The rate of successful development, regulatory approval and marketing of both new and follow-on biological treatments has continued to accelerate despite, and in some cases because of, a seemingly endless list of disturbing world events. This GaBI issue contains manuscripts discussing a variety of topics that are already or promise to be critical to maintaining this progress.
Interchangeability and substitution are related, but very distinct terms with respect to both biosimilars and generic drug products. The first Commentary by Rieger et al. from Western Sydney University details what the authors describe as the misleading use of the terms in promotional materials used by some competing biosimilar product manufacturers in Australia. The authors claim that the confusion created by such promotional materials as well as by the Australian Government’s ‘substitution’ rules have limited the uptake of biosimilars. They propose that the preferred solution to this problem is that physicians and pharmacists need to collaborate and then clearly communicate, ‘the boundaries, clinical goals, appropriate approaches to biosimilar substitution …’ The authors acknowledge that such an approach would require ‘substantial efforts’ and that, ‘there are no specific roadmaps’ for even opening discussions of such a collaboration. They suggest that the first step is to simply, ‘pick up the phone and strike up a conversation’. I totally agree with the need for increased and improved physician/pharmacist interactions concerning these issues. However, while I have minimal personal experience with Australian healthcare realities, I am skeptical that either physicians or pharmacists have the time or financial incentives to engage in such activities. I believe strongly in the need to base decisions on the answer to the WIIFM (What’s in it for me?) question. In my view, until/unless these busy professionals are compensated for such collaboration, those most likely to benefit from increased biosimilar uptake; health insurers and governments who are paying for the use of biologicals, must instead take responsibility for improving substitution rules, educating the public, controlling any misleading product promotion, and providing reimbursement for the time spent by providers promoting more rational medically/pharmaceutically indicated product selection.
Interchangeability is also the focus of the first Original Research by Mr Yuqi Li and Professor Dr Shein-Chung Chow from the Department of Statistics at Duke University. The authors present details of a statistical method, the interchangeability index. They claim their methods can predict, with a specified level of statistical assurance, whether a follow-on product, provided it meets certain specific criteria, would, ‘produce the same clinical result as the reference product in any given patient’. The authors make clear that the index is ‘only practical for a valid crossover switch design’ and that it only addresses the first interchangeability requirement of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). They present the results of multiple in-silico simulations that support their claims. They acknowledge the need for validation of their methods by performing Food and Drug Administration (FDA) approved switch or alternation design studies. Because of my limited statistical expertise, the decision to publish this manuscript was based solely on the opinions of external reviewers, but if/when such validation is provided, the methods might be used to decrease the number of clinical studies required to declare a biosimilar product to have met the criteria for interchangeability. I would be especially appreciative of any comments from readers, whether positive or not, about the validity or potential of the methods proposed.
The second Original Research by Piñeiro et al. presents an evaluation of the chiral switch ‘evergreening’ strategy used by the manufacturer (AstraZeneca) of omeprazole and esomeprozole. A very large number of common non-biological medications are racemic mixtures. Examples other than omeprazole include ibuprofen, cetirizine, ofloxacin, ketoprofen and fluoxetine. When the patent expires for an originator product that was originally marketed as a racemic mixture, it may be possible for the manufacturer to exclusively market a single enantiomer that is present in the racemic mixture (the switch strategy). Occasionally the single enantiomer has superior pharmaceutical characteristics and therefore produces superior clinical efficacy or less toxicity. Often however there is no rational justification for switching from a similarly effective racemic mixture to the patent protected, more expensive single enantiomer. As described in this case study, gaining marketing approval for the follow-on single enantiomer allows the manufacturer to benefit from the reputation and market share of the racemic mixture while gaining extended marketing exclusivity. Even if the removed enantiomer is merely inactive; the marketing can merely emphasize that an inactive or much less active chemical has been removed. When successful, such a marketing strategy can produce enormous profits as evidenced by the commercial success of esomeprozole. These strategies are likely to continue to produce difficult to justify healthcare costs unless/until payors develop successful ways to educate and convince both patients and prescribers to resist any unjustified use of such products. Hopefully, publishing manuscripts that explain the strategy will be part of the solution to this problem.
The Review Article by Adjunct Associate Professor Hoch et al. from Singapore covers, in detail, the manufacture, testing and regulation of the currently small, but rapidly growing number of important cell, tissue and gene therapy products (CTGTPs). The authors review how some CTGTP products work, the challenges associated with their manufacture, testing, quality control, and regulatory approval. Differences are reviewed that exist between CTGTPs and traditional biological products as well as the regulatory, manufacturing, quality assurance, technology, expertise and manpower issues these differences create. Finally, the authors propose potential solutions to these problems, including development of global regulatory frameworks, international regulatory harmonization, outsourcing of manufacturing expertise, and incorporation of automated manufacturing techniques. They also briefly discuss the need to provide expedited access to these important, but extremely expensive and often single patient, therapies, especially in resource poor environments. The manuscript, in my view, is required reading for anyone interested in this rapidly expanding therapeutic class; one that contains a growing number of products that provide revolutionary, often lifesaving, treatments for a growing list of both rare and common diseases.
The final, Sponsored Article summarizes an online roundtable discussion of how ‘front-loading’ of improved analytical, structural, and functional characterization of biological products can be used to reduce biosimilar development costs and decrease the number of clinical trials needed to obtain marketing approval (registration) of biological products in the UK. The speakers are all experts in this area who are actively involved in providing these services or advising the pharmaceutical industry on the development and application of such analytical techniques. While it is not clear how effectively such ‘front loading’ would decrease the number of clinical trials necessary to obtain approval outside the UK, the techniques mentioned clearly have great global potential to improve the non-clinical characterization and comparison of various biological products by both regulators and manufacturers.
Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal
Disclosure of Conflict of Interest Statement is available upon request.
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