Clinical data requirements for biosimilars in the EU

Biosimilars/Research | Posted 11/10/2019 post-comment0 Post your comment

In their article [1], authors from the Paul-Ehrlich-Institut, the European Medicines Agency (EMA) and the Federal Institute for Drugs and Medical Devices (BfArM) discussed the clinical data requirements for biosimilars in the European Union (EU).

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EMA generally requires one confirmatory randomized controlled trial to confirm biosimilarity in terms of efficacy, safety and immunogenicity. EMA guidelines state that the aim of clinical data is to address slight differences observed at previous steps and to confirm comparable clinical performance of the biosimilar and the reference product. However, clinical data cannot be used to justify substantial differences in quality attributes [2].

Comparative pharmacokinetic (PK) studies are a basic requirement for development of a biosimilar. However, in recent years, a dedicated comparative efficacy trial was no longer deemed necessary for several product categories (insulin, low-molecular-mass heparins and (peg)filgrastim), for which pivotal evidence for similarity may be derived from physicochemical, functional, PK and pharmacodynamic (PD) comparisons. Exceptions to this include complex, multifunctional biologicals, where comparative efficacy and safety clinical trials in patients are still viewed as a necessary component of the biosimilar development.

Efficacy endpoints
Clinical endpoints used in biosimilar comparability studies should ideally measure unconfounded pharmacological effects and be sensitive in detecting potential clinically relevant differences between the biosimilar candidate and its reference product.

Hard clinical endpoints, such as overall survival, are rather insensitive in this respect and are often influenced by disease- and patient-related factors. There has therefore been a shift due to both scientific advances, i.e. validation of new endpoints (pathological complete response [pCR] in breast cancer), or a shift towards endpoints that are viewed as more sensitive and thus more discriminatory (Disease Activity Score [DAS] 28 versus American College of Rheumatology [ACR]-20 in rheumatoid arthritis [RA] and objective response rate [ORR] in solid tumours and lymphoma).

PD endpoints that largely explain the clinical effect of the biological are the preferred endpoints to establish similar efficacy. These include:

For small less-complex proteins: absolute neutrophil count (ANC) for granulocyte-colony stimulating factor (G-CSF), blood glucose concentrations in clamp studies for insulins, magnetic resonance imaging-related endpoints for interferon-β and, more recently, serum calcium levels for teriparatide.

For low molecular weight heparins: anti-Factor X and anti-Factor II activity.

For larger molecules with a complex mechanism of action, e.g. monoclonal antibodies (mAbs): comparative studies in patients using conventional clinical efficacy endpoints are usually still required, but sensitive PD endpoints are also increasingly being discussed in the scientific community, e.g. bone mineral density (BMD) together with serum C-terminal crosslinks (CTX), a bone resorption marker, as co-primary efficacy endpoints for denosumab, a mAb used to treat and prevent osteoporosis.

Comparability margins
According to EU guidance [2], equivalence trials are the standard requirement to ensure that efficacy of the biosimilar is neither decreased nor increased compared with the reference product.

Comparability margins are established based on the knowledge of the effect size of the reference medicine and on clinical judgement. They should represent the largest difference in efficacy that would not matter in clinical practice; treatment differences within this range would then be acceptable because they have no clinical relevance. The acceptable equivalence margins depend on patient population, endpoints, backbone therapy and estimated treatment effect, and slight differences may occur depending on the selection of publicly available reference studies.

The authors of the research paper [1] declared that the views and opinions expressed in the paper are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agencies with which the authors are affiliated.

Conflict of interest
The authors of the research paper [1] declared that there was no conflict of interest.

Editor’s comment
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Clinical data requirements for biosimilars in the EU: PK and PD comparability

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Biosimilars applications reviewed in the EU

1. Wolff-Holz E, Tiitso K, Vleminckx C, Weise M. Evolution of the EU Biosimilar Framework: past and future. BioDrugs. 2019 Sep 20. doi: 10.1007/s40259-019-00377-y. [Epub ahead of print]
2. GaBI Online - Generics and Biosimilars Initiative. EU guidelines for biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Oct 11]. Available from:

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