The Biosimilars Guideline: Opportunity for Revision

From the desk of Henry Leng – In my post of three months ago (published May 21, 2022) I have argued that the time has come for SAHPRA to revise its guideline for the registration of biosimilars by, firstly, evaluating the need for in vivo pharmaco-toxicological studies and, secondly, the requirement for a Phase 3 comparative clinical trial to confirm similarity between a candidate biosimilar and reference product (RP). It is generally accepted that in vivo animal studies are not as sensitive and specific as in vitro assays for detecting product differences between a biosimilar and RP. Hence, in vitro comparative bioassays are pivotal for demonstrating biosimilarity. The only time when a need may exist for in vivo animal studies is if there is residual uncertainty of the similarity between the biosimilar and RP after the totality of quality and in vitro data have been reviewed by the regulator. This is expected to be a very rare occurrence based on global experience with the registration of biosimilars; thus, there should be no mandatory requirement for a biosimilar developer to perform animal studies before proceeding to human studies.

A comparative Phase 3 clinical trial is no longer a mandatory requirement for the authorisation of biosimilars by the UK Medicines and Healthcare Products Regulatory Agency (MHRA). As mentioned previously, the MHRA, which adopted this position in May 2021, considers a Phase 3 human trial only necessary if the combined comparative physicochemical, in vitro biological and pharmacokinetic and/or pharmacodynamic (PK/PD) datasets do not conclusively prove similarity between the proposed biosimilar and RP. The decision to conduct a comparative Phase 3 trial is, thus, left to the developer who must determine whether the degree of residual uncertainty with respect to biosimilarity can be addressed or removed with clinical data derived from a randomised, controlled and, ideally, equivalence trial between the biosimilar and RP for a specific indication.  From the MHRA perspective, the purpose of a Phase 3 trial is not to confirm biosimilarity but to convince the regulator to evaluate and authorise the product as a biosimilar and not to conclude that because of the differences observed in analytical, functional, and PK/PD studies, the submission should be a standalone application that must be supported with full quality, safety and efficacy data. Through this bold departure from the European Medicines Agency (EMA) biosimilar guidelines, the MHRA intends to authorise 20 more biosimilars over the next five to ten years, which will result in significant savings to the NHS as eight out of ten of the most expensive drugs used by the NHS are biologics1. The latest version of the WHO Guidelines on the evaluation of similar biotherapeutic products, published on April 22, 2021, also suggests that a Phase 3 trial may not be required for demonstration of biosimilarity, as can be inferred from the following statement (pg 28, Section 10.4):

A comparative clinical phase 3 trial will not be necessary, if sufficient evidence of biosimilarity can be drawn from other parts of the comparability exercise.”

The statement in the guideline that biosimilars are not interchangeable with their reference products should also be revised to bring South Africa in line with the practice in countries such as Australia, The Netherlands, Finland and others with stringent regulatory authorities to which SAHPRA is aligned. I have discussed this issue extensively in a post published in August of last year.

The reader may wonder why I am devoting this post to topics that I have dealt with previously. The reason is because the Biological Medicines Advisory Committee has begun with face-to-face meetings, which means that it is now in a position to expand its agendas beyond just dealing with evaluation reports and product registrations. Revision of our biosimilars guideline, which is long overdue, can now finally make its way onto an agenda of a meeting to be held this year. Readers are invited to list in the comments section other points that may further justify amendments to the guideline.


  1. Samuels M. New regulatory guidance could lead to UK biosimilar boom. European Pharmaceutical Review, June 29, 2021
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