Understanding the role of comparative clinical studies in biosimilars evaluation and approval
As biosimilars become more widely available in oncology, it is important that clinicians appreciate the distinct confirmatory role of comparative clinical studies in the biosimilar paradigm.
Biologics have a significant role in the clinical management of a range of medical conditions, including cancer and have the potential to provide cost savings and widen patient access to biologics. Despite the introduction of several therapeutic biosimilars, including monoclonal antibodies (mAbs), many oncologists in Europe and the USA remain uncomfortable or unfamiliar with their regulatory approval framework and use.
The FDA defines a biosimilar as “highly similar to the reference biologic with no clinically meaningful differences in terms of safety, purity, and potency”. Biosimilar development requires a stepwise hierarchical characterisation exercise to demonstrate structural and functional comparability to the originator and a comparative clinical trial to rule out any differences. This exercise may differ in study design and choice of endpoints to those of traditional phase III trials because the aim is to ascertain clinical equivalence, or biosimilarity between the products. As an example, cancer studies may include progression-free survival and overall survival as efficacy endpoints, whereas biosimilars may have short-term endpoints, such as overall response rate, which would be considered appropriate to expose any product-related differences. Determination of biosimilarity is based on the totality of evidence from all stages of development.
From scientific, cost, and ethical perspectives, biosimilars should not aim to replicate data acquired for the originator product in all its indications, but approval may be ‘extrapolated’ to these based on successfully demonstrating biosimilarity in one clinical scenario, if adequately justified. As an example, five trastuzumab biosimilars have been approved in Europe and the USA. During development, these five biosimilars each underwent comparative pharmacokinetic assessment in healthy volunteers and were then clinically compared to trastuzumab originator in patients with HER2-positive breast cancer. However, the five comparative clinical studies were conducted in different patient populations – three trials included patients with early breast cancer in neoadjuvant and adjuvant settings, whereas two of the studies assessed first-line treatment against metastatic breast cancer. These trial designs were all accepted by FDA and EMA as sufficiently sensitive to assess similarity, confirming there were no clinically meaningful differences between the proposed biosimilars and trastuzumab.
Thus, comparative clinical trials remain a central component of biosimilars development.
Clinical trials for biosimilars do not need to show clinical benefit against a disease but, instead, need to show clinical equivalence (biosimilarity) to the originator. Determination of biosimilarity is based on the totality of evidence from all stages of development and extrapolation of indications may be justified from results demonstrating clinical equivalence in one clinical scenario.