The second issue of the 2018 GaBI Journal volume is being published at a time of increasing uncertainty concerning trade, tariffs, regulations as well as international and even inter-ally co-operation. This issue contains manuscripts discussing some changes which are either being asked for, or which are already occurring, with the potential to increase the global development and use of generics and biosimilars.
The first Commentary in this issue entitled ‘Potential changes to the FDA approach to biosimilars have a global impact’ by Professor Pekka Kurki, This discusses the changes proposed in an article by Adjunct Professor Sarfaraz K Niazi, near the end of this issue, see page 84, to how the US Food and Drug Administration (FDA) regulates biosimilar products. Professor Niazi’s proposals are consistent with the anti-regulatory political rhetoric and administrative actions that are both becoming increasingly common in the US. And while certainly worthy of consideration they must be judged, as Professor Kurki points out, on how well they fit with FDA’s need ‘to balance innovation and safety with competition and availability. Professor Kurki provides important information about FDA’s plans to ‘revise its approach to biosimilars’. Readers are encouraged to evaluate and compare Professor Kurki and Niazi’s comments; including which measures are most likely to be successful in encouraging and accelerating biosimilar drug development; including how to deal with the anticompetitive strategies used by reference product manufacturers. Personally I would like to see more evidence-based evaluation of methods used to increase practitioners’ understanding and acknowledgement of the risks and benefits of biosimilar products. As Professor Kurki points out, while regulators must always make scientific judgements of the benefits and risks of new products based on incomplete knowledge of the true risks, the uncertainties at the time of licensing of a biosimilar are much smaller than they are when a new active substance is being considered.
Effective methods must be developed to educate practitioners, their professional organizations, patients and patient interest groups about the extensive, and generally very positive experience in real-world use of biosimilars. Ways must be found to minimize if not negate any unscientific, unjustified anti- or pro-biosimilar opinions generated in practitioners or patients by individuals or groups with interests which conflict with what is medically and scientifically best for patients.
One very positive change is the use of patient-reported outcomes (PROs) to assess follow-on products, generics or biosimilars. In an Original Research Perez-Nieves et al. analyse PROs reported in two previously published, randomized studies of a biosimilar and originator insulin products in the treatment of diabetes patients. The authors found no statistically significant differences in a number of PROs in these two (52 and 24 week) studies by these T1DM and T2DM patients. Studies such as this may, as the authors’ claim, ‘help build the confidence of patients and their healthcare providers alike in use of biosimilar insulins and inform their decisions regarding treatment options for basal insulin therapy’. An important unanswered question is whether/how much the results will increase confidence in and prescribing of such products by treating physicians. The authors/study designers should consider asking treating physicians whether their confidence/willingness to prescribe was changed by their participation. It would also be interesting to know whether non-participating physicians’ opinions are changed in any way after reading or being presented with the study results. Such a study should be relatively easy to do and would be of interest to our readers as well as to the studies’ sponsors.
Relevant analytical techniques are also evolving as illustrated in a Review Article by Emeritus Professor Roy Jefferis in which he describes how high-resolution analytical techniques can demonstrate structural micro-heterogeneity within endogenous proteins. The importance of this is that not all micro-particles are ‘seen’ as ‘self’ by the immune system. This is needed to establish immunological tolerance. This has potentially important implications for in vitro comparability studies. It also has implications for safety assessments of biologicals since an individual’s immunological response to such micro-particles is genetically influenced. Professor Jefferis notes that the ‘extensive polymorphisms within and between outbred human populations suggests that any given protein biotherapeutic may be allogenic, and potentially immunogenic, when administered across different population groups’. He postulates that all recombinant biologicals, ‘may be immunogenic, at least in a proportion of patients’, especially in patients treated chronically rather than just acutely with these products or those given products which differ structurally from endogenous proteins. He hypothesizes that gene sequencing techniques could allow for the identification of ‘susceptibility genes’ which could be used to stratify and select patients for treatment and points out that such stratification has major economic implications. Stratification has already identified increasingly small cohorts of patients for a number of diseases including cancer. This has already resulted in increasingly costly development and utilization of personalized therapies and unfortunately to date biosimilars have had relatively little impact on the cost of biological treatments. As pointed out by the author, ‘The conflict between our ability to deliver ever expanding therapies for human healthcare, from conception to death, and to provide equity in delivery will continue and become ever more contentious’.
The disconnect between potential and actual savings from the use of biosimilars is highlighted in a Perspective by Simoens et al. entitled ‘How to realize the potential of off-patent biologicals and biosimilars in Europe? Guidance to policymakers’. This manuscript attempts to offer guidance to policymakers on methods likely to successfully foster, ‘a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe’. The manuscript, which, ‘was commissioned by the Belgian National Institute for Health and Disability Insurance’ is the result of a series of roundtable discussions held in 2016−2017 between various stakeholders. It contains a wide variety of demand- and supply-side as well as gainsharing proposals, including suggestions concerning procurement, reimbursement, choice, switches, incentives and evidence. The authors propose that if implemented, the suggestions could do much to establish, ‘a long-term, multi-stakeholder, specific policy framework for off-patent biologicals and biosimilars’ and ‘a fair, competitive and sustainable market for off-patent biologicals and biosimilars in Europe’.
One obstacle to maximizing the impact of biosimilars is the lack of standardized approaches to their regulation. A Regulatory article entitled, ‘Regulation of copy biologicals in China’ describes how the Chinese Drug Registration Regulation (2007) pathway (and its later versions) classifies therapeutic biologicals and the principles and challenges of the copy biologicals guideline’. As noted in an Editor’s comment, the ‘copy biologicals’ approved in China might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union’. The lack of standardization and its implications have been mentioned in many prior GaBI publications and is the justification for describing, where available, country specific process descriptions, such as the subsequent article, ‘Biosimilar regulation and approval in Jordan’ by Ms Rana Musa Ali Al-ali “Malkawi” (Head of Clinical Studies Department, Jordan Food and Drug Administration) and colleagues.
GaBI has conducted a number of stakeholder meetings designed to improve understanding and standardization of best practice regulation of generics and biosimilars. The Meeting Report, ‘Quality assessment of biosimilars in Colombia – reducing knowledge gaps’ by Drs Elaine Gray, Paul Matejtschuk and Robin Thorpe (Deputy Editor-in-Chief of GaBI Journal) summarizes two such meetings. The first was an educational workshop held in 2016 to discuss evaluation of biosimilars and the second was a scientific meeting on quality assessment held in 2017. Both meetings were held in Bogota, Colombia provided a forum to exchange knowledge on best practices.
The Opinion entitled ‘Rationalizing FDA guidance on biosimilars—expediting approvals and acceptance’ by Professor Niazi which follows was the subject of the Commentary by Professor Kurki discussed above. Professor Niazi lists a number of specific proposals for how FDA could expedite biosimilar approval and use. The suggestions are clearly worthy of serious consideration. However, it should be noted that the author has a number of potential/real conflicts of interest mentioned in the competing interests paragraph of the article. Examples include his association with Karyo Biologics, LLC and Adello Biologics ‘which have several products at various stages of FDA approval’ and his consulting and publication activities. Conflicts of interest are both common and not necessarily problematic. I have my own both as GaBI Journal editor and in some of my other academic and commercial activities. Experts are often ‘conflicted’. It is only problematic when authors omit them from their conflict statements.
The final Abstracted Scientific Content entitled ‘A call for coherence in EU legislation to promote generics’ summarizes a recent proposal for improved biosimilar legislation published in the Journal of Pharmaceutical Policy and Practice. The major action proposed is the use of exclusivity waivers to improve biosimilar access. The authors point out that data exclusivity waivers are already in existence in some non-EU countries including Chile, Colombia, Guatemala and Malaysia and that EU governments have the right to also grant compulsory licences. The authors propose that such waivers should also be considered in the EU and that the lack of legal coherence within the EU prevents generic medicines from being able to more easily enter the market early.
While not all positive, change is clearly ‘in the air’ globally. As Yogi Berra said, ‘it is difficult to make predictions, especially about the future’. Hopefully some of the changes being made will improve the access of more patients to effective, affordable Generic and Biosimilar treatments.
Disclosure of Conflict of Interest Statement is available upon request.
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