Several attempts have been made in the past ten years or so to establish a local biosimilar manufacturing industry. A few start-up companies have been established and some even managed to obtain funding from the Technology Innovation Agency and other funding bodies, local as well as international. Unfortunately, there has been little progress in the development of these products beyond the proof-of-concept stage. The primary reason has been the cost of generating the data to obtain registration. A recent McKinsey report estimates that it costs between $100 to $300 million to develop a biosimilar and that it takes between six and nine years to go from analytical characterisation to regulatory approval1. As expected, comparative clinical trials (Phase III) account for most of the cost (~65%), with comparative PK/PD studies making up 10%, and drug product development, including comparative physicochemical and vitro preclinical studies, accounting for about 20 % of the total budget. It is, therefore, not surprising that all established pharmaceutical companies have shied away from investing in biosimilar manufacturing. The enhanced pharmacovigilance requirements, especially the submission of periodic safety update reports (PSURs) and in some cases post-marketing commitments to perform immunogenicity testing, or to provide clinical performance data in patients with HIV and TB, could also have served as disincentives.
This problem has been recognised by the MHRA in the UK and recently also by the FDA in the US, i.e., that the slow pace of biosimilar submissions was due to the time and costs associated with producing the required data packages to obtain approval. The MHRA has since abolished the requirement for comparative efficacy trials, as I’ve mentioned in a previous post. The FDA, under the Biosimilar User Fee Act (BsUFA) for fiscal year 2023 to 2027 (BsUFA III) will pilot a regulatory science program with two main aims: 1) advancing the development of interchangeable products, and 2) improving the efficiency of biosimilar product development. Two scientific areas that will be essential to achieve both aims include a) increasing the accuracy and capability of analytical (structural and functional), chemistry, manufacturing, and controls (CMC) characterisation, and b) developing alternatives to and/or reducing the size of clinical studies.
Currently, the FDA requires switching clinical studies to meet the interchangeability standard. Through the regulatory science program, FDA will investigate the use of real-world evidence, such as health data derived from medical claims, electronic health records, data captured using digital tools, data from registries, etc., to support a decision on interchangeability. Advancing the accuracy and capability of current analytical technologies could reduce the uncertainty associated with previous undetected or small differences in product quality attributes between the reference product and candidate biosimilar. More confidence from the analytical similarity assessment may decrease the need for clinical studies. From the above, it is clear that the FDA is also moving in the direction of the MHRA.
Thus, for the local biosimilar manufacturing industry to take off, the cost of bringing a biosimilar to market will have to be reduced by a significant margin. This is achievable if the SAHPRA can dispense with the requirement of comparative Phase III studies if the comparative physicochemical, in vitro biological, and comparative PK/PD studies convincingly demonstrate that there are either no structural difference between the reference product and proposed biosimilar or no structural or functional differences that could be clinically meaningful. This would half the development cost of a biosimilar and significantly accelerate the timeline.
- Miriam Fontanillo, Boris Körs, and Alex Monnard. Three imperatives for R&D in biosimilars. McKinsey & Co. August 2022. Available online: https://www.mckinsey.com/industries/life-sciences/our-insights/three-imperatives-for-r-and-d-in-biosimilars#/
- Niazi, S.K. The Coming of Age of Biosimilars: A Personal Perspective. Biologics 2022, 2, 107-127. https://doi.org/10.3390/biologics2020009.
- Biosimilar. Science and Research. https://www.fda.gov/drugs/biosimilars/biosimilars-science-and-research