By Kevin E. Noonan –

Henrik Ibsen's 1882 play, An Enemy of the People, engendered an aphorism having a longer lifetime than the play itself (except amongst the literati) which is unfortunate, because the play has some lessons about human nature that arise frequently, particularly in politics.

The play begins in an idyllic (albeit chilly) Norwegian town where the proprietor of a spa popular with tourists (and himself a physician) Dr. Stockmann finds that the spa is contaminated with bacteria.  It is well to remember that in 1882 Pasteur's germ theory of disease and Koch's famous postulates were new (indeed, Koch "discovered" the microorganism responsible for tuberculosis that same year) and that bacterial infections were serious health risks (for anyone wanting to get a feeling for how serious and who has a lot of time on their hands, Mann's The Magic Mountain illustrates the situation marvelously).  The doctor in a spirit of concern for the public's health informs the local newspaper which intends to run the story.  In the second act, the Mayor (the doctor's brother) urges the doctor to retract the story lest it be the (financial) ruin of the town, advocating for a "quieter" way of handling the problem and convinces the newspaper to print his own statement, extoling the safety of the baths.  The doctor calls a town meeting about the problem but is shouted down; this is the first instance in the play where he is called an enemy of the people.  The consequences of the doctor's attempt to "do the right thing" are evident in the final act, where his family's possessions are smashed, they are being evicted from their home, his wife has been fired from her job as a schoolteacher, and the doctor is blackballed from ever working in the town again.  This being Ibsen, the doctor stands firm on his principles and refuses to renounce his findings that the spa is unsafe.

This story comes to mind with the introduction in the Senate of Sen. Mike Lee's (R-UT; at right) bill entitled the Biosimilar Red Tape Elimination Act" (S.6), which in less purple prose is intended to permit biosimilar drugs to have the benefits of being interchangeable with the reference biologic product without the safety studies proscribed in the Biologics Price Competition and Innovation Act (BPCIA), enacted as part of "Obamacare" in 2010.  Sen. Lee's bill is short and to the point; after changing some of the language in Section 351(k) of the Public Health Service Act (codified in 42 U.S.C. § 262(k)) for consistency the bill provides that:

The Secretary may not require, for a determination of interchangeability described in subparagraph (A), that a biological product undergo studies that assess the risks of alternating or switching between use of the biological product and the reference product.

The statutory genesis of the need for this change is Sec. 7002(a)(2)(B) of the BPCIS, which added Section 351(k) to the PHSA and specifically in Sec. 351(k)(2)(B) the requirement that:

INTERCHANGEABILITY.—An application (or a supplement to an application) submitted under this subsection may include information demonstrating that the biological product meets the standards described in paragraph (4)[, i.e.,] that

(4) SAFETY STANDARDS FOR DETERMINING INTERCHANGEABILITY.—Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that— ''(A) the biological product— ''(i) is biosimilar to the reference product; and ''(ii) can be expected to produce the same clinical result as the reference product in any given patient; and ''(B) for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

One of the hallmarks of the BPCIA generally was that the Secretary of Health and Human Services, through the Food and Drug Administration (FDA) was given a great deal of leeway in deciding the standards upon which a determination of biosimilarity would be made.  This section is thus something of an anomaly, prescribing with particularity the need for the very switching studies that Sen. Lee's bill excoriates as "red tape" and in his rhetoric says are unnecessary.  It should be recalled that in addition to the strictures imposed by the statute (and consistent with the concerns motivating them) was a fear that switching could cause harm to individual patients.  In addition, there was an apprehension that clinical failures or deleterious outcomes occasioned by the FDA improvidently designating a biosimilar to be interchangeable with the reference biologic product would have a negative effect on patients and physicians towards using biosimilar products, particularly in view of the usual severity of the illnesses these drugs are used to treat.

The motivation for Sen Lee's bill is economic and aimed at reducing drug costs.  Biologic drugs are among the most expensive and are usually prescribed for chronic or serious diseases (or both).  In addition to this being a time where the mantra "drugs cost too much" is one that politicians of every stripe can recite (and expect to garner political capital from doing so), in the ten years since passage of the BPCIA, 38 biosimilar drugs have been approved, four of which are interchangeable with the reference biological drug product.  The FDA has promulgated several Guidances for Industry on the standards and requirements for biosimilarity and in 2019 set out a Guidance on interchangeability (see "FDA Issues Final Guidance Regarding Biosimilar Interchangeability").

Interchangeability is important for a variety of reasons, particularly with regard to biosimilar drug acceptance and the ability for the interchangeable biosimilar to be substituted for a reference biologic drug product without intervention or approval of a health care provider.  Accordingly, such drugs are rewarded with additional layers of exclusivity (indeed, the only exclusivity for biosimilar drugs contained in the statute, as set forth in the PHSA under § 351(k)(6)), wherein the FDA shall not grant interchangeability status for any second biosimilar drug until the later of:

(A) 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product; [or]
(B) 18 months after –
    (i) a final court decision on all patents in suit in an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
    (ii) the dismissal with or without prejudice of an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
(C)(i) 42 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has been sued under subsection (l)(6) and such litigation is still ongoing within such 42-month period; or
    (ii) 18 months after approval of the first interchangeable biosimilar biological product if the applicant that submitted such application has not been sued under subsection (l)(6).

So the incentive has been there for biosimilar drug makers to obtain the interchangeability designation but in practice only four interchangeable drugs have been approved.  And Sen. Lee would have the public believe that this is due to the proverbial "pointy headed bureaucrats" at the FDA holding back approval that would economically benefit the public.

Before being washed away in this latest tide of populism, it might be well to at least inquire whether the switching studies required under current law are (in addition to being more costly and retarding the progress of biosimilar to market as a drug interchangeable with the reference biologic product) necessary to protect public health.  These are scientific questions, not political or economic ones, and like Dr. Stockmann it may be the principled course to at least establish whether switching studies are necessary  (or at least prudent).  As recently as this past September 19, the European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA) enunciated a joint "Statement on the scientific rationale supporting interchangeability of biosimilar medicines in the EU" that declared that a biosimilar drug approved by the EMA should be considered to be interchangeable (noting however that the definition of interchangeable use in Europe "does not include automatic substitution at the pharmacy level," leaving that to each member state).  Context is everything, however; the Statement notes that "[t]he EU regulatory network has been assessing, authorising and monitoring biosimilars for over 15 years and has gained very profound understanding of biosimilars after reviewing more than one hundred biosimilar candidate submissions, and monitoring their safety once they are placed onto the market," considerably longer than the U.S. experience (where the first biosimilar, Zarxio™, was approved in 2015; see "FDA Approves Sandoz Filgrastim Biosimilar").  Moreover, "interchangeability of EU-licensed biosimilars has been confirmed," evidenced by published studies, including Ebbers et al., 2012, The safety of switching between therapeutic proteins, Expert Opinion Biol Ther. 12:1473-85; Kurki et al., 2017, Interchangeability of Biosimilars: A European Perspective, BioDrugs 31(2):83-91; Kurki et al., 2021, Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective, Drugs 81:1881-1896; and Barbier et al., 2022, Regulatory Information and Guidance on Biosimilars and Their Use Across Europe: A Call for Strengthened One Voice messaging, Frontiers in Medicine 9: 820755.  These studies have resulted in the conclusion that "when approval for a biosimilar is granted in the EU, additional systematic switch studies are not required to support the interchangeability at prescriber level" (see "Biosimilars in the EU – Information guide for healthcare professionals (europa.eu)").

And a recent study of 25 members of European national medicines agencies and pharmaceutical companies (both originator and biosimilar) agreed that "interchangeability was more than a scientific question of likeness between biosimilar and reference products: it also pertained to regulatory practices and trust."  Also, these participants were overall confident in the science behind exchanging biosimilar products for the reference products via switching, i.e., with physician involvement."

So it seems that there is a strong consensus building that the FDA's position on the requirements for interchangeability may need reconsideration and that the law may need to be changed to give the agency the needed flexibility.  But perhaps the better path than a rigid prohibition against switching studies or other methodologies to properly evaluate risk is one espoused by Daniel Alvarez and colleagues in a 2020 paper on interchangeability, where they write:

Interchangeability should be assessed on a case-by-case basis, considering the "totality of the evidence" and biologic plausibility.  Alternative approaches to statistical analysis (e.g., use of asymmetric rather than symmetric margins to test equivalence) and study designs that meet the FDA's expectations for demonstration of interchangeability should be considered.

(these comments coming in the context of a discussion of the potential for differing interchangeability requirements for insulin and monoclonal antibody therapies).

There are many good reasons for making available biosimilar alternatives to biologic drugs to as broad a segment of the public as possible.  But doing so merely for economic benefit without ensuring that the cost savings won't exact alternative costs in patient morbidity or mortality seems imprudent and suggests a more measured approach might meet economic goals without sacrificing human ones.