Lagging acceptance of generic and biosimilar drug products; the rest of the story

Generics and Biosimilars Initiative Journal (GaBI Journal). 2023;12(1):3-4.
DOI: 10.5639/gabij.2023.1201.001

Published in: Volume 12 / Year 2023 / Issue 1
Category: Editor's Letter
Page: 3-4
Visits: 833 total, 1 today

The articles in this issue of the GaBI Journal reminded me of The Rest of the Story radio programme originally hosted by Mr Paul Harvey that started each episode with, ‘And now for the rest of the story’. This is because these articles illustrate that sometimes what is not discussed in an article can be more interesting than what is.

In the first Editorial GaBI Journal’s Deputy Editor-in-Chief, Dr Robin Thorpe, responds to the Opinion article by Drs Sandeep N Athalye, Shivani Mittra, and Ankitkumar M Ranpur in which the authors present their arguments for why they think it is, ‘time for a paradigm shift’ in what the authors feel are excessively arduous regulatory requirements for marketing approval of biosimilars. Readers are encouraged to evaluate the points made in these two articles and to submit their comments as either articles or letters to the Editor. While I clearly have a conflict of interest since Dr Thorpe is my Deputy Editor-in-Chief, I felt that he presents a convincing ‘And now for the rest of the story’ rebuttal to the suggestions proposed in the Opinion piece. He points out that using the lack of problems with biosimilars that were approved using the ‘arduous’ system the authors propose to modify cannot be used to assume that products approved using a less arduous requirements are really biosimilars. In fact, there are multiple poor quality performance examples of follow-on biological products that were marketed in countries without having met arduous biosimilar requirements. Dr Thorpe also points out that biosimilar approval processes are already rapidly evolving and explains why some of the changes proposed either impractical or even impossible. Finally, he summarizes the dangers inherent in, ‘ill-advised, politically/financially driven pressures to inappropriately lower regulatory standards’ that, ‘could seriously damage the acceptability of biosimilars’. The acceptability of biosimilars is especially important since, as Dr Thorpe points out, ‘evidence suggests that reluctance to use/adopt biosimilars due to an unfounded suspicion of their quality, efficacy and safety by prescribers and patients and often too little difference between the price of the biosimilar and the originator products are more likely reasons’ for the inability of biosimilars to achieve their cost savings potential.

The two Original Research articles in this issue present results from two apparently straight-forward generic anti-diabetic product bioavailability studies. The first study compared a proposed biosimilar product Fortesia® tablets to the Merck Sharp & Dohm’s innovator Januvia® tablets (each containing 100 mg of sitagliptin). ‘And now for the rest of the story’. While only stated in the title, it appears that in this study both the follow-on proposed generic product and the reference Merck product contained sitagliptin monophosphate. The second study compared, ‘Fortreas® tablets containing 100 mg of sitagliptin as the hydrochloride to the originator Merck 100 mg sitagliptin as the monophosphate reference formulation. Neither manuscript mentions (‘the rest of the story’) is that sitagliptin has two possible (R and S) enantiomers The reference Merck product contains the monophosphate salt of the R enantiomer. It is assumed, but not stated by the authors, that the Fortesia® tablets used in the first study also contained the monophosphate salt of the R configuration. The second study also does not mention whether the proposed generic product contained the R enantiomer, but the authors make clear that it contained sitagliptin hydrochloride rather than sitagliptin monophosphate. The chemical composition of the sitagliptin used in a product is not a trivial legal/patent issue; as a recent court decision demonstrates [1]. While the products appeared to meet the regulatory requirements for declaring them to be bioequivalent, neither manuscript used a stereospecific assay. It is not possible to say whether the chiral or salt characteristics will affect the product’s performance. It is however important to avoid hidden differences that could be exploited by competitors to undermine confidence in a follow-on product. It is unfortunate that the authors did not disclose and discuss the issues of salt form and enantiomeric composition. It would be interesting to know whether these issues were raised by the regulators who have or will evaluate these studies. I personally would expect that regulators would require a stereospecific assay be used to evaluate the bioequivalence of chiral generic products unless there are data showing that the two enantiomers are pharmacologically equivalent. This is important because, as Dr Thorpe mentioned, anything that can be used to question the validity of the evaluation of follow-on products, generics or biosimilars, has the potential to limit confidence and acceptance of such products.

The issue of acceptance is a key component of the Meeting Report by Reilly et al. from the Alliance for Safe Biologic Medicines (ASBM) that focused on non-medical switching of biological products in Canada, Europe, and the US. This webinar was the latest in a series of meetings held in collaboration with the Generics and Biosimilars Initiative (GaBI). Of note, the majority of the ASBM’s funding comes from the pharmaceutical industry; including manufacturers of both innovator biological and biosimilar products. The report provides the content of the meeting and its conclusions in sufficient detail to give readers a sense of being present at this interesting meeting. However, (‘And now for the rest of the story’), while it is clearly important to examine stakeholder opinions and concerns, it is not clear whether these meetings or their reports result in increased or decreased acceptance of biosimilars on the part of the participants or readers of the report. It is hoped that the authors are correct when they conclude that, ‘continued regulatory reforms for biosimilars, more affordability with competition brought through biosimilars, and a fair healthcare system that passes the savings to the patients can make biosimilar development more sustainable in the future’ and that, ‘… apprehensions regarding biosimilars are already changing and in the future, a greater acceptance and faster adoption of biosimilars can be envisioned’.

I want to encourage all our readers and submitting authors to submit their ‘rest of the story’ comments, opposing viewpoints, or questions concerning any of these articles or my comments, as well as general comments about the acceptance of biosimilars in general.

1. Mylan failed to ‘immediately envisage’ the compounds in Merck’s patent covering Januvia. 14 October 2022. Available from:

Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal

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