Though the European Medicines Agency (EMA) has instituted guidelines for the development of biosimilars, approval of these drugs is possible even in cases in which the guidelines are not followed, and even in which primary endpoints in studies are not met.
While the European pathway for biosimilar approval is older and more developed than that of the United States, regulation of biosimilars is still evolving. A review, newly published in the British Journal of Clinical Pharmacology explains that novel strategies are emerging in the development of biosimilars for the European market, and that regulators seem willing to consider these alternative strategies.
The authors of the review say that, though the European Medicines Agency (EMA) has instituted guidelines for the development of biosimilars, approval of these drugs is possible even in cases in which the guidelines are not followed, and even in which primary endpoints in studies are not met.
The authors examine European public assessment reports (EPARs) published by the EMA, as well as information from PubMed and clinical trials databases for information on 17 biosimilars approved since August 2016, which referenced insulins, teriparatide, rituximab, adalimumab, and enoxaparin sodium (insulins, teriparatide, and enoxaparin sodium are, notably, not regulated as biologics in the United States, and follow-on products are not subject to the biosimilar approval pathway).
The review’s authors note the following trends in biosimilar development:
Providing More Data Than Required
In the cases of 2 insulin glargine and 1 insulin lispro biosimilars, the product developers submitted large efficacy and safety studies that were not required in product-specific guidance. In the case of insulin lispro, the EPAR for the product states that these studies are “are only considered as supportive for efficacy.”
Providing Fewer Data Than Required
In the case of an approved enoxaparin sodium biosimilar, the product sponsor did not conduct phase 3 studies (which were specified in product-specific guidance), only 20 healthy volunteers were included in a pharmacodynamic study, and no intravenous route of administration was included in a study. “In the case where a sponsor has a strong scientific rationale for a specific development [program], regulators in Europe still seem to be open minded to alternative development strategies, even for cases where a product‐specific guideline has already been issued by the EMA,” write the authors.”
Variable Choice of Study Population
Two biosimilars of etanercept have been approved in Europe, 1 on the basis of studies in patients with rheumatoid arthritis, and 1 on the basis of studies conducted in patients with plaque psoriasis. The product-specific guidance on monoclonal antibodies indicates that the “most sensitive” patient population and clinical endpoint should be used in development, and the Committee for Medicinal Products for Human Use (CHMP) has indicated a preference for the rheumatoid arthritis population for etanercept, and it is unclear why plaque psoriasis was selected by 1 of the 2 product developers.
Increasing Use of Bridging Studies, Adaptive Designs, and Multiple Switches
While crossover designs remain among the most frequently used study designs, in 6 of the applications that the authors examined, bridging studies—comparing the biosimilar with both a US-approved and EU-approved originator product—have been reported, and may point to global development programs for the proposed biosimilars. Typically, these studies include 3-period crossover designs.
Adaptive designs, in which there is no fixed sample size at the beginning of the trial, are also on the rise, with such designs reported in EPARs for approved biosimilars of teriparatide, insulin glargine, and adalimumab.
Switching studies—such as one conducted for an approved etanercept biosimilar—are growing in popularity as well, likely because such studies are forward-looking approaches to addressing US regulatory requirements for demonstrating interchangeability.
Noninferiority Studies Used in Place of Equivalence Studies
Generally, biosimilar product sponsors are asked to show equivalence, not noninferiority, of their products versus the reference drugs. However, in the cases of the 2 approved insulin glargine biosimilars and an approved rituximab biosimilar, the sponsors submitted data from noninferiority studies.
Post Hoc Choice of Margins
In the case of an approved rituximab biosimilar, efficacy using the mean change from baseline in the 28‐joint Disease Activity Score was evaluated, and an equivalence margin was chosen after the fact and justified by historical data. The product sponsor also provided a second study with the same primary endpoint, using the same equivalence margin. According to the authors, “it is not clear why…[the first study] was presented as the pivotal efficacy study,” though the choice of margins can be discussed and agreed upon with the EMA.
Growing Detail in EPARs
EPARs for approved biosimilars have become more detailed in recent years, write the authors, though there is a need for more information on study design, including justifications for equivalence margins in phase 3 trials.
The authors conclude that there is a “high variability” of submitted applications for biosimilars, and that “the EMA is still open to considering alternative and innovative approaches.” To that end, biosimilar developers, especially those who wish to use a scientifically justifiable alternative approach, should seek early advice from the EMA.
Mielke J, Jilma B, Jones B, Koenig F. An update on the clinical evidence that supports biosimilar approvals in Europe [Published online April 27, 2018]. Br J Clin Pharmacol. doi: 10.1111/bcp.13586.