A team of authors points out that, given batch-to-batch variation of all biologics that can be enhanced by manufacturing changes, no batches of biologics can be considered identical to one another. However, “they may be considered essentially equal and therapeutically indistinguishable,” which points to a clinically acceptable range of structural heterogeneity for any biologic.
In the European biosimilars context, interchangeability of a biosimilar with its reference product is a medical matter, and the term “interchangeability” refers, as the European Commission frames the issue, to the possibility of exchanging one medicine for another that is expected to have the same clinical effect. In the US context, however, interchangeability, as a matter of law, is a designation granted by the FDA that will allow for a biosimilar to be substituted for its reference product at the pharmacy level under applicable state laws.
The differences between these understandings of interchangeability have led to misunderstandings of the concept of interchangeability in the biosimilars context, particularly with respect to physician-led switching of patient from one product to another or to pharmacist-led substitution.
However, authors of a recent paper argue, “Interchangeability between a biological reference medicine and a corresponding biosimilar medicine should not be defined by its practical application.” Instead, interchangeability should be recognized as a scientific concept, and one that is inherent to the very nature of biosimilarity.
In the paper, appearing in the British Journal of Clinical Pharmacology, a team of authors points out that, given batch-to-batch variation of all biologics that can be enhanced by manufacturing changes, no batches of biologics can be considered identical to one another.1 However, “they may be considered essentially equal and therapeutically indistinguishable,” which points to a clinically acceptable range of structural heterogeneity for any biologic.
“As a consequence, many patients have likely been treated with structurally slightly different versions of any given reference biomedicine, which constitutes a de facto switch of insignificant therapeutic concern,” write the authors, adding that acceptable differences between biosimilars and reference drugs can be assessed in the laboratory setting, where differences in critical quality attributes must be shown not to exceed batch-to-batch variability of the reference.
“Because batches of an original biologic can be deemed to be interchangeable,” write the authors, “biosimilars and their corresponding reference medicines may also be safely reciprocally interchanged, as endorsed by EMA regulators.” They add that the best scientific claim for interchangeability is the demonstration of biosimilarity based on a robust clinical program.
Additionally, they point out, more than a decade of clinical experience with biosimilars has provided evidence of the safety of interchanging biosimilars for their references.
Despite the fact that the science supporting interchangeability is robust, the authors say, physicians should remain “relevant players” in the decision regarding switching, particularly where issues that extend beyond the active ingredient of the therapeutic product are concerned. For example, device-related issues or the potential for the nocebo effect may be relevant to patients’ care.
The current paper comes shortly on the heels of similar argument, published in July in Drug Discovery Today. In that paper, authors argued that interchangeability is at its heart a product characteristic that allows one medicine to be exchanged for another while producing the same clinical effect, regardless of whether that exchange takes the form of switching or pharmacy-level substitution.2
The authors in that case, too, said that there may be reasons, including device design, not to switch patients to biosimilars, but they argued that the default position of regulators should be that biosimilars are interchangeable “unless there is compelling evidence otherwise.”
1. de Mora F, Balsa A, Cornide-Santos M, et al. Biosimilar and interchangeable: inseparable scientific concepts? [published online September 4, 2019]. Br J Clin Pharmacol. doi: 10.1111/bcp.14089.
2. Ebbers HC, Schellekens H. Are we ready to close the discussion on the interchangeability of biosimilars? [published online June 26, 2019]. Drug Discov Today. doi: 10.1016/j.drudis.2019.06.016.