Biological medicines (‘biologics’) contain active substances from a biological source such as living cells, tissues, or organisms such as bacteria or yeast. Most contain active molecules which are proteins which may vary in size and structural complexity, from relatively simple proteins like insulin to relatively large and complex monoclonal antibodies.

In contrast to small molecule pharmaceuticals which are produced by chemical synthesis, biologics require advanced manufacturing and production processes which, when compared with small molecule drugs, make them relatively challenging and expensive to develop and produce. As they are produced from a biological source, they are more susceptible to variation during manufacture than small molecule drugs and also tend to be less stable, partly as result of their larger size.

What are biosimilar medicines?

Under EU law, biosimilar medicines are biologics which are highly similar in structural, functional and clinical terms to a ‘reference’ biologic medicine which has already been approved in the European Economic Area. Because they are produced by living cells via a complex process, such that very small differences in cell lines will have a large effect on the final product, it is impossible to precisely replicate a biologic drug.

In order to produce a biosimilar, in addition to determining the structure of the reference product, manufacturers need to reverse-engineer the manufacturing processes used to produce it. The continued development of molecular characterisation techniques is advancing the ease and speed of this process. Equivalence must then be demonstrated in terms of physicochemical properties (including protein structure, stability, purity, potency and other features such as glycosylation), then in terms of the molecule’s pharmacodynamic (PD) and pharmacokinetic (PK) profile, and clinically, including safety, efficacy and immunogenicity studies.

The regulation of biosimilars

The current approach of medicines regulatory authorities of biosimilars is evolving to reflect improvements in modern technologies. As an example, advances in mass spectroscopy techniques now enable the characterisation of the structure of biologics with a speed and accuracy that was impossible a decade ago, and which continues to improve. These technological advances are reducing the emphasis on, and need for, comparative efficacy studies as part of the data package required by regulators for marketing approval. The requirement for such trials is currently a topic of debate in the industry.

WHO and EMA guidelines

Following a period of consultation ending in January this year, the World Health Organisation (WHO) recently released its updated guidelines on evaluation of biosimilars which set out ‘key principles’ for the licensing of biosimilars, including the characterisation of PD/PK and safety parameters. The guidelines refer to the use of ‘state-of-the-art analytical methods capable of detecting potential differences between the biosimilar and the RP’ (reference product). The updated guidelines do not require clinical bioequivalence trials where they will not add any further information to the data package: ‘A comparative efficacy trial may not be necessary if sufficient evidence of biosimilarity can be inferred from other parts of the comparability exercise…’

The updated WHO guidelines reflect the approach of the European Medicines Agency (EMA), which now has over 15 years of experience with biosimilars in Europe, since the approval of the somatropin biosimilar Omnitrope® in 2006. The EMA appears to be giving greater consideration to the question of clinical efficacy trials for biosimilars. In the case of the highly characterised biologic pegfilgrastim, the EMA has authorised biosimilars without requiring evidence from a confirmatory efficacy trial. The aim is to avoid unnecessary clinical trials which add little or no significant additional evidence for judging equivalence between similar biologics.

It also accelerates the launch of drugs developed for rare or orphan diseases where robust clinical efficacy trials are not possible because the patient population is small or because it is unethical to do so. Overall, removal of the need for phase III clinical studies allows biosimilars to be launched more quickly and cost-effectively, and enables manufacturers to recoup their costs more quickly.

Evolving attitudes

The attitude of regulators to biosimilar drug approvals appears to be evolving as they gain more knowledge and experience over time. A review by Marta Zuccarelli et al of emerging trends in the regulation of biosimilars in the EU provides evidence of this. The authors reviewed marketing authorisation applications (MAAs) submitted to the EMA and other relevant publicly available documents, such as European public assessment reports (EPARs), up to December 2019. By this date, 53 biosimilars, based on 35 unique development programmes, had been approved for 14 different biologicals.

Although the total number of clinical trials increased over time (reflecting an increase in MAAs), the average number of both phase I and III trials fell. This result was in part due to some pegfilgrastim biosimilars being approved without phase III clinical trials being required by the EMA. Despite the smaller average number of clinical trials, the authors found that no new safety concerns were identified after product launch.

The authors also examined how closely the clinical development programmes of successfully approved biosimilars had followed relevant guidelines. One finding was that, for several biosimilars, PD studies to evaluate clinical comparability between the biosimilar and the reference product were not possible because no established PD markers which could predict efficacy were available at the time of the study. Only in vitro PD studies were carried out. In these cases, the EMA appears to have taken a pragmatic view of the totality of the evidence submitted in support of the successful MAA. Where the overall application showed biosimilarity, approval was granted.

The authors also noted that the EMA has developed product specific guidelines for some biosimilar products (including insulin, somatropin and epoetin) which continue to be revised. As an example, a current revised draft of the guideline for G-CSF biosimilars no longer requires confirmatory efficacy clinical trials.

Other revised guidelines, such as that for biosimilars of low-molecular-weight-heparins, have also dropped the requirement for phase III studies. In general, the approach of the EMA appears to be shifting to rely more on the evidence of what the EMA describes as ‘physicochemical, functional and pharmacodynamic comparisons’ and the results of phase I clinical studies.

There were also some interesting findings on the EMA’s extrapolation of data from studies of a biosimilar to other indications for the reference product. An example of this principle is that biosimilars of infliximab have the same indications as the originator product Remicade® (including for the treatment of rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis) despite only having been tested in patients with rheumatoid arthritis.

Extrapolation of safety and efficacy data to other indications was found to be a common approach in biosimilar MAAs. In the case of the pegfilgastrin biosimilars Udenyca® and Pelmeg®/ Pelfilgrastim Mundipharma®, no phase III trials on affected patients were carried out, so no comparative efficacy trial data was available for any indication. Instead, extrapolation of data was based on PK/PD results and safety and immunogenicity trials in healthy volunteers.

Regulation in the UK

In the UK, the Medicines and Healthcare products Regulatory Agency’s (MHRA) guidance on the licensing of biosimilar products issued in May 2021 confirmed that the MHRA has dropped the requirement in most cases for comparative efficacy trials where there is a sound scientific rationale to do so. The justification for this approach given by the MHRA is that the efficacy and safety of a biologic can usually be related to the biological events triggered by the activity of the molecule.

A biosimilar with comparable binding and other relevant functional characteristics to the reference product could therefore be expected to have an equivalent clinical effect. Where an applicant has argued that a phase III trial is not required, the MHRA require supporting data to include PK trial data confirming that the biosimilar has comparable safety and immunogenicity to the reference product.

This shift in the MHRA’s approach to biosimilar approvals provides biosimilar manufacturers with an opportunity to launch their products in the UK more quickly, and at a lower cost, than in other regions. Recent MHRA biosimilar approvals have considered the results of phase III studies (for example, the approval of the ranibizumab biosimilar Ongavia®, to be marketed by Teva), but it can be expected that the need to produce this kind of data will decrease in future.