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Two decades have elapsed since the initial biosimilar legislative frameworks were established. Vast improvements in assay technology and a deeper understanding of structural activity relationships mean that analytical methods now provide the greatest assurance of biosimilarity. Yet requirements for comparative efficacy trials remain largely unchanged, particularly in the case of the more complex proteins such as monoclonal antibodies.
Parexel has been at the forefront of biosimilar development and, through support of the design of multiple biosimilar comparative efficacy trials, understands the challenges and limitations of comparative efficacy trials:
In view of these challenges, regulators are starting to reconsider the current requirements for comparative efficacy studies. This was in focus at the US Food and Drug Administration (FDA) and the International Pharmaceutical Regulators Program (IPRP) Biosimilars Working Group (BWG) workshop in September 2023, with speakers from regulatory agencies and industry, including participants from UK MHRA, WHO, EMA, Health Canada, Japanese PMDA, Korean MFDS, US FDA.
UK MHRA perspective
A review of 20 complex biosimilars assessed in Europe “did not identify any instance where efficacy trials added crucial information to establish biosimilarity” noted Dr Bielsky of the UK MHRA, referring to a publication for which she was lead author. Consequently, MHRA guidelines now state that “in most cases, a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach.” Yet sponsors are still conducting comparative efficacy clinical trials, mainly due to requirements of other agencies, notably FDA and EMA. Dr Bielsky expressed that there is a strong need for harmonization of requirements across the major agencies.
“The WHO has found that state-of-the-art analytical and functional testing and robust PK and PD studies are sufficient to demonstrate biosimilarity, whereas in vivo animal studies and large confirmatory efficacy and safety studies were generally not needed”, advised Dr Hye-Na Kang of WHO. The WHO 2009 biosimilar guidelines have been updated and expanded to cover additional biological products. Vaccines remain excluded, but may be included later, particularly mRNA vaccines. The revised WHO guidelines refer to a “tailored clinical data package” and “state that the decision to authorize the requested indication will be dependent upon the demonstration of [extent of] similarity between the biosimilar and reference product”.
In general, the current EMA guidelines require an equivalence trial design. To date, there has been one exception made for a monoclonal biosimilar to eculizumab, which was approved without a comparative efficacy for an orphan indication as such a trial was not feasible to conduct. The EMA offers scientific advice for tailored development of a biosimilar; however, this requires a comprehensive product quality data package, which is often unavailable early on, when the comparative efficacy trial needs to be started. The EMA is developing new guidance to outline the level of similarity at the product quality level that could negate the need for comparative clinical efficacy trials. A concern with this approach is that it might prove too restrictive, particularly if statistical criteria are to be applied.
Health Canada perspective
The biosimilar working group in Canada is exploring if there is a continued need for clinical efficacy studies in all but exceptional cases. A draft of the revised guidelines is expected to be released for consultation in early 2024. Dr Bradley of Health Canada noted that current guidance was only guidance and that deviation from this was possible; he advised engagement with Health Canada to discuss.
There is increased confidence in comparative analytical data, and it is accepted that clinical endpoints are not as sensitive as analytical data to detect differences, noted Dr Ricci of the FDA. The agency is developing risk-based criteria to justify when a limited clinical assessment could be acceptable e.g., a single-dose PK study in healthy subjects supported by comparative quality analysis. FDA guidance would be updated as appropriate, but timing for release is unconfirmed. During the discussion, Dr Ricci added that it was incumbent on biosimilar developers to make the case that minor product quality differences would not impact immunogenicity. On interchangeability, Dr Ricci stated that concerns around switching drove the current recommendations – if immunogenicity concerns do not apply then they would not be needed.
After decades of experience, there are no data to show that comparative efficacy trials yield information that indicates a clinically meaningful difference between a biosimilar and the reference product. Dr Wolf-Holz formerly of Germany’s Paul Ehrlich Institute (PEI) and now with BIOCON, noted that of 33 monoclonal antibodies and three fusion proteins that have been evaluated by the EMA, there has been no instance where clinical data, including failed efficacy trials, has led to a negative overall decision to approve the biosimilar product. Additionally, analysis of the product quality and clinical data in the EMA marketing applications of all 23 monoclonal antibody biosimilar candidates found no cases where clinical trial data were necessary to resolve residual uncertainties regarding the biosimilar’s product quality. As such, the product quality data are generally adequate to support the marketing application of a biosimilar candidate. The collective vision for the biosimilar guidelines in Europe should be more streamlined to allow for more rational use of clinical resources and improve access to innovative and affordable medicines for patients.
Foundational to the proposed change to requirements for comparative efficacy studies is the issue of assuring biosimilar product quality, and a clear understanding of the impact of structural differences between the biosimilar and reference products.
Structural differences between the biosimilar and reference products are not unexpected, nor are structural differences unique to biosimilars. For example, structural differences in the reference product have also been observed following manufacturing changes introduced by the innovator. In those cases, from our experience at Parexel, there has been no associated regulatory requirement for supporting clinical data to justify the structural changes to the innovator’s reference product.
In some cases, structural changes between reference product batches have been discovered during the development of biosimilars and have translated into measurable differences in therapeutic response. However, the therapeutic impact of these structural changes to the reference product was already predictable from the nature of the observed product quality differences. In these cases, both involving a trastuzumab biosimilar, the products were approved because the applicants were able to construct a robust explanation for clinical results falling outside the prescribed equivalence margin (ontruzant-epar and kanjinti-epar ).
After a biologic drug is administered, the protein drug substance undergoes significant modification within the human body such that the physiologic impact of many structural differences of the biosimilar compared to the reference product may be quickly eliminated following drug administration.
Comparative efficacy trials of biosimilar products are challenging to conduct. Even when they can be performed, it is often not realistic to show with reasonable certainty (95 percent confidence) the preservation of greater than 50 percent of the therapeutic effect of the reference product. To conduct comparative efficacy trials with adequate sensitivity, there is sometimes the need to recruit more than a thousand patients. With numerous companies developing multiple biosimilars, this will result in hundreds of thousands of patients being siphoned away from new product research and result in a significant resource burden. Nearly one hundred recently approved monoclonal antibodies are still protected by patent and/or data exclusivity, indicating that biosimilar targets will increase exponentially over the next decade. As such, conducting large comparative clinical trials will become increasingly resource-demanding. Data shows that even now, half of the innovator products whose marketing exclusivity expired, or is close to expiry, do not have biosimilars in development; a major reason being that costs would not be recouped. Science-based streamlining of regulatory requirements for biosimilar approval would increase the number of biosimilars that could be developed, decrease associated development costs, increase affordability of these products and, in so doing, deliver state-of-the-art therapies to patients, who currently cannot access these treatments.
At Parexel we have played a pioneering role in the biosimilar field, supporting clinical development of some of the first approved biosimilars. We welcome the opportunity to support the drive to tailored biosimilar development. Get in touch to learn more.
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