The South African Biosimilars guideline (1) was finalised for implementation in August 2014. In the almost eight years since its publication, a significant amount of progress has been made in the development of this type of biologic, its regulatory assessment and clinical use. This has resulted in greater knowledge, experience and understanding by all stakeholders who have accepted the responsibility of promoting public access to them – not only of their molecular and biological properties, but also of their clinical performance, so much so that it is now possible to relate their safety and efficacy profiles with their underlying biological and physicochemical properties. Thus, the time has come to update the guideline to allow for these new insights to be reflected in the requirements for the registration of biosimilars.
The question though is how should the guideline be amended? I think we will all recognise that the current requirements were developed when there was still great uncertainty about the safety and efficacy of biosimilars compared to their reference products (RPs); hence, the requirement, for example, for in vivo comparative toxicity studies. The concern that a biosimilar may be less safe due to having more or different impurities than the RP has largely been laid to rest following advances in manufacturing and purification technologies as well as the increased sensitivity of modern analytical instruments used for demonstrating physicochemical and in vitro biological comparability. The regulatory requirement of having to use more than one method, i.e., the orthogonal method approach, whereby a secondary method is used to confirm the similarity obtained with the primary method for each critical quality attribute (CQA) between a biosimilar and its RP, further reduces the probability of a clinically significant difference between the two. The need for in vivo toxicity studies has, thus, become redundant and should be eliminated from the guideline. This is in line with current thinking by the EMA, whose guidelines we have formally adopted, as well as of the WHO.
What about the requirement for a comparative efficacy trial? The same reasoning used for advocating the abolishment of animal studies support the elimination of mandatory efficacy studies for biosimilars, with the added evidence that no biosimilar authorised by an EMA or US FDA aligned regulatory process, such as that of SAHPRA, has been withdrawn from the European or US market for safety or efficacy concerns (2). I want to emphasise though that I am not proposing that requirements for nonclinical and efficacy trials should be totally revoked, but that the automatic requirement or need for such studies be justified by the Applicant. To put it differently, the expectation or mindset that the regulatory authority should have is that comparative animal toxicity and human efficacy trials are not necessary to demonstrate or confirm biosimilarity because the comparative physicochemical and in vitro biological data conclusively demonstrated the absence of clinically meaningful differences between the candidate biosimilar and its RP. If an Applicant should present nonclinical and clinical efficacy data in a dossier it will mean that a significant difference in the quantitative or qualitative measurement of one or more CQAs were detected during the analytical and biological comparability studies. Comparative nonclinical and clinical studies were then performed to demonstrate that the differences do not impact clinical performance. Thus, these studies are used by the developer to justify the registration of their product as a biosimilar and not, as they are used in the current regulatory regime, to confirm biosimilarity. The purpose or goal of nonclinical and clinical studies is, thus, to convince the regulator that their product should not be regarded or classified as an innovator biologic in spite of the differences in critical quality attributes.
Will SAHPRA consider this approach as too risky or pioneering, given its recent reputation as a follower of EMA procedures? Perhaps, but the UK Medicines and Healthcare Products Regulatory Agency (MHRA) has already adopted this procedure in May 2021 (3). If SAHPRA is sincere in its advocacy of access to affordable medicines through efficient regulatory processes then it should make the revision of their biosimilar guideline high priority.
- Biosimilar Medicines: Quality, Non-clinical and Clinical requirements. August 2014.
- Schiestl, M., et al., (2020). The Path Towards a Tailored Clinical Biosimilar Development. BioDrugs 34: 297 – 306.
Guidance on the licensing of biosimilar products. 6 May 2021. https://www.gov.uk/government/publications/guidance-on-thelicensingof-biosimilar-products/guidance-on-the-licensing-ofbiosimilarproducts