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Investigators Question Use of Animal Toxicology Studies for Biosimilar Development


Animal toxicology studies contribute little to demonstrations of biosimilarity and yet these studies frequently must be done to satisfy international regulatory requirements, investigators conclude.

In vivo animal studies of biosimilars “have added little evidence to provide clinically relevant information for biosimilar development,” concluded investigators in an Amgen-sponsored review of the company’s findings from nonclinical animal studies during the development of 8 biosimilar candidates.

Demonstrating biosimilarity uses a “totality of evidence” approach. This starts with assessing structural and functional characteristics in analytical studies, possibly followed by nonclinical toxicology studies comparing the reference product and candidate biosimilar in animal models. Human clinical studies follow in the form of a clinical study to evaluate comparative pharmacokinetic and pharmacodynamic parameters and, potentially, a comparative clinical efficacy and safety study.

The authors shared their experiences and perspectives on the value of nonclinical toxicology studies, concluding animal studies “have provided little information to meaningfully inform clinical efficacy, safety, or immunogenicity.” They said that comparative clinical studies are the best way to confirm similarity in pharmacokinetics and pharmacodynamics, efficacy, safety, and immunogenicity between a biosimilar candidate and a reference product.

Different Approaches to Nonclinical Toxicology Studies

The authors noted the requirement for nonclinical toxicology studies differs by regulatory agency. In the United States, evidence from animal studies supporting biosimilarity is sought when the FDA considers that “uncertainties remain regarding the safety of the proposed product that need to be addressed” after analytical similarity has been demonstrated.

In contrast, the European Medicines Agency (EMA) requires animal toxicological studies only in some situations, such as “when the proposed biosimilar is produced in a different type of cell or organism, or when the formulation includes new [nondrug substances] not previously used.”

In Japan, the Pharmaceuticals and Medical Devices Agency determines if animal studies are required depending on the extent of biosimilarity demonstrated by analytical studies and the “degree of residual uncertainty” regarding similarity between the originator and biosimilar. World Health Organization guidelines are similar.

According to the authors, anticipation of a request from a regulatory agency in a specific country or region is the top reason biosimilar manufacturers conduct in vivo animal studies. They noted “conducting in vivo studies may take less time than waiting for feedback from regulatory authorities in some countries that may then request such data be included for evaluation of similarity.”

Amgen’s Findings on Animal Studies

The paper summarized in vivo studies conducted for 6 of 8 Amgen candidate biosimilars (neither the FDA nor EMA required in vivo studies for the other 2). All 6 candidate biosimilars and their reference products were tolerated by animals. There were no unexpected safety or toxicity findings, and toxicokinetics were similar between biosimilars and reference products. The authors noted similar findings were reported in a review of in vivo studies conducted by Covance and of in vivo data from European Public Assessment Reports.

Nonclinical Studies Should Be “Rare”

The investigators concluded, “Nonclinical studies to support biosimilar development should be reserved for the rare cases in which a targeted toxicology study could address specific questions around residual uncertainty that are unanswered by analytical and in vitro assessments.” For example, in Amgen’s development of an aflibercept biosimilar (ABP 938), “a toxicity study was considered justifiable based on the novelty of the formulation used and injection into the eye, a very sensitive compartment.”

Apart from that example, the investigators wrote, “In vivo studies usually do not have the power to resolve residual uncertainties following analytical and in vitro studies or changes in formulation,” whereas clinical studies can provide that statistical power.

They recommended, “In general, clinical trials should be conducted to determine whether residual uncertainties, after analytical and functional in vitro assessments, confer clinically meaningful differences between a proposed biosimilar and its reference product.”


Mihalcik L, Chow V, Ramchandani M, Hinkle B, McBride HJ, Lebbrec H. Use of nonclinical toxicity studies to support biosimilar antibody development. Regul Toxicol Pharmacol. Published online March 1, 2021. doi:10.1016/j.yrtph.2021.104912

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