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
Disclosure of Conflict of Interest Statement is available upon request.
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