Given the divergent long-term and immediate impacts of the infliximab biosimilar introduction of utilization and costs observed in different regions, we considered the differences in pricing strategy, reimbursement coverage, policy guidance, and competing products separately for India, Japan, and the USA. Additionally, we discuss the results for Australia, Canada, UK, Hong Kong, and Korea together as they had consistent changes in consumption and costs after the introduction of the infliximab biosimilar.

India currently does not have a mechanism for the reimbursement of biologics [28] and the high price of both the originator and biosimilar products might weaken the effect of biosimilar introduction, as cost is an important factor influencing the behavior of both the patient and prescriber [29]. A previous study reported that medicine costs could account for up to 70% of overall out-of-pocket health costs for people living in India [30]. The disease-related out-of-pocket health costs are associated with a greater risk of incurring catastrophic health expenditure [31]. Despite limited health insurance coverage, the list price of infliximab in India, the only lower-middle income economy in our study, remained relatively high compared with other developed countries. Consequently, among the countries in our study, India has the lowest infliximab consumption per 1000 inhabitants. In India, biologics are not currently listed on the National List of Essential Medicines, thus the pricing of biologics are not regulated [32] and despite a less costly biosimilar, the price is still prohibitive for many individuals on low incomes while those on higher incomes can afford infliximab regardless of the lower price of the biosimilar. Unfavorable economic conditions and a less well-regulated pharmaceutical market has changed the dynamics of policy intervention [33], which likely explains why increased utilization and reduced originator prices have not been achieved in India.

In Japan, the trend in infliximab consumption dropped substantially after the introduction of the infliximab biosimilar and overturned the original increasing trend in the pre-intervention period. Previous market analysis in Europe reported a similar phenomenon that in 21% of cases, the introduction of lower priced biosimilars was actually associated with a reduction in the overall number of patients treated [13]. While the reason for such reductions remains unclear, it could be attributed to the increased usage of other competing biologic agents. It has been reported that prescribers and patients may prefer more user-friendly agents (e.g., golimumab, tocilizumab, adalimumab) that can be self-administered subcutaneously, compared with infliximab that has to be administered by an intravenous infusion [9]. Regarding pricing, biosimilars listed on the National Health Insurance programme are priced 30% lower than originators according to a price-link policy [14]. Despite the marked price reduction, no policies designed to encourage biosimilar substitution have been implemented and physicians remain cautious in using biosimilars. Conversely, the current drug co-payment scheme in Japan covers medication costs exceeding a fixed threshold to control the financial burden on the patient. Consequently, as the cost of the infliximab biosimilar and originator remained the same, the subsidy system was therefore believed to disincentivize the demand for biosimilars, resulting in a limited uptake rate of infliximab in Japan [34]. This could explain the dramatic drop in the originator price when the biosimilar infliximab was introduced followed by a flat trend.

No national pricing or purchasing strategy currently exists to set drug prices in the USA [33]. Pharmacy benefit managers are third-party administrators responsible for deciding drug reimbursement and formulary inclusion for major commercial health plans, self-insured employer plans, Medicare Part D plans, the Federal Employees Health Benefits Program, and state government employee plans. Brand drug manufacturers pay rebates to pharmacy benefit managers to ensure their products are covered. How savings from rebates are used remains confidential. A 2019 study found only 14% of scenarios where a biosimilar was covered with priority to originators according to USA commercial health plans [35]. Manufacturers of listed originator drugs thus have limited incentive to reduce drug costs as there is limited competition from cheaper biosimilars [36]. In the absence of competition, brand drug manufacturers can set drug prices at will. According to the latest report to the White House, drug prices within the Medicare program increased more than twice the overall inflation rate in the past two decades [36]. Evidence comparing the use of the originator and biosimilar infliximab suggests that Medicare (one of the largest payers for infusion therapies) reimbursement policies in fact deter the use of biosimilars in an academic medical center, as opposed to a Veteran’s Affairs Medical Center [37]. Medicare cannot negotiate drug prices as opposed to the Veteran’s Affairs, which uses a centralized negotiating process and has a national formulary. This study showed that despite a lower average selling cost for the biosimilar infliximab, the potential institutional incentive under the Medicare Part B reimbursement policy was in fact greater for the originator. Moreover, Medicare Part B provides reimbursement at a rate of the average sales price plus a 4.3% add-on fee to cover administration costs for drugs (e.g., infliximab) that require a hospital-based injection, which potentially incentivize physicians to prescribe higher priced originators to gain higher add-on fees according to a report for Congress [38]. Consequently, limited biosimilars were prescribed and the manufacturers of originators were less likely to lower their prices. A two-quarter lag in the average selling price explains the higher price for the first 6 months after a biosimilar approval. This has been observed in Baker et al. [37] and is clear in both the MIDAS and Medicaid data. This could potentially explain the increasing originator price before the introduction of biosimilars and the uncommon biosimilar price, which was greater than its originator when first introduced (Fig. 3). Regarding the divergent price trend in the USA compared with all other regions, we additionally extracted USA Medicaid outpatient prescription data to verify the sales trends in MIDAS, which depicted almost identical price trends to the MIDAS data. Moreover, a recent study using Medicaid data incorporated rebates, which we failed to capture in MIDAS data, obtained similar decreasing infliximab originator price trends following a biosimilar introduction [39], thus supporting the robustness of our results.

These five regions demonstrated similar consumption and price changes after the biosimilar infliximab introduction. In terms of pricing, all five regions have mature pricing strategies such as tendering and negotiations, pharmacoeconomic evaluation, and reference pricing to ensure that drug prices are not excessive [40, 41]. Manufacturers must bid for a listing in either public or private formularies to gain a greater market share, which incentivizes the originator manufacturer to lower prices to compete with biosimilar manufacturers. Korea is an outlier in this group of countries; although the originator price decreased significantly upon the biosimilar introduction, the subsequent decreasing trend was stable, which might be a result of the trivial price difference between the biosimilar and originator. A similar phenomenon was previously identified with the insulin biosimilar, where the small price difference between the biosimilar and originator led to a modest uptake rate of the insulin biosimilar and restricted the impact of the biosimilar introduction [42]. In terms of consumption, all five regions showed increased consumption after introducing the biosimilar infliximab, which aligns with the experience in central European countries and Denmark [10, 43].

The nocebo effect refers to the negative outcome derived from patients’ negative expectations of treatment and not the drug’s pharmacological action [44]. Despite the similar efficacy and safety between biosimilars and the originator as demonstrated in clinical trials [4, 5], many healthcare professionals have concerns about switching from the originator to a biosimilar and remain resistant to prescribing biosimilars, even when made aware of the cost savings associated with biosimilar use [45]. Nocebo-reducing strategies are needed to enhance the benefits of biosimilars, including education on the risk versus benefits of biosimilars, and the adoption of a shared decision-making process with patients [44].

The results of this study have inherent limitations. First, we only accounted for the availability of the first infliximab biosimilar in our ITS analysis, while recent studies have revealed that the introduction of each successive biosimilar may also contribute to a further drop in the originator price [46, 47] and is directly applicable to Japan, UK, USA, Canada, Australia, and Korea where more than one infliximab biosimilar was subsequently introduced (Table 2 of the ESM). Second, we were unable to consider the impact of other newly introduced biologics with the same indications as infliximab (e.g., biosimilars of etanercept, adalimumab, rituximab, or newly developed sarilumab, upadacitinib) on the price and overall consumption of infliximab. Third, the long-term price can also be affected by other time-varying variables including market penetration rate and implementation of a national biosimilar policy and legislation. It should be emphasized that our study used infliximab as a case study, given its established use and long-term data after biosimilar introduction. Our findings may not be generalizable to other biologics. Finally, the list price of infliximab does not necessarily equate to the cost patients pay for the drug in clinical practice, given the complex nature of drug pricing in different healthcare systems. Future studies should focus on addressing the unmeasured confounding issue, and investigate how the national income level and healthcare system will react to the introduction of biosimilars.

To our knowledge, this is the first multi-country ITS analysis to quantitatively assess the effects of introducing biosimilars on the overall consumption and price of an originator biologic drug. This comprehensive study included eight diverse geographical regions, each with different healthcare systems, income levels, and market dynamics. The findings can enhance clinicians’ understanding about the use of infliximab and the trend towards a greater use of biosimilars. This evidence can also support clinicians in taking an active role in their health systems to facilitate greater competition amongst the available infliximab products and to choose the most cost-effective infliximab product within their local context. Our study allows clinicians and decision makers within the included regions to benchmark themselves to the other regions in terms of biosimilar adoption and could inform development of national policies to support demand side interventions to increase the use of infliximab biosimilars.