As for clinical investigation, the draft guideline suggests starting with pharmacokinetic and pharmacodynamic studies and then continuing with efficacy and safety studies. The pharmacokinetic properties should be compared in a crossover study for the route of administration applied. Healthy volunteers are considered an appropriate study population.
Researchers should select a dose in the sensitive part of the dose concentration curve and justify their use of a single or repeated dose. Pharmacokinetic parameters that should be considered include area-under-the-plasma or blood concentration time curve (AUC), the maximum level of a drug in a patient’s blood (Cmax), and half-life times (T1/2) or total clearance from serum (CL/F).
To measure pharmacodynamics, the draft guideline suggests using myxovirus resistance 131 protein A (MxA) and any of several other markers of interferon beta’s biological activity, including serum (2’–5’) oligo-adenylate-synthetase activity, neopterin, beta2–130 microgloblin, interleukin 10, and TNF-related apoptosis inducing ligand (TRAIL).
“A comprehensive comparative evaluation of some of these markers could be used to support the similarity of the biosimilar and reference products,” the draft stated, calling it the fingerprint approach. It added that MxA “is currently considered as one of the most sensitive markers of the biological activity of interferons type I and should be one of the selected markers.”
To prove clinical efficacy the draft guideline suggests an adequately powered, randomized, parallel group equivalence clinical trial, preferably double-blind, with a similar route of administration as the reference product. Relapse rate has been used as a primary endpoint in relapsing MS trials using interferon beta. But such clinical studies are not necessary for biosimilars, the guideline notes, since the focus is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se.
“For demonstrating clinical similarity of a biosimilar and reference product, magnetic resonance imaging (MRI) of disease lesions in relapsing MS may be sufficient. In addition, clinical outcomes such as relapse rate or percentage of relapse-free patients should be used as secondary endpoints in support of the MRI outcomes,” the draft stated.
Regarding the study design, assay sensitivity could be shown by a three-arm trial including a placebo arm for a short period of time (e.g., four months) sufficient to demonstrate superiority of both the biosimilar and reference products over placebo using an MRI endpoint. An alternative design could be a three-arm trial with the reference product and two doses of the biosimilar product.
However the study is designed, the trial should run at least 12 months or longer. The most sensitive patient population, which would enable detection of differences between the biosimilar and reference products, should be selected.
As for clinical safety, the draft guideline noted that comparative safety data from the efficacy trial should be sufficient for the required premarketing safety database. Adverse events of specific interest include influenza-like symptoms, injection reactions, and laboratory test abnormalities. EMA will, however, seek a comparison of the immunogenicity profile of the biosimilar and reference products over time. The draft calls for sponsors to submit a minimum of 12-month comparative immunogenicity data pre-authorization, with further assessment to be continued post-approval for at least six months for the biosimilar product.
“A strategy that includes serum sampling at baseline and at regular intervals is necessary for assessing the comparability of the dynamics of antibody development during therapy, e.g., every month in the beginning of the treatment followed by every three months,” according to the draft guideline.
EMA would require a validated, highly sensitive antibody assay, capable of detecting all antibodies of varying affinities, classes, and subclasses. After confirming antibody positive samples, researchers would also be required to further characterize them, including determining their ability to neutralize the biological activity of interferon beta and cross-reactivity: “It is recommended that the standardized MxA protein nAb assay or a nAb assay that has been validated against the MxA protein nAb assay is used.”