Re-Examining the “Totality of Evidence” Approach and Interchangeability

September 30, 2019

Biosimilars Team

A quartet of recent journal articles raise interesting questions about both (1) the need for the current “totality of evidence” approach to establishing biosimilarity between a biosimilar and its reference product and (2) the prevailing concept of interchangeability.

In the United States, a biosimilar is defined as “a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.” Highly similar is demonstrated first through an in-depth analytical characterization of the structure and function (e.g., purity, chemical identity, bioactivity) of the proposed biosimilar. No clinically meaningful differences—in terms of safety, efficacy, and purity—generally is demonstrated through human pharmacokinetic and pharmacodynamic studies, an assessment of clinical immunogenicity, and additional clinical efficacy studies (if needed). The determination of biosimilarity is based on the totality of this data and information.

In an August first online article in BioDrugs, Webster and colleagues propose an alternate paradigm—confirmation of sufficient likeness—that would rely on a comprehensive analytical characterization, nonclinical functional comparison, and human pharmacokinetic study alone. Webster et al. note that in highly regulated jurisdictions such as the European Union, the United States, Canada, and Australia, no biosimilar candidate that was found to be highly similar to its reference product by both analytical and human pharmacokinetic studies has ever failed to be approved because it was found not to be clinically equivalent to the reference product in a powered clinical efficacy study. They contend that the confirmation of sufficient likeness approach would be “substantially more efficient than totality of evidence while maintaining equivalent scientific rigor,” serving to remove unnecessary barriers to entry to the global biosimilars market without a loss of product quality.

This concept seems to be supported by a September first online article in BioDrugs in which representatives of three regulatory groups review the evolution of the European Union biosimilar framework. Because the authors were particularly interested in evaluating “the role and nature of clinical confirmation required in addition to analytical and functional in vitro data,” the article incorporates cases that show how the totality-of-the-evidence approach to biosimilar development has been handled by regulators, especially in complex situations with seemingly contradictory results from different aspects of the biosimilar/reference product comparison. The authors conclude that the pharmacokinetic study is emerging as a major gatekeeper in the clinical biosimilarity exercise—a “hurdle that needs to be overcome and all results fully justified before further clinical data can be deemed acceptable.” They also foresee a continuing reduction in clinical data requirements for biosimilar development.

The United States is the only country that distinguishes between biosimilar products and interchangeable products. An interchangeable product is a biosimilar product that meets additional requirements based on further evaluation and testing of the product. Interchangeable products may be substituted for the reference product without the involvement of the prescriber. Accordingly, the manufacturer of a proposed interchangeable product must demonstrate that the product is expected to produce the same clinical result as the reference product in any given patient. Also, if the interchangeable product will be administered to a patient more than once, the manufacturer must provide data and information that evaluate the risk, in terms of safety and decreased efficacy, of alternating or switching back and forth between the interchangeable product and the reference product.

The authors of a commentary published online in the British Journal of Clinical Pharmacology in September disagree with this approach. De Mora and colleagues argue that interchangeability should not be defined by a practical application, whether physician‐driven switch or pharmacist‐driven substitution. Because interchangeability is inherent to biosimilarity, they assert, it should be recognized as “a scientific concept that is inseparable from the biosimilar nature.” To support their assertion, de Mora et al. remind readers that “no approved biological medicine, whether original or not, is structurally identical to itself, due to an intrinsic batch‐to‐batch variability that can be enhanced by manufacturing changes.” The fact that many patients likely have been treated with structurally slightly different versions of any given reference biological product constitutes “a de facto switch of insignificant therapeutic concern.” Experience with these agents has demonstrated that no clinical comparison of efficacy and safety “can match the accuracy and sensitivity of a stringent physicochemical and functional comparability.”

Ebbers and Schellekens advanced a similar argument in a June Drug Discovery Today online first feature that contrasts FDA and European Medicines Agency (EMA) regulatory approaches toward interchangeability. They maintain that “based on currently available data…the default should be that biosimilars are interchangeable, unless there is compelling evidence otherwise.” The data include results of blinded randomized clinical trials over the past 12 years showing that switching to a biosimilar does not lead to loss of efficacy or an increase in adverse events. Consequently, Ebbers and Schellekens state, the FDA’s position to require blinded interchangeability studies aimed at identifying differences in pharmacokinetic or clinical parameters “is not likely to provide the definitive clinical evidence on switching in clinical practice.” Although there may be reasons to limit substitution, none is unique to biosimilars.


U.S. Food and Drug Administration. Biosimilar and interchangeable products. Updated October 23, 2017. Accessed September 30, 2019.

Webster CJ, Wong AC, Woollett GR. An efficient development paradigm for biosimilars. BioDrugs. 2019 Aug 6. doi: 10.1007/s40259-019-00371-4. [Epub ahead of print]

Wolff-Holz E, Tiitso K, Vleminckx C, et al. Evolution of the EU biosimilar framework: past and future. BioDrugs. 2019 Sep 20. doi: 10.1007/s40259-019-00377-y. [Epub ahead of print]

de Mora F, Balsa A, Cornide-Santos M, et al. Biosimilar and interchangeable: Inseparable scientific concepts? Br J Clin Pharmacol. 2019 Sep 4. doi: 10.1111/bcp.14089. [Epub ahead of print]

Ebbers HC, Schellekens H. Are we ready to close the discussion on the interchangeability of biosimilars? Drug Discov Today. 2019 Jun 26. pii: S1359-6446(19)30141-2. doi: 10.1016/j.drudis.2019.06.016. [Epub ahead of print]