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28 April 2021
What is a biological medicine?
What is a biosimilar?
What regulatory guidelines address biologics and biosimilars in South Africa?
What qualifies as a reference medicine?
How is the comparability of a biosimilar and reference medicine measured?
What quality requirements exist in relation to biosimilars?
What preclinical requirements exist in relation to biosimilars?
What clinical requirements exist in relation to biosimilars?
Does the South African biosimilar regulation provide for interchangeability or substitution?
What biosimilars are registered or awaiting registration in South Africa?
A 'biological medicine' is any medicine that:
Examples of biological medicines include:
A 'biosimilar' is a biological medicine that is manufactured to be similar but – unlike a generic pharmaceutical medicine – not necessarily identical to its reference medicine. Such medicines are assessed in terms of their quality, safety and efficacy compared with a reference biological medicine that has already been registered. No clinically significant differences should exist between the safety, efficacy, purity or potency of the reference medicine and the candidate biosimilar. Biosimilars are also known as 'follow-on biologics' or 'similar biotherapeutic products'.
Medicines, including biologics and biosimilars, are regulated by:
SAHPRA has published several guidelines to assist applicants which wish to register biological and biosimilar medicines.
One such guideline, which was published in 2012 and amended in 2014, applies to biosimilar medicines that are recombinant DNA-derived therapeutic protein medicines, including monoclonal antibodies. Biosimilar vaccines are excluded from the scope of this guideline document, even those which are manufactured by recombinant DNA technology.
In 2020 a further guideline took effect regarding how to demonstrate a biological medicine's stability, including its safety, quality and efficacy. However, this guideline applies only to well-characterised isolated or recombinant proteins and polypeptides and their derivatives or the products of which they are components. The guideline is relevant to the generation and submission of stability data for various products, including:
The guideline does not cover:
Instead, it refers to the World Health Organisation guidelines on vaccine stability evaluation.
In November 2020 SAHPRA published a guideline on the expedited or priority registration process for candidate COVID-19 vaccines.
Most recently, in March 2021 SAHPRA published a guideline on the amendment of registered biological medicines.
To qualify as a 'reference medicine' a medicine must have already been registered by SAHPRA with a full dossier (ie, an originator biological medicine) on the bases of safety, efficacy and quality. A reference medicine need not be sourced from South Africa but must be procured from an International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use country – namely:
SAHPRA prefers reference medicines to have been on the market for at least five years and therefore to have a safety record. Applicants must obtain and use several batches (ie, at least six) of the reference medicine throughout the biosimilar's development. The comparative data between the biosimilar and reference medicine must be based on the same dose, dosage form and administration route.
Comparability studies are structured to provide evidence that a biosimilar medicine has a similar quality, safety and efficacy to the originator reference medicine. Typically, these start with comprehensive analytical studies – performed according to the South African Guide to Good Manufacturing Practices – which characterise the biosimilar and reference medicines to show that the two products are highly similar. Thereafter, applicants perform animal studies, including toxicity testing, followed by one or more clinical studies. The clinical studies focus on the assessment of pharmacokinetics or pharmacodynamics and immunogenicity profiles of the reference and biosimilar medicines in at least one of the registered indications for which the reference medicine has been approved.
The extent of non-clinical and clinical studies that applicants must perform depends on how well the biosimilar has been characterised and how similar it is to the reference medicine. A high degree of similarity and extensive characterisation typically requires less non-clinical and clinical data.
Applicants must compare the following details of a biosimilar with the reference medicine at the level typically provided for an originator biological medicine:
Applicants must evidence the similarity of the medicines' primary physical structure (eg, amino acid sequence) since this relates to their biological functionality. Applicants must also demonstrate the medicines' similarity regarding post-translation modification (eg, glycosylation) and 3D structure. Applicants should follow the ICH Q5E and Q6B specifications when undertaking characterisation studies.
Preclinical studies are designed to be comparative and detect differences between the medicines' biological activity, efficacy and safety, rather than respond merely to the biosimilar. Applicants must perform both in vivo and in vitro validated assays, which aim to show the comparable functionality and clinical activity of the biosimilar and reference medicine. Examples of assays that are performed include:
Usually, applicants need not perform the following studies, unless they appear necessary based on the results of characterisation or other preclinical studies:
A clinical comparison between a biosimilar and its reference medicine first entails the performance of:
Depending on the biosimilar, these studies may be all that is required to demonstrate the medicines' comparability. However, applicants must usually also perform one or more clinical safety and efficacy trials.
When performing clinical comparability studies, applicants use equivalence designs. Therefore, the biosimilar's safety and efficacy must equal that of the reference medicine registered in South Africa. A risk-benefit analysis of the biosimilar medicine should provide similar results to that of the reference medicine.
Since the manufacturing process may be changed during optimisation prior to the registration application, applicants should perform the clinical Phase 3 comparability study using the biosimilar product produced by the final manufacturing process (ie, that with the final formulation and specifications and the same quality profile as the commercial batches). As with non-clinical studies, a competent and accredited laboratory must validate and conduct all clinical comparability assays.
Following the approval of any biological medicine, including biosimilars, manufacturers must submit pharmacovigilance studies with periodic safety update reports to SAHPRA. Manufacturers must also submit a risk management plan to monitor the biosimilar's immunogenicity and any safety issues that may result from impurities in the biosimilar or the biosimilar's properties.
Biosimilars are typically not identical to the reference medicine. Therefore, the active components may have different characteristics to the reference medicine and the formulations of the medicines may also differ. This may result in differences in clinical performance or adverse effects. Therefore, reference medicines may not be substituted with biosimilars and such medicines are not interchangeable.
In 2018 Cipla, in collaboration with Teva Pharmaceutical Industries Ltd, registered the first biosimilar in South Africa – Filgrastim Teva. In May 2019 Biocon registered Ogivri (trastuzumab), which was the first monoclonal antibody biosimilar to be registered in South Africa. Several other rastuzumab biosimilars are awaiting SAHPRA's approval. Other cancer monoclonal antibody biosimilars in the pipeline for registration include:
Non-cancer biosimilar medicines awaiting SAHPRA's approval include erythropoietin and insulin.
For further information on this topic please contact Joanne van Harmelen at ENSafrica by telephone (+27 21 410 2500) or email (email@example.com). The ENSafrica website can be accessed at www.ensafrica.com.
The materials contained on this website are for general information purposes only and are subject to the disclaimer.
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