Category: Editor’s Letter

The article 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.

Reference
1. Mylan failed to ‘immediately envisage’ the compounds in Merck’s patent covering Januvia. 14 October 2022. Available from: https://haugpartners.com/article/mylan-failed-to-immediately-envisage-the-compounds-in-mercks-patent-covering-januvia/

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

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2023 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

It seems as if the entire world is dealing with a lack of trust, even in many things that have enriched and sustained human development, including our neighbours, teachers, the press, corporations, politicians, religious leaders, scientists, academic institutions, governments, and even the basic concepts of democracy. Lack of trust is posing a direct threat to our health by limiting acceptance the use of even the most well-proven, basic medical advances such as vaccines.

Lack of trust also appears to be at least one factor limiting the adoption of biosimilars discussed in the first Original Research in this issue; a study funded by Arnold Ventures, a philanthropy founded by  Laura and John Arnold, dedicated to tackling some of the most  pressing  problems  in the United States. The author of this data rich report, Professor James C Robinson, presents his review of the associations between variations in biosimilar adoption in different Italianand German regions and measures of social trust. His review included analyses of national data from 20 European countries that compared measures of social and political trust to the uptake of 20 biosimilar products used for chronic immunologic and acute cancer treatments. He found that adoption of biosimilars was directly related to social trust and trust in government, but  not  to  the use of economic incentives. He suggests that for incentives to be effective they should ‘ensure that the benefits accrue to the populations most affected’. Unfortunately, no data were presented that prove that such redirection of incentives is effective, no details  were  provided  of  how this would best be done, and it is unclear whether or how redirecting incentives would impact the underlying lack of trust. The manuscript includes a reference to the important work of Andersen and Griffith (Milbank Quarterly. June 2022. https://onlinelibrary.wiley.com/doi/10.1111/ 1468-0009.12564) who have suggested ‘that the appropriate response to mistrust in healthcare organizations is not a doubling down on efforts to increase citizen trust but a redesign of those organizations to improve trustworthiness’. As past, current, and developing epidemics have demonstrated, a lack of trust is limiting the use and impact of both treatments and prevention methods that  have  been  proven to be effective. It appears, to this observer at least, that more research should be directed towards finding the most cost-effective ways to increase the trustworthiness of all our healthcare institutions.

Medical publications including GaBI Journal are not immune from issues of trust. This is because many potential and real conflicts of interest exist in the healthcare systems that generates manuscripts. The GaBI publication staff, including myself as well as our reviewers and readers, must evaluate such conflicts when a manuscript is evaluated or published. All medical publications, including ours, use peer-review processes that are designed to minimize the effects of real or potential conflicts of interest and increase trust. This need to evaluate the possible effects of bias is illustrated by the second Original Research in this issue. Possible bias on behalf of the authors, participants, reviewers, editors, and publication personnel all had to be considered during the evaluation of this manuscript.

The Alliance for Safe Biologic Medicines (ASBM), an organization that is financially supported by innovator and biosimilar producing pharmaceutical companies, sponsored the study reported here. The first author, Dr Ralph D McKibbin, is a practicing gastroenterologist who ‘provides disease state lectures’ for pharmaceutical companies that produce biosimilars and chairs the ASBM’s executive committee.

The third, Review Article by Dr Mihaela Buda from the European Pharmacopoeia Department, European Directorate for the Quality of Medicines & HealthCare describes the multi-stakeholder process that was used to develop the European Pharmacopoeia Commission’s Infliximab monograph. This was ‘a testcase for developing public standards for monoclonal antibodies’. The complex pharmacopoeia process described  was  designed to produce an informative, unbiased, product monograph for use by multiple stakeholders, including representatives of industry, practitioners, the public, and regulators. While the author cautions why the monograph ‘may therefore not be sufficient for a public standard’, the process and the monograph describe a method to develop unbiased, hopefully ‘trusted’, biological product evaluation information. This manuscript illustrates how conflicts of interest can influence medical publication. I am positively biased towards such a pharmacopoeia process because I spent 30 years as a volunteer member of the US Pharmacopoeia (USP). Readers, whether familiaror not with pharmacopoeias, should consider this potential bias when they read my comments, the Infliximab monograph, or this manuscript. I personally believe that if such monographs were both properly ‘marketed’ and modified to contain more information for lay readers, that both members of the public and practitioners might more often use such pharmacopoeia monographs as trusted sources of information when making decisions about therapeutic products.

The fourth and final Meeting Report by Mr Michael S Reilly and Professor Philip J Schneider describes the ASBM and GaBI co-sponsored, multi-stakeholder webinar. The webinar was funded by the ASBM. It was designed and conducted in collaboration with GaBI. The goals of the webinar included the uptake, physicians’ trust in prescribing and switching, European challenges, patients’ concerns, healthcare providers’ roles, and educational needs with respect to biosimilars. The manuscript describes in detail both the presentations given by experts and the content of panel discussions as well as specific questions posed by participants. These discussions included the role of trust in biosimilar acceptance and use in the USA, Europe, Canada, Australia, and developing countries. There were a variety of related issues discussed including the roles played by patient advocacy groups and biosimilar training programmes, attitudes towards and effects of forced substitution, the possibility of relaxing approval processes, and drug shortages. Readers are encouraged to consider both the material presented as well as any potential conflicts of interest that existed on behalf of either of the sponsors (ASBM or GaBI itself), the speakers, moderators, and even the participants. Whether or not there were potential, or even real conflicts, it is important to realize that data such as those presented during the webinar, as well as opinions expressed by participants, could be important resources to use when educating stakeholders.

As alluded to in my introductory comments about vaccines, some of the tragedies that have resulted from recent epidemics were the result of the ever-decreasing trust in both healthcare providers and our therapeutic products (including biosimilars). The lack of trust requires all stakeholders to search for ways to increase trust in both therapeutic products themselves and the information used to justify their use.

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

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2023 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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.

Copyright © 2022 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

The first GaBI Journal issue of 2022 comes at a time of both hope and despair. While the COVID-19 pandemic continues to cause significant global morbidity and mortality; especially in resource-poor countries, both the pace and direction of changes are beginning to produce some encouraging signs. Positive trends are in part the result of the continuing increase in our understanding of the virus itself, its treatment, and public health actions that are effective in limiting its spread. The availability of highly effective vaccines, antibodies, and antiviral medications have greatly limited infections and improved outcomes. Biological products, both innovator and biosimilar versions, as well as generic drug products are decreasing treatment costs and increasing the availability of effective treatments. Of special note is the increasing ability of resource-poor nations to produce their own versions of innovator products without patent constraints. Perhaps the most impressive example of this is, ‘The World’s COVID-19 ­Vaccine’ developed by the Texas Children’s Hospital at Baylor University and funding support of the Bill and Melinda Gates Foundation. This partnership has demonstrated that it is possible to overcome availability issues inherent in the for-profit pharmaceutical industry.

In contrast to the slowly improving outlook for the COVID-19 pandemic, the world is witnessing an increasing number of brutal hostilities both within, e.g. Syria, Libya, Mali, Ethiopia, and Yemen, and between nations that threaten human health. Especially dangerous examples include the invasion of sovereign nations by neighbouring countries, e.g. Georgia and Ukraine; that has produced a level of destruction and human suffering not seen in decades. These hostilities are causing untold suffering of innocent civilians, as well as of combatants. They have also blocked access to not only medicines, but also to medical treatment, hospitals, and health professionals. Global hostilities are depriving millions of people, including children, the disabled and the elderly of basic human needs. including shelter, food, and water, producing both medical and psychological damage that will consume health care and other resources for decades to come. Hopefully, future access to effective, reasonably priced generic and biosimilar drug products will help countries deal with these issues. This issue of the GaBI Journal contains articles that suggest some ways in which access to such products could be improved.

In a Letter to the Editor, Adjunct Professor Pekka Kurki reviews the history of switch studies done to approve EU marketing of biosimilars. The author concludes that such products should be made interchangeable with their reference products without the need for systematic clinical switch studies. The clinical evidence reviewed by Adjunct Professor Kurki includes 178 biosimilar clinical switch studies that failed to find any evidence of switch-related adverse effects, as well as recent reviews that also failed to find evidence of switch-related adverse effects. The author also cites the very limited power of such switch studies to identify or rule out rare adverse events and suggests that switch studies be replaced by pharmacovigilance and pharmaco-epidemiological studies instead. Readers, including those involved in the development of innovator products and those who simply disagree based on their own experience or their own review of the literature, are encouraged to submit letters presenting any alternative, supportive, or clarifying opinions.

The first Review Article was submitted by Drs Mihaela Buda, Olga Kolaj-Robin, and Emmanuelle Charton from the European Pharmacopoeia Department at the European Directorate for the Quality of Medicines & HealthCare (EDQM). Drs Buda et al., provides an overview of strategies to overcome the challenges of elaborating monographs on biotherapeutics. The opinions expressed in this article were based on discussions with various European stakeholders at scientific meetings, as well as on the experience of the authors in developing standards used to produce biosimilar pharmacopoeial monographs. The article should be very useful both for those who use or utilize the European or other pharmacopoeias. as well as for anyone unfamiliar with these useful publications.

The second Review Article by Adjunct Associate Professor Sia Chong Hock et al., from the National University of Singapore covers the timely topic of the challenges associated with the best-practices manufacture, storage, distribution, and regulation of both new and traditional vaccines. The COVID-19 pandemic has produced many examples of the problems remaining to be solved in, ‘the equitable distribution and availability of safe, efficacious and good quality vaccines’ in a way that increases the efficient use of vaccines to prevent or mitigate the effects of infectious diseases and safeguard public health. The authors discuss how a lack of adequate controls of the manufacture, storage, distribution, and possibly regulation of vaccines contribute to, ‘the continued existence of poor-quality vaccines’ as well as costly waste and decreased efficacy of vaccines. The review should be useful for anyone involved in the testing, evaluation, procurement, or administration of vaccines and vaccination programmes.

The final Review Article by Dr Robert Janknegt and Ms Marloes Dankers, describe the System of Objectified Judgement Analysis (SOJA) and then explains how it was used at Dr Janknegt’s hospital in the Netherlands to provide clinicians with an objective, evidence-based method to evaluate which of the increasing number of competing, long-acting insulin products to prescribe for their diabetic patients. Criteria utilized in the SOJA included: effectiveness, safety, tolerability, and ease of use. Dr Janknegt explains that because application of these criteria to long-acting insulin products produced essentially identical scores, it was decided that acquisition cost and individual patient characteristics be used to determine the choice of formulary products. The manuscript should be helpful for other hospitals when deciding on which long-acting insulins to include on their formularies. It is likely that the SOJA may also be useful to evaluate other medications. Comments are welcomed from readers who disagree with the use of the general approach described, or who want to discuss application of the SOJA to a different multisource product, as well as those familiar with different decision support systems.

The Opinion Article by Dr Pablo Matar raises an important issue concerning the possibility of, ‘loss of bioavailability over time’. Much has been written/claimed about how even minor changes in the manufacturing process can affect the qualities of a biological; whether an innovator or follow-on/biosimilar product. Less has been written about the fact that changes in manufacturing processes over time can also have important effects on originator products. Dr Matar points out that, ‘Current regulations do not require a given biosimilar to remain similar to its reference biological over time’ yet no post-marketing comparative bioavailability studies are required by regulators. Since any change in the manufacturing process can alter the final biological product, either of any two products deemed to be ‘biosimilar’ at one point in time are subject to divergent changes (‘drift, evolution and divergence’) that could result in later, undetected non-equivalence. To deal with this problem the author suggests: 1) pharmacovigilance systems should be strengthened; 2) interchangeability standards are needed to deal with this possibility; and 3) that harmonized regulatory definitions of comparability versus interchangeability need to be established. While the issues are clear, actual evidence-based recommendations for specific, proven effective changes needed in the regulatory approval or monitoring process were not well described. It is also not clear, to this reader at least, which (or even whether) pharmacovigilance programmes can reliably detect all clinically meaningful changes in biological product effects. The effects of manufacturing process changes over time need to be monitored for all innovator products, whether there are any approved biosimilar products available or not. Unfortunately, it is not clear which, if any, in vivo or in vitro methods, including those required by the US Food and Drug Administration to declare interchangeability, are adequate to detect all clinically important differences in product performance. Reader comments on this complicated, important issue are encouraged.

I will close with my wishes for a more peaceful world with more equitable distribution of all resources needed for a long, rewarding, and healthy life for all peoples of the world.

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

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2022 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

This issue of the GaBI Journal contains only a limited number of articles, but these include two scientific very data-rich articles and an interesting and important expose on the use and misuse of products to treat COVID-19 patients. All three articles have potentially major implications for the global struggle to deal with the current COVID-19 pandemic; either with respect to the proper use of biosimilar products to safely reduce COVID-19 related and non-related pharmaceutical expenditures, as well as to the effects of the pandemic on the criminal use and abuse of human and veterinary pharmaceuticals and other products, e.g. disinfectants.

The Original Research by Dr Lyndsay Davies et al. from Liverpool, UK investigates ‘the quality and in-use stability of the trastuzumab biosimilar ABP 980 (KANJINTI™) in both concentrated multi-dose bags and following dilution and extended storage in intravenous bags and elastomeric devices, to address the stability requirements of different global pharmacy practices’. The authors present results of their extensive, in-depth evaluation (funded by Amgen) of an important Herceptin® biosimilar product. The data presented should help pharmacies in both resource-rich and resource-poor countries to prepare and administer this important biosimilar product and thereby increase patient access to this product. 

The first Review Article by Ms Josette Sciberras et al. from Malta discusses their view of the impact of the European IP framework on accessibility of biological medicines and makes some recommendations on how to improve this access. They suggest ways to potentially mitigate the negative effects on patents, such as increased sharing of knowledge between originator and other companies, developing a less complex patent regulation in Europe and having more transparent prices and costs related to R & D, manufacturing and public funding. They suggest that such changes could allow biosimilars to come to the market earlier thus improve patient access to biological medicines. While (as pointed out by our reviewers) few if any of the suggestions are novel, the vast amount of data collected, analysed and presented could be of use to anyone interested in biosimilar product development, especially for the European market.

The second Review Article by Dr Esteban Ortiz-Prado et al. from Ecuador and the UK describes some aspects of the impact of the COVID-19 pandemic on the use and abuse of biological products, both originator and biosimilars, in Ecuador. The narrative is based on publicly available information, e.g. from newspaper reports and legal proceedings, personal experiences of the authors, as well as data on tocilizumab provided by Welkom Medicamentos de Especialidad. It describes the effect the pandemic had on the use and even criminal abuse of biological products in this resource-poor country. It is likely that the abuses described in this article also occurred in many other resource-poor and resource-rich countries. In the US, certain personalities, and even major political office holders, have either directly promoted or contributed to similar, ongoing misuse of unapproved, ineffective and even dangerous antidotes. What is perhaps most concerning is the promotion by such people of the replacement of scientifically proven products, including biological and generic drug products, by unproven and known or potentially toxic products. In addition to vaccines, there are many biological, generic, and repurposed pharmaceutical products that have either already been shown to be useful or are being actively investigated for the treatment of COVID-19 patients. What happened in Ecuador and what is continuing in the USA illustrate how easy and dangerous it can be to return to the promotion and use of unproven and even clearly dangerous ‘snake oil’ cures of the past.

Readers are encouraged to submit similar reports for comparison or comments on the events in the USA, Ecuador, or elsewhere.

I want to both thank the GaBI staff, as well as all our authors, reviewers, and readers for all you have done to make the GaBI Journal possible. Your continuing hard work and support allows us to pursue the GaBI mission, ‘to foster the worldwide efficient use of high quality and safe medicines at an affordable price, thus advancing and supporting the idea of accessible, affordable and sustainable health care’. Finally, I want to wish you all a healthy, Happy Holiday season and New Year.

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

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2021 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

This issue of GaBI Journal contains articles dealing with some very practical issues related to the evaluation, describing, and use of generic and biosimilar products. These issues include the uncertainty associated with extrapolating results of studies that used small, non-representative study populations, study sites, or product types. These problems are evident in the evaluation of three articles in this issue. Other articles illustrate difficulties evaluating published opinions without access to the original data upon which such opinions were based: the need to evaluate the possible effects of real or potential conflicts of interest; and the lack of consistent regulatory approaches to important, non-pharmaceutical chemicals.

The first Original Research by Harikrishnan et al. from Malaysia contains results of dissolution and relative bioavailability studies of a generic etoricoxib product. The results are likely to be used to obtain regulatory approval to market this product as being generic to the innovator drug product. However, while the authors claim that they performed a ‘bioequivalence’ study, there are many reasons the dissolution and comparative bioavailability studies did not (and could not) truly establish ‘bioequivalence’. While comparative bioavailability studies are used by regulators to assume bioequivalence, only studies that assess actual pharmacological effects can do this. Additionally, the clinical study enrolled only a small number (N = 26) of healthy, only male subjects. No elderly subjects or children were included. Perhaps most important, no women were enrolled. It is not possible to evaluate the authors’ explanation that they were ‘unable to recruit’ women since they do not provide a clear description of whether or how they attempted to recruit female volunteers who could not become pregnant, e.g. post-hysterectomy or post-menopausal women. In some countries inclusion of women is required for such studies. Apparently, this is not required in Malaysia. Despite the very small, unrepresentative population, the authors conclude that the generic product, ‘was therefore found to be bioequivalent with respect to the reference drug’. In fact, the data showed only that the product, ‘met regulatory requirements for bioequivalence’. Post-marketing studies that include evaluation of actual pharmacological and toxic effects in the general patient population, including in women, unhealthy or older adults, and children are needed to decide whether this, or any other generic product is truly bioequivalent. It is unfortunate that regulators in Malaysia and other countries do not require studies in a more representative population, especially in women. Requirements for marketing of generic drugs should, in my opinion, include some assessment of how well the characteristics of the population studied, including age and sex distribution, matches the population that is likely to receive the drug.

The second Original Research by Glerum et al. describes a pilot study of 207 drug switches made at 16 Dutch pharmacies. The authors report that ‘most’ of these switches were the result of either drug shortages (32%, N = 66), the Dutch price-based tender system (23%, N = 47), and the financially favourable margin such switches produce for pharmacists (11%, N = 21). The causes for drug shortages are important to understand, and the use of biosimilars and generics is an important way to mitigate the effects of such shortages. Studies of these issues are important, but the many limitations of this pilot study require that the findings be replicated and extended before definitive conclusions can be made. Limitations include the fact that only 19 of 200 pharmacies that were approached to provide date were willing to participate, and only 16 had actual visits included in the data. This greatly limits the generalizability of the study findings.

The first Review Article of Canadian biosimilar substitution policies by two representatives (Professor Philip J Schneider and Mr Michael S Reilly) of the Alliance for Safe Biologic Medicines. It presents their comparison of the Canadian approach to that used in the US and Europe. The authors state that they, ‘find evidence that in some cases non-medical switching may pose a risk to patients and suggest that Canada could learn from more mature markets, such as those in Europe, where switching policies better consider patient needs, preserve physician choice and promote market competition’. These conclusions and suggestions are limited by the lack of data showing that changes are either effective or needed.

The second Review Article by Adjunct Associate Professor Sia Chong Hock et al. reviews the microbiological, scientific, and regulatory aspects of hand sanitizers. This topic is clearly topical, and these are clear examples of products with a multitude of ‘generic’ commercial products available, but which are not regulated as drugs. The authors review many important, practical issues including the reality and relevance of claims that they, ‘kill > 99.9% of microbes’. They also review methods used to test these products as well as the microbiology of bacteria, fungi, and viruses; relevant US Food and Drug Administration (FDA) policies, methanol contamination, and their proper disposal. The authors explore some common myths and the lack of a regulatory framework for their evaluation. They propose some solutions including education of healthcare workers and the public. They conclude that, ‘hand sanitizers are assets to hand hygiene, especially during the COVID-19 panduic, provided they are used properly. Therefore, educating the public on hand sanitizers, including misleading claims and proper use, is crucial’.

The Pilot Study by Messrs Michael Wilcock and Andrew Pothecary presents results of how well the use of biologicals in dermatology conforms to NICE guidelines for the use of biologicals in Dermatology patients. The study is limited by its single (750 bed) secondary hospital center design as well as the small (N = 33) number of patients started on a biological. The study included only 17 newly started patients and 16 patients switched from a prior biological. In this limited population, the authors found that, ‘the local guideline was followed with patients commencing treatments other than biosimilar adalimumab’ and that these exceptions were made, “for valid reasons”. Studies in larger, more diverse populations are needed to evaluate how representative these results are to dermatology practices in either other UK or non-UK sites.

The Research News abstracted by Dr Charles L Bennett of a published study that described the use of a biosimilar epoetin product in the US. The authors (who declared relevant conflicts of interest) concluded that, ‘biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the US is variable’. The authors stated that, ‘Few oncologists understand substitution and interchangeability of biosimilars with reference drugs’. It is not clear what definition of ‘few’ was or what actual data supported this claim. It is also not clear what data supported the claims that, ‘Epoetin biosimilar is new to the market and physician and patient understanding is limited’ or that, ‘the development of epoetin biosimilar is not familiar to oncologists’. Evaluation of all these important claims will require interested readers to access to the data actually used by the authors to make these claims.

Neither the study, evaluation, use, or reporting/publishing on generic and biological products is simple. I want to take this opportunity to thank the authors, reviewers, and publishers for their efforts to provide data on these important issues.

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

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2021 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

The current pandemic has greatly amplified the already existing disparities in access to health care. Many countries are facing a lack of access to or funding to pay for the vaccines, medications, protective equipment, and supplies; even ­oxygen to deal with either COVID-19, wars, famine, and other life-threatening conditions. Patients, families and governments are all looking for ways to stretch their healthcare budgets to deal with these realities while faced with pandemic associated decreases in income and tax revenues. Finding ways to increase the use of generic and biosimilar therapeutics could provide at least a partial solution. However, as demonstrated by manuscripts in this as well in many previous GaBI Journal issues, the use of generics, biosimilars and other follow-on biologicals continues to generate only a small portion of what is possible. Manuscripts in this issue deal directly or indirectly with some of the many reasons for this economic underperformance including: a) the high costs associated with developing and marketing follow-on products; b) practitioners’ resistance to prescribing them; c) patients’ resistance to their use; and d) the failure of some governments and even some non-governmental payors to use every tool at their disposal to increase the use and decrease the cost of both originator as well as generic and biosimilar products.

The first Original Research by Kelly Canham and Claire Newcomb (both employees of Viatris/Mylan Pharma UK Ltd, the manufacturer of the product studied) used a simulation study design to evaluate the ability of study patients, caregivers and healthcare providers (HCPs, N = 79) to successfully use an autoinjector to deliver two doses of an etanercept biosimilar into a foam pad. While not stressed by the authors, simulations have the advantage of being much less expensive than clinical trials to perform. In addition, the inclusion of both patients and HCPs can decrease marketing costs while decreasing both patient and provider resistance to switching.

In the second Original Research, Somaily et al. describe the clinical outcomes in a small group of patients with rheu­mato­logical disorders in Saudi Arabia who switched from the originator infliximab to a biosimilar. The patients included 6 with rheumatoid arthritis (RA), 5 with ankylosing spondylitis (AS), and 2 with Behçet’s disease (BD) who were, ‘required to switch to the biosimilar version due to the originator becoming unavailable’. One year after the switch, the authors, ‘did not observe any significant differences in tolerability or efficacy between biosimilar and originator. Furthermore, disease activity significantly declined in RA patients following biosimilar treatment’. While limited by the small sample size, such ‘real-life’ studies can be useful to overcome clinician and patient’s biosimilar resistance.

The third Original Research by Godman et al. presents the large volume of data the authors collected concerning prices reimbursed by European countries between 2013 and 2017 for three oral oncology medicines (imatinib, erlotinib and fludarabine). The authors also examined how often prices were re-evaluated both before and after the introduction of generic versions. Prices varied widely in the European countries studied and there was limited price erosion over time in the absence of generics. The authors found no correlation between population size and price, infrequent re-evaluation of prices even when generics were introduced, and that prices of on-patent oral cancer medicines were higher in countries with higher gross domestic products per capita. The authors failed to find evidence of re-assessments of the ‘price, value and place in treatment of patented oncology medicines following the loss of patent protection of standard medicines’ and speculate that the use of such reassessments could be more effectively used as a negotiating tactic to ‘positively impact global expenditures for oncology medicines’. While the evidence provided by the authors’ hypothesis is largely anecdotal, and while failure to find evidence of reassessments does not necessarily mean there were none done, clearly there is a need to more effectively use generic oncology medicines to lower prices paid/charged for these drugs. The authors’ call for continual reassessment of the value (cost per benefit gained) of these drugs is clearly logical and worth exploring.

The first Review Article by Zuccarelli et al. discusses the European Union (EU) regulatory framework and emerging trends in biosimilar drug development. The authors examined all EU marketing authorization applications prior to December 2019. They noted an ongoing evolution in the authorization processes over time as well as a steady increase in total clinical trials, but a steady decrease in the average ­nu­­mber of trials per approved product. They also noted that products have been approved without requiring completion of any phase III clinical trial. Finally, no safety concerns were raised by their analysis of adverse event reports. These findings, if properly disseminated, might be useful to counter biosimilar hesitancy.

The second Review Article by Farhang Rezaei and Nassim Anjidani presents an overview of follow-on biological products in Iran. The authors found that while there has been a significant increase in the use of biological products in Iran, their proportional use compared to the total therapeutic market has recently remained constant. The authors conclude that Iranian patients’ access to life-saving biological medicines could be greatly improved if the use of follow-on, rather than originator, biologicals was increased. While Iran is facing many unfortunate geopolitical barriers, it is not the only country where use of follow-on and true biosimilar products is suboptimal. This underutilization decreases the savings generated and then used to pay for increased overall patient access to health care. Solutions are clearly needed to this problem globally.

The final Abstracted Scientific Content summarizes an article by Zhang et al. published in 2020 that reviewed the potential use of already approved (for other indications) non-oncology drugs for clinical cancer management. While there is clearly potential in this approach, this could also result in prolonged exclusivity, patent protection, and increased rather than decreased healthcare costs. The repurposing approach to drug development is more common than appreciated. It has been estimated that approximately 25% of the pharmaceutical industry’s income is generated by repurposed drugs [1, 2]. This topic is worthy of extensive discussion. Readers with expertise in this should consider submitting manuscripts dealing with such drug repurposing, also called repositioning, reprofiling, indication expansion, and indication shift.

All the suggestions mentioned in this issue, as well as others, are likely to be needed if the full potential of follow-on therapeutics to decrease healthcare costs are to be achieved. This could be an important step in slowing or reversing the growth in global disparities in access to health, food and all other basic human needs.

References
1. Naylor S, Kauppi MJ, Schonfeld JM. Therapeutic drug repurposing, repositioning and rescue part II: business review. Drug Discov World. 2015;16(2):57-72.
2. Talevi A, Bellera CL. Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics. Expert Opin Drug Discov. 2020;15(4):397-401.

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

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2021 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.