Submitted: 26 July 2018; Revised: 26 July 2018; Accepted: 27 July 2018; Published online first: 30 July 2018
The Opinion article of Adjunct Professor Niazi in this issue of GaBI Journal argues that the US Food and Drug Administration (FDA) could make several adjustments to its guidance in order to facilitate the development of biosimilars . The author points out that the current requirements have led to high costs and long development times which discourage small- and medium-sized enterprises from entering biosimilar development. Indeed, FDA Commissioner Scott Gottlieb has stated that the biosimilar market suffers from a lack of competition [2, 3]. Some of the proposals of the author deserve comments from a global perspective.
Bridging studies and substitution
Acceptance of a foreign-sourced reference product in clinical studies is highly desirable for global development programmes of biosimilars. Repetition of clinical trials in different regulatory regions is unnecessary, expensive and ethically questionable. Most regulatory agencies require ‘bridging studies’ to demonstrate that the foreign-sourced reference product and the corresponding domestic product are highly similar. FDA has the most stringent requirements, including not only analytical comparability but also additional human pharmacokinetic/pharmacodynamic (PK/PD) studies .
The author proposes that bridging studies should not be required if the foreign and domestic products have the same composition and have been licenced on the basis of the same documentation. In this case, products sourced from different but ‘highly regulated’ regions should be very similar and safe since they have been used over 10 years under regulatory surveillance. However, if there are significant differences in the regulatory history, there is a theoretical possibility that the two products have ‘drifted apart’ over the years because of different changes to their manufacturing processes. In addition, the waiver of bridging studies may face legal obstacles in some jurisdictions. Nevertheless, the developers should be able to get waivers for at least some bridging studies if they can demonstrate that, based on the regulatory history of the products, differences between the domestic and foreign reference product are highly unlikely. Collaboration and data sharing between the key regulatory agencies would facilitate the acceptance of a global reference product. Global development of biosimilars is in the interest of all countries, including the US. Therefore, FDA should act in a pragmatic way to promote global development of biosimilars.
The author argues that a waiver of bridging studies would not be possible in a study intended to support interchangeable status of a biosimilar product. This recommendation is based on the current FDA draft guideline on the interchangeable biosimilars . Unfortunately, the requirement may create a bottleneck for global development by promoting the use of a US reference product. Furthermore, it would harm the basic concept of biosimilarity by creating two levels of biosimilarity.
The author makes several proposals to reduce the requirements of PK evaluation. Most of them will not significantly change the burden of PK studies.
The author regards PK studies in healthy volunteers as ethically questionable and proposes PK studies in monkeys.
Single-dose comparative PK studies are recommended by regulators as a simple model with minimal confounding factors in cases where the product can be safely administered to healthy volunteers [6, 7]. The proposal to study disposition kinetics in monkeys is problematic from scientific, ethical and global development points of view. In addition, studies to convincingly demonstrate comparable PK in monkeys are hardly feasible from a practical point of view.
The author promotes the use of in vitro and in vivo non-clinical testing of immunogenicity to justify waivers of clinical immunogenicity studies. While such testing may be useful in the selection of the lead compound for development, the ability of in vitro tests to fully mimic the human immune system is still inadequately documented for regulatory purposes. The issue is not immunogenicity as such. FDA guidance speaks about clinical immunogenicity studies since the ultimate goal of these studies is to look for harmful immunogenicity. For the time being, this is possible only in the context of clinical safety and efficacy studies [8, 9]. Abandoning clinical safety and efficacy studies in a near future would be a strategic mistake considering the mindset of prescribers.
The ability and willingness to switch between originator products and their biosimilars are the keys to the economic benefits of biosimilars. The author does not comment on the draft interchangeability guideline  as it is assumed to be bound to the legal provisions outside the mandate of FDA.
It is assumed by some experts that the US legislation guiding the development of biosimilars is biased because of lobbying by the originator industry [10, 11]. The industry is also active in promoting a very conservative guidance, recently in case of the draft guideline for interchangeability . In general, the current US legislation and guidance may not ensure satisfactory availability biological therapy for patients because they allow anticompetitive behaviour .
In the EU, biosimilars are generally regarded as interchangeable under the supervision of the prescriber and in Australia, biosimilars may even be substituted at the pharmacy level . It is unfortunate that the leading regulatory authorities have adopted different policies with regard to interchangeability as it creates confusion and uncertainty among regulators and their stakeholders worldwide.
It would be beneficial for the global market if FDA would clearly separate interchangeability without (automatic) substitution from interchangeability associated with substitution at the pharmacy level and allow prescribers and local regulatory authorities to develop safe methods for switching between a biosimilar and its reference product. After all, FDA approved biosimilars and their reference products, by definition, are highly similar and have no clinically meaningful differences . Tens of clinical switching studies have not raised any significant efficacy or safety signals [14, 15]. The requirement of specific switching studies using the local reference product is a serious blow to the hopes for significant savings for the US healthcare system and may discourage global development of biosimilars.
The author requests FDA to intensify its information on the safety of biosimilars. FDA and other agencies that have licensed biosimilars are in a very unusual situation since the safety of biosimilars is widely and publicly questioned by some parts of the industry. According to the author, this has led to misunderstandings about the safety of biosimilars, ‘integrated into the minds of prescribers and the public by the products’ originator companies’. This situation is difficult to change because only originator companies (Big Pharma) have the resources and channels to reach each individual prescriber.
The problem is not the availability of information on biosimilars. Regulatory agencies, including FDA, have delivered information on the benefit-risk of biosimilar products and their approval process. However, this information is likely to reach only prescribers that have a genuine interest to seek and review the available data, such as opinion leaders who are drafting position papers for their specialties.
The recent consultation on FDA draft guidance on interchangeability clearly demonstrated that the views of physician societies are closely following the opinions of the innovator sector of the industry . This association may be partially due to the lack of understanding/acceptance of the comparability concept, on one hand, and the public health impact of biosimilars, on the other hand. Therefore, FDA is encouraged to engage in frank discussion with medical societies who issue position papers on biosimilars. In Europe, the physician societies originally discouraged biosimilar use  but have recently reversed their positions on controversial issues, such as extrapolation of therapeutic indications and interchangeability [18–20]. Such a change may happen also in the US .
How to balance innovation and safety with competition and availability – FDA dilemma
The author criticizes the FDA approach to manufacturing, analytical comparisons and clinical development of biosimilars. This discussion is important since FDA has recently published a plan to revise its approach to biosimilars, the Biosimilar Action Plan (BAP) . The goal is to restore the balance between protection of innovation, on one hand, and competition and access to biologicals, on the other hand. Interestingly, FDA will not only take measures to streamline its own processes but also pay attention to the anticompetitive strategies of the manufacturers of the reference products.
The BAP aims to streamline the biosimilar guidance in order to allow more focused development programmes, including critical quality attributes for different classes of biosimilars, development and validation of PD biomarkers tailored to biosimilar development and in silico modelling and simulation to evaluate PK and PD response versus clinical response relationships. In addition, FDA aims to provide additional guidance for biosimilar development. Most importantly, FDA will enhance collaboration with Canada, Europe and Japan aiming on regulatory harmonization as well as addressing the use of foreign reference products and real-world data. Furthermore, FDA will increase its information on biosimilar regulation for its stakeholders, especially healthcare professionals. Thus, many of the points raised in the article of Niazi will be considered.
In designing the regulatory framework for new areas of pharmacotherapy, regulators will initially have to perform a scientific judgement of the benefits and risks while the true risks are not completely known. A conservative approach is justified initially but it should not lead to obstruction of drug development. The same concept can be applied to biosimilars whilst keeping in mind that the uncertainties at the time of licensing are minute as compared to products with a new active substance. In addition, there is a wide experience in real-world use of biosimilars that is a striking contrast to the concerns entertained by the anti-biosimilar lobby and, to a certain extent, to some elements in the regulatory guidance. FDA now has an opportunity to show leadership to the regulation of biosimilars for the benefit of healthcare systems worldwide.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
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Author: Professor Pekka Kurki, MD, PhD, University of Helsinki, 19 Lukupolku, FI-00680 Helsinki, Finland
Disclosure of Conflict of Interest Statement is available upon request.
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