Clinical Trial Design

A pivotal clinical trial design for a biosimilar should be studied in a sensitive patient population that allows for appropriate assessment of similar efficacy, safety, and immunogenicity to the reference biologic.

In innovative drug development, three phases, and usually multiple studies per phase, of clinical research are required. In contrast, biosimilar clinical development can be abbreviated because of the breadth of understanding of the reference biologic and if the structure / function similarity of the biosimilar has been preliminarily demonstrated analytically.  While clinical requirements differ by regulatory agency, in general, two phases of clinical studies are required – a Phase I study to demonstrate similar pharmacokinetics (how a medicine moves through the body) and pharmacodynamics (effect of the medicine in the body) and a pivotal study (Phase 3) to demonstrate similar efficacy, safety and immunogenicity to the reference biologic.

Phase I Trials

Phase I trials performed in either healthy volunteers or patients are used to determine whether the pharmacokinetic and pharmacodynamic profile of the biosimilar is equivalent to the reference biologic. There are two ways to design Phase I biosimilar clinical trials: a parallel group or a cross-over study. In a parallel group study, enrolled subjects receive either the biosimilar candidate or the reference biologic for the duration of the study. In a cross-over study design, two groups of enrolled subjects first receive either the proposed biosimilar or the reference biologic initially and then are switched to receive the other treatment.

Statistical methods are used to determine if the proposed biosimilar is equivalent to the reference biologic. In general, bioequivalence is established within a pre-specified range, which is when a 90% confidence interval is within the 80%-125% range for effect being studied (e.g., serum concentration over time and area under the serum concentration-time curve). If this endpoint is met, the data is evidence to support that the proposed biosimilar is equivalent to the reference biologic.

Pivotal Trials (Phase 3)

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.

Clinical study design for a proposed biosmilar will differ from the reference product’s span of development that demonstrated safety and efficacy in terms of the number of trials, the endpoints studied, the timing of assessments, the duration of the trial, and the number of patients enrolled. Since the primary goal of biosimilar development is to demonstrate similarity to a known and understood reference biologic, an abbreviated approach to clinical development can be taken, but thoughtful consideration to clinical trial design is paramount to ensure similarity has been appropriately demonstrated.

Conceptual Schematic for Clinical Trial Design for Biosimilars 

Amgen biosimilar clinical trials