Author byline as per print journal: Michael S Reilly, Esq; Ralph D McKibbin, MD, FACP, FACG, AGAF

Submitted: 14 May 2024; Revised: 2 July 2024; Accepted: 9 July 2024; Published online first: 15 July 2024

Introduction

Biosimilars are safe and effective drugs designed to be cost-effective alternatives to higher-priced branded biologicals. However, biosimilars are not identical to their reference biologicals. While generic substitution for chemically-derived small molecule drugs is a long-standing, uncontroversial practice, the substitution of non-identical biosimilars for branded biologicals is of concern to physicians and patients [1–4] for many reasons, including the potential risk to patient safety.

Despite these concerns, recent policies have been proposed that would shift the substitution practices for non-identical biosimilar products to follow substitution practices for identical generic molecules for their reference products. Furthermore, these polices are blurring the distinction between biosimilars and ‘interchangeable’ biosimilars, to the potential detriment of patients. This may have unintended consequences for patients that policymakers need to consider when proposing biosimilar legislation.

Today, to earn the designation of interchangeable biosimilar, manufacturers must provide additional data demonstrating with near certainty that the biosimilar product will produce the same clinical result as the reference product in any given patient, and for a product administered more than once, that the risk of switching between a reference product and an interchangeable biosimilar must not be greater than the risk of using the reference product without switching [5]. The US Food and Drug Administration (FDA) has great flexibility regarding what data are required to make this determination; it may or may not require switching studies, for example. As of June 2024, 53 biosimilars approved by FDA, 13 have met the standards for interchangeability [6], with more seeking this designation. While all US biosimilars are substitutable in place of their reference products by the prescribing physician, under laws in all 50 states only interchangeable biosimilars may be automatically substituted by pharmacists without at least notification of the prescribing physician. State laws limiting pharmacy-level substitution of interchangeable medicines were supported by a broad coalition of medical societies, pharmacist societies, patient advocacy organizations, and both reference biological and biosimilar manufacturers. These laws were enacted nationwide between 2013 and 2021 and are in place to protect patients [7].

FDA-approved biosimilars are indisputably safe and effective medications and the physician may choose to prescribe one to either their patient, whether naïve or stable. The safety and efficacy of the biosimilar are not altered by its substitution by a third party per se. However, third-party biosimilar substitution raises a variety of issues pertaining to patient and physician consent, maintenance of accurate patient records, clear product identification and traceability, adequate pharmacist education, and clear communication between healthcare providers. While US physicians have historically expressed these concerns when surveyed about biosimilar substitution practices [8]; they have also specifically expressed concern with the potential impact of medication switches on patient stability [1–4]. Treatment plans are tailored to individual patients and generally do not fall into a one-size-fits-all approach. Treatment of chronic illnesses such as arthritis, Crohn’s disease, psoriasis, and various forms of cancer has evolved over years of trial and error with different products before a patient becomes stable or in a state of disease remission. Newly diagnosed patients, those experiencing a flare of their disease and those with multiple diagnoses require intensive management and complex decision-making. The patient physician relationship is the foundation of this crucial process. Physicians have concerns about so-called ‘non-medical switches’ which are initiated for reasons other than achieving the best health outcome. This concern is particularly acute for stable patients and includes the automatic substitution of a biosimilar for the originator biological, without physician involvement [1–4]. According to a 2021 survey, 89% of US prescribers have high confidence in the safety and efficacy of biosimilars; however, a majority (58%) of these prescribers oppose switching of a patient’s biological medicine for non-medical (e.g. cost, coverage) reasons or without the consent of the prescribing physician [9]. Further, 69% of physicians consider it very important or critical that patients and physicians decide together which biological is the most suitable. The interchangeability designation for biosimilars was intended by legislators and the FDA to promote confidence in the automatic substitution, i.e. pharmacy-level substitution, of biosimilars by third parties, such as insurers and pharmacy benefit managers (PBM). This has proven successful as 57% of physicians express a higher likelihood to prescribe an interchangeable biosimilar, and 59% indicated that an interchangeability designation makes them more confident with pharmacy-level substitution of a biosimilar in place of the originator [9].

Challenges to the interchangeability standard

Recent years have seen a sustained effort to change evidence standards to facilitate approval of biosimilars [10], particularly standards that support the designation of a biosimilar as interchangeable. In a recent systematic review and meta-analysis conducted by FDA [11], the risk of switching mostly clinically stable patients between reference biologicals and biosimilars was evaluated. Based on a highly selective review of abbreviated data from 44 randomized controlled trials and their extension studies from 21 different biosimilars with a switch treatment period in the study design, FDA came to the intended conclusion that there was no difference in the safety profiles or immunogenicity rates between patients who were switched and those who remained on a reference biological or a biosimilar. Based on this highly selective and admittedly limited analysis, the authors of the study concluded that these findings support a reduction in the regulatory burden of switching studies as the default approach for addressing the switching standard for the interchangeable designation. They further concluded that the findings call for a reassessment in the need for switches to be included in clinical studies for candidate biosimilars since an approved biosimilar will be analytically highly similar to its reference product [11]. Subsequently in June 2024, FDA released a Draft Guidance for Industry ‘Considerations in Demonstrating Interchangeability With a Reference Product: Update’. The Guidance cited the conclusions of Herndon et al. to support their position that ‘the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product’ [12].

Notably, in this meta-analysis white paper FDA looked at three safety profiles, and did not address efficacy, yet FDA regulatory approval for these products is based on demonstrating that treatment efficacy is not negatively affected. Comparing randomized controlled trials (RCTs) and extension studies of biological products for safety/immunogenicity does not equate to the other multifactorial considerations for switching patients from a reference product to a biosimilar product such as treatment efficacy or other treatment considerations that will be discussed later in this paper.

These conclusions are over-reaching as they are based on the pooling of data from studies across therapeutic areas. These limitations do not support the broad generalized recommendations. The data were not grouped by individual therapies, indications, or by the number of switches between biosimilar and reference biological [11]. The inclusion of 28 single-switch studies and 16 multi-switch studies in a combined analysis results in an inappropriate extrapolation of multi-switch safety based on the disproportionate use of single-switch studies. Although most of the individual analyses pooled in the FDA meta-analysis showed negative point estimates (i.e. negative outcomes) with switching, the conclusion reported no significant difference. This conclusion was drawn due to the substantial variability and uncertainty in the data, as indicated by large variances in sample sizes and broad error bars [11].

Also, pooled data management across large populations fails to address individual patient variability, history, and needs. Drawing overly broad conclusions based on pooled data is especially concerning for vulnerable populations such as paediatric and marginalized patients. For example, multi-disease patients or those who are at an increased risk for hypersensitivity, anaphylaxis, neutralizing antibody, or other reactions may have been included in the study but were not evaluated separately.

A further limitation of the analysis is that real-world outcomes of non-medical switching, such as the nocebo and placebo effects, were not considered. This is an important consideration as studies suggest that the risk of a nocebo effect is higher following a mandated non-medical switch [13]. The authors of the meta-analysis recognized the potential for confounding of results due to the recognized nocebo effects observed in real-world studies of biosimilars and therefore included only randomized clinical trials and their extension studies. While clinical trials minimize confounding with strict eligibility criteria that results in a more homogenous population, real-world studies can lack robustness and consistency due to heterogeneity in patient demographics and physician prescribing patterns. Since randomized clinical trials are unlikely to capture the complexity of responses observed in the real-world experience, the recommendation to change evidence standards for biosimilars based on the findings of this meta-analysis are risky and short-sighted [14].

This meta-analysis, and the draft guidance it has influenced new bills and regulations at the federal level as well as state legislation and proposals, threaten to undermine the hard-won gains of the patient and physician communities to ensure that only interchangeable biosimilars are substituted without physician approval and the informed consent of every patient. One emerging proposal that does away with the interchangeability standard is the Biosimilar Red Tape Elimination Act [15]. Proposed Federal legislation that would do away with the interchangeability standard under the guise of ‘streamlining the biosimilar approval pathway’ and ‘improving the requirements for making a determination of interchangeability’, would deem all biosimilars interchangeable upon approval; as well as severely restricting FDA’s ability to consider switching studies as part of the data package to receive an interchangeable designation [15]. This bill would thus render all biosimilars pharmacy-substitutable by third parties, e.g. insurers, PBMs, and disincentivize manufacturers from gathering clinical data regarding any safety and efficacy impacts of switching. Proponents of third party, e.g. insurer, PBMs, automatic substitution of non-interchangeable biosimilars consider the interchangeability standard to be an impediment to biosimilar uptake [16]. In reality, this designation has boosted physician and patient confidence in biosimilars and reduced the barrier to biosimilar uptake and their associated savings [17]. US biosimilar uptake rates are comparable to those in the European market (20% to 80% uptake, depending on the country and product) [18]. 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 [19]. Adalimumab biosimilars, after slow uptake their first year, recently achieved 36% market share [20]. 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.

Cost cutting, rather than patient care is driving this effort to blur the distinction between biosimilars and interchangeable products. President Biden’s FY 2025 Department of Health and Human Services Budget is another example of cost- rather than care-driven policy. The budget proposal includes a provision that would eliminate the separate biosimilar and interchangeable designations, deeming all approved biosimilars to be interchangeable with their reference product, without the need for switching studies [21], as in the Biosimilar Red Tape Elimination Act. Previously, the Senate Committee on Health, Education, Labor and Pensions’ (HELP) Primary Care and Health Workforce Expansion Act included a proposal to ‘enhance access to affordable biosimilar biological products’ by deeming all biosimilars interchangeable without the need for switching studies [22]. Legislative reversal of scientifically-based and carefully crafted policy is short-sighted at best.

In April 2024, the Centers for Medicare & Medicaid Services (CMS) released its Medicare Advantage and Part D final rule permitting Medicare Part D plan sponsors ‘to substitute upon 30 days’ notice any biosimilar biological product for its reference product’ [23]. According to CMS, this rule is aligned with the administration’s commitment to competition. Also in an April 2024 interview, Dr Sarah Yim, Director of FDA’s Office of Therapeutic Biologics and Biosimilars, called upon Congress to eliminate the distinction between biosimilars and interchangeable biosimilars, offering as justification nearly identical language to the Biden Administration’s HHS ­Budget in Brief document [24] announcing its intent to eliminate the distinction. 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, as this paper will demonstrate.

Legislative challenges to the standard have appeared at the state level as well. A recent proposal crafted by the Prescription Drug Affordability Board in Oregon recommended a change in Oregon’s statute language regarding biosimilar substitution requirements that would permit the automatic substitution of non-interchangeable biosimilars [25]. Although the recommendations have not yet been finalized at this writing, it is important to note that state laws currently in place to permit pharmacy-level substitution of biosimilars gained the support of medical societies and patient advocacy organizations on the contingency that the legislation only allowed substitution of interchangeable biosimilars (meeting higher data standards) without prescriber approval. Elimination of these higher standards would also allow automatic substitution of one non-interchangeable biosimilar for another—the effects of which have not been well studied.

The fallout of compromising standards

Data supported by good clinical ­evidence, e.g. double-blind controlled studies able to be reviewed by stakeholders and including diverse populations, is particularly critical to public and stakeholder confidence in biological medicines due to their size and complexity as well as their capacity to cause unwanted immune response. Furthermore, unlike traditional chemical drugs that are structurally stable and uniform, biologicals are created as a product of biological activity in living cells, and while biological products are held to manufacturing and characterization specifications per product label, there is potential to drift in molecular characteristics over time [26]. As it stands, the abbreviated approval pathway for biosimilars relies more on analytical data and post-marketing surveillance than it does on clinical data. Therefore, reducing biosimilar evidence requirements even further – whether for approval or interchangeability status – can undermine the confidence established in this class of medicines.

The aphorism absence of evidence is not evidence of absence is acutely applicable to the importance of switching studies in the demonstration of interchangeability. Without conducting switching studies, it is unknown whether efficacy diminishes or if side effects arise more frequently following a switch. Given the complexity of the human immune system and the challenges of treating patients with chronic disease and comorbidities, these less optimal outcomes are likely to be seen as individual patient responses rather than a pattern of concern. Therefore, the elimination of studies to identify negative outcomes, i.e. switching studies, is very different from the absence of negative outcomes in studies conducted to identify them, i.e. an affirmative demonstration that switching does not diminish safety and/or efficacy. Again, in the case of the meta-analysis by Herndon et al.; the authors confine their analysis only to safety and do not evaluate any impacts of switching on efficacy. Diminishing or eliminating clinical data requirements for third-party pharmacy substitution of biosimilars inappropriately conflates two classes of biosimilars that are currently distinguishable by their data requirements. This does not serve the needs of patients and policymakers and legislators should not go beyond the limitations of this study.

Physician surveys have demonstrated their willingness to prescribe biosimilars, particularly those deemed interchangeable; however, a physician’s prescribing patterns are strongly influenced by insurance coverage and PBMs. Proponents of third-party biosimilar substitution, e.g. health plans and PBMs, often inflate the potential savings of biosimilars over reference products. The presence of biosimilars drives reference product sponsors to drop prices, demonstrating the success of biosimilars as a source of competition. Yet a designation of biosimilarity does not seem to determine uptake. For example, nine FDA-approved adalimumab biosimilars have launched in the US in the last year; however, the Humira reference product retained 96% market share for the first year until in March 2024 the leading PBM, CVS Caremark removed the reference product in favour of its own non-interchangeable co-branded version [20]. As CVS Caremark controls 34% of the market, within a week this move boosted adalimumab biosimilar market share from about 5% to 36% [27]. Even though four of the 10 available [28] adalimumab biosimilars have been granted the interchangeable designation nonetheless the extent of biosimilar uptake seems more likely related to PBM formulary design and rebate practices than a biosimilar’s interchangeability designation. There are several bipartisan legislative efforts [29] underway in Congress to create more transparency regarding these practices. The ability for PBMs to quickly and dramatically shift market share highlights how PBM reform represents a more productive – and less medically troubling – policy avenue for those seeking to boost biosimilar uptake.

Proponents [4] of eliminating the interchangeability standard in US law cite EMA’s declaration that all biosimilars are interchangeable, believing that elimination of the interchangeable distinction would bring the US on par with Europe – well-known for an established biosimilars market. This belief is based on a misunderstanding of interchangeability in the EU. It is true that the EMA does not have two categories of biosimilars and has stated that all approved biosimilars are interchangeable with their reference products, meaning that they may be ‘prescribed interchangeably’ by a physician. EMA also states that this does not refer to pharmacy substitution, which is left to Member States to decide [9]. Like their US counterparts, most European physicians (73%) strongly oppose substitution of biosimilars by someone other than the prescribing physician, especially for non-medical reasons such as cost. Accordingly, this controversial practice is extremely rare in Western Europe and largely banned except in Norway (which has a single-winner tender system) and a handful of resource-constrained Eastern European nations that permit the practice. These policies are mirrored by the substitution policies US states, all of which permit automatic substitution only for interchangeable biosimilars (i.e. those which have demonstrated through additional data that they may be substituted in a manner like generics). Thus, were the US suddenly to permit biosimilars to be substituted at the pharmacy in the manner of generics, this would represent a dramatic contrast to European practices, not an alignment with them.

As noted by CMS [30], ‘moving too often from one drug to a different drug for non-clinical reasons could also pose undue threats to enrollee health’. In other words, excessive or inappropriate third-party substitution may pose undue health risks to patients. These concerns suggest considerable potential for negative consequences to patients if non-interchangeable biosimilars are broadly substituted without first establishing that their safety and efficacy in switching studies of diverse populations.

There may also be an increased financial burden for patients and health systems. Research has indicated that non-medical switching results in increased treatment abandonment, errors, adverse events, ­longer patient visits, more lab costs, higher out of pocket expenses, and greater overall healthcare resource utilization (HCRU) [31]. Greater HCRU has also been linked to increased financial burden for patients from additional out of pocket co-pays for office visits, laboratory tests, and procedures [32]. Some patients also experience psychosocial stress when faced with medication changes; this should also be considered when making non-medical medication switches.

Automatic pharmacy substitution of non-interchangeable biosimilars has the potential to undermine the ­patient-physician relationship—especially for patients who suffer from chronic diseases or from vulnerable patient populations. In a cross-sectional online survey of over 1,000 physicians, nearly 75% reported that non-medical switching undermines their clinical judgement, and 81% of physicians surveyed agreed that it forces them to take responsibility for a medication decision that they did not make, i.e. made by a payer [33].

The most consequential fallout of non-medical switching is the potential for treatment instability or discontinuation of treatment. Switching patients from a reference product to a biosimilar presents important logistical and ethical implications including potential forced treatment changes without appropriate patient consent [34]. These considerations are even more pressing for vulnerable and disadvantaged patient communities. Many patients have worked tirelessly with their physicians to find a solution for their long-term disease management, and their therapeutic choices should rightly remain between them and their providers.

Conclusions

Biologicals are not small molecule generics and should not be treated as generics for pharmacy-level substitution. This is reflected in the substitution policy of nearly every Western European country, which do not freely substitute biosimilars for the reference product at the pharmacy level, contrary to popular misconception. The US should likewise support biosimilar substitution policies which provides continuous, unbiased information on biosimilars, stimulates manufacturer competition, are non-discriminatory towards either originator or biosimilar medicines, and allow the healthcare providers and their patients to choose the most appropriate biological medication. FDA’s current interchangeability standards ensure that all FDA-approved biosimilars are safe and effective, while accounting for pharmacy-level substitution when appropriate for the unique treatment needs of individual patients. Any change to a patient’s medication, including the substitution of a biosimilar for the originator biological without physician involvement, can pose a significant risk to patient stability.

While FDA’s meta-analysis on the safety of switching between biosimilars and their reference biologicals reports encouraging results, the data are inadequate to support the broad scale elimination of switching studies when deemed applicable by FDA for candidate biosimilars seeking an interchangeable designation. There are potentially negative consequences to patients if non-interchangeable biosimilars are broadly substituted without first establishing their safety and efficacy in appropriate studies. Inappropriate third-party substitution may pose undue health risks to patients, increase their financial burden, or subject them to unnecessary psychosocial stress. Furthermore, the automatic pharmacy substitution of non-interchangeable biosimilars potentially harms the patient-physician relationship.

FDA currently has the discretion to determine what data are needed to earn the interchangeable designation, including the requirement for switching studies. Limiting the use of switching studies, either through guidance or legislation would jeopardize the confidence that physicians have placed in interchangeable biosimilars. Furthermore, establishing policies that deem ALL biosimilars interchangeable (and thus substitutable at the pharmacy level) would betray the assurances made to physicians and patients nationwide that only those biosimilars which had provided additional safety and efficacy data would ever be substituted without physician approval.

Funding sources

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. Visit www.SafeBiologics.org to learn more.

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.

Authors

Michael S Reilly, Esq
Ralph D McKibbin, MD, FACP, FACG, AGAF

810 Valley View Boulevard, Altoona, PA 1660, USA

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