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Analysis of Pharmacokinetic and Pharmacodynamic Parameters in EU- Versus US-Licensed Reference Biological Products: Are In Vivo Bridging Studies Justified for Biosimilar Development?

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Abstract

Background

Bridging studies are mandatory in the EU and USA if the reference biological product used in the biosimilar comparability exercise is foreign sourced. However, it has been argued that the duplication of bridging studies may limit biosimilar development.

Objective

The aim of the study was to explore whether it is necessary to conduct pharmacokinetic (PK)/pharmacodynamic (PD) bridging studies for biosimilars. This study examines similarities and differences between EU- and US-licensed reference biological products, based on literature-reported PK and/or PD data.

Methods

We searched PubMed, Drugs@FDA, and European Medicines Agency (EMA) databases to identify biosimilar bridging studies designed to evaluate similarities between EU- and US-licensed reference biological products. PK and/or PD parameters were retrieved; the ratio of the parameter value of the EU-licensed product to that of the US-licensed product and its corresponding 90% confidence intervals (CIs) were calculated. Similarity was declared if the 90% CIs for the ratios of the PK or PD parameters were within the range of 80–125%.

Results

Thirty-one bridging studies were identified for 11 biosimilars, including adalimumab (n = 10), bevacizumab (n = 4), epoetin alfa (n = 1), etanercept (n = 2), filgrastim (n = 1), infliximab (n = 3), insulin glargine (n = 1), insulin lispro (n = 1), PEGfilgrastim (n = 2), rituximab (n = 2), and trastuzumab (n = 4). Most studies showed PK and/or PD similarities between the EU- and US-licensed reference biological products. However, among the 31 studies, only three studies (accounting for two biologics, PEGfilgrastim and adalimumab) showed dissimilarity between the EU and US reference products. Although one bridging study on PEGfilgrastim (Sandoz) indicated dissimilar PKs (maximum observed plasma concentration [Cmax] and area under the concentration–time curve [AUC]) between the reference products, the other study (Mylan) demonstrated similar PK. Moreover, two of ten studies involving adalimumab failed to demonstrate similarities between the reference products. However, for both cases, PK similarities were later confirmed in the follow-up bridging studies with larger sample sizes.

Conclusion

Our analysis reveals that, in most cases, the reference biological products originated from the EU and those from the USA are almost indistinguishable in terms of PK/PD properties. Additional in vivo bridging studies between reference products from different global regions may not be required if similar physicochemical and structural properties are evident in vitro.

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Acknowledgements

The authors would like to thank the anonymous reviewers for their valuable suggestions.

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Authors and Affiliations

  1. Division of Pharmaceutical Science, Center for Drug Evaluation (CDE), Taipei, Taiwan

    Chien-Lung Tu & Yi-Lin Wang

  2. Faculty of Pharmacy, National Yang-Ming University, Taipei, Taiwan

    Teh-Min Hu

  3. Center of Consultation, Center for Drug Evaluation (CDE), 3F, No.465, Sec.6, Zhongxiao E. Rd., Taipei, 11557, Taiwan

    Li-Feng Hsu

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Contributions

L-FH wrote the manuscript and designed the research; C-LT, Y-LW, and T-MH analyzed the data.

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Correspondence to Li-Feng Hsu.

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Conflict of interest

Chien-Lung Tu, Yi-Lin Wang, Teh-Min Hu, and Li-Feng Hsu declare that they have no conflicts of interest.

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The views expressed in this article are the author’s personal opinions and not necessarily recommendations of the Taiwan Center for Drug Evaluation (CDE).

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Tu, CL., Wang, YL., Hu, TM. et al. Analysis of Pharmacokinetic and Pharmacodynamic Parameters in EU- Versus US-Licensed Reference Biological Products: Are In Vivo Bridging Studies Justified for Biosimilar Development?. BioDrugs 33, 437–446 (2019). https://doi.org/10.1007/s40259-019-00357-2

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