“If there is residual uncertainty about biosimilarity after conducting structural analyses, functional assays, animal testing, human PK and PD studies, and the clinical immunogenicity assessment, the sponsor should then consider what additional clinical data may be needed to address that uncertainty (section VII.D.3) adequately”, according to the BPCIA. However, having additional clinical data does not necessarily imply a clinical efficacy investigation; it might include in silico pharmacokinetic research, as indicated by the FDA in its Biosimilar Action Plan [87]. EMA stated that “generally, clinical data aim to address slight differences shown at previous steps and to confirm the comparable clinical performance of the biosimilar and the reference product”. Clinical data cannot be used to justify substantial differences in quality attributes [91]. Therefore, the first argument relates to identifying “slight differences” or, as the FDA labels it, “residual uncertainty”. Are we not able to ascertain these differences and uncertainties? If so, then clinical trials are irrelevant. If there are no differences, why test, and if there are differences, why not reject them?

Clinical safety and efficacy studies add substantial cost and time to the approval of biosimilars. However, this argument will have little weight if these studies were able to add additional value over and above the rest of the testing. Thus far, no biosimilar products have been rejected based on clinical efficacy and safety testing if they passed the rest of the testing. This means either the products were biosimilar or the testing was too insensitive to detect any difference [92,93]. In both cases, this testing becomes irrelevant. This concept of real-time testing is now also questioned by the FDA, which stated that clinical efficacy testing is “broken” [94] and that new digital technologies and real-world evidence (RWE) are required, as outlined in the 21st Century Cure Act [95].

The European Medicines Agency (EMA) has begun work on a pilot clinical trial program aiming to advise how to decrease or eliminate clinical testing in biosimilar development [96]. Comparative clinical trials are increasingly seen as sloppy techniques for assessing biological agent similarity. As a result, the testing of biosimilars in patients is more of a checkmark than a meaningful indication.

Biosimilars “may be approved based on PK and PD biomarker data without a comparative clinical study with efficacy endpoint(s)”, according to FDA guidance [97]. The use of PK and PD biomarker data in healthy participants or patients enables shorter and less expensive clinical investigations and provides more sensitive testing than clinical efficacy with endpoint(s), as demonstrated with filgrastim [98]. The FDA acknowledged this and granted approval for filgrastim-aafi, filgrastim-sndz, pegfilgrastim-jmdb, pegfilgrastim-cbqv, and epoetin alfa-epbx based solely on PD evaluation. Furthermore, the FDA identified the features of PD biomarkers in its advice to assist sponsors in using PD biomarkers as part of biosimilar development programs [96].

Another reason why the clinical efficacy testing of biosimilars can be fallacious is due to the testing models used: equivalence or non-inferiority. In the equivalence testing mode, we first determine the M1 or total efficacy value of the reference product—a highly variable but available parameter; second, we select an acceptable range of difference, the M2, based on a clinical judgment that usually cannot be definitive—at best, it is an arbitrary choice. As a result, since both products are expected to be identical, equivalency studies are least likely to fail. On the other hand, non-inferiority testing is contraindicated because a biosimilar product showing a higher efficacy may also have more safety issues.

Many drugs, including anticancer drugs, require the homogeneity of the study population, which is unlikely. Patients are inevitably exposed to multiple drugs and treatment modalities; additionally, anticancer drugs have a low efficacy rate, further reducing the statistical probability of identifying any difference. Oncology or other terminal illness treatment efficacy studies face specific hurdles, such as enrolling a comparable group of naive patients. Such investigations further fail due to the brief lifespans of patients, which can disrupt the study design.

Another argument against clinical efficacy testing is the extrapolation of indications allowed for the biosimilar product. If there are any doubts about the safety or efficacy, then they should be tested in all indications, not just one selected by the developer, even where the modes of action are the same. A good example is conducting a psoriasis study for adalimumab approval instead of testing in psoriatic arthritis.

Interchangeability is a legally defined path in the US biosimilar guidance. While it does not fall under the responsibility of the EMA in Europe, the practice of interchangeability means that the individual member states are left to decide their policies regarding switching and substitution. In addition, while the FDA has singular guidance, in the EU, there are many different frameworks and available advice, making this a highly complex issue [99]. In several European countries, switching and substitution are forced, and for years this practice has resulted in no untoward effects. For example, in Denmark and Norway, the interchangeability is automatic without consultation with prescribers or patients.

In the US, an interchangeable status can be secured for an approved biosimilar after switching and alternating studies to assure that the response from a biosimilar product will be the same as that of the reference product every time. In July 2021, the FDA approved the first interchangeable biosimilar in the U.S. for Viatris’ Semglee (insulin glargine-yfgn), referencing the long-acting insulin, Lantus. The approval was significant for a multitude of reasons: Not only is Semglee the first interchangeable biosimilar but the first biosimilar in diabetes care and the first biosimilar that is primarily dispensed at retail pharmacies; therefore, it is billed under the pharmacy benefit.

A new federal executive order requires the FDA to clarify the assignment of interchangeability status. The first clarification needed is that a biosimilar product is expected to have “no clinically meaningful difference” from the reference product. How this determination differs from interchangeability is not discussed by the FDA. Second, since many biological products are given a single dose, how would one test switching and alternating protocols? The anticipated guideline changes in the FDA are likely to allow developers to conduct simpler testing to qualify for the interchangeability status that awards them exclusivity for automatic substitution as the first to secure this status [100].

A common misconception is that interchangeable biosimilars must meet higher standards for approval than non-interchangeable biosimilars. However, all biosimilars—whether interchangeable or not—undergo rigorous testing.