Regulators, especially the FDA, function within the authorities given to them by statute. Sometimes, this allows regulatory initiatives not otherwise specified in the law, for example, the FDA’s comparability guidance in 1996 [23]. In general, absent a public health disaster, the FDA evaluates medicines made available to the US public and states recognize the FDA’s determinations of safety, efficacy, and quality. Courts enforce the FDA’s authorities but usually defer to the FDA’s judgment on scientific matters. This will likely include any determination of interchangeability for a biologic (just as is the case for therapeutic equivalence for a generic small-molecule drug). Occasionally public health emergencies, such as the coronavirus disease 2019 pandemic, alter the standard steps in product development, and exceptional powers are invoked such as emergency use authorizations [24]. This is rare.

However, history matters. The US precedent of regulating drugs and biologics under different statutes was interpreted by the FDA to allow generic small-molecule drugs, but not to support anything similar for biologics [25] (even though the flexibility of the PHS Act was arguably already there, and even though aspects of Hatch Waxman were already applied to PHS Act licensed biologics, such as patent term extensions [11], as well as insulins and other biologics being regulated as drugs [15]). Nonetheless, the FDA is being largely consistent in approaches to generics and biosimilars where reasonable to do so (e.g., labeling). The FDA shows particular respect to its own precedents [25]. The FDA has published guidance for biosimilars and this continues to evolve [26].

The European Union (EU) took a different approach, both with their guidelines (2003 comparability applied intra-sponsor and inter-sponsor [27]) and in terms of their pharmaceutical legislation more generally, in which a single statute encompasses both drugs and biologics even as it was revised in 2004 to enable biosimilars [28]. However, the same regulatory science was applied [29], and subsequently adopted by the World Health Organization [30]. The common science being applied allows the EU experience with biosimilars to be relevant in the USA. European Union regulators have stated that they consider all their approved biosimilars to be interchangeable as a clinical matter [31]. While not a legal designation in Europe, this is a scientific one with clinical ramifications.

The FDA did not adopt an oversight role on biosimilars until the new regulatory pathway for them was explicitly created in BPCIA in 2010 [5]. In that law, an additional category of interchangeable biologics was created that is not given to any other regulatory authority in the world. This was not because biosimilars would not be interchangeable as a clinical matter, but because the states adjudicate substitution of products by other than the prescriber through their practice of pharmacy laws and an official FDA designation was expected to be helpful in those circumstances where pharmacy substitution could apply (much like occurs for generic drugs under Hatch Waxman 1984 [11]). Substitution is not a federal decision (any more than it is a European Commission decision) because the FDA does not regulate the practice of pharmacy. Nor does the FDA regulate the practice of medicine in which a prescription medicine can be prescribed for any purpose, including beyond the FDA label, subject to state law.

Biosimilars in USA are never “not interchangeable” to the extent that they are just not yet designated as interchangeable by the FDA. This situation for biosimilars is very like that under the EU law, which is silent on interchangeability. While the first step to biosimilarity is essentially the same in the EU and the USA, the second step of an interchangeability designation is simply available in the USA and not in the EU (where such decisions are country based like all healthcare and not an authority awarded centrally to the European Medicines Agency).

For most biologics, given their special attributes (such as particular care on storage and transport temperature limitations and rarely administered orally), the prescriber is usually responsible for their administration to the patient. As such, an opportunity for substitution by other than the prescriber does not exist. However, in a few cases, patients do administer their own biologic medicines (e.g., insulin, adalimumab, etanercept) and in these cases there may be an opportunity for generic-type substitution at a pharmacy.

That physicians might themselves perceive the need for an interchangeability designation to assist in their own decisions to switch patients was not a consideration during the drafting of the legislation, and there was no suggestion that interchangeable biologics were better biosimilars. Afterall, a physician can use a medicine on or off label as appropriate to the patient, and have routinely switched products, even closely related ones, as a means to optimize care. Physicians in the USA can preclude substitution of any drug or biologic on any prescription they write, although this may lead to additional requirements with payers if the medicine they prefer is not on the available formulary. However, physicians may be vulnerable to misinformation especially when a new brand name appears [19, 32].

The creation of a new legal term of art “interchangeable” in BPCIA, applicable only to substitution at the pharmacy level, has caused general confusion. This is because the word also has common usage and is generally applied by the leading biosimilar regulator, the European Medicines Agency, to indicate “the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect” [33]. This applies to every biosimilar. Indeed, the European regulators, in their independent capacities, have observed that all of their biosimilars are already interchangeable by this definition, and as such they can be switched for their reference in the practice of medicine [31] (as opposed to legally substitutable by other than the prescriber, which is not a European Commission decision). The FDA has agreed with this conclusion for the purposes of physician prescribing [34]. As a clinical matter, the outcomes for the patient will be the same whether the switch is made by the physician or pharmacist, but the authorities are quite distinct as a legal matter. Some countries are choosing to impose such switches, either centrally or regionally, for economic reasons, but ultimately in each case a physician must write the prescription [35].

However, just as quality and good manufacturing control is important for every biologic, the same concept of comparability between manufacturing changes can be applied between the reference and the biosimilar [36]. Different versions of the originator products have been interchangeably used by both definitions—both clinically and at the pharmacy level—usually unconsciously; and based on less substantiated data than are required for a biosimilar. They are expected to have no clinically meaningful impact, and only rarely have done so [37, 38]. Similarly, experience with naïve patients and patients already established on a biologic who are switched to another product (reference biologic or any biosimilar to that reference) has also shown no change in clinical outcomes [39,40,41,42,43,44,45]. Likewise, no evidence has been presented showing a concern when switching between biosimilars to the same reference product. As a scientific matter, given that biosimilars are each comparable to their reference products they are also comparable to each other, just as any given biologic is to itself over time, hence building a bridge all the way back to the clinical studies on the originally approved biologic upon which they all depend [46, 47]. As such, no exceptional issues would be expected for any biosimilar any more than we do for any biologic over its lifetime.