The authors, based at Biocon Biologics in India, outline four suggestions to streamline biosimilars development in a regulated market:

1. The authors suggest that policies that encourage ‘totality of evidence’ but with an optimally customized trial design for each molecule, are required. They give the example of denosumab, as a biosimilar with low immunogenicity that does not benefit from single-switch studies that can lengthen the duration of clinical trials. They highlight that to date biosimilars approved by the US Food and Drug Administration (FDA) have not shown any major safety or immunogenicity concerns after single or multiple switches (if done), underscoring the importance of either completely waiving off the single-switch studies or only considering these for highly immunogenic drugs. They suggest that granting interchangeability claims for such low immunogenic molecules should be allowed based on the safety and efficacy trial data.
2. The authors highlight that the use of ‘one global reference product’ for biosimilar development trials can bring down the costs dramatically. The high cost of reference listed drugs (RLDs) is prohibitive. They suggest that bridging pharmacokinetic (PK) studies between biosimilars and approved reference products are not necessary and two-arm clinical PK studies can replace three-arm studies to substantially reduce the trial complexity, duration, and cost. A World Health Organization (WHO) survey in 2019‒2020 in 20 countries has recognized the challenges related to the RLDs, which include limited access to information on the RLDs, financial constraints due to their price, and difficulty in obtaining RLD samples to assess comparability [2]. To address these challenges and to bring about harmonization towards single global reference products, exchanging information between national regulatory authorities builds confidence in accepting foreign-sourced reference products, thus avoiding unnecessary bridge studies.
3. The authors note that there is a strong need to have common statistical methods  to assess biosimilarity and hence to calculate the sample size for the equivalence and efficacy trials [3]. The large sample size and cost of reference products for trials can become a barrier for companies developing biosimilars globally. Hence, having a uniform method to arrive at a trial size, with an intent to keep the totality of evidence approach, can be helpful in simplifying biosimilar development.
4. In addition, when it comes to conducting a clinical trial on orphan drugs, this can become costly due to recruitment challenges, and operational costs escalate due to the longer duration of the trial and the reference product cost. Removing the need for the clinical efficacy similarity trial for orphan drugs can significantly reduce the cost of development with the burden of proof shifting to CMC (chemistry, manufacturing and controls) similarity, sensitive functional assays, PK data. In some cases, innovative trial designs and statistics for smaller trials should be accepted because of the non-availability of PD markers.

The authors conclude that continued regulatory reforms for biosimilars, more affordability with competition brought through biosimilars, and a fair healthcare system that passes the savings to the patients can make biosimilar development more sustainable in the future.

Related articles
A global overview of manufacturers of follow-on biologicals

DARS: advancing biosimilar development in the US

Highlights of the revised WHO guideline on evaluation of biosimilars

References
1. Athalye SN, Mittra S, Ranpura AM. Biosimilars drug development: time for a paradigm shift? Generics and Biosimilars Initiative Journal (GaBI Journal). 2023;12(1):17-22. doi:10.5639/gabij.2023.1201.005
2. Kang H-N, Thorpe R, Knezevic I, et al. Regulatory challenges with biosimilars: an update from 20 countries. Ann N Y Acad Sci. 2021;1491(1):42-59.
3. Kang SH, Kim Y. Sample size calculations for the development of biosimilar products. J Biopharm Stat. 2014;24(6):1215-24.

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Copyright – Unless otherwise stated all contents of this website are © 2023 Pro Pharma Communications International. All Rights Reserved.