Recent weeks have seen heightened debate over the need for phase 3 confirmatory trials for biosimilars, with some stakeholders calling these trials unnecessary and others going so far as to call them unethical. During the SMi 9th annual conference on Biosimilars and Biobetters, held September 26-27 in London, United Kingdom, Uwe Gudat, MD, who serves as head of clinical safety and pharmacovigilance at Fresenius Kabi, weighed in. “The subject I raise is rather provocative,” he acknowledged.
Recent weeks have seen heightened debate over the need for phase 3 confirmatory trials for biosimilars, with some stakeholders calling these trials unnecessary and others going so far as to call them unethical.
During the SMi 9th annual conference on Biosimilars and Biobetters, held September 26-27 in London, United Kingdom, Uwe Gudat, MD, who serves as head of clinical safety and pharmacovigilance at Fresenius Kabi, weighed in. “The subject I raise is rather provocative,” he acknowledged, adding that he was expressing personal views that may not align with those of his organization.
The classical approach to product development, said Gudat, is “a pretty complex affair, and you’ve got a lot of questions to answer,” but the same is not necessarily true of biosimilars, where the goal of clinical trials is to address residual uncertainty. “We use the same tools” as innovator developers, he said, “with different objectives.”
Given advances in analytical methods for understanding the structure—function relationship of biologic medicines, developers now have less residual uncertainty concerning their molecules. “Once I know what I’ve got, I pretty well know what it does,” he said. Given this fact, “Why bother with clinical studies? Why are we doing this?”
Said Gudat, “There’s a backroad that we sometimes forget. The clinic informs what type of analytical characterization is underlying, which informs of the structure [of the molecule]. The human body is a catch-all assay,” he added, that can potentially find a rupture in the analytical characterization of the biosimilar.
However, despite the fact that the clinical trial is being used as a safety net for potential errors, approaches to conducting these trials are remarkably variable. Biosimilars of rituximab, for example, are being tested in a wide variety of indications with small sample sizes in each indication. “There seems to be no single answer to the clinical study question” in terms of study population, despite the need to test these products in the most sensitive population. “There’s confusion in the space,” said Gudat. Furthermore, given that large sample sizes would likely be necessary to truly reduce residual uncertainty about a molecule, and given that clinical trials carry an inherent risk for patients, further consideration about the need for these trials may be warranted.
Gudat also noted that the current EU clinical trials directive holds that repetitive tests should not be carried out; this fact raises the question of whether repeatedly characterizing the safety profile of a drug in healthy volunteers in order to facilitate biosimilar studies is merely generating evidence that is already known, as well as the question of whether the practice contradicts the directive.
However, Gudat did not go so far as to say that clinical trials for these products should become a thing of the past. Instead, in his view, they may warrant rethinking. In undertaking clinical trials, he said, developers may be underutilizing biodynamic markers as a way to address residual uncertainty.
Pharmacodynamic (PD) markers, he explained, have been developed and used as stand-ins for clinical endpoints, and according to the FDA, use of an established PD marker can be used to add to the overall demonstration of biosimilarity. Using a broader panel of biomarkers, said Gudat, could have value.
In closing his talk, Gudat noted that “do we still need clinical trials for biosimilars?” may be the wrong question altogether. Instead, he proposed, “do we need to approach clinical development of a biosimilar with a completely different mindset?” may be the more important question.