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

Abstract:
The US biosimilar program has been highly successful with 53 biosimilars approved by the US Food and Drug Administration (FDA) for 17 reference products. As in most advanced nations of Europe, all FDA-approved biosimilars may be substituted in place of the reference product by the physician. To be substitutable at the pharmacy level. However, US state law requires these to be FDA-approved as ‘interchangeable biosimilars’– a designation earned through additional data showing no loss of safety or efficacy is expected even after multiple switches, relative to a patient who remained on the reference product. Thirteen biosimilars have earned this designation. FDA currently has the flexibility to determine how these data requirements are met; this can include switching studies, however, multiple interchangeable biosimilars have been approved without them. This data-driven approach has significantly bolstered physician and patient confidence in biosimilar safety and efficacy, particularly regarding pharmacy substitution. Yet there has recently been a push by policymakers at many levels of government to limit the types of data the FDA can consider, or otherwise lower the data requirements.

The authors critically examine a meta-analysis frequently cited by policymakers supportive of these efforts. They argue that the study’s conclusions – and the policy proposals – are unsupported by the data, which do not address efficacy impacts and extrapolate multi-switch safety despite a disproportionate reliance on single-switch studies. Rushing to dismantle proven standards based on these and other misconceptions, the authors argue, poses a potential risk to patient treatment stability and confidence in biosimilars. Preserving the quality standards that have defined the introduction of interchangeable biosimilars in the US, and the FDA’s flexibility to seek additional data when needed, will help ensure that patient care remains personalized and the integrity of the patient–physician relationship is maintained.

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 is 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 [8] biosimilar substitution practices; 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 FDA to promote confidence in the automatic, i.e. pharmacy-level substitution of biosimilars by third parties, e.g. insurers, 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].

Submitted: 14 May 2024; Revised: 2 July 2024; Accepted: 9 July 2024; Published online first: 22 July 2024

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This manuscript has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.