A review article contends that providers need to know more about the approval process for biosimilars and what data points are examined.
The clinical equivalence of a biosimilar to its reference product may be demonstrated by a great deal of evidence, yet physicians, particularly oncologists, still may be hesitant to prescribe biosimilars. Authors of a review article in the Journal of Clinical Oncology argue it is important for prescribers to understand how the biosimilars approval process differs from that of reference products—and why.
Oncologists may be unfamiliar with the regulatory process for biosimilars because the use of monoclonal antibody biosimilars for cancer treatment is relatively new. For example, the earliest approval of a trastuzumab biosimilar was in 2017 (Ogivri). Authors state that oncologists may be more comfortable using supportive care biosimilars.
A major point of confusion may be the role of the comparative clinical efficacy and safety study, the authors said. The aim of a comparative clinical study is to demonstrate there are no clinically meaningful differences between the biosimilar and the originator based on prespecified margins. An analysis of safety and immunogenicity is also central to this process. Rather than being the major piece of evidence demonstrating biosimilarity, the comparative clinical study plays a confirmatory role.
The comparative clinical efficacy and safety study in at least 1 relevant indication of the originator is typically the last step in the process of demonstrating equivalence of a biosimilar to its reference product. The authors describe the data from the comparative clinical study as just a fraction of the data needed by regulators for an approval application. Most data are derived from analytical testing, nonclinical in vivo studies (when required), and a pharmacokinetic and pharmacodynamic comparison study in healthy participants.
What may not be sufficiently recognized or understood, according to the authors, is that the analytical methods are generally more sensitive for detecting potential differences between a biosimilar and its reference product than a clinical study.
In fact, regulatory agencies do not require comparative clinical studies under all circumstances. The requirement for and scope of the clinical studies depends on the degree of uncertainty of biosimilarity based on analytical and other previous testing.
“For granulocyte colony-stimulating factor, for example, structure, physicochemical characteristics, and biologic activity can be well characterized, and clinically relevant PD parameters are available…. For many biosimilar mAbs; however, the absence of robust PD efficacy measures, as well as their importance to clinical outcome, means that comparative clinical trials will likely remain necessary,” the authors wrote.
Physicians may also be wary of extrapolating results of a clinical study in one indication to another. However, once biosimilarity has been demonstrated in 1 indication, conducting studies in other indications is often not warranted for scientific, cost, and ethical reasons, the authors said.
Another question the review addresses is whether testing requirements for biosimilars are excessive. They note that no biosimilar that was found to be highly similar to the reference product via the use of analytical and pharmacokinetic in-human studies ever failed to gain approval because it failed an efficacy study for equivalence.
They discuss a number of factors that could influence the need for comparative clinical studies, including complexity of the reference product, differences in structure, and level of understanding of the mechanism of action.
However, the authors propose that for many biosimilar monoclonal antibodies, comparative clinical studies will remain necessary, due to the lack of robust measures of pharmacodynamic efficacy and the importance of these measures to clinical outcomes. They expect this will likely be especially true in oncology, where biosimilars could be used with “curative intent,” making the assessment of comparative clinical data a priority for prescribers.
Stebbing J, Mainwaring PN, Curigliano G, et al. Understanding the role of comparative clinical studies in the development of oncology biosimilars [published online February 14, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02953.