From the desk of Henry Leng – One of the limitations in the development of biosimilars is the availability of reference products for use in comparability studies. Generally there are two options open to biosimilar manufacturers to obtain reference products – either directly from the innovator manufacturer (direct sourcing) or from the market (open-market sourcing). Some multinational innovator companies may be prepared to supply their products to biosimilar manufacturers as part of their corporate responsibility to support global access to medicine; however, many will be reluctant to do so as it would encourage competition with their own products. In the US a policy was developed, the CREATES Act, that allows biosimilar developers to legally challenge innovator companies that refused to sell them samples of their product.1 Needless to say,South Africa does not have such a policy. Biosimilar manufacturers may also not be prepared to opt for direct sourcing as they would prefer not to alert the innovator manufacturer (or other biosimilar competitors) of their biosimilar project and also because of the higher prices they will most likely have to pay.
Open-sourcing has the benefit of remaining inconspicuous when acquiring samples of the reference product. However, key hurdles identified with open-sourcing include2:
- Concurrent availability of multiple batches of the RP in the market at a given time point.
- Even if several batches are available, the quantity of product required per batch for the various comparability tests and studies (physicochemical, functional and clinical) can be difficult to obtain, especially from one jurisdiction.
- Increase development costs due to large quantities of the RP required for the comparability studies.
- Limited variability as several final product batches of the RP can be manufactured from a single drug substance lot. This could force the biosimilar manufacturer to set stringent analytical specifications that may result in manufacturing difficulties such as batch failures.
- Should the innovator manufacturer implement approved amendments to its manufacturing process that lead to changes in the physicochemical and functional properties, and hence, specifications for its product, a new development process with new batches for the innovator may need to be initiated by the biosimilar manufacturer.
These difficulties and others, such as the requirement by some regulatory authorities that only RPs from their own jurisdiction be used, or that bridging studies must be done if a foreign reference was used for the comparability studies, which further increase the development costs, make it imperative that a global comparator product, accepted by all regulatory authorities, be made available for biosimilar development. This will be especially feasible if a tailored approach to clinical trials3, as proposed in the May blog post, is adopted, i.e., that comparative Phase 3 trials and in vivo nonclinical studies not be routinely required for biosimilar approval. The WHO would be the ideal institution for the development and dissemination of such global comparator products beginning with those biologics that have been included in its essential medicines list (EML).
- 1. Access to product samples: The CREATES Act. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/access-product-samples-creates-act
- Current Regulatory Requirements for Biosimilars in Six Member Countries of BRICS-TM: Challenges and Opportunities. Rahalkar H., Sheppard A., Santos G.M.L., Dasgupta C., Perez-Tapia S.M., Lopez-Morales C.A., Salek S (2021). Frontiers in Medicine, 8 , art. no. 726660. https://doi.org/10.3389/fmed.2021.726660
Schiestl, M., Ranganna, G., Watson, K. et al. The Path Towards a Tailored Clinical Biosimilar Development. BioDrugs34, 297–306 (2020). https://doi.org/10.1007/s40259-020-00422-1