If pharmacokinetic and/or pharmacodynamic equivalence has been demonstrated, the next step in biosimilar development is to conduct a pivotal clinical trial. The objective of the pivotal trial is to demonstrate that there are no clinically meaningful differences between the proposed biosimilar and the reference biologic. This means that the proposed biosimilar is neither inferior nor superior to the originator biologic medicine with respect to efficacy, and that it is not worse with respect to safety or immunogenicity. A clinical trial designed around a sensitive patient population is important to demonstrating biosimilarity. A biosimilar clinical trial should be performed in a population that is sensitive enough to detect clinically meaningful differences between the proposed biosimilar and the reference product. Two aspects considered in the selection of a sensitive patient population are 1. the homogeneity of the patient population including comorbidities and 2. the use of the reference biologic as a monotherapy (for example, no concomitant chemotherapy or immune suppression).
The use of a sensitive population can reduce the number of patients needed in a pivotal trial and reduce variability in the data which is particularly important since biosimilars will be evaluated for extrapolation to indications where the biosimilar has not been studied, but are approved for the reference biologic.
In addition to the sensitivity of the patient population, the selected efficacy endpoints and the time point of measurement to demonstrate clinical similarity are important in the clinical trial design. For example, if the time point of measurement is not selected appropriately, it may not elucidate similarity (i.e., if the point of measurement is conducted prior to immunogenic response as seen in the reference biologic).
Other considerations are that the endpoint of the biosimilar may differ from the endpoint studied for the reference biologic. In oncology, where overall survival is considered a gold standard for proving clinical benefit, overall response rate and/or complete response may be suitable endpoints to demonstrate similar effect to a reference biologic. This is because the goal is to evaluate for potential differences, as opposed to re-demonstrating an overall clinical benefit that is already well established.