This issue of the GaBI Journal is being published during one of the most turbulent periods in over a century. A deadly pandemic is raging, the global economy is stressed, and the negative impacts of global weather changes as well as both the number and impact of regional conflicts are all increasing rapidly. While these facts make it difficult to concentrate on what might seem routine, it is important to consider how important scientific publications are to surviving such crises, including the role of scientific publications to the development of vaccines and identifying best practices to treat newly emerging diseases. The health of our families and our environment remain our primary focus, but all of us involved in publishing scientific research must acknowledge how critical it is for all of us, including those involved with publishing medical journals, to pursue truth through science. This role includes countering ‘fake news’ and the fear it generates so that proven therapies are utilized, and unproven or even dangerous nostrums are rejected. By doing so we can help to make scientific advancements both more available and accepted by the entire world population. It is with this goal that our work continues.
The Editorial in this issue by Professor Alain Astier concerns a study reported in the prior issue of the GaBI Journal that compared injection pain after administration of either an adalimumab biosimilar or the original formulation of the originator product. Professor Astier made the claim that, ‘As with new molecules, the published clinical trials of biosimilars mainly focus on major side effects, such as haematological, cardiac or neurological disturbances. As a result, effects without major clinical consequence from the medical practitioner’s point of view, such as pain during injections, low intensity itching or even slight fatigue, are poorly reported and thus underestimated. This is even more evident in the clinical trials requested for the registration of a biosimilar. However, these effects often cause discomfort for patients and can play a fundamental but poorly evidenced role in the acceptability of the biosimilar and in the prescriber’s willingness to use it’.
While most would agree that minor adverse effects can have a major effect on patient adherence and that these are seldom ‘focused on’, they are in fact investigated, reported. For example, the European Commission’s Humira registration document (https://ec.europa.eu/health/documents/community-register/2006/2006060111606/anx_11606_en.pdf) includes the following statement, ‘Injection site reactions: In the seven controlled trials, 17% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 11% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product’. In addition, the US Food and Drug Administration (FDA) patient package information includes injection site reactions as one of ‘Most common adverse reactions (incidence; 10%)’. This document states that, ‘The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions … compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation’. While such information is not emphasized by manufacturers, these data are gathered and reported. However, as pointed out by Professor Astier, the clinical implications of these data should be given more attention. Because these reactions play a fundamental role in the acceptance and use of these products, practitioners who prescribe these products need to be aware of such information, to consider the role of injection reactions in adherence, and both ask about and report all adverse effects to regulators, even if considered ‘minor’. This issue is likely to be an important influence in how well, for example, any or all of the COVID-19 vaccines are accepted. This acceptance will be critical in determining how long it takes for the herd immunity we need to defeat this virus to be achieved. It should be noted that practitioners also must be aware of how such data can be misused in the marketing of various products. For example, as I have previously stated in the Latest features in GaBI Journal, 2020, Issue 3, the comparison reported was made between the older, citrate containing Humira formulation rather than to the newer, currently available, citrate free originator formulation. The original study and this follow-up discussion of its implications also illustrate the importance of product formulation changes. Practitioners (and perhaps patients as well) need to carefully read and periodically review product inserts, studies that compare products, and any marketing materials that cite these studies. There is also a need for regulatory guidance about which product formulation changes require additional studies as well as what kind of studies need to be done when either an originator or biosimilar is reformulated. Finally, this issue is not confined to the many (five in the UK, for example) adalimumab products on the market. Citrate is used to control the pH of many other subcutaneous pharmaceuticals including etanercept (Erelzi), anakinra, somatropin (Nutropin, Saizen), and dulaglutide. Comments from our readers on any aspect of this and related topics are always welcomed.
The Commentary in this issue is ‘A white paper: US biosimilars market on pace with Europe’ by Dr Madelaine Feldman and Mr Michael S Reilly from the Alliance for Safe Biologic Medicines. These authors present data in support of the hypothesis that, ‘Although the European Medicines Agency (EMA) pioneered the framework for biosimilar regulation, the US Food and Drug Administration (FDA) is moving at approximately the same pace as EMA based on the number of approvals at the same time after implementation of its regulatory pathway’. The authors reviewed anti-competitive behaviours used by originator manufactures to delay approval of follow-on products. They discuss in detail the 2018 US FDA’s Biosimilars Action Plan (BAP to facilitate the development of the biosimilars market and increase competition for biological drugs. The BAP was designed to: a) make biosimilar and interchangeable product development and approval more efficient; b) clarify the scientific and regulatory requirements for biosimilar product development; c) improve understanding of biosimilars among patients, healthcare providers and payers; and d) make it more difficult to ‘unfairly delay market competition’. The article provides useful data and perspective. While it is understandable, given when the article was written and submitted, it is unfortunate that it does not include a discussion of COVID-19 vaccines and the ‘Warp Speed’ programme. We look forward to receiving articles from our readers that discuss the role of generics, biosimilars and vaccines in dealing with global pandemics.
The first Original Research by Dr Jolita Seckute et al. reports results of their study of the purity and physicochemical stability of a bevacizumab biosimilar (ABP 215), after preparation and storage in intravenous bags. They reported that recommended concentrations of the product maintained stable quality and activity following dilution, extended storage and simulated infusions that represent worst-case handling conditions. They concluded that the data ‘supports the advance preparation and storage of ABP 215 in intravenous bags for infusion’. This is a very practical and clinically meaningful conclusion, especially given the cost of bevacizumab products. There is a clear and obvious desire to be able to avoid immediate reconstitution prior to use. Additional regulatory quality studies are encouraged to see how this stability compares to that seen for other bevacizumab products. It would be useful to know whether it would be possible to administer portions of a single IV bag to multiple patients. This would be especially useful and cost saving for use of these products in paediatric patients since such use would however be ‘off-label’ since the current product labelling does not allow for the use of a single vial to treat multiple patients or even to treat the same patient on multiple occasions.
The second Original Research by Dr Arianna Bertolani and Mr Claudio Jommi examines the important questionable relationship between local biosimilars policies and the healthcare savings they are expected to generate. The authors examined whether/which policies designed to increase use (uptake) of biosimilars by Italian Healthcare Organisations (HCOs) are accompanied by logical, realistic and effective methods to reallocate any savings generated. The authors found ‘a high level of proactivity by Italian HCOs regarding actions on prescribing behaviour for off-patent biologicals. However, it seems that structured actions aimed at appropriately reallocating resources gained through patent expiration are still lacking’. It is not clear whether or how unique this situation is; however, if this deficiency persists, in Italy or elsewhere, it will undermine support for the use of biosimilars from practitioners and patients. In the Perspective by Godman et al. at the end of this issue, the implications of this study are discussed by Dr Brian Godman et al. who conclude that it ‘is important to stimulate increasing use of biosimilars in a way that addresses the accelerating resource challenges brought about by the expanding use of medicines in ageing populations as well as the need to pay for new, high-priced medicines that address areas of previously poorly or untreatable diseases’.
The Review Article by Adjunct Associate Professor Sia Chong Hock et al. discusses the important issue of pharmaceutical Data Integrity. While data integrity has been a focus of the pharmaceutical industry for many years, recent, often inflammatory rhetoric concerning claims of intellectual property and data theft with respect to COVID-19 vaccine development has recently increased interest in this topic. As the authors note, ‘With the growing use of computerized systems and rising prevalence of outsourcing manufacturing processes, ensuring data integrity is becoming more challenging in an increasingly complex pharmaceutical manufacturing industry ’. The authors discuss some recent legislative and regulatory attempts to deal with this problem and observe that, ‘their overall effectiveness is yet to be determined ’. They also conclude that, ‘these legislation and guidance are insufficient in maintaining data integrity in the industry when used alone ’. Finally, the authors review some potential solutions which the authors suggest, ‘if successfully implemented, can address the issues associated with data integrity, and raise the standard of pharmaceutical and biopharmaceutical manufacturing worldwide ’. While it remains to be proven that these or other solutions will be effective, more effective solutions are clearly needed.
I would like to close with a quote from Albert Einstein: ‘The right to search for the truth also implies a duty; one must not conceal any part of what one has recognized to be the truth’.
Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal
Disclosure of Conflict of Interest Statement is available upon request.
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