The interruption in international supply chains, which ensued in the wake of the COVID-19 pandemic led to critical shortages in many essential medicines in South Africa and other low and middle income countries (LMIC) that are dependent on the importation of medicines for their healthcare needs. This led to the adoption of resolution WHA74.6 at the seventy-fourth World Health Assembly on the 31st of May, 2021, which emphasised the important role of local production for improving access to quality, safe, effective and affordable health products, and especially, for safeguarding health security during normal and pandemic times. The WHO essential medicines list1 (EML) includes several biologics, such as rituximab, trastuzumab, filgrastim, bevacizumab, epoetins, enoxaparin and insulin (soluble and intermediate-acting filled in vials, as well as long-acting analogues in cartridges and pens). I have often found it surprising that none of the companies interested in, or working on, a project to produce a biosimilar locally, ever considered or chose insulin. I am aware that there are a number of obstacles to entry into the insulin market, the main one probably being the administration device patent protection2; yet with respect to registration, it would be one of the least complicated biosimilars to register as a comparative pharmaco-dynamic study will suffice instead of a comparative Phase III clinical trial3. Interchangeability should also not present a major issue as insulin is a relatively simple molecule (only 51 amino acids) and is non-glycosylated4. This apparently already seems to occur in the public sector, where the major criterion for insulin brand selection appears to be cost5. Manufacturing of insulin, which occurs by means of bacterial or fungal fermentation, will also be less expensive and simpler than that of a monoclonal antibody (e.g., trastuzumab, bevacizumab, etc.) or glycosylated recombinant protein hormone (e.g., epoetin) that require mammalian cell culture. Additional requirements, to which biologics of mammalian cell origin are subject to, such as demonstration of viral safety, also will not apply to insulin. Although administration devices may present a major limitation to the development of an insulin biosimilar, there is still a great need for soluble and intermediate-acting insulin products filled in vials.
In February 2020, WHO published a pilot procedure for the prequalification of human insulin6. The first announcement of this prequalification programme was already made on 13 February 2019, a day before World Diabetes Day7. The procedure included both biotherapeutic insulins (innovators) and similar biotherapeutic products. The reasons given for including insulin in the pilot programme was because it was a life-saving medication, current prices were a barrier to treatment in most LMIC, and that WHO guidelines were available for assessment of recombinant biotherapeutric products, including for biosimilars. Similar pilot procedures were initiated for trastuzumab and rituximab in July of 20188, which led to the first trastuzumab biosimilar being prequalified in December 2019 and the first Rituximab biosimilar in May 2020. Two years after the human insulin pilot project was launched, an insulin biosimilar has still not been prequalified. This is surprising as the trastuzumab and rituximab biosimilars were prequalified in less than two years after the launch of their pilot programmes. It almost appears as if no applications have been made, even by the market leaders whose products are registered by stringent regulatory authorities and, thus, would be eligible for abbreviated assessment9 that should not take longer than three months. Nevertheless, the insulin pilot procedure presents a good opportunity for any biosimilar manufacturer to gain access to a very significant market.
- World Health Organization Model List of Essential Medicines, 22nd List (2021). WHO/MHP/HPS/EML/2021.02. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.02.
- Beran. D, et al. (2021). A global perspective on the issue of access to insulin. Diabetologia, 64:954–962.
- Biosimilar medicines: Quality, Non-clinical and Clinical Requirements. https://www.sahpra.org.za/wp-content/uploads/2020/04/SAHPRA-Biosimilar-Medicines-Guidance_Aug14_v3.pdf
- Weiss M, Steiner DF, Philipson LH. Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships. [Updated 2014 Feb 1]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279029/
- The 2017 SEMDSA Guideline for the Management of Type 2 Diabetes. JEMDSA 2017 Vol. 22(1) (Suppl. 1), p. S1-S196. www.jemdsa.co.za
- WHO Pilot Procedure for Prequalification of BTPs: human insulin version 10 Feb 2020 https://www.who.int/medicines/regulation/prequalification/01_Pilot_PQ_procedure_insulin_Feb2020.pdf
- 1st Invitation to Manufacturers of human insulin to Submit an Expression of Interest (EOI) for Product Evaluation to the WHO Pre qualification Team – Biotherapeutic Products (BTPs). https://extranet.who.int/pqweb/sites/default/files/documents/1st_EOI_Insulin_November2019.pdf
- WHO to Start Pilot Pre qualification of Biosimilars for 2 Cancer Treatments. https://www.centerforbiosimilars.com/view/who-to-start-pilot-prequalification-of-biosimilars-for-2-cancer-treatments.
- Pre qualification Procedures and Fees: FPPs, APIs & QCLs. https://extranet.who.int/pqweb/medicines/prequalification-procedures-and-fees