Abstract:
The US FDA proposed eliminating the distinction between biosimilars and interchangeable biosimilars, aiming to align with European policy and enhance biosimilar uptake. However, this move is misguided, as biosimilars differ from generics and require individualized treatment plans. Physician confidence in biosimilars remains high, and the interchangeable standard has effectively built trust. Additionally, biosimilar uptake is influenced by formulary design, not interchangeability. Targeting pharmacy benefit managers practices could better support biosimilar adoption.

Submitted: 3 May 2024; Revised: 9 May 2024; Accepted: 9 May 2024; Published online first: 10 May 2024

It was reported in April 2024 that the US Food and Drug Administration (FDA) is calling on Congress to enact a law eliminating the distinction between biosimilars (which can be prescribed in place of their reference products by the prescribing physician) and ‘interchangeable’ biosimilars, which under state laws can be automatically substituted by pharmacists the way generics are [1, 2].

Enacting the Administration’s proposal would be a mistake; one that by undermining regulatory standards would undermine physician confidence in biosimilars. It would also jeopardize treatment stability for many patients. It is also unnecessary – biosimilar uptake is steadily growing. Furthermore, calls to eliminate the standard stem from a misunderstanding of what factors contribute to successful biosimilar uptake.

Dr Sarah Yim, Director of the FDA’s Office of Therapeutic Biologics and Biosimilars, offered as justification nearly identical language to the Biden Administration’s announcement on the same topic in March 2024 [3]. The administration said this move is needed to address confusion among healthcare providers, would align US policy with that of other regulators including the European Medicines Agency (EMA), and would increase biosimilar uptake in the US. All of these assertions are incorrect.

First, biosimilars are not generics and should not be treated as such. While all biosimilars are safe and effective drugs, it is an indisputable scientific fact that unlike generics, biosimilars are not exact copies of their reference products. This is why, with the creation of a biosimilar approval pathway just 14 years ago, new substitution policies are needed in the US and worldwide.

A 2021 survey of 401 US physicians showed physicians are not confused at all about biosimilars: while 89% have high confidence in their safety and efficacy, a majority (58%) nonetheless oppose third-party switching for non-medical (e.g. cost, coverage) reasons, as is widely accepted with generics (and as the Administration’s proposal would permit for biosimilars) [4]. Sixty-nine per cent consider it ‘very important or critical’ that patients and physicians – not insurers or pharmacy benefit managers (PBMs) – decide the most suitable biological to use, either the reference product or one of its biosimilars. Physicians are reluctant to let a third-party switch a patients’ biological because treatment plans are not ‘one-size fits all’. Rather they are the result of a physician and patient working together, often for years, trying several different safe and effective medicines in order to find the one that best stabilizes a chronic condition in that particular patient. They do not want a third-party to switch a patient’s medicine unnecessarily or inappropriately and risk that hard-won stability.

Second, not only has the interchangeable standard not sown confusion, but it has also worked precisely as intended – by building physician confidence in biosimilars, including in biosimilar substitution. The interchangeable standard effectively addresses physicians’ concerns about switching by providing additional data to the FDA, demonstrating that safety and efficacy do not diminish even if a patient is switched repeatedly between the reference product and the biosimilar. It accounts for individual patient variability by requiring that this be true for any given patient (FDA is afforded great flexibility to determine what specific data are needed to demonstrate this, on a case-by-case basis). Fifty-seven per cent of physicians said they would be more likely to prescribe an interchangeable biosimilar, and 59% said that an interchangeability designation makes them more comfortable with a pharmacy-level substitution of a biosimilar in place of the prescribed reference product [4].

Third, this policy would not align us with European policy, as the Administration incorrectly claims; it would do just the opposite. Although Europe does not have an interchangeable biosimilar status, Europe also has no pharmacy-level substitution. Physicians in Europe strongly oppose automatic pharmacy-level substitution. Opponents of the interchangeable standard often cite EMA’s declaration that it considers all its biosimilars to be interchangeable [5]. Yet EMA is clear this means only that the prescriber may prescribe one in place of another – just like US physicians/healthcare providers can. In other words, all US biosimilars are already interchangeable, under the EMA definition.

If we are to align ourselves with European biosimilar substitution practices, we should first note that EMA has explicitly stated it does not weigh in on biosimilar substitution decisions; that Member States determine which biosimilars are substitutable by the pharmacy; and nearly every Western European country has decided that this is not acceptable. A 2019 survey revealed a strong majority (73%) of Europe’s physicians, like their US counterparts, oppose third-party biosimilar substitution [6].

US states have also made their determinations: 50 US state legislatures were not confused when from 2013–2021 they passed legislation permitting automatic substitution only for interchangeable biosimilars (meaning those meeting additional data requirements). Nor were state medical societies confused when they supported state legislation allowing pharmacy-level substitution – conditional on substitution being limited to interchangeable biologicals. Upending this arrangement to now treat biosimilars as generics is a bait-and-switch of the highest order and is decidedly not what Europe does.

Fourth, the interchangeable standard has not negatively impacted US biosimilar uptake, which is comparable to and fast overtaking that of Europe. Looking at Europe for a baseline, we can see that biosimilar uptake ranges between 20% and 80%, varying by country and product [7]. In the US, filgrastim, trastuzumab, and bevacizumab biosimilars have an uptake rate of 80%; Rituximab biosimilars; 60% and infliximab, pegfilgrastim, and erythropoietin-stimulating agent biosimilars have 40% market share [8]. Adalimumab biosimilars, after a slow uptake in their first year, recently achieved 36% market share [9]. Given the faster rate of biosimilar adoption relative to Europe, if the US interchangeable standard has any net effect on biosimilar uptake rates, it would appear to be a positive rather than a negative one [10].

Fifth, biosimilar uptake is determined by formulary design, not by a biosimilar’s interchangeable designation (or lack of one). Insurance companies and PBMs choose which biological to cover – the reference product or one of the biosimilars. The top three PBMs, vertically integrated between insurers and specialty pharmacies, control 78% of the US market. While their formulary design process is deliberately opaque, it is well known that products are chosen for preferred formulary placement based upon their profitability to the PBM after manufacturer rebates and incentives, not whether or not they are interchangeable/automatically substitutable.

With nine adalimumab biosimilars available now (in 14 different variations at discounts ranging from 5% to 86%) the reference product Humira retained 96% market share in the first year as PBMs stuck with it [11]. But on 29 March 2024, CVS Caremark (the largest PBM controlling 34% of the market) removed Humira and gave preferred placement to a biosimilar. While inappropriately limiting physician choice, this move is a perfect demonstration of the PBMs’ role as the prime mover of market share. CVS did not choose one of the two marketed interchangeable products, but rather Hyrimoz (adalimumab-adaz), cobranded by CVS’s Cordavis subsidiary with Sandoz at an 81% discount to the reference product [12, 13]. Within one week, adalimumab biosimilar market share rose from 5% to 36% as physicians wrote more than 8,300 new prescriptions for Hyrimoz. Its lack of substitutability by a pharmacist posed no obstacle. Physicians quickly authorized the PBM’s switch to the citrate-free, high-concentration biosimilar (which offers more comfortable injections and faster therapeutic action for patients than some competitors) [14]. A small fraction who felt the switch might be inappropriate for a particular patient may have appealed; the vast majority clearly did not.

Uptake is steadily – and in some cases rapidly – increasing. The same is true for physician confidence in biosimilars, due in part to FDA’s robust data requirements. These need not and should not be weakened in a misguided attempt to further speed these processes. The US biosimilar programme is by FDA’s own admission, a profound success, with 50 different biosimilars approved for 15 different reference biologicals, saving more than US$23.6 billion since the first biosimilar product was approved in 2015 [15]. Collectively, patients have used biosimilars for almost 700 million days of therapy, 344 million days of which patients received care they otherwise may not have received. Similarly, the interchangeable biosimilar standard is working as intended: building physician confidence through data and providing a biosimilar option physicians can be certain will not jeopardize the treatment stability of a patient for whom maintaining it is a critical concern. There are several promising bipartisan legislative efforts underway in Congress bring more transparency to PBM formulary design and rebate practices. These represent a far more productive – and medically appropriate- target for reform efforts for those seeking to boost biosimilar uptake [16].

The article was funded by the Alliance for Safe Biologic Medicines (ASBM).

ASBM is a coalition of patient advocacy organizations, physicians, pharmacists, biopharmaceutical manufacturers, and others working to advance patient-centred health policy at the state, federal, and international level. Learn more at www.SafeBiologics.org

Competing interests: Mr Michael S Reilly, Esq is the Executive Director and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002 to 2008.

Provenance and peer review: Not commissioned; internally peer reviewed.

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Author: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA

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