Pegfilgrastim is a long-acting, pegylated form of human recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim), which is expressed by Escherichia coli (E. coli). The originator is Neulasta. When designing the Pelmeg clinical studies to demonstrate comparability to Neulasta, it became apparent that existing regulatory guidelines were in need of reform, considering the latest science on comparability of G-CSF biosimilars. The guidelines stated that confirmatory pharmacodynamic/pharmacokinetic (PK/PD) studies may be sufficient if an accepted surrogate marker for efficacy is available and explicitly mentions absolute neutrophil count (ANC) as a validated and accepted biomarker for the efficacy of G-CSF. However, it was not clear as to whether clinical trials in patients could be waived altogether.

Following this realization, in 2015, scientific advisory meetings were held with European national regulatory authorities and the European Medicines Agency (EMA) to discuss Pelmeg’s clinical development. It was agreed that clinical studies in patients could be waived. This led to the creation of a concept paper on the revision of the guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant G-CSF that was published by EMA in July 2015. Specifically, this recommended revisions to the guidance on similar medicinal products containing recombinant G-CSF. Ultimately, in 2018, this became draft of the guideline for biosimilar development of G-CSFs, stating that efficacy and safety studies in patients are not necessary.

Following the discussions with regulators, Pelmeg’s clinical programme was conducted between August 2015 and June 2017. As a result of the discussions, which demonstrated flexibility in the guidelines, the Pelmeg biosimilar was developed using a targeted approach. This involved full characterization of the reference product Neulasta, against which the biosimilarity of Pelmeg was assessed by a head-to-head analytical characterization. State-of-the-art, orthogonal analytical methods were undertaken to characterize the structural and functional characteristics of both drugs and to demonstrate their analytical similarity. As a product containing recombinant G-CSF, a surrogate endpoint for efficacy was available which meant that its clinical development programme was limited to PK and PD studies and phase III studies were waived. This led to its European Union (EU) approval in 2018.

This study highlights that Pelmeg’s development programme was guided by scientific discussion with regulatory authorities. This demonstrates that scientific discussion with regulators offers valuable opportunities for dialogue regarding scientific progress related to the comparability of biosimilars.

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Reference
1. Roth K, Wessels H, Höfler J, Scholz U, Lehnick D. Pelmeg®, a biosimilar pegfilgrastim developed in the context of evolving regulatory guidelines. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(3):125-31. doi:10.5639/gabij.2020.0903.021

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