An Economic Outlook on Biosimilar Competition in Europe

Introduction

Biosimilars, and more generally biological medicines, have been getting increasing amounts of attention from health authorities and regulators across Europe. A medicine is generally considered a biosimilar if it is sufficiently similar to a ‘reference’ biological medicine that has already been approved for use, such that any differences between the two ‘are not clinically meaningful in terms of safety or efficacy’.^[2] As such, biosimilars provide clinically effective alternatives to biologicals akin to the role of generic medicines for chemical drugs. As a class of treatment, biologicals are often cutting-edge therapies and have significantly grown in importance, particularly in treating serious, chronic conditions such as cancer, diabetes and autoimmune diseases. The proportion of prescription medicines expenditure that is spent on biologicals in the EU has increased from 23 per cent in 2010 to 34 per cent in 2021. Recent growth rates for expenditure on biologicals have surpassed that of chemical drugs – between 2016 and 2020, expenditure on biologicals increased at an annual rate of 10.5 per cent, compared to 2.7 per cent for chemical drugs.^[3]

Competition provided by biosimilars therefore offers an opportunity for substantial savings for health systems. In a recent report, IQVIA estimated that, in 2020, across all European Economic Area countries, biosimilar competition resulted in total savings of €5.7 billion at list prices (excluding rebates and discounts, which would increase these savings). This is consistent with earlier studies,^[4] and is driven by a clear regulatory push towards biosimilars. For example, while between 2006 and 2016 the European Medicines Agency approved roughly two new biosimilars per year, in 2017–2018 alone a further 25 were approved followed by further approvals.^[5] Alongside the increasing approvals and availability, familiarity of medical practitioners and patients with biosimilars is increasing and, in certain cases, the extent of biosimilar competition is becoming more effective. For example, the first biosimilar for infliximab launched in 2013, was followed by only two further biosimilars and led to an overall biosimilar uptake of 30 per cent in three years. In contrast, following the first biosimilar for adalimumab in 2018, we have witnessed entry of seven further biosimilars within two years and an overall uptake rate of 50 per cent.^[6]

Still, concerns remain regarding the effectiveness of biosimilar competition and whether more savings can be achieved more quickly by health systems.

In this chapter, we discuss the key aspects of biosimilar competition from an economic perspective. In doing so, we explore the key features of biosimilars and how they affect the competitive dynamics, contrasting with traditional generic competition where relevant. We also discuss recent antitrust investigations in Europe that have scrutinised how commercial practices adopted by incumbent suppliers may hinder biosimilar competition. We then discuss the implications of these cases for businesses and what key aspects to be mindful of when pricing biologicals, followed by some concluding thoughts on promoting a holistic approach to biosimilar competition going forward.

Features relevant for biosimilar competition

The benefits of competition from traditional generic suppliers are, in general, well established, and, in principle, biosimilars could deliver similar outcomes for biological medicines. The extent to which biosimilars can provide effective competition, however, depends on a number of key features.

Bioequivalence

Unlike generic medicines that are chemically equivalent to the originator drug, biosimilars are not bioequivalent to the originator product (for example, due to variations that can arise in the manufacturing process). Although approved biosimilars are clinically very similar to the originator medicine, the lack of exact bioequivalence can discourage switching. For example, in the sector inquiry by the Dutch competition authority (ACM) into tumour necrosis factor (TNF)-alpha inhibitors (a class of biologicals), it was noted that while acceptance of biosimilars among patients and doctors has improved over the past few years, there remain patients that are reluctant to switch. This is exacerbated by the fact that TNF-alpha inhibitors treat chronic conditions (such as rheumatic arthritis) for which patients take medicines on a regular basis and this contributes to the reluctance to switching if the medicine is working for them.^[7] Similarly, the UK Competition and Markets Authority (CMA) noted in its investigation into Remicade (discussed further below) that the lack of bioequivalence means that the substitution to biosimilars is not automatic, unlike in the case of generic medicines.^[8] This factor may therefore limit the ability of biosimilars to reach the penetration levels that have been seen for many generic medicines.

Costs of development and regulatory approval

Biosimilars are more complex to manufacture than generics because of their large and complex molecular structure. Biological medicines in general have the potential to induce unwanted or unexpected immune reactions, and hence the manufacturing processes needs to be tightly controlled to produce a consistent product, and thereby is more expensive to develop and produce. For example, a biosimilar may take between five and nine years to develop at a cost of over US$100 million compared with approximately two years at a cost of US$1 million to US$2 million for generics.^[9] This can limit the pool of potential suppliers of biosimilars to larger firms with sufficient resources. Having said that, an increasing number of companies are developing biosimilars at lower cost, thereby lowering barriers to entry.^[10]

The cost of obtaining regulatory approvals is another factor that affects biosimilar competition. In general, these costs are higher for a biosimilar than for a generic. For example, generic suppliers must demonstrate bioequivalence and provide data on pharmaceutical quality, while biosimilars must provide additional quality studies and must demonstrate biosimilarity through comparability studies against the reference medicines (for a range of criteria, including chemical structure, biological function, safety and efficacy).^[11]

Switching costs due to method of administration

Biosimilars are often administered via injection, which can be either intravenous (generally administered in hospital) or subcutaneous (which can be self-administered by the patient using a lancing device once the patient has been shown how to use the device by hospital staff). Whether a biosimilar is administered intravenously or subcutaneously can have important implications for biosimilar competition. For example, it can be more costly for hospitals to switch patients to a biosimilar when it is administered subcutaneously because patients must be taught how to use a new lancing device; hence, the biosimilar must be priced sufficiently below the price of the originator to offset the switching costs. It was noted in the ACM sector inquiry into TNF-alpha inhibitors that patients can be more accepting of a switch to a biosimilar administered intravenously because it is less obviously a ‘new’ medicine; while for a subcutaneous drug, the patient can see different branding and must use a different lancing device.^[12]

The switching costs, together with perceptions of non-bioequivalence, therefore mean that it is common for a biological medicine to have a group of ‘residual’ – or non-contestable – patients that will not or cannot switch to the relevant biosimilars for that biological medicine.

Pricing strategies

Related to the above, biosimilar competition largely occurs at the hospital level. Furthermore, depending on the specific healthcare system and the procurement process of the hospital, competition is often driven by discount schemes or similar strategies rather than list prices.

As with any discount scheme, whether and how this would affect biosimilar competition will depend on the structure of the scheme. For instance, if the originator is operating a conditional discount scheme, the existence of residual patients (as noted above) could disincentivise the hospital from switching other patients to biosimilars because the hospital may have to pay a higher (undiscounted) price for the residual patients. While the effect of discounts would depend on a range of factors, if the group of residual patients is sufficiently large, the higher prices for this group could outweigh any savings made by switching other patients to biosimilars.

Other pricing strategies could also affect competition. For example, price matching guarantees by an incumbent supplier could reduce the incentive for biosimilar suppliers to offer lower prices, or even to invest in developing a product at all if future returns are uncertain, thus resulting in fewer entrants and reduced price competition in the future.^[13] At the same time, these clauses can deliver significant benefits to hospitals by lowering prices from existing suppliers while avoiding the costs of switching patients to new suppliers or products.

Antitrust scrutiny in recent years

Given the features described above and the potential ability of certain pricing strategies to discourage biosimilar entry, the sector has witnessed increased scrutiny from competition authorities in recent years. For example, competition authorities in the UK and the Netherlands have investigated some biological suppliers, specifically in relation to their discount schemes and other contract terms with hospitals. There have also been concerns in the US regarding strategies to delay biosimilar entry; for example, through intellectual property infringement cases brought by the incumbent supplier against the biosimilar (and any subsequent settlements of the litigation) and alleged (unjustified) disparagement of biosimilars.

Investigations into discount schemes

The antitrust investigations in Europe have largely related to discount schemes offered to hospitals by incumbent suppliers of biological products.

In 2018, the ACM opened a sector inquiry into five different biologicals within the class of TNF-alpha inhibitors following concerns about the lack of biosimilar uptake and lack of price decline despite availability of lower-priced biosimilars. The ACM explored the drivers (or lack thereof) of competition, including pricing strategies of incumbents and procurement processes of hospitals.

Following the inquiry, the ACM opened two antitrust investigations: (1) an investigation into Humira, the originator brand for adalimumab manufactured by AbbVie; and (2) an investigation into Enbrel, the originator brand for etanercept manufactured by Pfizer. Both investigations concerned allegedly anticompetitive discount schemes in the contracts with hospitals. The schemes offered discounts conditional on the hospitals buying all or a large proportion of their demand from the incumbents, such that a switch to a biosimilar would mean that the hospitals would pay a higher price for the residual patients that they could not switch. While the ACM did not conclude these investigations fully, there were strong indications that these would be found anticompetitive, and in both cases the incumbents committed to cease the relevant schemes.

Humira

In 2019, the ACM opened its investigation into the supply of Humira (adalimumab) by AbbVie. The case related to the fact that, following expiry of the patent on adalimumab in October 2018, AbbVie introduced a discount scheme for hospitals that required exclusive purchasing of Humira for existing patients (i.e., hospitals would only get a discount (of up to 89 per cent) if all existing patients continued to use Humira rather than a biosimilar). The ACM’s concern was that the discount scheme created a disincentive for hospitals to switch to biosimilars because they would still need to purchase Humira (at higher prices) for the residual patients (that could not, or did not want to, switch). The ACM concluded that AbbVie sought to prevent biosimilar entry through its discount scheme, but that the effect was limited because AbbVie removed the exclusivity following a complaint by a competitor. AbbVie gave commitments to not include exclusivity clauses (or any clauses with a similar effect) in its commercial contracts.^[14]

Enbrel

In 2021, the ACM opened an investigation into Pfizer due to similar concerns about its discount scheme for the anti-rheumatic drug Enbrel (etanercept). Pfizer’s patent on the active ingredient expired in 2015 following which two biosimilars entered. Similar to Humira, the ACM’s concern related to conditional discounts by Pfizer, whereby it could significantly reduce the discount it offered to hospitals for future volumes (of Enbrel) if the purchased quantities decreased by more than a pre-specified percentage. The ACM found that this could create a financial disincentive for hospitals to switch to a biosimilar as, following such a switch, the price of Enbrel for the residual patients could have increased four times. The ACM preliminarily considered that these discount clauses were anticompetitive.^[15]

Remicade

A similar investigation was opened in the UK by the CMA in 2015,^[16] which, in contrast to the above, was ultimately closed based on a lack of exclusionary effect.

This case related to a discount scheme operated by Merck, Sharp & Dohme (MSD) for Remicade, the originator brand of infliximab (again, a TNF-alpha inhibitor). Like the ACM, the CMA’s concern was that the Remicade discount scheme disincentivised the National Health Service (NHS) from switching to much cheaper biosimilars. In particular, the scheme was such that the NHS had to purchase at least 85 per cent of its infliximab from MSD to qualify for any discount and this discount increased with volumes purchased beyond this 85 per cent threshold (the 85 per cent was based on MSD’s expectation that biosimilars could only get 15 per cent to 20 per cent due to the expected reluctance to switch patients). While the CMA found that the discounts were not retroactive and hence the financial incentive for the NHS to not switch was weaker, the discounts made it almost impossible for biosimilars to compete with Remicade unless the contestable demand increased. The CMA considered that the scheme was anticompetitive as it ‘was designed to limit or delay the market entry or expansion of competing medicines’ and had the potential to foreclose biosimilars.^[17]

However, upon further analysis of the specific market context (including the circumstances of when the scheme was introduced and the likely reaction of the NHS as customers), the CMA found that the scheme was not likely to produce an exclusionary effect and closed the case. One key factor in this decision was that the actual contestable part of the demand was higher than what MSD had expected and used to design the scheme. In particular, hospitals in some regions were willing to switch a large proportion of existing patients to (much cheaper) biosimilars relatively quickly, and to use biosimilars for new patients, which meant that they could avoid a financial loss.^[18] The fact that the discounts were not individualised (i.e., different for different hospitals) and not retroactive contributed to the lack of exclusionary effect. The CMA also found that some other assumptions from MSD on which the exclusionary effect of the discount scheme depended were incorrect.

Excessive pricing allegations

Excessive pricing has also arisen as an allegation in recent months. In particular, in February 2023, a claim was brought in the Netherlands against AbbVie for abuse of dominance through excessive charges to the Dutch healthcare system for its supply of Humira during the period of exclusivity and before its patents expired in 2018 (i.e., before AbbVie introduced the discounts that the ACM scrutinised).^[19] This claim is relatively novel in various aspects. One, it is about excessive pricing while the drug is on-patent (which would entail analysis of fair price accounting for research and development costs). Two, along with competition law it also uses tort law alleging a breach of social duty of care and human rights law. Three, the claim alleges that the harm arises not only from the high pricing of Humira but also from the displacement of other healthcare due to the higher costs of the healthcare system. If successful, this case could lead the way for many other cases in the sector.

Antitrust concerns over patent disputes and denigration

There have also been other antitrust concerns in the supply of biologicals, such as denigration of biosimilars and other delaying strategies.

Allegations of denigration as anticompetitive conduct is not new in the pharmaceutical sector and there are now several cases where these allegations have been considered. In the widely cited investigation of Sanofi–Aventis (Sanofi), the French Competition Authority found that Sanofi abused its dominant position in the supply of Plavix by pursuing a strategy of denigration of generic competitors (through a systematic campaign that cast doubts on the efficacy and safety of the generics prior to their launch). The authority found that Sanofi successfully deterred doctors from switching to generic alternatives to the detriment of patients and fined Sanofi €40 million. Factors that contributed to this finding included evidence of an intent to foreclose generics and awareness that the statements were untrue, as well as the degree of Sanofi’s dominance.^[20] The risk of these antitrust issues is of particular relevance in the context of biosimilars given the lack of bioequivalence and the greater scope for perceived differences in efficacy and safety, relative to traditional generics.

Antitrust concerns could also arise in relation to patent litigation and any subsequent settlements. For instance, an incumbent may bring litigation against the biosimilar claiming infringement (similar to traditional generics) and subsequently settle the litigation under conditions that may delay biosimilar entry. These patent settlement agreements have been scrutinised in Europe and the US, with many of these cases culminating in a finding of competition law infringement.^[21]

A recent example of these concerns arising in the biologicals sector involves the strategy adopted by AbbVie in relation to Humira in the US. In 2021, a group of lawmakers requested the Federal Trade Commission to open an antitrust inquiry into AbbVie’s conduct in relation to its litigation against biosimilars (alleging that it was sham litigation) and its settlements of past litigation against biosimilars, although in August 2022 the US Court of Appeals of the Seventh Circuit dismissed a private action on the same issue, noting that the settlements were traditional resolutions of patent litigation that did not violate antitrust laws.^[22]

Economic analysis to assess risks

The above antitrust issues are a part of a broader trend of scrutiny into various types of unilateral conduct, including ‘traditional’ cases of loyalty rebates and more ‘novel’ cases of settlements or denigration. The focus on discount schemes is particularly topical following recent developments in European courts on Intel,^[23] concerning how to assess whether or not a conditional discount scheme is anticompetitive. After years of debate, the most recent General Court judgment of January 2022 (following the European Court of Justice ruling in 2017) confirmed the critical role of economic analysis and of the ‘as-efficient competitor’ (AEC) principle in cases of loyalty rebates (and more generally, in price-based abuses).^[24]

In the context of biologicals and biosimilars, these developments have a number of implications for businesses looking to assess antitrust risks or concerns.

Degree of dominance

As confirmed by Intel, in the assessment of a rebate structure (or many other types of conduct), all the circumstances of the case should be examined, including the degree of dominance (which, from an economic perspective, amounts to an assessment of the degree of market power). This makes economic sense, as a company with a near monopoly has a greater ability to foreclose competitors than a company with a 50 per cent market share (all else being equal), and yet both may be considered to be ‘dominant’ under competition law. Therefore, in the context of an antitrust concern, it would be relevant to analyse whether and to what extent there is competition between different biological medicines and if biosimilar entry in one biological affects the demand for an incumbent supplier of another biological (this was, for example, analysed in the ACM sector inquiry).^[25] Such an assessment will not only be relevant for rebates, but also for other issues such as disparagement.

Structure, duration and coverage of rebates

In general, a retroactive rebate scheme, and schemes that are specifically designed for individual customers (here, hospitals), are more likely to raise concerns. For example, under the AEC principle and the economic analysis of the AEC test, a key factor influencing whether or not a discount scheme is likely to have foreclosure effects is the non-contestable share (i.e., the proportion of residual patients that are unlikely to switch to the biosimilar.) The higher the size of this group (beyond a certain threshold), the higher the risk of foreclosure, all else being equal (provided that the discounts are retroactive and sufficiently large). In this context, a rebate scheme (including potential retroactive scheme) that uses the proportion of residual patients of a specific hospital to design the target volumes needed for that hospital to receive the rebates will raise more concerns than a non-retroactive and non-individualised scheme (as was the case in Remicade).

Cost benchmark

As confirmed by Intel, the choice of cost benchmark is another key parameter in the analysis of discount schemes. The AEC principle aims to prevent foreclosure of competitors that are as efficient as the incumbent (i.e., their cost structure is similar to that of the incumbent). This is why in implementing the AEC principle, the cost of the incumbent is typically used. This is based on the principle that the aim of competition law is not to protect inefficient competitors. However, this raises an important debate in the context of biologicals because the cost of production of a biosimilar can be higher than the cost of the incumbent, unlike in generic medicines (as discussed above, this is due to development costs, regulatory costs and costs of marketing to prescribers). Therefore, the ‘as-efficient’ principle may not suffice for a biosimilar to compete with a discount scheme of an incumbent while also covering its costs. Instead, a competition authority may use a 'reasonably efficient’ principle to account for the higher costs of the biosimilar. This would mean that the effective price of the incumbent after the discount would need to be higher than the costs of a reasonably efficient biosimilar. While none of the recent cases involving biosimilars have used this approach, it has been used in other sectors by regulators, particularly when the market features increase entry barriers (for example, in water or in energy).

Internal risk assessment

Overall, given the features of the market and recent developments in antitrust cases, it would be important for companies active in the supply of biologicals or biosimilars to conduct a thorough internal risk assessment of their pricing and other schemes and degree of dominance (including factual analysis of documents and economic analysis). For example, with regard to the foreclosure effect of a rebate scheme, analysing the key parameters and conducting scenario analyses (with varied assumptions and sensitivity checks around contestable share and cost benchmark) can produce valuable indicators and provide a reasonable level of certainty of the overall conclusions of these assessments (or, at the very least, clarity around the conditions that need to hold for a rebate scheme not to be considered anticompetitive).

Way forward: a need for a holistic approach

Overall, the inherent features of biologicals (such as high costs and longer approval times) raise some fundamental challenges in increasing biosimilar competition. While antitrust assessments and scrutiny can limit some of the barriers (as above), it is unlikely to be sufficient as a tool for promoting biosimilar entry and uptake. There is instead a need for a more holistic approach with material regulatory and institutional changes. These changes – involving reduction of entry barriers and increase in patients’ and doctors’ willingness to switch – would be critical to accelerate uptake of biosimilars.

Recent scientific advancements and increased experience of biosimilars by the regulatory approval agencies, with the associated knowledge and data sharing, offer the opportunity to streamline the approval processes for biosimilars. For instance, in recently updated guidance, the UK Medicines and Healthcare Regulatory Agency was able to relax the requirements for certain clinical tests.^[26] In the US, the Food and Drug Administration has begun providing an ‘interchangeability’ designation, which enables pharmacists to switch a patient from biological to biosimilar without the doctor’s intervention.^[27] To the extent that regulators are able to accelerate and simplify the review process, this would act to reduce entry barriers and allow biosimilar companies to recoup investment costs more quickly.^[28]

Notwithstanding more biosimilar entry and lower costs, the rate of uptake may still be limited depending on the procurement processes of the relevant institution. In particular, for a specific biosimilar to be able to compete for a hospital’s demand for a biological, the relevant tendering process needs to be transparent and support a level playing field. For instance, a tender specification that involves joint procurement of multiple biological medicines (instead of separate tenders for separate medicines) may not allow a biosimilar supplier of only one such medicine to compete (albeit, the effect will depend on the exact structure of the tender).

There is also scope for revisiting the pricing and reimbursement rules across different countries. For example, in the Netherlands, one of the ACM’s proposals to increase biosimilar competition was that the health insurance companies temporarily pay a higher reimbursement price for biosimilars to partially compensate for the higher costs that entrants have to bear compared with the incumbents.^[29] A move towards a market-based rule, whereby actual prices charged for biological medicines (net of any discounts by incumbents, for example) are used to set the reimbursement price, could help biosimilar competition in certain cases (e.g., some countries, such as the UK, adopt market-based pricing for generic medicines).

Overall, while the full benefits of generic competition may be difficult to replicate in the case of biosimilars given the inherent differences in characteristics, a holistic approach that seeks to identify an optimal combination of antitrust law and regulatory and institutional levers can help unlock the benefits of increased competition. Crucially, from an economic perspective, the higher upfront development costs required for biosimilar entry implies that it may not be feasible (or even desirable) to seek to replicate the levels of pricing pressures that some generic medicines experience, especially in light of the cost asymmetry between incumbent and entrant. Any intervention may be more effectively focused on measures that seek to facilitate entry, which includes preserving the incentives and returns of any required long-term investments, with the resulting increase in competition then delivering cost savings for health systems in the medium and long term.

Notes