently of manufacturer price adjustments.

In order to circumvent the potential distortions caused by regulatory changes and the confidentiality of rebate contracts, the ex-factory price (APU) was utilized as the basis for cost-saving analyses, instead of the pharmacy selling price. Consequently, the identified cost savings in absolute numbers may be lower than the actual savings.

The market value of epoetin alfa is calculated using two approaches: fixed prices (APU_fixed) and list prices (AVG APU). These calculations use the following formulas:

And

Cost savings were determined by calculating the differential between the market value derived from list price calculation (list price_APU) and the market value based on the price baseline prior to the introduction of respective biosimilar products to the market (market value APU_fixed) using the formula:

We calculated annual means and percentage changes to assess trends in pricing and volume, yielding a concise illustration of market trends, price fluctuations and the uptake of biosimilars over the investigated study period (2008–2023). AVG APU (month) was calculated per individual PZN and is an average value. APU_fixed, on the other hand, describes the average of all packages available on April 1st, 2007. The actual cost-savings analyses are calculated as the sum of the PZNs listed according to ABDATA for the analysis period. The exclusion of regulatory effects and confidential discounts was necessitated by two factors: firstly, the imperative of ensuring the comparability of the data; secondly, the recognition that confidential discounts are typically negotiated on an individual basis and are not available to the public. Assumptions were applied for the purpose of consistency, such as treating missing data within IQVIA Pharmascope as zero sales. Data extraction and integration were performed using ABDATA and IQVIA tools.

The range of epoetin alfa preparations available in the German market following their regulatory approval within Europe in 2007 is presented in Table 1. In order to assess the impact of epoetin alfa within the market, we analysed annual market shares (2008–2023) of epoetin alfa in comparison to other epoetin derivatives, including epoetin beta, theta, and zeta, based on unit volume (number of packs sold per year). The results, presented in Table 2, indicate that epoetin alfa maintained the largest market share, contributing to 64% of total unit volume in 2023 (on average 57% unit volume between 2008 and 2023). Over the observed period, epoetin alfa demonstrated a remarkable growth of 23% in unit volume (Table 2). In contrast, the market share of other epoetin derivatives (e.g., beta, zeta and theta) exhibited a significant decline, with a cumulative reduction of 10%, indicating an increased adoption for epoetin alfa. The overall change in unit volume for all epoetin derivatives was +9% in 2023 compared to 2008.

During the investigated time period, a dramatic shift from originator products to epoetin biosimilar consumption was recorded, with biosimilar market shares rising from 42% in 2008 to 92% in 2023 (Supplementary Table S1).

Building on these findings, a detailed market analysis of epoetin alfa usage across different nephrological (1,000 IU to 10,000 IU) and oncological strengths (20,000 IU to 40,000 IU) was undertaken to ascertain market trends (Table 3). The analysis revealed an average market share of 93% in 2023 (95% accumulated from 2008 to 2023) for nephrological strengths. Furthermore, distinct patterns of adoption over time were identified, providing valuable insights into the dynamics of market utilization. Between 2008 and 2023, the nephrological strengths of 4,000 IU and 2,000 IU were observed to have the highest utilization rates (27 and 20% market share in 2023, respectively, within the nephrological strength segment). Among these, epoetin alfa 4,000 IU showed a significant growth in unit volume (12%), indicating an increasing preference in clinical practice. In contrast, epoetin alfa 2,000 IU exhibited a decline in unit volume of 24%. The remaining strengths demonstrated consistent usage patterns.

These utilization patterns are closely linked to the economic implications of epoetin alfa adoption, particularly following the introduction of biosimilar epoetin alfa in 2007, the APU decreased consistently over the subsequent 6 years (2007–2012) for all available products, achieving a significant reduction of 47% (Table 4). From 2013 onwards, the price differences between the originator product and epoetin alfa biosimilars diminished, also due to adaptations of a fixed reference price. The relevant fixed reference price group encloses drugs to treat anemia and includes the molecules Darbepoetin, Erythropoetin (alfa, beta, theta, zeta) and PEG-Erythropoetin (Methoxy-Polyethylenglycol-Epoetin beta). These price developments resulted in cumulative cost-savings of €505,731,202 for the German SHI, encompassing all nephrological strengths of epoetin alfa between 2008 and 2023 (Figure 1; Supplementary Table S2).

To further delineate the sources of these economic effects, an analysis of cost savings per drug strength revealed that the nephrological strength of a 4,000 IU formulation of epoetin alfa contributed the most to overall savings, amounting to €143,720,363 and corresponding to 28% savings from 2008 to 2023 (Table 5). The disproportionately high contribution of the strength of 4,000 IU reflects its dominant role in clinical practice and the associated economic benefits stemming from its widespread adoption.

A comparison of the cost saving effects of defined nephrological strengths and oncological strengths revealed that nephrological strengths account with a share of 79% of total savings, representing the largest impact.

The 8th iteration of the ‘Impact of Biosimilar Competition in Europe‘(IQVIA observation 2022) has demonstrated a notable increase in the utilization of biosimilar products and market competition in Europe during the present decade (18). Biosimilars play a vital role in the European healthcare system, helping to manage healthcare costs by generating savings for payers, providing room for innovation, and increasing patient access to biologic therapies (18). In Germany, the biopharmaceutical market has demonstrated robust growth in gross sales since 2006 with biosimilar products inducing the highest market share (19).

Our analysis of unit volume data from 2008 to 2023 of epoetin alfa biosimilars from ABDATA and IQVIA Pharmascope databases is the first analysis investigating the economic impact of the introduction of epoetin alfa biosimilars to the German pharmaceutical market. This analysis revealed that the epoetin alfa products have the highest market share compared to other epoetin derivatives, indicating the highest preference and utilization in Germany. To the best of our knowledge, we are the first to report the overtime improvement of market dynamics of epoetin alfa derivatives in the German healthcare system. We observed a significant price development, with a robust decline in the ex-factory price of overall epoetin in nephrological strengths over a period of 6 years (2007 to 2012). Over 15 years this has been converted to a cumulative cost-saving of €505,731,202 for the German SHI. Such financial relief is attributed to increased competition among biosimilars, which drives prices down and enhances access to essential therapies for patients.

A similar cost-saving analysis on epoetin alfa biosimilars in European Union G5 countries by Aapro et al. revealed that the average treatment costs associated with epoetin alfa biosimilars are significantly lower than those of the originator products. Their study showed that the costs over a 15-week treatment period amounted to €4,643 for a dose of 30,000 IU and €6,178 for 40,000 IU of biosimilar epoetin alfa. In contrast, treatment with the originator epoetin alfa averaged around €7,168, while epoetin beta and darbepoetin alfa incurred higher costs of €7,389 and €8,299 (once weekly) or €9,221 (once every 3 weeks), respectively (20). Furthermore, Hörbrand et al. reported on cost savings of €2.23 per defined daily dose when erythropoiesis stimulating agent (ESA) biosimilars were preferred over originator products in patients suffering from renal anemia (21). A population-based study in a comparable patient population reported similar consumption rates of biosimilar and originator ESAs (22), which appears to contrast our findings. Nevertheless, despite the equivalent utilization of ESA biosimilars and originator products observed by Hörbrand et al., particularly within the nephrological setting, the demonstrated economic benefit of prescribing biosimilars over originator products or other treatment options underscores our findings regarding epoetin alfa.

As market dynamics continue to evolve, it is anticipated that further cost reductions will emerge as biosimilars gain broader acceptance and utilization within healthcare systems (18, 19). Competitive pricing strategies employed by manufacturers, alongside potential rebates and discounts defined by healthcare providers within open house contracts, are likely to contribute to sustained economic benefits over time.

In Germany, pricing developments in the ESA market were also shaped by the revision of the fixed reference price in 2013, including epoetin alfa, epoetin beta, epoetin theta, epoetin zeta, PEG-Erythropoetin and Darbepoetin. Under this system, the reference price is determined by list price differentials and the market share of individual suppliers—meaning that a higher market share of lower-priced products leads to a lower overall reimbursement level. To avoid additional patient co-payments, manufacturers with higher list prices must align their prices with the defined reimbursement level, which in turn drives further price reductions and additional cost savings for the healthcare system.

The utilization of epoetin alfa biosimilars in Germany indicates a significant progression in the delivery of cost-effective healthcare for patients requiring ESAs. The substantial cost-savings observed when comparing biosimilar treatment to originator products not only alleviate financial pressures on healthcare systems but also enhance patient access to necessary therapies. It is therefore essential to continue monitoring of biosimilar utilization and pricing strategies in order to maximize these economic advantages in the future.

A major strength of this budget impact analysis is the incorporation of reliable data sources to support the cost-saving assessment. However, it should be noted that the calculations based on the ex-factory price do not reflect the actual costs within the German SHI system. A proportion of the market, notably in the dialysis sector, is procured through centralized purchasing mechanisms and invoiced outside the purview of drug price regulation (approximately half of the volume based on epoetin alfa). Therefore, the market for epoetin alfa biosimilars is generally underestimated within this study. Moreover, the use of ex-factory prices may not fully provide an adequate basis for cost calculation, since reimbursement also encompasses costs associated with trade levels, such as wholesalers and pharmacies. In addition, the estimation of cost savings did not account for possible price fluctuations prior biosimilar market entry. As historical price data for individual PZNs were only available from 2007 onwards, pre-biosimilar pricing dynamics could not be examined. Therefore, potential fluctuations in drug prices unrelated to biosimilar competition cannot be entirely excluded.