When it comes to approval of biosimilars, the need for clinical studies may depend on indications, size and complexity of the biological and the clinical indications sought.

Possible scenarios and examples of different types of clinical programmes outlined by Dr Wolff-Holz included:

• Single-dose plus multiple-dose pharmacokinetic (PK)/pharmacodynamic (PD) with safety and immunogenicity in healthy volunteers and patients for single chain non-glycosylated polypeptide
  • Filgrastim (20 kDa)
  • Interferon (20 kDa)
  • Somatropin (22 kDa) 

• Single-dose PK/PD data with safety and immunogenicity in healthy volunteers
  • Insulin (6 kDa, two-chain non-glycosylated polypeptide)

• Single-dose bioequivalence study with safety and immunogenicity in healthy volunteers
  • Teriparatide (3,7 kDA, non-glycosylated, 34 aminoacid fragment)

• Single-dose PK in one therapeutic area plus one comparative phase III trial in other therapeutic area
  • mAb: rituximab (Truxima/Rixathon)

• Single-dose PK plus one comparative phase III trial in one representative indication
  • mAb: infliximab (Remsima/Inflectra)
  • Fusion protein aflibercept (VEGF-Fc)
  • Etanercept (TNF-Fc)

• Single-dose plus multiple-dose PK/PD with safety and immunogenicity in healthy volunteers and patients plus one phase III trial in representative patient population
  • Epoetin

Future molecules to consider include mAb (monoclonal antibody) fragments, e.g. ranibizumab (VEGF-Fab: 50 kDa).

As the requirements for clinical trials decrease further the importance of adequate functional assays increases. There is therefore a need to address general issues for all in vitro functional assays in guidance documents. In order to facilitate the production of adequate guidance a Joint BMWP/BWP review group, composed of 10 members, meets regularly. Their recommendations are expected to be published in Q2 of 2019 as a Q&A document supplementing the overarching guideline on non-clinical and clinical development of biosimilars (EMEA/CHMP/BMWP/32775/2005_Rev.1).

Questions that will be addressed in the Q&A document include:

• How well has the relationship between the functional assay and clinical efficacy or safety been established?
• What are the modes of action considered relevant for the different indications?
• Which assays are available for evaluating the functional effects?
• How suitable are these assays for a comparability exercise, i.e. to detect a difference? What is their specificity, sensitivity and robustness?
• How is comparability addressed in the assays, e.g. comparability range, statistical methods?
• Have the assays been formally validated?

According to the overarching guideline on non-clinical and clinical issues for biosimilars (EMEA/CHMP/BMWP/42832/2005 Rev. 1) a modified clinical programme may be allowed under certain circumstances. In the guideline it states that comparative PK/PD studies may be sufficient [and replace efficacy study(ies)] to demonstrate clinical comparability of the biosimilar and the reference medicinal product, provided that the following conditions are met:

• absolute neutrophil count for G-CSF
• euglycaemic clamp test to compare two insulins
• magnetic resonance imaging to compare two beta interferons
• serum calcium level in healthy volunteers for teriparatide

The first PD markers for mAbs are being discussed by EMA. Under discussion are eculizumab and denosumab. In addition, a single-arm trial could be allowed for orphan drugs.

With respect to non-inferiority trials, the guideline on non-clinical and clinical issues for biosimilars (EMEA/CHMP/BMWP/42832/2005 Rev. 1) states that these:

• may be acceptable if justified on the basis of a strong scientific rationale and taking into consideration the characteristics of the reference product
• may only be accepted where the possibility of significant and clinically relevant increase in efficacy can be excluded on scientific and mechanistic grounds.

According to Dr Wolff-Holz, other considerations are ongoing but so far use of a non-inferiority trial is not acceptable to EMA’s Committee for Medicinal products for Human Use (CHMP).

Conflict of interest
The author of the presentation [1] stated that the views presented in the presentation were her own and do not necessarily reflect the views of the Paul-Ehrlich-Institut.

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Reference
1. Wolff-Holz E. Initiatives at a glance: EMA perspective. 16th Biosimilar Medicines Conference – Biosimilar Medicines: unlocking the full potential of biologics; 26-27 April 2018; London, UK.

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