Submitted: 8 December 2022; Revised: 8 December 2022; Accepted: 18 December 2022; Published online first: 8 December 2022

In the Opinion entitled Biosimilars drug development: time for a paradigm shift? in this issue of GaBI Journal, the authors question the need for what they consider to be the arduous regulatory requirements for approval of biosimilars [1].  The Opinion repeats already proposed and often published possibilities for changing and particularly abbreviating the established biosimilar approval process. These are the personal opinions  of  the  authors and others will agree or disagree largely depending on their view of the current regulatory systems for assessing biosimilars and how these affect biosimilar development.

A significant factor which the authors claim supports their proposals is that, to date approved biosimilars have been shown to have noefficacy or safety concerns. This is certainly largely true for real biosimilars approved by experienced regulatory authorities (mainly in developed nations). But all of these have been approved using the current regulatory guidelines! Most of the approved biosimilars have been produced by ‘Big Pharma’ or subsidiaries of Big Pharma who have much experience with producing biological products andsignificant resources for this. Where this has not been the case, e.g. for copy products marketed in developing nations problems have arisen and quality, efficacy and safety of some of these products is suspect if not clearly compromised. It is therefore a possibility thatloosening the requirements for approval of biosimilars would result in unsatisfactory products.

Biosimilar approval requirements as detailed in the various guidelines produced by the relevant regulatory agencies are constantlyevolving, and  are  continuously  updated to take account of experience gained and scientific, technical and clinical advances. The guidelines are thus living documents and not inflexible ‘tablets set in stone’. An example of this flexibility is the most recent draft of thebiosimilar guideline adopted by the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, which includes clearindications where clin ical efficacy trials are not needed. This type of trend is reflected in guidance from other regulatory jurisdictions. The general move towards more reliance on quality (chemistry, manufacturing, and controls, CMC) assessment (including the quality comparability assessment) and on clinical pharmacokinetics/pharmacodynamics (PK/PD) and less need for clinical efficacy andsometimes  immunogenicity  assessments is clearly ongoing, but the authors seem unaware of it. The authors’ opinion gives theincorrect impression that inflexible, unjustified regulations are hindering production of biosimilars; this does not seem to be the case at least in the developed world.

The desirability of ‘One  global  reference product’ is mentioned in the letter. There are two possible alternatives for this. Firstly, a ‘physical’ global reference product could be provided by some suitable organization, which could  be  used for biosimilar development by those who require it. Although this may seem rea- sonable (it has been proposed  several times previously) there are serious problemswith it, such as who provides the product, who characterizes it, who dis- tributes it and how its stability and sustainability is guaranteed.Also, how does it relate to products used in the country in which the biosimilar is being developed and  how  are  users  and  regulators to be convinced  that  it  is  an  appropriate reference product for use in their jurisdiction?

A second approach would not provide the reference product as such, but nominate a commercially available reference product from one source which could be globally’ adopted by those who want to use this approach. This suffers from similar problems to the first approach mentioned above. In addition there are possible issues with continued availability of this as a reference product and ensuring consistent prod uct characteristics, as commercial products undergo development and change unpredictably over time. These are just some of the problems with this ‘global reference product’ concept.

The authors blame over arduous, unnecessary regulatory requirements for apparently poor uptake of biosimilars. However, evidence suggests that reluctance to use/ adopt biosimilars due to an unfounded suspicion of their quality, efficacy and safety by prescribers andpatients  and often too little difference between  the price of the biosimilar  and  the  originator products are more likely reasons for this.

Biosimilars are now firmly established in most developed nations as copy biologicals with a clear and effective regulatory route for approval, which allows marketing of safe and efficacious biosimilar products. Although the regulatory requirements must (and do) evolve as experience and science progresses, this must be carefully evaluated to ensure that efficacy and safety are not compromised. If biosimilars are to increase in uptake as acceptable biological products it is important that they are perceived as being as accept- able as stand-aloneproducts by all involved in their production and use. Any perception that ill-advised, politically/financially driven pressures to inappropriately lower regulatory standards for their approval could seriously damage the acceptability of biosimilars.

Competing interests: None.

Provenance and peer review: Commissioned; internally peer reviewed.

Reference
1. Athalye SN, Mittra S. Biosimilars drug development: time for a paradigm shift? Generics and Biosimilars Initiative Journal (GaBI Journal). 2023;12(1):17-22. doi:10.5639/gabij.2023.1201.005

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