From the Desk of Henry Leng
The availability of biosimilars provides an affordable treatment option for many patients suffering from debilitating chronic diseases (rheumatoid arthritis, psoriasis, several cancers, etc.) who previously had no access to biologics because of the high cost of the patent-protected innovator medicines. However, the full potential of biosimilars in South Africa will only be realised once they become interchangeable with their reference products. Many countries, such as The Netherlands, Finland, the UK, Ireland, Germany, Australia, New Zealand, France, Norway and Canada (1, 4) with whose national regulatory authorities (NRA) the SAHPRA is aligned with, allow for interchangeability or switching of patients from a reference biologic to its biosimilar under specific conditions. It is interesting to note that the US FDA designation of an interchangeable biosimilar equates with (generic) substitution in terms of Section 22F of Act 101 of 1965 in South Africa, in that such a biosimilar can be dispensed in place of the reference product by a pharmacist without prior consent of the prescribing physician. I must hasten to add, however, that the FDA requires additional switching studies in patients during which biosimilar dosing in one arm of a comparative study alternates with that of the reference product, while patients in the control arm continue to receive the reference medicine only. Results must show no difference in efficacy and safety between subjects in the two arms for the biosimilar to qualify as interchangeable (2). Currently only Semglee®, which is an insulin glargine biosimilar to Lantus®, has been approved by the FDA as an interchangeable biosimilar (3).
The approach used by SAHPRA in the evaluation of biosimilars is exactly the same as that used by the EMA and other NRAs with which it is aligned in that it is based on the comparability concept. A candidate biosimilar must be compared to its reference medicine in side-by-side analysis in terms of structure, potency and purity using a range of sophisticated orthogonal techniques. If shown to be highly similar to its reference medicine at this physicochemical and biological level, similarity must be confirmed with comparative safety and efficacy data (for at least one indication) in nonclinical and clinical studies. Only then will the product be registered by SAHPRA as a biosimilar. It is important to note that the position of the EMA on interchangeability is to leave that decision to the NRAs of the respective member states. In a recent publication written by staff of NRAs of Finland, The Netherlands, Germany and Norway (1), the authors claim that experience gained over two decades from assessing comparability data in support of manufacturing changes to biological medicines, has shown that such changes very rarely led to adverse events when patients were switched from pre- to post-manufacturing change versions. This, coupled with the relatively long history of use of biosimilars in Europe since the first one (Omnitrope®) was approved in 2006, led them to conclude that switching patients from the original medicine to the biosimilar can be considered safe.
My view is that the time has come for the SAHPRA to update its biosimilars guideline to specifically allow for interchangeability of a reference biological medicine with its biosimilar, but under conditions that include (but are not limited to) approval by the treating physician, clinical monitoring of the patient during the switch and patient education on the biosimilar. One caveat that I would like to add is that interchangeability, without the requirement for switching clinical studies, be limited to biosimilars that are recombinant proteins and well-characterised. Biosimilars of tissue-derived biologics, which are often not homogenous preparations, should be excluded, or alternatively, be shown to have equivalent safety and efficacy profiles to the innovator in comparative clinical studies with multiple (≥ 3) switches.
References:
- Kurki P, van Aerts L, Wolff-Holz E, Giezen T, Skibeli V, Weise M. Interchangeability of Biosimilars: A European Perspective. BioDrugs. 2017 Apr;31 (2):83-91. doi: 10.1007/s40259-017-0210-0. PMID: 28120313.
- Afzali A, Furtner D, Melsheimer R, Molloy PJ. The Automatic Substitution of Biosimilars: Definitions of Interchangeability are not Interchangeable. Adv Ther. 2021 May; 38(5):2077-2093. doi: 10.1007/s12325-021-01688-9. Epub 2021 Mar 21. PMID: 33745111; PMCID: PMC8107170.
- FDA Approves Semglee Insulin Glargine as First Interchangeable Biosimilar. https://www.centerforbiosimilars.com/view/fda-approves-semglee-insulin-glargine-as-first-interchangeable-biosimilar
- GaBI Online – Generics and Biosimilars Initiative. International policies for interchangeability, switching and substitution of biosimilars. https://gabionline.net/reports/International-policies-for-interchangeability-switching-and-substitution-of-biosimilars