Repurposing non-oncology drugs for cancer treatment

Submitted: 15 March 2021; Revised: 17 March 2021; Accepted: 18 March 2021; Published online first: 24 March 2021

Cancer is one of the leading causes of mortality in the world today. The development of new drugs can reduce death rates, but these products are extremely expensive in terms of development time and money. This has led to the strategy of drug repurposing; whereby drug products already approved for noncancer indications are identified as potential cancer therapies. A review, published in Signal Transduction and Targeted Therapy [1], presents various promising repurposed non-oncology drugs for clinical cancer management.

The study also summarizes approaches used for drug repurposing and discusses the main barriers to uptake [2].

Drug repurposing and cancer treatment: an overview

When an already approved drug product is repurposed, pharmacokinetic, pharmacodynamic, and toxicity profiles of drugs have been already established in preclinical and phase I clinical studies. These drugs can thus rapidly progress to phase II and phase III clinical studies and the associated development time and cost of the cancer treatment can be significantly reduced.

The study notes that our understanding of cancer biology and the associated characteristics of cancer is increasing. If this is successfully coupled with repurposing studies that apply systematic screening of the entire pharmacopoeia together with advanced bioinformatics, new drugs for cancer treatment can be identified faster and at reduced cost.

The study provides a summary of non-oncology compounds that are already used for cancer therapy which are outlined below. It highlights the specific cancer characteristics targeted and distinguishes between those agents suitable for monotherapy or as drug combinations. For all the treatment options outlined, the study also provides a detailed discussion of how they effectively regulate at least one characteristic of cancer; or exert comprehensive anticancer effects by regulating multiple targets mediated by various alternative signalling routes.

Non-oncology drugs suitable for cancer monotherapy

Proliferative signal inhibitors
Cancer cells have an ability to maintain chronic proliferation. Non-oncology drugs which work by inhibiting proliferative signalling include rapamycin, prazosin, indomethacin. These had original applications as an immunosuppressant and anti-restenosis agent; in hypertension; and in rheumatic disease, respectively.

Cancer cell death inducers
Apoptosis causes cell death and prevents tumourigenesis once the cell is damaged or is placed under various physiologic stresses. Non-oncology drugs which work by inducing cell death include artemisinin, chloroquine and their related derivatives. Both of these medications are used to treat malaria and chloroquine is also a treatment for rheumatoid arthritis.

Cellular metabolism regulators
Cancer cells often have reprogrammed energy metabolism which supports malignancy by sustaining key characteristics of cancer, including uncontrolled cell proliferation, evading growth suppressors, and resisting cell death. Non-oncology drugs which work by regulating of cellular metabolism include etformin and disulfiram. The former is used to treat obese type-2 diabetes and the latter is an alcohol aversion drug.

Antitumour immunity activators
Some cancers, especially virus-induced cancers, can avoid immune surveillance or limit being eliminated by the immune system by somehow regulating both the innate and adaptive immune systems. Non-oncology drugs which work by activation of antitumour immunity include infectious disease vaccines:

Non-oncology drugs suitable for drug combination therapy

The study notes that, in some cases, compounds may not be considered for drug repurposing screening due to their low anticancer activity at known tolerated plasma drug doses described in previous indications. However, drugs that may be effective at higher dosage can be utilized through drug combination therapy. Here, a synergistic effect is produced by targeting alternative signalling pathways associated with certain cancer characteristics.

Tumour suppressor reactivators
There is now a bank of evidence that indicates a lack of crucial tumour suppressors can stimulate tumour growth. Many non-oncology drugs are being repurposed to target cancer cells that evade growth suppressors. Non-oncology drugs which work by reactivating growth suppressors include quinacrine and ritonavir. The former has previous indications for malaria, giardiasis, rheumatoid arthritis, and the latter for human immunodeficiency virus (HIV) treatment.

Cancer cell division interrupters
In cancer cells, the specialized DNA polymerase, telomerase, is expressed at high levels to counteract the normal cell growth and the division cycle. Non-oncology drugs which work by targeting telomerase and interfering with replication include curcumin, used to treat dermatological diseases, and genistein, used in the treatment of the menopause, osteoporosis and obesity.

Angiogenesis reducers
Tumour cells also stimulate angiogenesis to generate neovasculature, an important mechanism by which tumours obtain nutrients and evacuate waste products. Non-oncology drugs which work by decreasing angiogenesis include the infamous thalidomide, originally used to treat the symptoms of morning sickness, which is now used as a sedative and antiemetic drug; and itraconazole, an antifungal agent.

Cell invasion and metastasis suppressors
Tumour invasion is the mechanism by which tumour cells spread to the surrounding environment, while tumour metastasis is where cancer cells leave the primary tumour and migrate to a new location where they generate new (secondary) tumours. Some non-oncology drugs work by suppression of invasion and metastasis. These include Barberine, used to treat bacterial diarrhoea and niclosamide, an antihelminthic drug.

Genome instability disruptors
Genome instability is a major characteristic of malignancy. This allows some favourable mutant tumour genotypes to survive under stress conditions, particularly those induced by traditional cancer treatment methods, such as chemo- and radiotherapy. As such, to enhance the therapeutic index of traditional cancer therapies, drugs could be repurposed as sensitizers of genotoxic therapy to inhibit DNA damage response. Non-oncology drugs which work by disrupting the DNA damage response include spironolactone and mebendazole, which are respectively diuretic and antihelminthic drugs.

Tumour-promoting inflammation reducers
Inflammation is typically associated with tumourigenesis as it supports and accelerates tumour growth. Some non-oncology drugs work by targeting tumour-promoting inflammation. These include aspirin, a common pain and fever relief medication, and thiocolchicoside, used to treat rheumatologic and orthopaedic disorders.

Conclusions
The study stresses the urgent need to develop effective, safe, cheaper, and readily available anticancer agents. The repurposed drugs outlined that act on specific characteristics of cancer, show that there is therapeutic potential in this strategy.

Editor’s note
Oncology drugs
Proliferative signal inhibitors, cancer cell death inducers, cellular metabolism regulators, antitumour immunity activators,

Non-oncology drugs suitable for drug combination therapy
Tumour suppressor reactivators, cancer cell division interrupters, angiogenesis reducers, cell invasion and metastasis suppressors, genome instability disruptors, and tumour-promoting inflammation reducers

Competing interests: The work of the paper [1] was supported by grants from the Chinese NSFC (nos. 81821002, 81790251, and 81773143), and Guangdong Basic and Applied Basic Research Foundation (2019B030302012).

Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.

Alice Rolandini Jensen, MSci, GaBI Journal Editor

References
1. Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui , et al. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020;5(1):113.
2. GaBI Online – Generics and Biosimilars Initiative. Technological approaches to drug repurposing for cancer treatment [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Mar 17]. Available from: www.gabionline.net/Generics/Research/Technological-approaches-to-drug-repurposing-for-cancer-treatment

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.


Last update: 01/07/2021

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What to look forward to in GaBI Journal, 2021, Issue 2

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.


Last update: 16/01/2022

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The EU regulatory network and emerging trends – a review of quality, safety and clinical development programmes

Author byline as per print journal:
Marta Zuccarelli1, PharmD; Benjamin Micallef1, PharmD; Mark Cilia1, PharmD; Anthony Serracino-Inglott1,2, PharmD; John-Joseph Borg1,3, PhD

Introduction/Study Objectives: The development of biosimilars is challenging due to the complexity of the active substances as well as the strict regulatory requirements to show similarity with a reference medicinal product. This review aims to describe the regulatory experience of approving biosimilars in the European Union (EU) within the EU framework, identify emerging trends in the EU regulatory pathway when approving biosimilars and discuss where the EU biosimilar framework is heading.
Methods: Marketing authorisation applications (MAAs) submitted up to 2019 were retrieved from the public domain. The European public assessment report database was searched for approved biosimilars and clinical development programmes of biosimilars belonging to the same class were reviewed. In order to observe if biosimilars released onto the market increased safety concerns, we compared disproportionate adverse event reports pre- and post-licensure.
Results: Up to December 2019, 90 MAAs were submitted and 53 biosimilars were approved for 14 different biologicals. Total number of clinical trials (both phase I and III) steadily goes up driven by an increase number of approvals in later years, while the average number of both phase I and III trials decreased over time with some with Pegfilgrastim biosimilars being approved without conducting any phase III clinical trials. No new safety concerns were identified from the analysis of disproportionate adverse event reports.
Discussion: Clinical development programmes of biosimilars and the requirements set for biosimilars approval are changing over time. Biosimilars approved seem to be as well tolerated as the reference products when approved based on stringent regulatory requirements.
Conclusion: Regulation of biosimilars is progressing as more knowledge is gained.
Keywords: Biosimilars, clinical development programmes, EMA, EPARs, regulatory, safety

Submitted: 3 December 2020; Revised: 11 February 2021;Accepted: 15 February 2021; Published online first: 1 March 2021

Introduction/Study Objectives

The regulatory framework in the EU
According to the European Union (EU) law, a similar biological medicinal product or ‘biosimilar’ is a biological medicinal product which is similar, but not identical, to a reference biological medicinal product [1]. Biosimilar products in the EU would have demonstrated similarity to the reference medicinal product in terms of physicochemical characteristics as well as safety and efficacy through a comprehensive comparability exercise [2].

It is important to note that different regions worldwide have varying definitions of biosimilar products or equivalent terms, see Table 1, and have different requirements surrounding biosimilar clinical interchangeability, switching and substitution [3].

Table 1

In order to understand the complexities of the EU regulatory framework surrounding the approval of biosimilars, it is important to clarify that the approval of a biosimilar in the EU is based on an ‘abridged’ marketing authorisation application (MAA), where similar biological products do not require full scientific data as for new biological applications [4]. In principle, biosimilars can be developed for any well characterized biological product [5] which is produced by biotechnological methods, however, biosimilars are unlikely to be produced for vaccines, allergens, blood or plasma-derived products and gene/cell therapy products.

In the EU, the regulatory framework on biosimilars is built on guidelines, with the European Medicines Agency (EMA) issuing the first guideline on similar biological medicinal products in 2005 [5]. This overarching guideline provided complementary directions to the legal basis set out by the Directive 2001/83/EC in 2004 [1]. Since 2005, an additional two overarching guidelines dealing with non-clinical and clinical issues and on quality were also published [6]. Furthermore, product-specific guidelines ­laying down scientific recommendations for the development of biosimilars were issued for similar biological medicinal products containing monoclonal antibodies, recombinant follicle stimulation hormone, recombinant interferon beta, recombinant erythropoietin, low-molecular-weight heparins (LMWHs), recombinant interferon-alfa, recombinant granulocyte colony stimulating-factor (G-CSF), somatropin and recombinant human insulin [7], see Figure 1.

Figure 1

As a consequence of the regulatory framework set up in the EU since 2005, there has been a steady increase in the number of biosimilar medicinal products during the last 20 years, with successful use in treating and managing many chronic, debilitating and life-threatening diseases, such as autoimmune diseases and various forms of cancer [8].

Biosimilarity is proven through the use of a stepwise approach, first in quality, then in the non-clinical setting [using comparability exercises in pharmacokinetics (PK) and pharmacodynamics (PD) both in vitro and in vivo and then clinically [9].

In this study we aimed to describe and discuss the regulatory experience of approving biosimilars in the EU (from 2005–2019), through qualitative and quantitative evaluations. In addition, we discuss how the EU regulatory network has fared and what are the noteworthy emerging trends in biosimilar development as identified through a review of quality, safety and clinical development programmes. The results of this review are of interest to both developers and regulators and may help in understanding the changing landscape of biosimilar regulation.

Methods

Review of clinical development programmes
The number of MAAs for biosimilar medicinal products submitted for regulatory review up to December 2019 was retrieved from the EMA website [10]. The applications submitted for biosimilars were grouped as MAAs currently under review and MAAs which reached the post-authorization phase. The latter group was further subdivided in line with the opinion given to each biosimilar (either positive or negative) and MAAs which were withdrawn. Biosimilar medicinal products which received a positive opinion and maintained a valid authorization were further analysed. To detect emerging trends, a comparison of clinical development programmes of biosimilar products with comparable clinical development was carried out.

Using the EMA database of European public assessment reports (EPARs), biological originators and the number of biosimilars for each originator were retrieved. The EPARs of biosimilar medicinal products with a valid marketing authorization (up to December 2019) were used as the main source of information [11-58].

Information on clinical development programmes of each biosimilar were compared with the approved guidelines [7] to detect any notable considerations and consequent justification. The extrapolation of indication was analysed for applicable biosimilar me­­dicinal products.

It should be noted that not all biosimilar medicinal products analysed were different products. Some companies conducted one clinical development programme for the biosimilar and then marketed the same product under different names. Biosimilar products having the exact same clinical development programme, but different trade names are indicated with a slash, e.g. Inflectra®/Remsima®, in the results section.

Safety
Since the safety of biosimilar medicinal products could be of a ‘potential’ concern, static reporting odds ratio (ROR) reports [at the System Organ Class (SOC) level] concerning each biosimilar medicinal product were retrieved from the EudraVigilance data analysis system (EVDAS). SOCs ‘product issues’ and ‘social circumstances’ were excluded a priori because they were not considered relevant for the purpose of this review. To detect any new disproportionate reporting that may have arisen in the post-marketing phase, adverse event data were captured separately for the period before the authorization date of the first biosimilar reaching the market and period after authorization (up to a cut-off date 25 June 2020). Adverse event data from the two periods was then compared.

The expectedness of new disproportionate reporting identified from period after the first biosimilar authorization was evaluated in line with the summary of medicinal product characteristics (SmPCs) of the reference product. For each new disproportionate SOC reaction, the following SmPC sections were evaluated; 4.4 – Special warnings and precautions for use, 4.6 – Fertility, pregnancy and lactation, and 4.8 – Undesirable effects.

For SOCs which were deemed unexpected, i.e. not listed in the above-mentioned sections of the SmPCs, another static ROR evaluation was performed to identify which preferred terms (PTs) were disproportionately reported within each SOC. PTs which were disproportionately reported were evaluated for expectedness in line with the SmPC of the reference product (as described previously). Disproportionate PTs which were unexpected were then compared to EMA’s designated medical event (DME) list [59]. The PT, ‘fetus malformation’ was also considered (in addition to DMEs) as a serious adverse event of interest for the analysis we carried out. Disproportionate PTs which were unexpected, and which were also DMEs were further assessed by performing a causality assessment using the French imputability method [60] to confirm or confute potential signals of disproportionate reporting.

Results

The experience gained reviewing biosimilar marketing authorisation applications
Since 2004, EMA has gained significant experience in the scientific evaluation of biosimilar applications and revision of the regulatory scientific guidelines for the European markets was observed, see Figure 1.

Up to December 2019, 90 MAAs had been submitted to EMA for review. Figure 2 shows the authorization status of each MAA as well as applications under review. Fifty-three biosimilar products held valid marketing authorization in Europe as of December 2019. These 53 biosimilars resulted from 35 unique development programmes and were based on 14 different reference biologicals (adalimumab, bevacizumab, enoxaparin sodium, epoetin, etanercept, filgrastim, follitropin alfa, infliximab, insulin, pegfilgrastim, rituximab, somatropin, teriparatide, trastuzumab).

Figure 2

Biosimilar guidelines: evolution in EU – totality of evidence founded on quality data
In Europe, guidelines were issued for biosimilars to help applicants prepare MAAs. The first guidelines for similar biological medicinal products was published in October 2005. Since 2005, an additional two overarching guidelines (one on non-clinical/clinical issues and one on quality), eight product-specific guidelines and one reflection paper were published, see Figure 1. The reflection paper will be addressed as a product-specific guideline throughout this review. The first product-specific guideline was published in 2006 to discuss non-clinical and clinical studies recommended during the development of insulin’s biosimilars. Following the first guidelines on insulin, product-specific guidelines on somatropin, recombinant G-CSF, epoetin, interferon alfa (IFN-α), LMWH, monoclonal antibodies (mAbs), interferon beta (IFN-β) and recombinant follicle-stimulating hormone (follitropin) were published between 2006 and 2012. Six out of nine product-specific guidelines (insulin, somatropin, G-CSF, epoetin, LMWH, follitropin) were revised between 2015 and 2019, see Figure 1. It was observed that for certain biosimilar classes, revision of guidelines was related to more experience and knowledge gained by regulators over time. For example, the first guidelines on G-CSF emphasized the performance of ‘at least one repeat dose toxicity study in a relevant species’ and the performance of ‘confirmatory clinical trials to compare efficacy and safety of the biosimilar and reference’. In the revised draft of the guidelines for G-CSF, in vivo studies are no longer recommended, and confirmatory efficacy clinical trials are not deemed necessary as ‘pivotal evidence for similar efficacy will be derived from the similarity demonstrated in physicochemical, fu­­­­-­nc­­­­­­­­­­­­­tional, pharmacokinetic and ph­­ar­­-macodynamic comparisons’ [61-62]. Another example of guideline revision is the LMWH guideline. In the first issue of the LMWH guidelines, in vivo PD studies were always deemed necessary, but in the revised guidelines, in vivo PD studies are not required as part of the comparable studies unless physicochemical and biological comparability has not been already demonstrated. According to the revised LMWH guidelines, toxicological studies are only required in specific cases, while in the first issue of the same guideline, at least one repeated dose toxicity study in one relevant species was requested. In addition, according to the revised LMWH guidelines, clinical efficacy studies are not required any longer as efficacy data will be ‘derived from the similarity demonstrated in physicochemical, functional and pharmacodynamic comparisons’ [63-64].

The biosimilar guidelines are not meant to be prescriptive step-by-step guides on how to design a clinical study programme to obtain approvals for biosimilars but rather these guidelines contain scientific recommendations to facilitate development of biosimilars through comparability programmes with a reference medicinal product. The biosimilar comparability exercise is pivotal to understanding the degree of similarity between test and reference products and is crucial in the benefit-risk assessment of biosimilar products. Initially, biosimilar guidelines could have been considered as conservative when ­laying down clinical requirements required by a manufacturer to prove biosimilarity. Where, for example, in the case of epoetins: two clinical studies are required in titration and maintenance phase with additional emphasis on animal data to be provided before licensure. Also, the number of patients, number of studies and duration of studies are three important parameters that should be taken into consideration whilst designing a clinical development programme as these para­meters determine the success and efficiency of a clinical developmental programme. Notwithstanding these considerations, it is interesting to note that revised product-specific guidelines have re-considered the regulatory requirements on clinical data and in general, have shifted to rely more on extrapolation with usage of PD markers for clinical endpoints as a surrogate for efficacy and additional supportive evidence from relevant non-clinical in vivo studies. The strategy behind this shift is to have an increased reliance on the detailed and comprehensive quality data required in the marketing authorization dossier. This shift in regulatory requirements is based on the regulatory experience obtained to date approving biosimilars by EU regulators. In order to better understand the experience we have to date in approving biosimilars, we reviewed the clinical development programmes of 11 biosimilar active substances (adalimumab, bevacizumab, epoetin, etanercept, filgrastim, follitropin alfa, infliximab, insulin glargine, pegfilgrastim, rituximab, trastuzumab) to identify any emerging common trends between classes as described in their EPARs. A comparison was also made between biosimilars clinical development programmes of the same class.

Clinical development programmes of biosimilars
Clinical development programmes of 48 out of the 53 currently authorized biosimilar medicinal products were compared. Enoxaparin sodium, insulin lispro and somatropin were not included because only one biosimilar medicinal product was developed or maintained a valid authorization at the time of review, therefore a comparison could not be performed. Teriparatide was not included in the comparison exercise since the two biosimilars authorized were based on the same development programme and were then sold under different brand names.

When considering the 48 biosimilar medicinal products compared, it was observed that, in general, total number of clinical trials (both phase I and phase III) across all biosimilars increased over time, see Figure 3a. This is not unexpected since the total number of biosimilar approvals increased over time, with the number of approvals peaking in 2018 when 16 biosimilars were approved based on 14 clinical development programmes, see Table 2. The number of studies leading to approval changed over time. In 2007, the average ­number of phase I clinical trials was 3.5 and the average number of phase III clinical trials was 3. In 2019, the average number of phase I clinical trials was 1.67 and the average number of phase III clinical trials was 1, see Figure 3b, with certain biosimilars of pegfilgrastim, such as Pelmeg®/Pegfilgrastim Mundipharma® and Udenyca®, not having carried out any phase III clinical trials.

Figure 3a

Figure 3b

Enrolled subjects
The total number of subjects enrolled in clinical trials (phase I and phase III combined) across all biosimilars compared was observed to have generally increased through time although a high variability in the number of enrolled subjects per development programme was noted. We also evaluated the number of subjects enrolled in phase I and phase III clinical trials (not combined), see Figure 4a. Figure 4a shows an increased total number of subjects enrolled in phase I and phase III clinical trials through time although the increased number of biosimilar medicinal products authorized in more recent years should be considered. For this reason, we evaluated the average ­number of subjects enrolled in clinical trials as shown in Figure 4b. From Figure 4b, it can be appreciated that the average number of subjects enrolled in phase I clinical trials was mostly stable. In phase III clinical trials, it can be observed that the average number of subjects enrolled steadily increased between 2010 and 2017 and decreased from 2017 to 2019.

Healthy volunteers were enrolled for phase I clinical trials for all biosimilars clinical development programmes, except for insulin glargine biosimilars (where both healthy volunteers and patients with type 1 diabetes mellitus were enrolled), infliximab biosimilars (where only patients with rheumatoid arthritis (RA) were enrolled and in the case of Inflectra®/Remsima® in addition to RA patients, patients with ankylosing spondylitis were also enrolled) and rituximab biosimilars (where only patients with RA and diffuse large B-cell lymphomas were enrolled).

Figure 4a

Figure 4b

Table 2

Table 2

Table 2

Table 2

Table 2

Primary endpoints to support pivotal data
Demonstration of pharmacokinetic (PK) equivalence between the test product and reference product is deemed necessary for the approval of a biosimilar. PK was observed to be mainly studied in phase I clinical trials on healthy volunteers since a cohort of healthy volunteers is considered to be a more heterogeneous population. Supportive PK data are derived from phase III clinical trials. During the clinical development programmes of insulin glargine biosimilars, infliximab biosimilars and rituximab biosimilars, PK studies were conducted on patients where, AUCinf, AUClast and Cmax with an acceptance level of between 0.8 and 1.25 with 90% confidence interval (CI) were the primary PK endpoints used to evaluate bioequivalence between test product and reference product, see Table 2.

There have been examples where therapeutic equivalence was demonstrated despite PK study results not falling within the pre-specified acceptance level. During the development of adalimumab biosimilars Hyrimoz®/Hefiya®/Halimatoz®, a second phase I PK clinical trial (study GP17-104) was deemed necessary after two out of three primary PK endpoints (AUCinf and AUC0last) were above pre-specified acceptance level in the first phase I PK clinical trial (study GP17-101) carried out. In the second PK study, the study design was adapted, and the primary endpoints were reduced to two (with AUCinf, Cmax and AUClast not calculated). The results obtained from the second PK study were within the pre-specified acceptance level of 0.8–1.25 with 90% CI. In this case, PK was further investigated in a phase III clinical trial (study GP17-301) before biosimilarity between the test product and the reference product could be definitively confirmed [13-15].

It is observed that, in some cases, the acceptance level of PK parameters was changed in post-hoc analysis and such an approach was considered acceptable when considering the justification provided. For epoetin zeta biosimilars, the primary endpoints were evaluated with 90% CI and the acceptance level for Cmax was widened by the applicant to 0.7%–1.43% in the post-hoc analysis. In the EPAR, it is explained that the applicant ‘referred to the Scientific Advice given by CHMP in April 2004 that stated that the concept of “comparability” cannot use bioequivalence but that similar PK profiles of SB309 and the reference product would strengthen the choice of reference in the clinical trials. The advice concluded that for this purpose descriptive statistics will suffice’ [23, 24].

PD studies to evaluate clinical comparability between test product and reference product are recommended by the guidelines, however, for active substances adalimumab, bevacizumab, epoetin, etanercept, infliximab and trastuzumab, no established PD surrogate markers were available at the time when the studies were conducted. Due to lack of accepted PD markers there were cases in which no PD studies were carried out. Clinical comparative PD studies were not conducted for any of the adalimumab biosimilars as no specific and accepted PD markers to predict efficacy exists. For all adalimumab biosimilars except for Hulio®, the EPAR states that only in vitro PD studies were carried out during the development of the products. For Hulio®, the mechanism of action (MOA) is described, but no PD studies are mentioned [16].

PD surrogate markers were explored by applicants for certain products. For example, during the clinical development programme of epoetin alfa biosimilars (epoetin alfa hexal®/Abseamed®/Binocrit®), PD studies were conducted as part of PK studies with PD markers set by the applicant [20-22]. However, during the clinical development programmes of epoetin zeta biosimilars, no studies were conducted to define the PD profile.

During the clinical development programme of Erelzi®, PD was indirectly evaluated in a phase III clinical trial. The PD marker serum high-sensitivity C-reactive protein (hs-CRP) was measured, showing a similarity between Enbrel® and Erelzi®. However, in the EPAR it is stated that data on serum hs-CRP should be considered as supportive since this is not a specific biomarker [26]. It is interesting to notice that there are no specific biomarkers available for tumour necrosis factor-alpha (TNF-α) inhibitor and that clinical comparability can be demonstrated also by clinical evidence other than PD surrogate [65, 66].

Another example for which no PD markers are accepted surrogates is represented by infliximab biosimilars although the applicant explored CRP for Inflectra®/Remsima® and Zessly®. In the Zessly®’s EPAR it is stated that ‘CRP is a marker of disease activity but does not have a clear relationship to therapeutic effect’ [39]. By comparing CRP differences between the reference products and the test product, similarity was evaluated. For well-known active substances, such as filgrastim, more stringent PD criteria were required by regulators, as observed for both Filgrastim Hexal® and Zarzio®, where the PD bioequivalence criteria (80% to 125%) at 95% CI was not accepted as an acceptance criterion for PD studies, as stricter acceptance criteria were expected (+/- 10%). The rationale for a stricter acceptance criterion is explained in the EPAR as follows, ‘The predefined equivalence boundaries were derived by the applicant from published data on the effect observed for Neupogen compared to placebo. It was assumed that the smallest clinically relevant difference in PD response between the test and reference product was 15% of the effect observed for Neupogen® compared to placebo in the published study. Decreasing this margin to 10%, which approximately corresponds to half the increase in the area under the effect curve (AUEC) between the 2.5 µg/kg and 5 µg/kg doses, would result in more acceptable equivalence intervals; indeed, the 95% CI for ANC AUEC and Emax in study EP06-103 would still fall within these tighter equivalence boundaries’ [29, 30].

Data also show that for highly characterized active substances, such as in the case of pegfilgrastim biosimilars Udenyca®, Pelmeg® and Pegfilgrastim Mundipharma®, no phase III clinical trials were required, see Table 2.

Extrapolation of indication
According to the CHMP, safety and efficacy data can be extrapolated from studies of a biosimilar for a different indication than the one studied during a clinical trial. Extrapolation of safety and efficacy data is based on physicochemical, functional, non-clinical and clinical data available showing similarity between the biosimilar and the reference product. A dedicated section on extra­polation of data is present in eight out of nine product-specific guidelines (insulin, somatropin, G-CSF, epoetin, IFN-α, LMWH, mAbs, IFN- β and recombinant follicle-stimulating hormone).

During the review of the clinical development programmes, it has been observed that extrapolation of data has been a ­common approach when approving biosimilars that usually have the same therapeutic indications as the originator in spite of the fact that the biosimilar may not have been studied in any indication or has been studied in only one indication.

For example, biosimilars of infliximab have the same indications as the infliximab originator Remicade® even though biosimilars of infliximab have only been tested in patients with RA (and in the case of Inflectra®/Remsima® also in ankylosis spondylitis), while originator Remicade® was tested in patients with rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosis spondylitis and psoriatic arthritis. To allow for extrapolation of data from the clinical development programme of Remicade®, the biosimilarity of Inflectra®/Remsima® was demonstrated through a comparability exercise as is detailed in the product-specific guidelines. Based on the robust comparisons of the physicochemical and in vitro and ex vivo biological analyses, and together with clinical data demonstrating pharmacokinetic and therapeutic equivalence in rheumatology conditions, Inflectra®/Remsima® was considered biosimilar to the reference product Remicade and extrapolation to all other indications of Remicade was considered appropriate [36, 37]. The choice of using patients with RA during the development of Inflectra®/Remsima® to prove clinical efficacy is due to the more sensitive endpoints used in RA compared to endpoints used in Crohn’s disease and ulcerative colitis.

Extrapolation of indication does not always require comparability of efficacy data. In the case of clinical development programmes of Udenyca® and Pelmeg®/Pegfilgrastim Mundipharma® no phase III clinical trials on affected patient populations were carried out. Only clinical trials on healthy volunteers were submitted and therefore no comparability efficacy data were generated. Extrapolation of the indication was performed based on PK/PD similarity data, immunogenicity and safety. The absolute neutrophil count (ANC), a well-established PD marker, was used to established PD comparability. This is in line with the EMA biosimilar guidelines on recombinant granulocyte-colony stimulating factor (EMEA/CHMP/BMWP/31329/2005), according to which extrapolation of indication can be done if PD similarity with the reference product is demonstrated on healthy volunteers using ANC as a marker [61, 62].

In certain cases, the extrapolation of indication is restricted to certain specific indications. In the application of Silapo®/Retacrit®, the indication ‘reduction of allogeneic blood transfusions in adult non-iron deficient patients prior to major elective orthopaedic surgery’ was not granted because of lack of safety and efficacy data for the subcutaneous (SC) route of administration. The EPARs of Epoetin Alfa Hexal®/Abseamed®/Binocrit® state that ‘the claimed indications initially included also reduction of allogeneic blood transfusions in adult non-iron deficient patients prior to major elective orthopaedic surgery. However, during the CHMP scientific assessment it became evident that ‘efficacy and safety of Epoetin zeta have not been demonstrated for the SC route of administration in immunocompetent patients’ as well as ‘The benefit-risk ratio is not considered positive for the major orthopaedic surgery indication because immunogenicity of SC administered SB309 has not been assessed in immunocompetent individuals’ [20-22].

Extrapolation of safety and efficacy data is addressed by regulators in a specific section within the EPAR. For example, in the EPAR of Biograstim® (approved in 2008; biosimilar of Neupogen® (filgrastim)), information on extrapolation of safety and efficacy data is reported in the EPAR section ‘Overall conclusions, risk/benefit assessment and recommendation’ within the ‘Risk-benefit assessment’ subsection. The extrapolation of data was accepted with uncertainties and the outstanding issue was then tackled post-authorization in the products’ life cycle as an issue within the risk management plan. In the EPAR of Accofil®, a biosimilar containing filgrastim approved in 2014, extrapolation is discussed in the benefit-risk balance section, in the ‘Uncertainty in the knowledge about the beneficial effects’ subsection. In the EPARs of Biograstim® and Accofil®, uncertainties on biosimilarity are addressed differently. In the EPAR of Biograstim®, the mobilisation of peripheral blood progenitor cells is the only area of uncertainty and was due to the lack of complete understanding of the MOA. The case of Biograstim® indicates that there are uncertainties on extrapolation which are tackled in the risk management plan (RMP). In the EPAR of Accofil!®, the totality of quality, non-clinical and clinical data are considered when proving biosimilarity [67].

Safety concerns
In Malta, the Medicines Authority receives feedback from clinicians during annual stakeholder meetings. According to Maltese clinicians, concerns on the safety of biosimilars is one of the barriers to the uptake of biosimilars. For this reason, we investigated this perceived notion by checking for emerging safety concerns by comparing disproportionate adverse event reports pre- and post-biosimilar licensure. Sixteen biosimilar active substances authorized between 2007 and 2019 were evaluated and results are shown in Table 3.

Table 3

Medical Dictionary for Regulatory Activities (MedDRA) SOC reactions for the 16 biosimilars were retrieved. A total of 144 disproportionality reports (DRs) were observed, 18 of which were only present in the pre-approval phase (only with the originator), 42 of which were only present in the post-approval phase and 84 of which were present in both pre-approval and post-approval phases.

New reports of disproportionality (DR only present in the post-approval phase) were further analysed and out of 42 DRs, 33 were expected/listed while nine were not expected/not listed according to the originator product’s SmPCs. Since 33 DRs were expected/listed, the increase in the number of reports to the point of disproportionality could be explained by constant pharmacovigilance monitoring of biosimilars.

To verify if the safety specification of the biological is changing post-biosimilar licensure, the nine non-expected/non-listed DRs were further analysed. For each SOC DR, the corresponding PTs within the SOC MedDRA hierarchy were retrieved from EVDAS and matched with the EMA list of designated medical events (DMEs). Two potential ‘signals’ that were serious enough to warrant further investigation were identified. These were deafness for insulin lispro and foetal malformation for etanercept. Causality assessment of deafness for Insulin Lispro showed that out of 50 Individual Case Safety Reports (ICSRs), 48 were classified as uncertain, one was classified as unlikely, and one was classified as probable as per the French method. Causality assessment of foetal malformation for etanercept showed that all 226 ICSRs were uncertain (it is pointed out that during the case review, 225 out of 226 ICSRs were found to duplicates of the same case). From this analysis of post-marketing adverse event data, we did not observe any emerging safety concerns related to biosimilars. Since 2005, no new safety issue has arisen when biosimilars have been authorized in line with the EU framework.

Discussion

Since setting up a regulatory framework on biosimilars in 2005, more experience has been gained by the EU regulatory network in approving biosimilar medicinal products, as evidenced by the increased number of marketing authorizations granted over time. Guidelines on the development of specific biosimilars have been described as ‘living documents’ [68] since they are constantly revised and updated as needed.

During the review of EPARs it was observed that, in general, the product-specific guidelines were followed by applicants. There were some cases where some deviations from guidelines occurred, however, approval was still granted since the overall application still showed biosimilarity.

Applicants often sought to engage with the regulators during the product development to obtain scientific advice concerning different quality, non-clinical and clinical aspects of the biosimilar’s development. This is reflected in the number of scientific advice requests which were logged on adapting clinical and chemistry development programmes for biosimilars in one region to meet the EU requirements, see Figure 5. In addition to this, in 2017 the EMA started a pilot project on tailored scientific advice to support companies in carrying out appropriate studies on biosimilars [69].

Figure 5

The review of clinical development programmes of ­biosimilars currently marketed within the EU showed that the average ­number of phase I clinical trials was generally higher than the number of phase III clinical trials, except for biosimilars approved in 2016 in which the average number of phase I and phase III clinical trials were the same. It was also observed that, in general, the average number of both phase I and phase III clinical trials decreased in the reviewed period (2007–2019). It was also observed that certain clinical development programmes consisted of only phase I clinical trials without phase III studies. Phase III clinical trials are usually carried out with the intent to support clinical equivalence between the biosimilar and originator following full quality data and phase I clinical trials. In the literature, some authors have argued that an informative and robust CMC package together with meaningful and well-planned phase I clinical trials may reduce the uncertainty on biosimilarity to such an extent that, in certain cases, additional large and expensive phase III clinical trials to confirm biosimilarity may not be needed [70, 71].

Generally, the total number of patients enrolled in phase I clinical trials is lower than the number of patients enrolled in phase III clinical trials, however, there have been cases where the number of patients enrolled in phase I trials was greater than the number of patients enrolled in phase III trials, see Table 2. As already said, some biosimilars were also approved when no phase III clinical trials were conducted, as in the cases of certain Pegfilgrastim biosimilars. However, it was also noted that approval in such cases was dependent on the adequate scientific justification of the absence of phase III studies and, in addition, the scientific advice being sought during the clinical development programme phase.

For phase I clinical trials, mainly healthy volunteers were enrolled. Exceptions to this common trend was observed in the clinical development plan (CDPs) of biosimilars of rituximab, insulin glargine and infliximab. In the clinical development programmes of bevacizumab, etanercept and trastuzumab, it was observed that only healthy male volunteers were enrolled. Under-representation of women in clinical trials is a well-known issue present when studying most medicinal products and is mainly related to the fact that women have childbearing potential and their exclusion from clinical trials is in an attempt to protect fetuses from unknown side effects [72, 73].

Extrapolation of indication was a common approach. Concerns on extrapolation of indication are present since biosimilars can be authorized with the same indications for which the biological originator is approved, without conducting clinical trials with the biosimilar on a specific disease state. Extrapolation for the other indications is permitted if it is properly justified. Regulatory agencies operate strict control when assessing supporting data provided by the applicant for extrapolation of indication [9]. However, extrapolation of an indication remains a challenge from a regulatory perspective, since demonstrating safety and efficacy of a biosimilar is challenging, due to their biological differences. Moreover, each product-specific guideline provides recommendations on studies to be carried out to potentially allow the extrapolation of indication. In certain cases, extrapolation was restricted to some indications as biosimilarity was not shown in all route of administrations. Although extrapolation was based on scientific ground, concerns related to safety of biosimilars are still present in clinical practice.

Results from the analysis of MedDRA SOC reactions showed that 58.3% of SOC reactions occurred in both the pre-approval phase (only with the originator) and in the post-approval phase (following approval of the first biosimilar medicinal product), suggesting a high degree of similarity in the safety profile of biological originators and their biosimilars. Also, from the analysis of PTs, it was observed that 78.6% of the reaction were expected and listed in biosimilar’s SmPCs, therefore are already known and labelled. Among the two non-expected adverse events, it was observed that the PT reactions which matched with the DME list, and hence deserve further analysis, (deafness for insulin lispro and foetal malformation for etanercept) were unlikely to be related to the use of the relevant biosimilar. Deafness has several aetiologies, including diabetes and patients’ ages [74]. In addition, data retrieved from EVDAS did not indicate any causality between the identified PTs and the use of etanercept and insulin glargine biosimilars.

Conclusions

Clinical development programmes of biosimilars and the approval requirements set up by regulatory agencies are changing over time. The EU regulatory framework focuses on CMC and biosimilarity. Therapeutic equivalence is arrived at through PK/PD endpoints, extrapolation, PD markers and PK reliance. This integrated way of proving biosimilarity, reduces the ­number of clinical trials needed to show biosimilarity and, over time, may lead to shorter clinical development programmes and faster access to medicinal products for patients. Scientific advice is a useful regulatory tool that allow applicants to discuss their development strategies with the regulator early during the development phase, which facilitates the development of safe and efficacious biosimilar medicinal products. Following the regulatory experience of approving biosimilar in the EU, guidelines are being updated to reflect new knowledge on biosimilars gained. Analysis of the spontaneous reports indicates that the above-mentioned framework results in robust quality, safety and efficacy of biosimilar medicinal products, as no increase in safety concerns is observed. These results show that the EU framework of biosimilar is moving in the right direction.

In conclusion, regulation of biosimilars is progressing as more knowledge is being gained and this is reflected in the application of the product-specific guidelines.

For patients

A biosimilar is a medicine which is similar, but not identical, to a reference biological medicine which is already being utilized in clinical practice. Similarity between a biosimilar and a reference biological medicine is demonstrated via physicochemical, clinical safety and clinical efficacy characteristics. In the EU, the regulatory framework for biosimilars is built on guidelines, with EMA issuing the first guideline on similar biological medicinal products in 2005. Since 2005, a total of 12 guidelines have been issued, nine of which were updated in line with new knowledge gained by regulators. Using these guidelines as a direction to be followed, 90 applications for various biosimilars have been submitted by applicants to EMA and 53 biosimilars are marketed in 2019 (biosimilars of adalimumab, bevacizumab, enoxaparin sodium, epoetin, etanercept, filgrastim, follitropin alfa, infliximab, insulin glargine, insulin lispro, pegfilgrastim, rituximab, somatropin, teriparatide, trastuzumab). The safety review carried out does not show emergence of any new adverse events following biosimilars reaching the market. The European framework supports the development and authorization of good quality, safe and efficacious biosimilar medicinal products.

Funding sources

None.

Competing interests: The authors declare no direct or indirect potential conflicts of interest.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Marta Zuccarelli1, PharmD
Benjamin Micallef1, PharmD
Mark Cilia1, PharmD
Professor Anthony Serracino-Inglott1,2, PharmD
Professor John-Joseph Borg1,3, PhD

1Malta Medicines Authority, Sir Temi Żammit Buildings, Malta Life Sciences Park, San Ġwann SĠN 3000, Malta
2Department of Pharmacy, Faculty of Medicine and Surgery, University of Malta, L-Università ta’ Malta Msida, MSD 2080, Malta
3School of Pharmacy, Department of Biology, University of Tor Vergata, Rome, Italy

References
1. The European Parliament and the Council of the European Union. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. OJ L 311, 28.11.2001, p 67.
2. European Medicines Agency. Guideline on similar biological medicinal products. CHMP/437/04 Rev 1. 23 October 2014 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf
3. Challand RH, Gorham H, Constant J. Biosimilars: where we were and where we are. J Biopharm Stat. 2014;24(6):1154-64.
4. Minghetti P, Rocco P, Cilurzo F, Del Vecchio L, Locatelli F. The regulatory framework of biosimilars in the European Union. Drug Discov Today. 2012;17(1-2):63-70.
5. European Medicines Agency. Guideline on similar biological medicinal products. CHMP/437/04. 2005. London, 30 October 2005 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-first-version_en.pdf
6. GaBI Online – Generics and Biosimilars Initiative. EU guidelines for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Feb 11]. Available from: https://www.gabionline.net/Guidelines/EU-guidelines-for-biosimilars
7. European Medicines Agency. Multidisciplinary: biosimilar [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-biosimilar
R8. Stevenson JG. Clinical data and regulatory issues of biosimilar products. Am J Manag Care. 2015;21(16 Suppl) s320-30.
9. Tesser JR, Furst DE, Jacobs I. Biosimilars and the extrapolation of indications for inflammatory conditions. Biologics. 2017;11:5-11.
10. European Medicines Agency. Medicines [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines
11. European Medicines Agency. Amgevita. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/amgevita
12. European Medicines Agency. Imraldi. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/imraldi
13. European Medicines Agency. Hyrimoz. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/hyrimoz
14. European Medicines Agency. Hefiya. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/hefiya
15. European Medicines Agency. Halimatoz. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/halimatoz
16. European Medicines Agency. Hulio. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/hulio
R17. European Medicines Agency. Idacio. 2019 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/idacio
18. European Medicines Agency. Mvasi. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/myasi
19. European Medicines Agency. Zirabev. 2019 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/myasi
20. European Medicines Agency. Epoetin alfa Hexal. 2007 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/epoetin-alfa-hexal
21. European Medicines Agency. Abseamed. 2007 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/abseamed
22. European Medicines Agency. Binocrit. 2007 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/binocrit
23. European Medicines Agency. Silapo. 2007 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/silapo
24. European Medicines Agency. Retacrit. 2007 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/retacrit
25. European Medicines Agency. Benepali. 2016 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/benepali
26. European Medicines Agency. Erelzi. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/erelzi
27. European Medicines Agency. Tevagrastim. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tevagrastim
28. European Medicines Agency. Ratiograstim. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/Ratiograstim
29. European Medicines Agency. Filgrastim Hexal. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/filgrastim-hexal
30. European Medicines Agency. Zarzio. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/zarzio
31. European Medicines Agency. Nivestim. 2010 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/nivestim
32. European Medicines Agency. Grastofil. 2013 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/grastofil
33. European Medicines Agency. Accofil. 2014 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/accofil
34. European Medicines Agency. Ovaleap. 2013 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ovaleap
35. European Medicines Agency. Bemfola. 2014 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/bemfola
36. European Medicines Agency. Inflectra. 2013 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/inflectra
37. European Medicines Agency. Remsima. 2013 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/remsima
38. European Medicines Agency. Flixabi. 2016 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/flixabi
39. European Medicines Agency. Zessly. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/zessly
40. European Medicines Agency. Abasaglar (previously Abasria). 2014 [home­page on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/abasaglar-previously-abasria
41. European Medicines Agency. Semglee. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/semglee
42. European Medicines Agency. Pelgraz. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/pelgraz
43. European Medicines Agency. Udenyca. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/udenyca
44. European Medicines Agency. Fulphila. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ fulphila-0
45. European Medicines Agency. Ziextenzo. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ziextenzo
46. European Medicines Agency. Pelmeg. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/pelmeg
47. European Medicines Agency. Cegfila (previously Pegfilgrastim Mundi­pharma). 2019 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/pegfilgrastim-mundipharma
48. European Medicines Agency. Grasustek. 2019 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/grasustek
49. European Medicines Agency. Truxima. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/truxima
50. European Medicines Agency. Blitzima. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/blitzima
51. European Medicines Agency. Ritemvia. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ritemvia
52. European Medicines Agency. Riximyo. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/riximyo
53. European Medicines Agency. Rixathon. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/rixathon
54. European Medicines Agency. Ontruzant. 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ontruzant
55. European Medicines Agency. Herzuma. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/herzuma
56. European Medicines Agency. Kanjinti. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/kanjinti
57. European Medicines Agency. Trazimera. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/trazimera
58. European Medicines Agency. Ogivri. 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ogivri
59. European Medicines Agency. Designated Medical Event (DME) list. EMA/326038/2020. 15 June 2020 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/other/designated-medical-event-dme-list_en.xlsx
60. Miremont-Salamé G, Théophile H, Haramburu F, Bégaud B. Causality assessment in pharmacovigilance: the French method and its successive updates. Therapie. 2016;71(2):179-86.
61. European Medicines Agency. Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor. EMEA/CHMP/BMWP/31329/2005, London, UK 2006 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/annex-guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins_en.pdf
62. European Medicines Agency. Guideline on similar biological medicinal products containing recombinant granulocyte-colony stimulating factor (rG-CSF) Draft. EMEA/CHMP/BMWP/31329/2005 Rev 1. 26 July 2018 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-similar-biological-medicinal-products-containing-recombinant-granulocyte-colony_en.pdf
63. European Medicines Agency. Guideline on non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight-heparins. EMEA/CHMP/BMWP/118264/2007, London, UK 2009 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-clinical-development-similar-biological-medicinal-products-containing-low_en-0.pdf
64. European Medicines Agency. Guideline on non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight-heparins. EMEA/CHMP/BMWP/118264/2007 Rev. 1, 10 November 2016 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-clinical-development-similar-biological-medicinal-products-containing-low_en.pdf
65. European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies—non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010. 30 May 2012 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-monoclonal-antibodies-non-clinical_en.pdf
66. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005 Rev1. 18 December 2014 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-2.pdf
67. Cazap E, Jacobs I, McBride A, Popovian R, Sikora K. Global acceptance of biosimilars: importance of regulatory consistency, education and trust. Oncologist. 2018;23(10):1188-98.
68. Wolff-Holz E, Tiitso K, Vleminckx C, Weise M. Evolution of the EU Biosimilar Framework: past and future. BioDrugs. 2019;33(6):621-34.
69. European Medicines Agency. Tailored scientific advice to support step-by-step development of new biosimilars. 16 December 2016 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.ema.europa.eu/en/news/tailored-scientific-advice-support-step-step-development-new-biosimilars
70. Frapaise FX. The end of phase 3 clinical trials in biosimilars development? BioDrugs. 2018;32(4):319-24.
71. Webster CJ, Woollett GR. Comment on “The end of phase 3 clinical trials in biosimilars development?”. BioDrugs. 2018;32(5):519-21.
72. Oertelt-Prigione S. Gender differences and clinical trial design. Clin Invest. 2011;1(2):187-90.
73. Labots G, Jones A, de Visser SJ, Rissmann R, Burggraaf J. Gender differences in clinical registration trials: is there a real problem? Br J Clin Pharmacol. 2018;84(4):700-7.
74. Horikawa C, Kodama S, Tanaka S, Fujihara K, Hirasawa R, Yachi Y, et al. Diabetes and risk of hearing impairment in adults: a meta-analysis. J Clin Endocrinol Metab. 2013;98(1):51-8.
75. U.S. Food and Drug Administration. Biosimilar and interchangeable products. 23 October 2017 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.fda.gov/drugs/biosimilars/biosimilar-and-inter­­­­changeable-products
76. World Health Organization. Expert Committee on Biological Standardization – Sixtieth Report Annex 2 – Guidelines on evaluation of similar biotherapeutic products (SBPs). Geneva, Switzerland 2009 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.who.int/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=
77. Health Canada. Biosimilar biologic drugs in Canada: Fact sheet. 23 August 2019 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/brgtherap/applic-demande/guides/Fact-Sheet-EN-2019-08-23.pdf
78. Chow SC. Biosimilars: design and analysis of follow-on biologics. Chapman and Hall; 2014. p. 55.
79. Choy E, Jacobs IA. Biosimilar safety considerations in clinical practice. Semin Oncol. 2014;41 Suppl 1:S3-14.

Author for correspondence: Professor John-Joseph Borg, Post-Licensing Directorate, Medicines Authority, Sir Temi .ammit Buildings, Malta Life Sciences Park, San .wann, S.N 3000, Malta

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.


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Biosimilars in Saudi Arabia: a single-centre, open-label case series examining infliximab switching

Author byline as per print journal:
Mansour Somaily1, MD; Hana Alahmari1, MD; Wejdan Abbag2; Shahenda Yousif4, MD; Nawar Tayfour4, MD; Nouf Almushayt2; Saleh Alhusayni3, MD; Saeed Almajadiah4, MD

Background: A biosimilar version of infliximab (CT-P13) was recently approved for use in Saudi Arabia. Clinical data support its use in the treatment of rheumatic disease, however, there is a lack of local data regarding the efficacy and tolerability of CT-P13 among patients with rheumatological disorders in Saudi Arabia.
Objectives: To investigate the feasibility, tolerability and immunogenicity of switching from originator infliximab to biosimilar infliximab, CT-P13, in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and Behçet’s disease.
Methodology: The study included patients who were being treated with originator infliximab in the Department of Rheumatology in Khamis Mushayt General Hospital, Saudi Arabia, and were required to switch to biosimilar infliximab (CT-P13) between January 2018 and June 2019. Patient follow-up was carried out every three months for one year. The disease activity score 28 (DAS28) was used to assess RA severity. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was used to measure disease activity in patients with AS, while Behçet’s disease activity was based on clinical assessment.
Results: In total, 13 patients (six with RA, five with AS and two with BD) were switched to biosimilar infliximab. The majority (n = 11/13) remained on biosimilar infliximab throughout the follow-up period with no reported major adverse events. Overall, there was a significant improvement in RA disease activity following biosimilar treatment, with the mean DAS28 decreasing from 3.61±1.24 before biosimilar therapy to 2.63±1.54 one year after switching.
Conclusion: In patients with AS, BD, or RA who switched from originator infliximab to the biosimilar, CT-P13, we 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.

Submitted: 16 September 2020; Revised: 30 January 2021; Accepted: 8 February 2021; Published online first: 22 February 2021

Introduction

Tumour necrosis factor (TNF) is an inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA) [11]. It is produced by a number of cell types in the human body, including those in the synovial membrane and fluid of RA patients [2, 3]. Blocking TNF has been shown to have anti-inflammatory and protective effects in RA [4]. TNF is also important in the pathogenesis of ankylosing spondylitis (AS) [5] and previous studies have identified high levels of TNF mRNA expression near the site of new bone formation and increased TNF protein levels in serum in patients with AS [6, 7].

Infliximab was one of the first TNF inhibitors (TNFI) to be used clinically for the treatment of RA, AS and other inflammatory diseases [8]. In 2013, the first infliximab biosimilar, CT-P13, was approved by the European Medicines Agency (EMA) based on randomized controlled trials in RA and AS, demonstrating no statistically significant differences in safety profile compared with the originator [9-11].

CT-P13 was launched on the market in Saudi Arabia at the end of 2016. Clinical data support its use in the treatment of a ­number of rheumatological diseases, however, there is a lack of local data regarding its safety profile and efficacy among patients in Saudi Arabia. Therefore, the present study was carried out to explore the pharmacological, therapeutic and clinical effects of CT-P13 in patients with RA, AS and BD, encountered during clinical practice in the Department of Rheumatology in Khamis Mushayt General Hospital, Saudi Arabia.

Methodology

This study included 13 patients seen at the Department of Rheumatology in Khamis Mushayt General Hospital. All patients were being treated with originator infliximab and were required to switch to the biosimilar version due to the originator becoming unavailable. Patients were recruited between January 2018 and June 2019. Biosimilar infliximab was given as a standard (3–7.5 mg/kg) IV infusion every 8 weeks. Patients were followed up once every three months, for 12 months.

The RA disease activity score 28 (DAS28) was used for clinical assessment of RA patients. The DAS28, which is a validated tool to define remission in established cases of RA, includes measurement of the number of swollen and tender joints, levels of inflammatory markers in blood (Erythrocyte Sedimentation Rate (ESR)), and assessment of patient general health.

Assessment of AS patients was dependent on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. This clinically validated index takes into account fatigue, neck, back and hip pain, and other joint symptoms, in addition to assessment of overall discomfort, e.g. areas tender to touch.

The assessment of BD patients depended on clinical assessment of the major manifestations of BD, such as orogenital ulceration, and ocular, musculoskeletal and cutaneous manifestations.

Information about infliximab and its possible adverse effects were described in detail and consents were given in all cases. The study proposal was also approved by the Research Ethics Local Committee, College of Medicine, University of Bisha.

The Shapiro-Wilk test revealed that the data were abnormally distributed. As such, a Wilcoxon signed ranks test was used to compare clinical scores before and after starting treatment with the biosimilar (CT-P13). A p-value < 0.05 was considered significant in all cases.

Results

In total, 13 patients (six with RA, five with AS and two with BD) were switched to biosimilar infliximab (CT-P13) between January 2018 and June 2019. Table 1 summarizes the demographic and clinical characteristics of the patients. Patients were aged between 25 and 55 years (mean age = 39.7±11.7) and 61.5% were women. The majority (n = 11/13) maintained treatment with CT-P13 throughout the follow-up period with no reported major adverse events, excluding two patients with RA who had upper respiratory infection.

Table 2 shows significant improvement in RA disease activity, as measured by the DAS28. The mean DAS28 score was 3.61±1.24 prior to infliximab biosimilar therapy, which reduced to 2.63±1.54 at one year of follow-up (p = 0.046).

Table 1

Table 2

Discussion

Several studies have assessed the safety, efficacy and immunogenicity of switching from the infliximab originator to the CT-P13 biosimilar version. However, the majority of these studies have not included control arms and have been observational in nature, in addition to investigating a single switch only. Importantly for Saudi Arabia, none of these studies were carried out in the locality. Therefore, this study was carried out to investigate the therapeutic and clinical effects of CT-P13 in patients with RA, SA and BD, and demonstrates local experience with the biosimilar.

A number of previous studies have investigated the effects of switching between the infliximab originator and the biosimilar, CT-P13. For example, in the second-year extension to the PLANETAS study [12], adverse events associated with biosimilar treatment were observed in 71.4% of patients who switched compared with 48.9% of those who continued receiving treatment with the originator. In addition, in the DANBIO register [13], approximately 6% of patients stopped treatment within three months of switching from originator infliximab to CT-P13 due to adverse events or lack of efficacy. In a study carried out on AS patients who switched from originator infliximab to its biosimilar, 11% of patients from the biosimilar group and 7% of the reference group discontinued the study during the 18-month follow-up period. Of those who discontinued biosimilar treatment, 80% did so due to adverse effects and 20% because of loss of efficacy [14].

The present case study did not identify any statistically significant differences in efficacy or tolerability between CT-P13 and originator infliximab in this small group of subjects in Saudi Arabia. This is in line with previous studies, such as the work of Jørgensen KK et al. [15], who reported that, according to a prespecified non-inferiority margin of 15%, the frequency of serious adverse events was not statistically different between patients treated with originator infliximab and those treated with CT-P13.

Additional observational studies and data from the extensions of the PLANETRA and PLANETAS studies identified few concerns regarding the efficacy and/or safety of CT-P13 [12, 16-19]. A recent systematic literature review including 70 full articles or abstracts evaluated the safety and efficacy of switching between originator and biosimilar infliximab in patients with inflammatory disorders. This review reported that most studies were observational, not containing a control group, and included only six randomized controlled trials (RCTs). It also concluded that no clinically relevant efficacy or safety concerns were associated with switching [20].

An additional survey carried out among adult patients in the United States (US) with RA, AS, and psoriatic arthritis who switched from infliximab to infliximab-dyyb biosimilar therapy evaluated the safety and efficacy of the biosimilar treatment, as well as patient awareness of biosimilar therapy. This paper concluded that patients were generally satisfied with their current therapy, whether this was originator infliximab or infliximab-dyyb. However, patients had concerns about switching, in particular, relating to price, safety, and efficacy [21].

The present study reported improvement in RA disease activity following biosimilar treatment (mean DAS28 of 3.61±1.24 prior to switching, compared to 2.63±1.54 one-year post-switching). However, another RCT identified no significant change in DAS28 between RA patients treated with the originator and those treated with the biosimilar [22].

In addition, in the present study, the five patients with AS who were switched from the originator to its biosimilar exhibited an improvement in their disease activity index (the BASDAI mean score reduced from 3.3±0.7 before biosimilar therapy to 0.28±0.52 after one year of biosimilar therapy, however, the result was not significant), see Table 3. This can be compared to the results of another study, where the BASDAI score was 3.7±0.4 in a group of AS patients treated with biosimilar infliximab, compared to 3.8±0.2 among those treated with the originator [23].

Table 3

In terms of limitations, this study includes data from a limited number of patients (n = 13) and was not randomized nor ­double-blinded. However, the aim of the study is to report experiences with switching to biosimilar infliximab in Saudi Arabia, which has not previously been examined. The findings from this study suggest that CT-P13 has comparable tolerability and efficacy to originator infliximab and may reduce disease activity in RA patients. However, a larger, double-blind RCT is recommended to ensure the safety and efficacy of the biosimilar. These findings provide important preliminary data and are considered the first evidence (after a literature search in the PubMed and Google Scholar) on switching between originator infliximab to a biosimilar infliximab product in Saudi Arabia.

Conclusion

The findings from this study suggest that CT-P13 has comparable tolerability and efficacy to originator infliximab and may reduce disease activity in RA patients. However, a larger double-blind randomised controlled trial (RCT) is recommended to ensure the safety and efficacy of the biosimilar. These important preliminary data are considered the first evidence (based on a literature search of PubMed and Google Scholar conducted up to ­November 2020) on switching from originator infliximab to a biosimilar infliximab product in Saudi Arabia.

Ethics approval

This study received approval of the ethical clearance from the Research Ethics Local Committee of the College of Medicine, University of Bisha (UBCOM-RELOC) (registration no. H-06-BH-087) based on the recommendation of the committee issued on 15 August 2020.

Competing interests: There was no support of any kinds (including for presentation of data, travel or publication) provided to any of the authors by the manufacturer prior to or after the study was conducted.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Mansour Somaily1, MD
Hana Alahmari1, MD
Wejdan Abbag2
Shahenda Yousif4, MD
Nawar Tayfour4, MD
Nouf Almushayt2
Saleh Alhusayni3, MD
Saeed Almajadiah4, MD

1Department of Medicine, Rheumatology Division, King Khalid University Medical City, 3294 Al Muruj District, Unit number 300, Building No. 8294, 62527-3989 Abha, Saudi Arabia
2College of Medicine, King Khalid University, Almahala Street, 62562 Aseer-Abha, Saudi Arabia
3Asser Central Hospital, Bani Malik Street, 62526 Abha, Saudi Arabia
4Department of Medicine, Rheumatology Division, Khamis Mushayt General Hospital, Almahala Street, 62562 Aseer-Abha, Saudi Arabia

References
1. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2(6):473-88.
2. Chu CQ, Field M, Feldmann M, Maini RN. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 1991;34(9):1125-32.
3. Saxne T, Palladino MA Jr, Heinegård D,Talal N, Wollheim FA. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988;31:1041-5.
4. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163-96.
5. Hreggvidsdottir HS, Noordenbos T, Baeten DL. Inflammatory pathways in spondyloarthritis. Mol Immunol. 2014;57(1):28-37.
6. Gratacós J, Collado A, Filella X, Sanmartí R, Cañete J, Llena J, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol. 1994;33(10):927-31.
7. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 1995;38(4):499-505.
8. Yoo DH, Oh C, Hong SS, Park W. Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal product. Expert Rev Clin Immunol. 2015;11 Supp1:S15-24.
9. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Assessment report: Remsima (infliximab). 27 June 2013. EMA/CHMP/589317/2013 [homepage on the Internet]. [cited 2021 Jan 30]. Available from: www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_ass­­e­­s­­­s­­­­mentreport/human/002576/ WC500151486.pdf
10. Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk, S, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613-20.
11. Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Pedro Miranda P, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72(10):1605-12.
12. Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Ureña S, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis. 2017;76(2):346-54.
13. Glintborg B, Juul Sørensen I, Vendelbo Jensen D, Krogh NS, Loft AG, et al. Three months’ clinical outcomes from a nationwide non-medical switch from originator to biosimilar infliximab in patients with inflammatory arthritis, results from the DANBIO registry. Ann Rheum Dis. 2016;75(Suppl 2):142.
14. Kaltsonoudis E, Pelechas E, Voulgari PV, Drosos AA. Maintained clinical remission in ankylosing spondylitis patients switched from reference Infliximab to its biosimilar: an 18-month comparative open-label study. J Clin Med. 2019;8(7):956.
15. Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304-16.
16. Buer LC, Moum BA, Cvancarova M, Warren DJ, Medhus AW, Hoivik ML. Switching from Remicade® to Remsima® is well tolerated and feasible: a prospective, open-label study. J Crohns Colitis. 2017;11(3):297-304.
17. Smits LJT, Derikx LAA, de Jong DJ, Boshuizen RS, van Esch AAJ, Drenth, JPH, et al. Clinical outcomes following a switch from Remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: a prospective observational cohort study. J Crohns Colitis. 2016;10:1287-93.
18. Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. 2017;76(2):355-63.
19. Vergara-Dangond C, Sáez Bello M, Climente Martí M, Llopis Salvia P, ­Alegre-Sancho JJ. Effectiveness and safety of switching from innovator infliximab to biosimilar CT-P13 in inflammatory rheumatic diseases: a real‐world case study. Drugs R D. 2017;17(3):481-5.
20. Feagan BG, Lam G, Ma C, Lichtenstein GR. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Aliment Pharmacol Ther. 2019;49(1):31-40.
21. Chau J, Delate T, Ota T, Bhardwaja B. Patient perspectives on switching from Infliximab to Infliximab-dyyb in patients with rheumatologic diseases in the United States. ACR Open Rheumatol. 2019;1(1):52-7.
22. Genovese MC, Sanchez-Burson J, Oh MS, Balazs E, Neal J, Everding A, et al. Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis. Arthritis Res Ther. 2020;22(1):60.
23. Kaltsonoudis E, Pelechas E, Voulgari PV, Drosos AA. Maintained clinical remission in ankylosing spondylitis patients switched from reference Infliximab to its biosimilar: an 18-month comparative open-label study. J Clin Med. 2019;8(7):956.

Author for correspondence: Mansour Somaily, MD, Consultant, Department of Medicine, Rheumatology Division, King Khalid University Medical City, 3294 Al Muruj District, Unit number 300, Building No. 8294, 62527-3989 Abha, Saudi Arabia

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.


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Variation in the prices of oncology medicines across Europe and the implications for the future

Author byline as per print journal:
Brian Godman1,2,3, BSc, PhD; Steven Simoens4, MSc, PhD; Amanj Kurdi1,5, BSc, PhD; Gisbert Selke6; John Yfantopoulos7, PhD; Andrew Hill8, PhD; Jolanta Gulbinovič9, MD, PhD; Antony P Martin10,11, MA, PhD1; Angela Timoney1,12, BPharm, PhD; Dzintars Gotham13, MBBS; Janet Wale14, PhD; Tomasz Bochenek15, PhD; Iva Selke Krulichova16, MSc, PhD; Eleonora Allocati17, MSc; Iris Hoxha18; Admir Malaj19; Christian Hierlander20; Anna Nachtnebel20, MSc, MD; Wouter Hamelinck21, MSc; Zornitza Mitkova22, PhD; Guenka Petrova22, PhD; Ott Laius23, PhD; Catherine Sermet24, MD, PhD; Irene Langner6; Roberta Joppi25, PhD; Arianit Jakupi26; Elita Poplavska27, PhD; Ieva Greiciute-Kuprijanov28; Patricia Vella Bonanno1, PhD; JF (Hans) Piepenbrink29; Vincent de Valk29; Robert Plisko30, Magdalene Wladysiuk30, MD, PhD; Vanda Marković-Peković31, PhD; Ileana Mardare32, PhD; Tanja Novakovic33; Mark Parker33; Jurij Furst34; Dominik Tomek35, PharmD, MSc, PhD; Katarina Banasova36; Merce Obach Cortadellas37; Corrine Zara37; Caridad Pontes37,38; Maria Juhasz-Haverinen39, MScPharm; Peter Skiold40, BSc; Stuart McTaggart41; Durhane Wong-Rieger42; Stephen Campbell43,44, PhD; Ruaraidh Hill45, PhD

Introduction/Objectives: Health authorities are facing increasing challenges to the sustainability of their healthcare systems because of the growing expenditures on medicines, including new, high-priced oncology medicines, and changes in disease prevalence in their ageing populations. Medicine prices in European countries are greatly affected by the ability to negotiate reasonable prices. Concerns have been expressed that prices of patented medicines do not fall sufficiently after the introduction of lower-cost generic oncology medicines. The objective of this study was to examine the associations over time in selected European countries between the prices of oral oncology medicines, population size, and gross domestic product (GDP) before and after the introduction of generic versions. Evidence of periodic reassessments of the price, value, and place in treatment of these medicines was also looked for. The goal of this review was to stimulate debate about possible improvements in approaches to reimbursement negotiations.
Methodology: Analysis was performed of reimbursed prices of three oral oncology medicines (imatinib, erlotinib and fludarabine) between 2013 and 2017 across Europe. Correlations were explored between GDP, population size, and prices. Findings were compared with previous research regarding prices of generic oral oncology medicines.
Results: The prices of imatinib, erlotinib and fludarabine varied among European countries, and there was limited price erosion over time in the absence of generics. There appeared to be no correlation between population size and price, but higher prices of on-patent oral cancer medicines were seen among countries with higher GDP per capita.
Conclusion: Limited price erosion for patented medicines contributed to increases in oncology medicine budgets across the region. There was also a concerning lack of evidence re-assessments of the price, value, and place in treatment of patented oncology medicines following the loss of patent protection of standard medicines. The use of such proactive re-assessments in negotiating tactics might positively impact global expenditures for oncology medicines.

Submitted: 11 October 2020; Revised: 21 January 2021; Accepted: 21 January 2021; Published online first: 3 February 2021

Introduction/Objectives

Globally, increases in expenditure on medicines has accelerated in recent years. Expenditures have been driven principally by increased prescribing volumes and the high prices of new medicines, especially those for oncology and orphan diseases [1-4]. The prices of new oncology medicines have risen ten-fold or more during the last decade [5-8], with prices per life year gained rising four-fold during the last twenty years after adjusting for inflation [6, 9]. As a result, expenditure on oncology medicines now dominates pharmaceutical expenditure in high income countries. Expenditure is expected to accelerate as there are over 500 companies actively pursuing new oncology medicines for over 600 indications [10, 11], all with high price expectations [12, 13]. The continuously rising cost of cancer care already accounts for up to 30% of the total hospital expenditure across Europe [14, 15], and global expenditure on oncology medicines is estimated to reach US$237 billion by 2024 [16].

This growth is putting considerable strain on universal access to European healthcare systems [4, 13, 17, 18]; leading to increasing calls for prices to be linked to minimum improvements in clinical benefits, such as a minimum of three to six months additional survival [19-23]. Such linkage would reverse recent policies in European countries (based on the emotive nature of this disease area) that have funded payments even for new, high-priced cancer medicines that offer limited health gains [12, 24]. Sustainability concerns have led to world-wide calls for alternative pricing and funding approaches to new oncology medicines, including fair pricing models [25-30]. Fair pricing models necessarily include greater transparency in how prices are set; a goal of the World Health Organization (WHO).

WHO has called for improved access to new medicines for all patients, including those with cancer [31, 32]. Calls for fairer pricing of new medicines are growing; based on recognition of both the low production cost of some cancer medicines (due to low costs of raw materials and improved manufacturing), and the appreciable discounting of original biological medicines by pharmaceutical companies that have occurred after the introduction of biosimilar competition [33-35].

Excessive pricing is particularly problematic in the US where prices for both existing on-patent oncology medicines as well as new cancer medicines continue to increase rapidly as a result of a lack of formal pricing and reimbursement processes. US oncologists have requested price moderation for new oncology medicines [36]; however, this has failed to materialize. By recent estimates, net expenditure in the US would be US$39.5 billion for 46 new oncology medicines approved in 2018 (17 novel medications and 29 new indications for existing medications), if all eligible patients received them [37]. Potential expenditure in 2018 on oncology medicines in the US could have been even greater, as this figure does not include the cost of other oncology medicines [37].

In Europe, when prices for medicines are established, there appears to be limited price erosion until multiple source products become available. This is unlike the situation in the US [38, 39]. There also appear to be limited differences between European countries regarding prices for patented biological oncology medicines. For example, it was reported that there was only a 13% difference between the prices for various medicines, including bevacizumab and ipilimumab, across 16 European countries while there were much greater differences for lower-priced medicines [40]. Similarly, limited differences were observed in the monthly treatment costs for new oncology medicines among European countries. However, the costs of medicines in the US were a median of 2.31 times higher than those seen in Europe, reflecting the current lack of pricing controls in the US [39, 41]. The situation in Europe may reflect extensive external reference pricing for new medicines [30, 42], although considerable differences in the pricing of multi-sourced oncology medicines exist among European countries [34].

Prices of cancer medicines have recently been reviewed in a number of publications [38, 40, 41]. There is a need to build on these findings to provide useful guidance for health authorities as they struggle with their budgets for oncology medicines. This includes assessing the potential influence of gross domestic product (GDP) and population size on reimbursed prices of patented medicines across Europe. This is important because countries with smaller populations and less economic power could be at a disadvantage during pricing negotiations. If true, this could result in higher negotiated prices despite the existence of extensive external reference pricing data across Europe [41, 42]. These concerns triggered the development of cross-country European consortia, designed to enhance negotiating power for new, premium-priced medicines [43]. These consortia include Beneluxa, Valleta and the Nordic consortium [32, 43-45]. It has been shown that the prices of oral generic cancer medicines were not dependant on the European country’s population size or their economic status and that, over time, appreciable price reductions were observed [34]. However, this trend may be different for on-patent oral cancer medicines.

Given the unsustainability of current systems, it is hoped that this review can stimulate further debate regarding possible new approaches to reimbursement negotiations. Debate should include how the negotiation of prices of existing patented oncology medicines should change after a standard oncology medicine loses its patent protection, potentially appreciably altering the cost-effectiveness ratio of existing patented medicines and their overall value. In addition, the pricing of new, on-patent oncology medicines across Europe should consider the use of fair pricing models. This review builds on current initiatives from WHO, the European Commission, and European insurers, that all call for greater transparency in pricing negotiations [18, 22, 26, 32].

Europe was chosen for study because of its goals of providing equitable and universal healthcare; including for patients with oncologic and rare diseases. Europe has also introduced multiple, ongoing activities designed to improve the quality and efficiency of prescribing of both new and established medicines [20, 21, 30, 46-50]. In addition, European countries have formal pricing and reimbursement processes in place and there are processes in place to review and refine approaches within the jurisdiction of each Member State [30, 39, 51]. This contrasts with the US, which currently has no formal pricing or reimbursement systems in place. As a result of this deficiency, the US is currently responsible for over 40% of global pharmaceutical spending despite having only 4.5% of the world’s population [39].

This study represents a payer perspective since payers are the key stakeholders involved in funding and reimbursement decisions for oncology medicines across Europe. Health authority databases were used as they are regularly audited and reflect the prices paid by health authorities for these medicines with or without value added tax (VAT), depending on the country [34, 52-54].

Methodology

The methodology used has been previously described [34]. The European countries examined were Albania, Austria, Belgium, B&H (Republic of Srpska), Bulgaria, Cyprus, Estonia, France, Germany, Greece, Italy, Kosovo, Latvia, Lithuania, Malta, Netherlands, Norway, Poland, Romania, Serbia, Slovenia, Slovakia, Spain (represented by pricing data from Catalonia with list prices similar across Spain), Sweden, and Scotland [as a representative of the United Kingdom (UK) as tariff prices are consistent across the UK]. The countries chosen include a wide range of geographies, populations, and GDPs. They also provided access to robust data from their administrative databases. Pricing data from health authorities are reliable and robust because their systems are regularly audited [34, 55]. This approach has also been used previously in multiple cross-national publications assessing utilization and expenditure patterns for different medicines and disease areas across Europe [34,52-54, 56-58].

This study concentrated on reimbursed prices for imatinib (L01XE01), erlotinib (L01XE03) and fludarabine (L01BB05) in Western European countries [59]. Generics were unavailable in 2015 for imatinib, and in 2017 for erlotinib and fludarabine. External reference pricing is infrequently used in these countries [34, 42, 52]. The delayed availability of generic versions of these oral cancer medicines in Western European countries provided a longer time period over which any price erosion could be monitored. These data build on earlier findings that involved assessing reimbursed prices for generic busulfan (L01AB01), capecitabine (L01BC06), chlorambucil (L01AA02), cyclophosphamide (L01AA01), flutamide (L02BB01), imatinib (L01XE01), melphalan (L01AA03), and temozolomide (L01AX03) over time across Europe [34].

Reimbursed prices were used where possible. However, in a minority of countries, procured and total prices were used instead (e.g. Kosovo) when it was not possible to break prices down into individual components. Total prices include pharmacy remuneration and any patient co-payments. In some countries, VAT was also included in the price. In some cases it was difficult to determine the exact proportion for each component to the total price from the information provided. Documented prices could also include any discounted prices arising from managed entry agreements (MEAs); sometimes referred to as risk sharing arrangements [50, 60]. However, MEAs were rare for individual oncology medicines in Europe prior to the recent rapid increase in the requested prices for new oncology medicines [60-63]. In some countries, reimbursed prices were listed, but the medicines are typically dispensed in hospitals where further, confidential discounts are provided, such as in Norway and Italy.

Reimbursed prices were generally recorded between 2013 and 2017 and were based on tablet strength. Tablet strengths were chosen for comparative purposes as opposed to defined daily doses (DDDs) used in previous cross-national research [52-54, 56, 57], as generally there are no DDDs for oral cancer medicines [59]. The tablet strength chosen reflects the most commonly used strength.

Initially, prices were documented in the country’s currency if not listed in Euros. Subsequently, where relevant, prices were converted to Euros for comparative purposes based on current exchange rates and were validated by co-authors to enhance the robustness of the findings [34, 64-71]. Prices were then converted to US$ based on mid-year European Central Bank exchange rates for comparison with the Organisation for Economic Co-operation and Development (OECD) GDP per capita data for 2015 and 2017 [72-74]. However, prices were retained in Euros when calculating any price erosion of the on-patent oral oncology medicines over time. Euros were also used for comparing prices of different generic oral cancer medicines, as one of the principal aims of this study was to compare prices across countries, as well to consider any price reductions achieved [34].

The OECD data on GDP per capita in US$ in 2015 and 2017 were supplemented with additional data if OECD data for these years were not available [72], e.g. 2018 OECD data were used for Albania and Cyprus and alternate data sources were used for Kosovo, Malta, Romania, and Serbia [75-78]. For consistency, the OECD data were also used for population sizes in 2015 and 2017; however, data from other sources was also used where required [78-81]. Country abbreviations were based on the International Organization for Standardization abbreviations, see Table 1A in the Appendix, [82].

Differences in country prices were visualised as violin plots to enhance interpretation of the data. Non-parametric Spearman’s rank tests were used to assess any correlation between prices and the countries’ population size, as well as their GDP per capita. Correlations were presented as Spearman’s rank correlation coefficients which range from -1 (perfect negative correlation) to +1 (perfect positive correlation). A p-value less than 0.05 was considered statistically significant. No correction for multiple comparisons was made. The correlations were also visually presented using scatter plots. Calculations were performed using R 3.6.1 software [83].

No ethical approval was obtained since only aggregate, anonymised data were used. This is in accordance with methods used in similar studies using administrative databases [34, 46, 53, 56, 84]. The definition of terms used, including external reference pricing, managed entry agreements (MEAs), and value-based pricing, follow those used for reforms and initiatives introduced across Europe [30].

Results

Prices of generic oral cancer medicines across Europe
A prior 2019 study showed that there were variable approaches made to the pricing of generic oral oncology medicines across Europe. This situation is similar for the pricing of other generic medicines [34, 49, 52, 85, 86]. The different approaches used can be consolidated into three categories [34]:

  • prescriptive pricing policies (price regulated market): policies using established percentage reductions for successive generics
  • market forces (free market): where there is typically free pricing for generics with market forces helping to drive down prices
  • mixed approach (combination): that incorporates prescriptive approaches, market forces, and other mechanisms, including external reference pricing, commonly used across Europe.

Differences in the approaches adopted by the various European countries resulted in appreciable differences in the reimbursed prices for generic oral oncology medicines across Europe. In addition, appreciable differences in the price reductions were seen for generic medicines in many European countries versus prices prior to loss of patents, see Box 1.

Box 1

Reimbursed prices were not indication specific, i.e. there were no differential prices once the first indication had lost its patent. In addition, contrary to prior reports [34], the generic oral oncology medicine prices in 2017 did not appear to be correlated with the country’s population size or to its GDP (Central and Eastern Europe (CEE) versus Western European countries). There were also no apparent concerns expressed about substitution with generic oral oncology medicines [34]. This is encouraging as such concerns have been reported to limit the extent of savings possible following the availability of generics [87].

Prices of originator, on-patent oral cancer medicines across Europe
Imatinib
Table 1 documents the prices for originator 400 mg imatinib tablets among Western European countries in 2015 prior to generic availability. Figure 1 presents the range of prices across all the countries studied. Generic imatinib was already available prior to 2015 in CEE countries, e.g. Albania, Estonia, Latvia, Lithuania, Romania, Serbia and Slovakia in 2013 or before, and in Poland and Slovenia in 2014 [34], and originator prices typically fell in these countries when generics became available [34, 49, 85].

While the minimum price of imatinib was 12.8% below the median (US$90.13), and the maximum price 4.6% above the median (excluding the outlier Germany at +38.3%), the results of the Spearman’s rank test indicated no correlation (r = –0.100; p = 0.776) between the price of imatinib and the country’s population size, see Appendix Figure 1 A. However, there was a moderate, statistically insignificant positive correlation (r = +0.527; p = 0.100) between imatinib prices and GDP per capita, see Figure 2.

Table 1

Figure 1

Figure 2

Erlotinib
In 2017, no generic erlotinib (150 mg) was available in the selected Western European countries or in a number of the studied CEE countries [34]. Consequently, it was possible to survey prices of this on-patent product in 16 European countries. Prices varied from 20.9% below the median price (US$73.44) to 23.2% above the median (disregarding the outliers Germany and Italy at 49.0% and 58.8%, respectively), see Table 2; Figure 1. There was no significant correlation (r = 0.303; p = 0.253) between the prices of erlotinib and country’s population size, see Figure 2A in the Appendix, but there was a significant moderate positive correlation (r = 0.532; p = 0.036) between erlotinib prices and GDP per capita, see Figure 3.

Figure 3

There were limited differences in prices for originator erlotinib over time in these selected Western European countries, see Table 2. However, once multiple generic versions became available in 2017, prices fell rapidly in some countries. For example, in the Republic of Srpska prices fell to 26.9% of the 2013 originator prices, and in Bulgaria, Romania, and Lithuania prices fell to 34.3%, 45.7% and 54.4% of 2013 originator price, respectively. Similar trends have been observed across Europe for other oral cancer medicines once generics became available [34].

Fludarabine
In 2017, no generic fludarabine was available in Western European countries or in a number of CEE countries. As a result, prices from 16 selected European countries were included in the analysis.

Table 2

Documented prices, see Table 3 and Figure 1, ranged from 53% below to 29% above the median (US$28.09). There was no correlation (r = 0.035; p = 0.900) between the price of fludarabine and population size in these selected countries, see Figure 3A, but there was a significant moderate positive correlation (r = 0.515; p = 0.044) observed between fludarabine prices and GDP per capita, see Figure 4.

Prices for both erlotinib and fludarabine were relatively stable between 2013 and 2017 in these selected Western European countries, see Table 4.

Table 3

Table 4

Figure 4

Discussion

This study investigated reimbursed prices over time for both on-patent originator and generic oral oncology medicines across a number of European countries. Contrary to prior concerns [34, 88], but consistent with other studies [41, 89, 90], prices of the three selected oral oncology medicines were not correlated with population size. It is not clear why the price differences found in this study were greater than those reported in some prior studies [40, 41]. Consequently, further research is needed to confirm these findings and whether they reflect the impact of the recent, growing implementation of external reference pricing and of MEAs [50, 61, 63].

It is counterintuitive that the prices of patented oral cancer medicines tend to be higher in countries with greater economic power, see Figures 2 to 4. These countries should have been more able to successfully negotiate confidential discounts or rebates as part of MEAs. As a result, patients in CEE countries that use prices in countries with more economic power in pricing negotiations may be faced with higher co-payments. These issues need to be further investigated and addressed. Potential solutions include greater pricing transparency coupled with growth in pan-European purchasing consortia [91, 92].

While it has been reported that there were no differences in the pricing approaches for multisource oral oncology versus non-oncology medicines, the situation differs for new, patent protected oncology medicines. Unlike in other disease areas, new oncology medicines are granted premium prices even if they provide limited health benefits [11, 12]. It is encouraging that prices for multisource products have been reported to be similar across indications, including for indications still under patent [34]. This is unlike the situation when generic versions of pregabalin were first launched, when general practitioners in some countries were threatened with legal action if they prescribed generic pregabalin for an indication still under patent [93]. The substantial price reductions (up to 98.8%) reported across Europe following the availability of oral generic oncology medicines, see Box 1 [34], are also encouraging. However, care must be taken to ensure that lower prices for generic medicines do not lead to manufacturer created shortages or even the removal of oncology medicines from the market [94, 95]. In contrast to the situation seen previously with generic oral oncology medicines [34], limited price erosion was observed over time for on-patent oral oncology medicines in this study, see Table 4. Hopefully, in the future there will be greater re-evaluation of the prices of many other on-patent oncology medicines as more of these medicines that are used as benchmarks for pricing and reimbursement negotiations lose their patents [96, 97].

The need for more successful, continuously re-evaluated, value-based price negotiations will only increase as a result of the effects on healthcare systems from rising prices for new oncology medicines coupled with ageing populations and a concomitant increase in oncology disease prevalence. The potential impact of value-based pricing considerations is considerable, based on the level of price reductions that are now being seen for oral generic oncology medicines (e.g. up to 97.8%), biosimilars (e.g. 83% reduction in expenditure on adalimumab among Danish hospitals following biosimilars), and even originator medicines faced with the imminent launch of biosimilars (e.g. 89% price reduction in the Netherlands for Humira® just before biosimilars were launched) [33, 34, 98-100]. In addition, the impact is increasing because of ongoing measures in European countries to rapidly switch from use of originators to new biosimilars for both oncology and rheumatoid arthritis patients in a way that conserves valuable resources without compromising care [101-105].

Value-based pricing (VBP) means ‘ that countries set prices for new medicines and/or decide on reimbursement based on the therapeutic value which medicine offers, usually assessed through health technology assessment (HTA) or economic evaluation’ [30]. The use of VBP should result in major decreases in the prices for on-patent oncology medicines as more standard medicines used as benchmarks for pricing and reimbursement negotiations lose their patents. Alternatively, health authorities could seek appreciably greater discounts from companies for continued reimbursement of on-patent medicines as part of any existing MEA.

There are many limitations to this study, including the fact that in a minority of countries, procured and total prices had to be used because it was not possible to break prices down into individual components. VAT was also included for some countries when it was not possible to remove this component. Prices used may have been distorted somewhat when prices were converted to US$ based on mid-year European Central Bank exchange rates for comparison with GDP per capita. Information was also limited on whether or how often negotiating methods were evaluated or changed. Despite these limitations, it is thought that the findings are useful in providing direction to European health authorities responsible for negotiating and re-evaluating medicine prices and value.

Conclusion

This study has revealed that prices of on-patent oral cancer medicines tend to be higher in countries with greater economic power and the reasons behind this need to be understood. Lack of universal, substantial lowering of oral oncology medicine prices after the introduction of generic version is a concern because this contributes to increases in oncology medicine budgets across the region. Also of concern is the possible lack of re-assessments of the price, value, and place in treatment of patented oncology medicines following loss of patent protection of reference medicines. Monitoring the use of such proactive re-assessment will be increasingly essential given the likely future growth in global expenditure for oncology medicines being driven by rising cancer prevalence rates, coupled with the introduction of a number of expensive oncology medicines.

Competing interests: Most of the co-authors work for health authorities and health insurance companies across Europe or are advisers to them. Steven Simoens previously held the EGA Chair of the “European policy towards generic medicines”. All the authors have no other conflicts of interest to declare. The study was self-funded.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Brian Godman1,2,3, BSc, PhD
Steven Simoens4, MSc, PhD
Amanj Kurdi1,5, BSc, PhD
Gisbert Selke6
John Yfantopoulos7, PhD
Andrew Hill8, PhD
Jolanta Gulbinovi9, MD, PhD
Antony P Martin10,11, MA, PhD
Angela Timoney1,12, BPharm, PhD
Dzintars Gotham13, MBBS
Janet Wale14, PhD
Tomasz Bochenek15, PhD
Iva Selke Krulichová16, MSc, PhD
Eleonora Allocati17, MSc
Iris Hoxha18
Admir Malaj19
Christian Hierländer20
Anna Nachtnebel20, MSc, MD
Wouter Hamelinck21, MSc
Zornitza Mitkova22, PhD
Guenka Petrova22, PhD
Ott Laius23, PhD
Catherine Sermet24, MD, PhD
Irene Langner6
Roberta Joppi25, PhD
Arianit Jakupi26
Elita Poplavska27, PhD
Ieva Greiciute-Kuprijanov28
Patricia Vella Bonanno1, PhD
JF (Hans) Piepenbrink29
Vincent de Valk29
Robert Plisko30
Magdalene Wladysiuk30, MD, PhD
Vanda Markovi31, PhD
Ileana Mardare32, PhD
Tanja Novakovic33
Mark Parker33
Jurij Fürst34
Dominik Tomek35, PharmD, MSc, PhD
Katarina Banasova36
Mercè Obach Cortadellas37
Corrine Zara37
Caridad Pontes37,38
Maria Juhasz-Haverinen39, MScPharm
Peter Skiold40, BSc
Stuart McTaggart41
Durhane Wong-Rieger42
Stephen Campbell43,44, PhD
Ruaraidh Hill45, PhD

1Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK
2Division of Clinical Pharmacology, Karolinska Institute, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden
3School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, Gauteng, South Africa
4KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
5Department of Pharmacology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
6Wissenschaftliches Institut der AOK (WIdO), 31 Rosenthaler Straße, DE-10178 Berlin, Germany
7School of Economics and Political Science, University of Athens, 6 Pandoras Street, Ekali, GR-14578 Athens, Greece
8Institute of Translational Medicine, University of Liverpool, UK
9Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Suduvos g. 4-4, LT-14259 Vilnius, Lithuania
10Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK
11HCD Economics, The Innovation Centre, Keckwick Ln, Daresbury, Warrington WA4 4FS, UK
12NHS Lothian Chair Scottish Intercollegiate Guidelines Network (SIGN), 2-4 Waterloo Place, Waverleygate EH1 3EG, Edinburgh, UK
13Independent researcher, London, UK
14Independent consumer advocate, 11a Lydia Street, Brunswick, Victoria 3056, Australia
15Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, PL-31531 Krakow, Poland
16Department of Medical Biophysics, Faculty of Medicine in Hradec Králové, Charles University, 870 Simkova, CZ-50003 Hradec Králové, Czech Republic
17Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, 2 Via Mario Negri, IT-20156 Milan, Italy
18Department of Pharmacy, Faculty of Medicine, University of Medicine, 28 Rr Isa Boletini, AL-1001 Tirana, Albania
19University of Medicine, 28 Rr Isa Boletini, AL-1001 Tirana, Albania20Dachverband der österreichischen Sozialversicherungen, 21 Kundmanngasse, AT-1030 Vienna, Austria
21Statistics Department, APB, 11 Rue Archimède, BE-1000 ­Brussels, Belgium
22Faculty of Pharmacy, Department of Social Pharmacy and Pharmacoeconomics, Medical University of Sofia, 2 Dunav Strasse, BG-1000 Sofia, Bulgaria
23State Agency of Medicines, 1 Nooruse, EE-50411 Tartu, Estonia
24IRDES, 117 bis rue Manin, FR-75019 Paris, France
25Pharmaceutical Drug Department, Azienda Sanitaria Locale di Verona, Azienda ULSS 9 Scaligera, 7 Via S D’Acquisto, IT-37122 Verona, Italy
26UBT – Higher Education Institut, A2 – Pharmaceutical Consulting, Nr 19, H18 Nurije Zeka, Mother Teresa Boulevard, 10000 Prishtina, Kosovo
27Medicines Marketing Authorisation Department, State Agency of Medicine, Riga, Latvia
28Department of Pharmacy, Ministry of Health of the Republic of Lithuania, 33 Vilniaus Gatve, LT-01506 Vilnius, Lithuania
29National Health Care Institute (ZIN), 4 Eekholt, NL-1112 XH Diemen, The Netherlands
30HTA Consulting, 17/3 Starowiślna Str, PL-31038 Cracow, Poland
31University of Banja Luka, Faculty of Medicine, Department of Social Pharmacy, 14 Save Mrkalja, Banja Luka, Republic of ­Srpska, Bosnia and Herzegovina
32Faculty of Medicine, Public Health and Management Department, “Carol Davila” University of Medicine and Pharmacy Bucharest, Room 224, et 2, 1-3 Dr Leonte Anastasievici Street, RO-050463 Bucharest, Romania
33ZEM Solutions, 9 Mosorska, RS-11000 Belgrade,
34Health Insurance Institute, 24 Miklosiceva, SI-1507 Ljubljana, Slovenia
35Faculty of Medicine, Slovak Medical University in Bratislava, 33 Gercenova, SL-85101 Bratislava, Slovakia
36Slovak Society for Pharmacoeconomics, 12 Budovatelska, SL-82108 Bratislava, Slovakia
37Drug Area, Catalan Health Service, 131 Travessera de les Corts, Edifici Olimpia, ES-08028 Barcelona, Spain
38Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Plaça Cívica, Bellaterra, ES-08193 Barcelona, Spain
39Stockholm County Council, Health Care Management, Region Stockholm, 98 Lindhagensgatan, Box 6909, SE-10239 Stockholm, Sweden
40TLV (Dental and Pharmaceutical Benefits Agency), 18 Fleminggatan, SE-10422 Stockholm, Sweden.
41NHS National Services Scotland, Gyle Square, 1 South Gyle Crescent, Edinburgh, UK
42Canadian Organization for Rare Disorders, Suite 600, 151 Bloor Street West, Toronto, Ontario M5S 1S4, Canada
43Centre for Primary Care, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M13 9PL, UK
44NIHR Greater Manchester Patient Safety Translational Research Centre, School of Health Sciences, University of Manchester, Manchester, UK
45Evidence Synthesis, Health Services Research, University of Liverpool, Liverpool, UK

References
1. OECD. Health at a Glance 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-2017_health_glance-2017-en
2. Luzzatto L, Hyry HI, Schieppati A, Costa E, Simoens S, Schaefer F, et al. Outrageous prices of orphan drugs: a call for collaboration. Lancet. 2018;392(10149):791-4.
3. Prasad V, De Jesus K, Mailankody S. The high price of anticancer drugs: origins, implications, barriers, solutions. Nat Rev Clin Oncol. 2017;14(6):381-90.
4. Gyawali B, Sullivan R. Economics of cancer medicines: for whose benefit? New Bioeth. 2017;23(1):95-104.
5. Kelly RJ, Smith TJ. Delivering maximum clinical benefit at an affordable price: engaging stakeholders in cancer care. Lancet Oncol. 2014;15(3):e112-8.
6. Howard DH, Bach P, Berndt ER, Conti RM. Pricing in the market for anticancer drugs. J Econ Perspect. 2015;29(1):139-62.
7. Prasad V, Wang R, Afifi SH, Mailankody S. The rising price of cancer drugs – a new old problem? JAMA Oncol. 2017;3(2):277-8.
8. Memorial Sloan Kettering Cancer Centre. Price & value of cancer drug [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.mskcc.org/research-programs/health-policy-outcomes/cost-drugs
9. Bach PB, Saltz LB. Raising the dose and raising the cost: the case of pembrolizumab in lung cancer. J Natl Cancer Inst. 2017;109(11).
10. IMS Institute for Healthcare Informatics. Global oncology trend report. A review of 2015 and outlook to 2020. June 2016 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.scribd.com/document/323179495/IMSH-Institute-Global-Oncology-Trend-2015-2020-Report
11. Godman B, Bucsics A, Vella Bonanno P, Oortwijn W, Rothe CC, Ferrario A, et al. Barriers for access to new medicines: searching for the balance between rising costs and limited budgets. Front Public Health. 2018;6:328.
12. Haycox A. Why cancer? PharmacoEconomics. 2016;34(7):625-7.
13. Godman B, Wild C, Haycox A. Patent expiry and costs for anti-cancer medicines for clinical use. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(3):105-6. doi: 10.5639/gabij.2017.0603.021
14. Simoens S, van Harten W, Lopes G, Vulto A, Meier K, Wilking N. What happens when the cost of cancer care becomes unsustainable. Eur Oncol Haemat. 2017;13(2):108-13.
15. Wilking N, Lopes G, Meier K, Simoens S, van Harten W, Vulto A. Can we continue to afford access to cancer treatment? Eur Oncol Haemat. 2017;13(2):114-9.
16. Waters R, Urquhart L. EvaluatePharma® World Preview 2019, Outlook to 2024. 2019.
17. Ghinea H, Kerridge I, Lipworth W. If we don’t talk about value, cancer drugs will become terminal for health systems. 2015.
18. European Commission. Communication from the commission to the European parliament, the council, the European economic and social committee and the committee of the regions. Pharmaceutical Strategy for Europe – {SWD(2020) 286 final}. November 2020 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:52020DC0761&from=EN
19. Bentley C, Costa S, Burgess MM, Regier D, McTaggart-Cowan H, Peacock SJ. Trade-offs, fairness, and funding for cancer drugs: key findings from a deliberative public engagement event in British Columbia, Canada. BMC Health Serv Res. 2018;18(1):339.
20. Wild C, Grossmann N, Bonanno PV, Bucsics A, Furst J, Garuoliene K, et al. Utilisation of the ESMO-MCBS in practice of HTA. Ann Oncol. 2016;27(11):2134-6.
21. World Health Organization. Access to new medicines in Europe: technical review of policy initiatives and opportunities for collaboration and research. 2015 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.euro.who.int/__data/assets/pdf_file/0008/306179/Access-new-medicines-TR-PIO-collaboration-research.pdf?ua=1
22. World Health Organization. Pricing of cancer medicines and its impacts. 2018 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://apps.who.int/iris/bitstream/handle/10665/277190/9789241515115-eng.pdf?sequence=1&isAllowed=y
23. Grössmann N, Del Paggio JC, Wolf S, Sullivan R, Booth CM, Rosian K, et al. Five years of EMA-approved systemic cancer therapies for solid tumours-a comparison of two thresholds for meaningful clinical benefit. Eur J Cancer. 2017;82:66-71.
24. Cohen D. Cancer drugs: high price, uncertain value. BMJ. 2017;359:j4543.
25. Suleman F, Low M, Moon S, Morgan SG. New business models for research and development with affordability requirements are needed to achieve fair pricing of medicines. BMJ. 2020;368:l4408-l.
26. AIM. Aim proposes to establish a European drug pricing model for fair and transparent prices for accessible pharmaceutical innovations. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.aim-mutual.org/wp-content/uploads/2019/12/AIMs-proposal-for-fair-and-transparent-prices-for-pharmaceuticals.pdf
27. Uyl-de Groot CA, Löwenberg B. Sustainability and affordability of cancer drugs: a novel pricing model. Nat Rev Clin Oncol. 2018;15(7):405-6.
28. Hsu JC, Lin J-Y, Lin P-C, Lee Y-C. Comprehensive value assessment of drugs using a multi-criteria decision analysis: an example of targeted therapies for metastatic colorectal cancer treatment. PloS One. 2019;14(12):e0225938-e
29. Wilking N, Bucsics A, Kandolf Sekulovic L, Kobelt G, Laslop A, Makaroff L, et al. Achieving equal and timely access to innovative anticancer drugs in the European Union (EU): summary of a multidisciplinary CECOG-driven roundtable discussion with a focus on Eastern and South-Eastern EU countries. ESMO Open. 2019;4(6):e000550-e
30. Vogler S. Fair prices for medicines? Exploring competent authorities’ and public payers’ preferences on pharmaceutical policies. Empirica. 2019;46(3):443-69.
31. Moon S, Mariat S, Kamae I, Pedersen HB. Defining the concept of fair pricing for medicines. BMJ. 2020;368:l4726.
32. World Health Organization. WHO guideline on country pharmaceutical pricing policies, second edition. 2020 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://apps.who.int/iris/bitstream/handle/10665/335692/9789240011878-eng.pdf
33. Sagonowsky E. AbbVie’s massive Humira discounts are stifling Netherlands biosimilars: report. 2019. Fierce Pharma. 2019 Apr 2.
34. Godman B, Hill A, Simoens S, Kurdi A, Gulbinovi J, Martin AP et al. Pricing of oral generic cancer medicines in 25 European countries; findings and implications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2019;8(2):49-70. doi:10.5639/gabij.2019.0802.007
35. Hill A, Redd C, Gotham D, Erbacher I, Meldrum J, Harada R. Estimated generic prices of cancer medicines deemed cost-ineffective in England: a cost estimation analysis. BMJ Open. 2017;7(1):e011965.
36. Tefferi A, Kantarjian H, Rajkumar SV, Baker LH, Abkowitz JL, Adamson JW, et al. In support of a patient-driven initiative and petition to lower the high price of cancer drugs. Mayo Clin Proc. 2015;90(8):996-1000.
37. DeMartino PC, Miljkovic MD, Prasad V. Potential cost implications for all US Food and Drug Administration oncology drug approvals in 2018. JAMA Intern Med. 2020;e205921.
38. Vogler S, Schneider P, Zimmermann N. Evolution of average European medicine prices: implications for the methodology of external price referencing. Pharmacoecon Open. 2019;3(3):303-9.
39. Emanuel EJ, Zhang C, Glickman A, Gudbranson E, DiMagno SSP, Urwin JW. Drug reimbursement regulation in 6 peer countries. JAMA Intern Med. 2020. doi:10.1001/jamainternmed.2020.4793.
40. Vogler S, Zimmermann N, Babar ZU. Price comparison of high-cost originator medicines in European countries. Expert Rev Pharmacoecon Outcomes Res. 2017;17(2):221-30.
41. Vokinger KN, Hwang TJ, Grischott T, Reichert S, Tibau A, Rosemann T, et al. Prices and clinical benefit of cancer drugs in the USA and Europe: a cost–benefit analysis. Lancet Oncol. 2020;21(5):664-70.
42. Leopold C, Vogler S, Mantel-Teeuwisse AK, de Joncheere K, Leufkens HGM, Laing R. Differences in external price referencing in Europe: a descriptive overview. Health Policy. 2012;104(1):50-60.
43. Eatwell E, Swierczyna A. Emerging voluntary cooperation between European healthcare systems: are we facing a new future? Medicine Access@Point of Care. 2019;1-8.
44. O’Mahony JF. Beneluxa: what are the prospects for collective bargaining on pharmaceutical prices given diverse health technology assessment processes? Pharmacoeconomics. 2019;37(5):627-30.
45. European Commission. Defining value in “value based healthcare”. Report of the Expert Panel on effective ways of investing in Health (EXPH). 2019 [home­­page on the Internet]. [cited 2021 Jan 21]. Available from: https://ec.europa.eu/health/sites/health/files/expert_panel/docs/024_defining-value-vbhc_en.pdf
46. Godman B, Wettermark B, van Woerkom M, Fraeyman J, Alvarez-Madrazo S, Berg C, et al. Multiple policies to enhance prescribing efficiency for established medicines in Europe with a particular focus on demand-side measures: findings and future implications. Front Pharmacol. 2014;5:106.
47. Moorkens E, Vulto AG, Huys I, Dylst P, Godman B, Keuerleber S, et al. Policies for biosimilar uptake in Europe: an overview. PloS One. 2017;12(12):e0190147.
48. Godman B, Malmström RE, Diogene E, Jayathissa S, McTaggart S, Cars T, et al. Dabigatran – a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs. Front Pharmacol. 2014;5:109.
49. Vogler S. The impact of pharmaceutical pricing and reimbursement policies on generics uptake: implementation of policy options on generics in 29 European countries–an overview. Generics and Biosimilar Journal (GaBI Journal). 2012;1(2):93-100. doi:10.5639/gabij.2012.0102.020
50. Ferrario A, Arāa D, Bochenek T, Ĉatić T, Dankó D, Dimitrova M, et al. The implementation of managed entry agreements in Central and Eastern Europe: findings and implications. Pharmacoeconomics. 2017;35(12):1271-85.
51. Vella Bonanno P, Bucsics A, Simoens S, Martin AP, Oortwijn W, Gulbinovic J, et al. Proposal for a regulation on health technology assessment in Europe – opinions of policy makers, payers and academics from the field of HTA. Expert Rev Pharmacoecon Outcomes Res. 2019;19(3):251-61.
52. Godman B, Shrank W, Andersen M, Berg C, Bishop I, Burkhardt T, et al. Policies to enhance prescribing efficiency in Europe: findings and future implications. Front Pharmacol. 2010;1:141.
53. Moon JC, Godman B, Petzold M, Alvarez-Madrazo S, Bennett K, Bishop I, et al. Different initiatives across Europe to enhance losartan utilization post generics: impact and implications. Front Pharmacol. 2014;5:219.
54. Vonĉna L, Strizrep T, Godman B, Bennie M, Bishop I, Campbell S, et al. Influence of demand-side measures to enhance renin-angiotensin prescribing efficiency in Europe: implications for the future. Expert Rev Pharmacoecon Outcomes Res. 2011;11(4):469-79.
55. Vogler S, Schneider P. Assessing data sources for medicine price studies. Int J Technol Assess Health Care. 2019;35(2):106-15.
56. Godman B, Petzold M, Bennett K, Bennie M, Bucsics A, Finlayson AE, et al. Can authorities appreciably enhance the prescribing of oral generic risperidone to conserve resources? Findings from across Europe and their implications. BMC Med. 2014;12:98.
57. Godman B, Shrank W, Andersen M, Berg C, Bishop I, Burkhardt T, et al. Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications. Expert Rev Pharmacoecon Outcomes Res. 2010;10(6):707-22.
58. Godman B, Bishop I, Finlayson AE, Campbell S, Kwon HY, Bennie M. Reforms and initiatives in Scotland in recent years to encourage the prescribing of generic drugs, their influence and implications for other countries. Expert Rev Pharmacoecon Outcomes Res. 2013;13(4):469-82.
59. WHO Collaborating Centre for Drug Statistics Methodology. ATC/ DDD Index. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.whocc.no/
60. Adamski J, Godman B, Ofierska-Sujkowska G, Osinska B, Herholz H, Wendykowska K, et al. Risk sharing arrangements for pharmaceuticals: potential considerations and recommendations for European payers. BMC Health Serv Res. 2010;10:153.
61. Zampirolli Dias C, Godman B, Gargano LP, Azevedo PS, Garcia MM, Souza Cazarim M, et al. Integrative review of managed entry agreements: chances and limitations. Pharmacoeconomics. 2020;38(11):1165-85.
62. Pauwels K, Huys I, Vogler S, Casteels M, Simoens S. Managed entry agreements for oncology drugs: lessons from the European experience to inform the future. Front Pharmacol. 2017;8:171.
63. Darbà J, Ascanio M. The current performance-linked and risk sharing agreement scene in the Spanish region of Catalonia. Expert Rev Pharmacoecon Outcomes Res. 2019;19(6):743-8.
64. British pound to Euro spot exchange rates for 2013 from the Bank of England. Pound Sterling Live 2020.
65. British pound to Euro spot exchange rates for 2014 from the Bank of England. Pound Sterling Live 2020..
66. British pound to Euro spot exchange rates for 2015 from the Bank of England. Pound Sterling Live 2020.
67. Sveriges Riksbank. Search interest & exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.riksbank.se/en-gb/statistics/search-interest–exchange-rates/?g130-SEKEURPMI=on&from=28%2F12%2F2017&to=29%2F12%2F2017&f=Day&c=cAverage&s=Comma
68. Narodowy Bank Polski. Exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.nbp.pl/homen.aspx?f=/kursy/kursyen.htm
69. National Bank of Serbia. Exchange rate [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.nbs.rs/export/sites/default/internet/english/scripts/kl_srednji.html
70. Norges Bank. Exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.norges-bank.no/en/topics/Statistics/exchange_rates/
71. Banca Naţionala a României. Exchange rates [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.bnr.ro/Exchange-Rates–3727.aspx
72. OECD Stat. Level of GDP per capita and productivity [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://stats.oecd.org/Index.aspx?DataSetCode=PDB_LV
73. European Central Bank. Euro foreign exchange reference rates. 1 July 2015 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.ecb.europa.eu/stats/exchange/eurofxref/shared/pdf/2015/07/20150701.pdf
74. European Central Bank. Euro foreign exchange reference rates. 3 July 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.ecb.europa.eu/stats/exchange/eurofxref/shared/pdf/2017/07/20170703.pdf
75. Institute of Statistics. Population of Albania, 1 January 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.instat.gov.al/en/themes/demography-and-social-indicators/population/publication/2017/population-of-albania-1-januar-2017/
76. World Population Data. Malta [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://worldpopulationreview.com/countries/malta-po­­­­­­p­­u­­­­­­­­lation/
77. OECD Stat. Population data [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://stats.oecd.org/Index.aspx?DataSetCode=EDU_DEM
78. Republic of Cyprus demographic report, 2017 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.mof.gov.cy/mof/cystat/statistics.nsf/All/6C25304C1E70C304C2257833003432B3/$file/demographic_report-2017-301118.pdf?OpenElement
79. Zamfir R. Romania is losing its people! Over 0.6 percent of the population vanished in just one year. Business Review. 2018 Aug 29.
80. Statistical Office of the Republic of Serbia. Estimates of population of the Republic of Serbia by sex, age and type of settlement 2013-2017. 2019 [home­page on the Internet]. [cited 2021 Jan 21]. Available from:http://publikacije.stat.gov.rs/G2018/PdfE/G201815012.pdf
81. The World Bank. Kosovo. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://data.worldbank.org/country/kosovo
82. International Organization for Standardization (ISO). ISO 3166 Country Codes Alpha-3. 2013 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.iso.org/obp/ui
83. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: https://www.R-project.org/
84. Godman B, Kurdi A, McCabe H, Johnson CF, Barbui C, MacBride-Stewart S, et al. Ongoing initiatives within the Scottish National Health Service to affect the prescribing of selective serotonin reuptake inhibitors and their influence. J Comp Eff Res. 2019;8(7):535-47.
85. Simoens S. A review of generic medicine pricing in Europe. Generics and Biosimilar Journal (GaBI Journal). 2012;1(1):8-12. doi:10.5639/gabij.2012.0101.004
86. Godman B, Wettermark B, Bishop I, Burkhardt T, Fürst J, Garuoliene K, et al. European payer initiatives to reduce prescribing costs through use of generics. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):22-7. doi:10.5639/gabij.2012.0101.007
87. Godman B, Acurcio F, Guerra Junior AA, Alvarez-Madrazo S, Faridah Aryani MY, et al. Initiatives among authorities to improve the quality and efficiency of prescribing and the implications. J Pharma Care Health Sys. 2014;1(3):1-15.
88. McKee M, Stuckler D, Martin-Moreno JM. Protecting health in hard times. BMJ. 2010;341:c5308.
89. Markovic-Pekovic V, Skrbic R, Godman B, Gustafsson LL. Ongoing initiatives in the Republic of Srpska to enhance prescribing efficiency: influence and future directions. Expert Rev Pharmacoecon Outcomes Res. 2012;12(5):661-71.
90. Garuoliene K, Godman B, Gulbinovi J, Wettermark B, Haycox A. European countries with small populations can obtain low prices for drugs: Lithuania as a case history. Expert Rev Pharmacoecon Outcomes Res. 2011;11(3):343-9
91. Office of the Deputy Prime Minister and the Ministry for Health of Malta. Valletta Technical Group continues to grow. 2018 [homepage on the Internet]. [cited 2021 Jan 21]. Available from: http://www.livenewsmalta.com/index.php/2018/01/31/valletta-technical-group-continues-to-grow/
92. O’Mahony JF. Beneluxa: what are the prospects for collective bargaining on pharmaceutical prices given diverse health technology assessment processes? Pharmacoeconomics. 2019;37(5):627-30.
93. Godman B, Wilcock M, Martin A, Bryson S, Baumgärtel C, Bochenek T, et al. Generic pregabalin; current situation and implications for health authorities, generics and biosimilars manufacturers in the future. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):125-35. doi:10.5639/gabij.2015.0403.028
94. Dylst P, Vulto A, Godman B, Simoens S. Generic medicines: solutions for a sustainable drug market? Appl Health Econ Health Policy. 2013;11(5):437-43.
95. Bochenek T, Abilova V, Alkan A, Asanin B, de Miguel Beriain I, Besovic Z, et al. Systemic measures and legislative and organizational frameworks aimed at preventing or mitigating drug shortages in 28 European and Western Asian Countries. Front Pharmacol. 2017;8:942.
96. Huang HY, Wu DW, Ma F, Liu ZL, Shi JF, Chen X, et al. Availability of anticancer biosimilars in 40 countries. Lancet Oncol. 2020;21(2):197-201.
97. Derbyshire M, Shina S. Patent expiry dates for biologicals: 2017 update. Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(1):29-34. doi: 10.5639/gabij.2019.0801.003
98. Godman B, Allocati E, Moorkens E. Ever-changing landscape of biosimilars in Canada; findings and implications from a global perspective. Generics and Biosimilars Initiatives Journal (GaBI Journal). 2019;8(3):93-7. doi:10.5639/gabij.2019.0803.012
99. Hollis A. Sustainable financing of innovative therapies: a review of approaches. Pharmacoeconomics. 2016;34(10):971-80.
100. Jensen TB, Kim SC, Jimenez-Solem E, Bartels D, Christensen HR, Andersen JT. Shift from adalimumab originator to biosimilars in Denmark. JAMA Intern Med. 2020;180(6):902-3.
101. Godman B. Biosimilars are becoming indispensable in the management of multiple diseases although concerns still exist. Bangladesh Journal of Medical Science. 2021;20(1):5-10
102. Godman B, Allocati E, Moorkens E, Kwon H-Y. Can local policies on biosimilars optimize the use of freed resources – experiences from Italy. Generics and Biosimilars Initiative Journal (GaBI Journal). 2020;9(4):183-7. doi:10.5639/gabij.2020.0904.029
103. Moorkens M, Godman B, Huys I, Hoxha I, Malaj A, Keuerleber S, et al. The expiry of Humira® market exclusivity and the entry of adalimumab biosimilars in Europe: an overview of pricing and national policy measures. Front Pharmacol. 2021;11:591134.
104. NHS Scotland. Secondary care national therapeutic indicators 2019/20. 2019 [homepage on the Internet]. [cited 2021 Jan 21]. Available from:https://www.therapeutics.scot.nhs.uk/wp-content/uploads/2020/10/Secondary-care-NTIs-2019-20-final.pdf.
105. Lee SM, Jung JH, Suh D, Jung YS, Yoo SL, Kim DW, et al. Budget impact of switching to biosimilar trastuzumab (CT-P6) for the treatment of breast cancer and gastric cancer in 28 European countries. BioDrugs. 2019;33(4):423-36.

Author for correspondence: Brian Godman, BSc, PhD, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK

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An overview of the current status of follow-on biologicals in Iran

Author byline as per print journal: Farhang Rezaei, PharmD; Nassim Anjidani, PharmD

Background: The advent of follow-on biologicals in Iran and biosimilars worldwide have provided various treatment options for several severe and chronic diseases. The goal of the present study was to provide an overview of their current status in Iran.
Methods: A comprehensive search of clinical trial registry sites and other databases that publish scholarly articles, such as PubMed and Google scholar, enabled the current follow-on biologicals landscape in Iran to be mapped. In addition, the annual national wholesale data of pharmaceutical products published by the Iranian pharmaceutical regulatory were analysed. The share of biotechnological therapeutics in terms of the whole medicines market, was evaluated, along with the share of follow-on biologicals and the potential and actualized cost-saving associated with using them. Data were collected and analysed over the 2013–2018 time period.
Results: At the time of writing, 21 follow-on biologicals were available in Iran and these represent 17 different originator molecules. In 2018, approximately 13.5% of medicines spending in Iran was devoted to biotechnological therapeutics. Follow-on biologicals comprised approximately 47.2% of the biotechnological therapeutics’ total market value, up from 35.2% in 2013. The use of follow-on biologicals in Iran was associated with more than US$300 million cost-saving in 2018. A number of follow-on biological candidates, mostly monoclonal antibodies, are under development and will be subject to head-to-head clinical trials against originator products prior to regulatory approval and marketing.
Conclusion: Despite a significant rise in the use of follow-on biologicals in Iran, the proportional use of biotechnological therapeutics compared to the total medicines market has remained constant in recent years. Iranian healthcare authorities can improve patients’ access to life-saving biological medicines through promoting the use of follow-on biologicals instead of costly originators after making sure of the quality, efficacy and safety of the follow-on biologicals. The significant cost saving associated with using follow-on biologicals can also be utilized for other biotechnological medicines that are not currently in Iran’s drug list.

Submitted: 5 September 2020; Revised: 13 January 2021 ;Accepted: 13 January 2021; Published online first: 29 January 2021

Introduction

Since the development of human insulin via recombinant DNA technology in 1982, several medicinal biotechnological therapeutics have been marketed. These products have broadened the treatment armament for use against life-threatening and chronic diseases [1]. Due to costly manufacturing processes and the considerable investment in research and development required prior to their approval, these products are generally high priced. The mean daily cost of treatment with biotechnological therapeutics is estimated to be 22 times higher than conventional small-molecule medicines [2]. Therefore, despite biologicals’ well-known benefits, including providing more specific and life-saving treatments for a variety of diseases, their use will be restricted by ever-increasing healthcare costs. Healthcare authorities have been eager to find more affordable choices to facilitate patients’ access to these therapies. Follow-on biologicals are potentially less expensive options that can deliver the same benefits of originator biotechnological therapeutics.

According to the US Food and Drug Administration (FDA) definition, a biosimilar is a biological product that is highly similar to an already-approved biological with no clinically meaningful differences from the originator [3]. The European Medicines Agency (EMA) was the first regulatory agency to lay down a biosimilar approval framework in 2005 [4]. Following this, in 2006, somatropin became the first biosimilar molecule that was granted European Union (EU) marketing authorization. Since then, several biosimilar products have been launched in Europe. In 2013, an infliximab biosimilar was the first biosimilar monoclonal antibody that received EMA approval. Due to the complex macromolecular structure of biologicals and their manufacturing procedures’ sensitivity to small variations, approval frameworks outline the rigorous quality control and quality assurance measures required to ensure biosimilar and reference products’ comparability. In addition, they define when clinical studies are required to demonstrate that a biosimilar product is highly similar to the originator in terms of efficacy and safety [5].

Following the development of EMA’s biosimilar approval framework, the World Health Organization (WHO) and FDA established their own biosimilar authorization pathways [6, 7]. According to the guidelines published by EMA, FDA and WHO, several countries have established country-specific guidelines for biosimilar approval [8]. The Iranian pharmaceutical regulatory authority (Iran Food and Drug Administration, IFDA) developed its national biosimilar guidance based on WHO guidelines in 2010 [9].

The pharmaceutical industry in Iran began over 80 years ago [10]. In recent years, the commercial potential of producing follow-on biologicals and the favourable economic returns they offer, have encouraged several science-based companies to move towards producing biotechnological therapeutics. In 2000, Interferon alfa-2b was the first follow-on biological that was marketed in Iran. Since then, several other products have been developed and marketed in the country. This product, and other follow-on biologicals that were marketed before the issuance of IFDA biosimilar guidance in 2010, cannot be called biosimilars. This is because many of these follow-on products have not registered or published head-to-head clinical trials with the reference product and have not demonstrated that they are highly similar to their reference product, see Table 1.

Table 1

The present study had several goals: (1) To identify the follow-on biologicals in the Iranian market and summarize the available information regarding their market entry and related clinical trials; (2) To assess the share of biotechnological therapeutics in Iran’s pharmaceutical market and provide an overview of follow-on biologicals’ share in terms of the number of units sold (sales volume), total sales (sales value), and domestic production/imports; (3) To estimate the potential and actualized cost-saving associated with the use of follow-on biologicals; (4) To summarize information regarding follow-on biological candidates that might enter the market in the future.

Methods

Information from the Iranian Registry of Clinical Trials (IRCT), clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) was used to identify related phase I and III clinical trials between 2013 and 2018. A PubMed and Google Scholar search was also conducted to find related scholarly articles. The descriptive search terms selected to retrieve data from online sources included the brand name, company name, generic name, biosimilar, clinical trial registration identifier, and Iran. The basic Boolean operator “AND” was used to combine the search terms in various ways in an effort to ­narrow down search results. Several articles were found using the snowball method by referring to article’s bibliography to pinpoint other relevant articles. In addition, information regarding marketing approval date, brand name and pipeline products of the companies were gathered through referring to reliable pharmaceutical, organizational and governmental sites, as well as via Google search in both English and Persian.

The information regarding pharmaceutical products sales was obtained from IFDA database. This database, which is updated annually, compiles information from all the pharmaceutical wholesale and distribution companies in Iran. The information includes the generic and brand name, dosage form, administration route, producer company, sales volume, and value. The proportion of healthcare spending on biotechnological therapeutics was calculated by dividing total sales of biotechnological products by the total sales of pharmaceutical products in Iran. By identifying the originators and follow-on biologicals for each molecule in the database, the total number of units sold (sales volume) and the total sales (sales value) of biotechnological products were obtained for follow-on biologicals and originators. Also, by determining the finished product producer, the share of domestic production and imported products was calculated in terms of sales volume and sales value. The compound annual growth rate (CAGR) was calculated ­during the 2013–2018 period. Since most biotechnological therapeutics were available in different potencies, the number of units sold was converted into a specific potency for each molecule (unified sales volume). The unit price was obtained by dividing the sales value by sales volume for each product. All the sales values and unit prices were converted into United States Dollar (USD), based on the average annual exchange rates provided in the customs administration of Iran (IRICA) website.

The actualized and potential cost savings associated with using follow-on biologicals were calculated using two scenarios. The actualized cost saving was determined by subtracting the total sales value of the molecule (originator and biosimilar/follow-on biological) from the product of multiplication of total sales volume of the molecule (originator and biosimilar/follow-on biological) in originator’s unit price. The potential cost saving that could be realized by using follow-on biologicals instead of originators was calculated by subtracting the product of the sales volume of originators in the unit price of the biosimilar/follow-on biological by year (if such an option was available that year) from the product of total sales volume (originator and biosimilar/follow-on biological) in the originator’s unit price.

The quantitative data were analysed using Microsoft Excel 2016 (Microsoft Corporation, USA).

Results

At the time of writing, 21 follow-on biologicals are produced and marketed in Iran, see Figure 1.

Figure 1

These products are related to 17 different reference products. Information regarding these follow-on biological products, including details of head-to-head studies with reference products, and their related publications, is summarized in Table 1.

The total biologicals market in Iran reached approximately US$745 million in 2018 (6-year CAGR = 21.51%). The proportion of healthcare spending on biologicals was 13.5% in 2018 (5-year CAGR = 1.38%).

In 2018, follow-on biologicals comprised approximately 47.2% of the total sales value of biotechnological therapeutics, up from 35.2% in 2013 (6-year CAGR = 28.6%). Despite demonstrating an upward trend (6-year CAGR = 16.64%), the proportional annual sales value of originators compared to the total sales value of biotechnological therapeutics decreased from 64.8% in 2013 to 52.8% in 2018, see Figure 2A. Conversely, in terms of the sales volume (number of units sold) the 6-year CAGR of follow-on biologicals (15.74%) was lower than the originators (43.49%). The proportional sales volume of follow-on biologicals in 2018 decreased to 34.6% from 60.7% in 2013. While originators proportional sales volume reached to 65.5% in 2018 up from 39.3% in 2013, see Figure 2B.

Figure 2

As is the case for originator products, some follow-on biologicals used in Iran are imported from other countries. Figure 3 represents the proportional share of the domestic production or import of the biotechnological therapeutics in Iran, in terms of sales value, see Figure 3A and sales volume, see Figure 3B. In 2018, 42.5% of the follow-on biologicals in the Iranian pharmaceutical market were produced domestically, up from 27.8% in 2013 (6-year CAGR = 28.86%). The proportional sales value of the imported products decreased from 72.2% in 2013 to 57.5% in 2018, despite having a positive 6-year CAGR of 16.64%, see Figure 3A. The 6-year CAGR of domestic products (15.29%) was lower than that for imported products (40.56%) with respect to sales volume. The proportional sales volume of domestic products declined from 53.2% in 2013 to 29.7% in 2018. While the proportional sales volume of the imported products reached 70.3% in 2018, up from 39.3% in 2013, see Figure 3B.

Figure 3

From 2013 to 2018, IFDA priced the follow-on biologicals on average at 54.3±17.8% (mean ± standard deviation) of the originators’ price. during this time, the price of follow-on biologicals was 12%–78% lower than the originators.

The actualized cost saving associated with using follow-on biologicals has increased in recent years, with a 6-year CAGR of 8.91%, see Figure 4. The significant increase in cost saving in 2017 and 2018 has been mainly driven by an increase in the use of rituximab, adalimumab and trastuzumab follow-on biologicals. The potential cost-saving associated with using follow-on biologicals is also shown on Figure 4. The proportion of actualized cost saving to the potential cost saving was 82.68% on average. This means that it is possible to increase the uptake of follow-on biologicals and benefit from their associated cost savings.

Figure 4

As summarized in Table 2, several biosimilar candidates are under development in Iran. They may be granted marketing authorization in the future if they provide satisfactory comparative efficacy and safety results. These are biosimilar candidates for aflibercept, alteplase, cetuximab, denosumab, ocrelizumab, omalizumab, peginterferon beta-1a, pertuzumab, and tocilizumab. These biosimilar candidates are mostly monoclonal antibodies used to treat several life-threatening and debilitating conditions.

Table 2

Discussion

In the present study, the current status of follow-on biologicals in the Iranian market has been investigated by evaluating their ongoing and completed clinical trials. The article has highlighted that, as some products were approved as follow-on biologicals prior to the issuance of IFDA biosimilar guidance, they have not registered or published head-to-head clinical trials against the reference product. As biosimilars offer exciting therapeutic opportunities for healthcare authorities and patients in Iran in the future, all efforts should be made to ensure that true biosimilars are approved that are highly similar to reference products in terms of quality, efficacy and safety.

The annual national wholesale data on pharmaceutical products suggests that the use of biologicals in Iran has increased considerably in recent years in terms of both sales value and sales volume. However, there was only a slight increase in the proportional share of biotechnological therapeutics with respect to the total medicines market (from 12.7% in 2013 to 13.5% in 2018). According to the IQVIA reports, in 2018, biologicals represented 29.9% of the total medicines market in Europe with a CAGR of 1.93%. In the US, 42% of healthcare costs for medicines were devoted to biotechnological therapeutics (5-year CAGR = 8.78%) [23, 24]. Despite an increasing trend in the use of biological therapeutics in Iran, the proportion of healthcare expenditure on biotechnological therapeutics here is considerably lower than in Europe and the US, see Figure 5. The unwillingness of the Iranian healthcare authorities to add new molecules, specifically biotechnological therapeutics, to Iran’s national drug list may be a contributing factor to the comparatively low uptake of these products. This issue may stem from the greater cost associated with using biotechnological therapeutics and connected increase in healthcare burden. The importance of biotechnological therapeutics in the treatment of a wide range of severe and chronic diseases, together with escalating healthcare costs highlights the importance of using biosimilars as a lower-priced substitute for originator biologicals. The use of biosimilars can significantly reduce healthcare expenditure on biotechnological therapeutics. According to an evaluation by Mulchay et al. [25], it was projected that the emergence of biosimilars would reduce US healthcare spending by US$54 billion in 2026. The proportional difference in the use of biotechnological therapeutics in Iran compared to other regions might also be explained by various different pricing strategies adopted for biosimilars and follow-on biologicals. For example, in Europe, biosimilar developing companies have to price their products at least 30% lower than the originator [4]. According to a recent review of literature, the price difference between biosimilar developing companies and their originators ranges between 15%–30% [4]. While in Iran, from 2013 to 2018, follow-on biologicals’ price has been approximately 54.3% of originators.

Figure 5

In recent years, the share of follow-on biologicals produced domestically has increased considerably in terms of sales value. At the same time, the trend of the increase in sales volume was moderate compared to sales value. This might suggest that pharmaceutical and biotechnology companies in Iran have been more willing to invest in high-value, low-volume production. This tendency is also apparent in the biosimilar candidates in the companies’ pipelines. The majority of these products are monoclonal antibodies that usually have a high unit price.

The introduction of follow-on biologicals has offered significant cost saving for the Iranian healthcare system as actualized cost saving through follow-on biologicals use reached over US$300 million in 2018. These savings were influenced by the rate of ­follow-on biologicals use and the difference in unit price between follow-on biologicals and originators. Rituximab, adalimumab and trastuzumab were the main drivers of the ­significant cost saving in 2017 and 2018. This figure is likely to increase in the upcoming years due to the market entry of other biosimilars/follow-on biologicals currently under development.

The pharmaceutical landscape of Iran has changed significantly in the past 20 years. In recent years, some biopharmaceutical companies in Iran (CinnaGen and AryoGen) have endeavoured to move towards regulated markets, such as Europe. As a preliminary step, they have acquired EU-good manufacturing practice (GMP), the certificate of GMP, that has been published on EMA’s database [6, 7]. In 2017, CinnaGen initiated pharmacokinetics (PK) and pharmacodynamics (PD) studies of its interferon beta-1a biosimilar (CinnoVex®) in Finland [8]. As such, it seems that by the development of high-quality biosimilars bolstered by satisfactory non-clinical and clinical studies, Iranian pharmaceutical companies can expand their presence in regulated and semi-regulated markets.

Conclusion

Although biotechnological therapeutics have offered life-saving therapies to many critical diseases, their proportional uptake in Iran has remained constant in recent years. It seems that healthcare authorities can improve patients’ access to these medicines through promoting the use of biosimilars/follow-on biologicals instead of costly originators once their quality, safety, and efficacy have been ensured. The significant cost saving associated with using biosimilars/follow-on biologicals can be allocated to helping new biotechnological medicines to be included in Iran’s drug list.

Competing interests: Farhang Rezaei and Nassim Anjidani work in the medical department of Orchid Pharmed company which is in collaboration with AryoGen Pharmed and CinnaGen companies with respect to conducting clinical trials.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Farhang Rezaei, PharmD
Nassim Anjidani, PharmD

Medical Department, Orchid Pharmed Company, No 42. Attar Streeet, North Kurdistan Highway, 1994766411 Tehran, Iran

References
1. Espiritu MJ, Collier AC, Bingham J-P. A 21st-century approach to age-old problems: the ascension of biologics in clinical therapeutics. Drug Discov Today. 2014;19(8):1109-13.
2. Cheraghali AM. Biosimilars; a unique opportunity for Iran national health ­sector and national pharmaceutical industry. Daru. 2012;20(1):35.
3. U.S. Food and Drug Administration. Biosimilar and interchangeable products. 2017 [homepage on the Internet]. [cited 2021 Jan 13]. Available from: https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products
4. Kabir ER, Moreino SS, Sharif Siam MK. The breakthrough of biosimilars: a twist in the narrative of biological therapy. Biomolecules. 2019;9(9):410.
5. O’Callaghan J, Barry SP, Bermingham M, Morris JM, Griffin BT. Regulation of biosimilar medicines and current perspectives on interchangeability and policy. Eur J Clin Pharmacol. 2019;75(1):1-11.
6. GaBI Online – Generics and Biosimilars Initiative. MENA region biologicals maker CinnaGen receives EU GMP certification [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 13]. Available from: http://gabionline.net/Pharma-News/MENA-region-biologicals-maker-CinnaGen-receives-EU-GMP-certification
7. GaBI Online – Generics and Biosimilars Initiative. MENA mAb manufacturer AryoGen receives EU GMP approval [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 13]. Available from: http://gabionline.net/Pharma-News/MENA-mAb-manu­­­­­­­­­­facturer-AryoGen-receives-EU-GMP-approval
8. Cinnagen. Comparative trial of the pharmacokinetics and pharmacodynamics of intramuscularly injected CinnoVex® and Avonex® in healthy volunteers clinicaltrials.gov; 2018. Report No.: NCT03614715 [homepage on the Internet]. [cited 2021 Jan 13]. Available from: https://clinicaltrials.gov/ct2/show/NCT03614715
9. The Iranian national biosimilar guidance [homepage on the Internet]. [cited 2021 Jan 13]. Available from: http://fdo.behdasht.gov.ir/index.aspx?siteid=114&pageid=40850&siteid=114
10. Majid Cheraghali A. Current status of biopharmaceuticals in Iran’s pharmaceutical market. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):26-9. doi:10.5639/gabij.2013.0201.008
11. Jamshidi A, Gharibdoost F, Vojdanian M, Soroosh SG, Soroush M, Ahmadzadeh A, et al. A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inferiority clinical trial to compare efficacy and safety of biosimilar adalimumab (CinnoRA®) to the reference product (Humira®) in patients with active rheumatoid arthritis. Arthritis Res Ther. 2017;19(1):168.
12. Jamshidi A, Sabzvari A, Anjidani N, Shahpari R, Badri N. A randomized phase I pharmacokinetic trial comparing the potential biosimilar adalimumab (CinnoRA®) with the reference product (Humira®) in healthy volunteers. Expert Opin Investig Drugs. 2020;29(3):327-31.
13. Rezvani H, Mortazavizadeh SM, Allahyari A, Nekuee A, Najafi SN, Vahidfar M, et al. Efficacy and safety of proposed bevacizumab biosimilar BE1040V in patients with metastatic colorectal cancer: a phase III, randomized, double-blind, noninferiority clinical trial. Clinical Ther. 2020;42:848-59.
14. Norouzi Javidan A, Shahbazian H, Emami A, Yekaninejad MS, Emami-Razavi H, Farhadkhani M, et al. Safety and efficacy of PDpoetin for management of anemia in patients with end stage renal disease on maintenance hemodialysis: results from a phase IV clinical trial. Hematol Rep. 2014;6(3):5195.
15. Azmandian J, Abbasi MR, Pourfarziani V, Nasiri AA, Ossareh S, Ezzatzadegan Jahromi S, et al. Comparing therapeutic efficacy and safety of epoetin beta and epoetin alfa in the treatment of anemia in end-stage renal disease hemodialysis patients. Am J Nephrol. 2018;48(4):251-9.
16. Faranoush M, Abolghasemi H, Toogeh Gh, Karimi M, Eshghi P, Managhchi M, et al. A comparison between recombinant activated factor VII (Aryoseven) and Novoseven in patients with congenital factor VII deficiency. Clin Appl Thromb Hemost. 2015;21(8):724-8.
17. Faranoush M, Abolghasemi H, Mahboudi F, Toogeh G, Karimi M, Eshghi P, et al. A comparison of efficacy between recombinant activated factor VII (Aryoseven) and Novoseven in patients with hereditary FVIII deficiency with inhibitor. Clin Appl Thromb Hemost. 2016;22(2):184-90.
18. Abolghasemi H, Panahi Y, Ahmadinejad M, Toogeh G, Karimi M, Eghbali A, et al. Comparative evaluation of the safety and efficacy of recombinant FVIII in severe hemophilia A patients. J Pharmacopuncture. 2018;21(2):76-81.
19. Nafissi S, Azimi A, Amini-Harandi A, Salami S, Shahkarami MA, Heshmat R. Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: A double blind randomized clinical trial. Clin Neurol Neurosurg. 2012;114(7):986-9.
20. Toogeh G, Faranoush M, Razavi SM, Jalaeikhoo H, Ravanbod MR, Zarrabi F, et al. A double-blind, randomized comparison study between ZytuxTM vs MabThera® in treatment of CLL with FCR Regimen: non-inferiority clinical trial. Int J Hematol Oncol Stem Cell Res. 2018;12(2):84-91.
21. Tabatabaei-Malazy O, Norani M, Heshmat R, Qorbani M, Vosoogh A, Afrashteh B, et al. Efficacy and safety of the biosimilar recombinant human parathyroid hormone Cinnopar® in postmenopausal osteoporotic women: a randomized double-blind clinical trial. Iran J Public Health. 2018;47(9):1336-44.
22. Farahani MF, Maghzi P, Aryan NJ, Payandemehr B, Soni M, Azhdarzadeh M. A randomized, double-blind, parallel pharmacokinetic study comparing the trastuzumab biosimilar candidate, AryoTrust®, and reference trastuzumab in healthy subjects. Expert Opin Investig Drugs. 2020;29(12):1443-50.
23. Troein P, Newton M, Patel J, Scott K. The impact of biosimilar competition in Europe. IQVIA. 2019.
24. Aitken M. Biologics market dynamics: setting the stage for biosimilars. IQVIA Institute for Human Data Science. 2020.
25. Mulcahy AW, Hlavka JP, Case SR. Biosimilar cost savings in the United States. Rand Health Q. 2018;7(4):3.

Author for correspondence: Farhang Rezaei, PharmD, Medical Department, Orchid Pharmed Company, No. 42, Attar Street, Attar Square, North Kurdistan Highway, 1994766411 Tehran, Iran

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.


Last update: 07/04/2022

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Summative usability evaluation of the YLB113 etanercept biosimilar autoinjector via simulation

Author byline as per print journal: Kelly Canham1, BSc Hons; Claire Newcomb2, MSc

Introduction/Study Objectives: Etanercept is a tumour necrosis factor inhibitor indicated for the treatment of several inflammatory disorders. Patients with these diseases may experience manual dexterity challenges. Autoinjectors may improve dose accuracy, treatment adherence and quality of life; and reduce injection-site reactions. Studies have indicated patients prefer autoinjectors to other injection methods, however, patients must be able to demonstrate safe and effective use of an autoinjector for it to be a viable option. The YLB113 etanercept autoinjector may be a substitutable biosimilar to reference etanercept (Pfizer Manufacturing, Puurs, Belgium). This study sought to confirm intended users of the YLB113 etanercept autoinjector could demonstrate safe and effective use.
Methods: The evaluation was performed among 79 participants representative of intended YLB113 etanercept autoinjector users; and included patients, caregivers and healthcare providers (HCPs).
Results: All participants successfully delivered two simulated doses of etanercept into the foam pad using the autoinjector. Some participants experienced user errors, use difficulties, or close calls while simulating injection or answering knowledge questions.
Discussion: In this usability evaluation, study patients, caregivers and HCPs demonstrated a high rate of injection success using the YLB113 etanercept autoinjector.
Conclusions: The study results support demonstration of safe and effective use of the YLB113 etanercept autoinjector, a substitutable biosimilar to reference etanercept.

Submitted: 12 October 2020; Revised: 11 February 2021;Accepted: 15 February 2021; Published online first: 1 March 2021

Introduction/Study Objectives

Etanercept is a tumour necrosis factor inhibitor indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and adult and paediatric psoriasis [1]. Patients suffering from the diseases for which etanercept is indicated may experience difficulties with manual dexterity that limit their ability to self-administer injections [2]. Autoinjectors (AIs) have been shown to offer several benefits to patients, including improved dose accuracy, ease of use, improved treatment adherence, and a reduced number of injection-site reactions [2]. In addition, studies suggest patients prefer AIs to other injection methods [3, 4]. However, for an AI to be a viable option, patients must be able to demonstrate safe and effective use [2]. Mylan, in collaboration with Lupin, is developing an etanercept AI, referred to here as the YLB113 etanercept AI, as a substitutable biosimilar product to Enbrel® (Pfizer Manufacturing, Puurs, Belgium) in the SureClick® AI. The etanercept solution is supplied in a single-use, disposable AI containing 50 mg/mL, as shown in Figure 1. Figure 2 shows a complete chronological task list for the injection process. In general, to administer a dose, the user must remove the needle cap and press the AI against the injection site. When the button is pressed, the AI clicks to indicate the start of the injection. A second click indicates the end of the injection. Following the second click, the AI must be held in place for an additional 15 seconds to ensure a full dose is delivered. After 15 seconds, the user can remove the AI from the skin and discard it in a sharps container.

The objective of this study was to confirm the intended users of the YLB113 etanercept AI could demonstrate safe and effective use through usability criteria predefined through risk assessment of the tasks. This is consistent with guidance from the European Union and United States regulatory authorities that, when needed, a human factors/usability study with the final version of the device should be completed to validate users’ performance with representative users in the environment of use [5-7].

Figure 1

Figure 2

Methods

The study was conducted in accordance with the principles of Good Clinical Practice and the provisions of the Declaration of Helsinki of 1964 and its later amendments. Participants eligible for study recruitment had the nature, purpose and risks of the study explained to them by the moderator. Informed consent was given by all participants and those aged younger than 18 years completed assent forms and were accompanied by a parent or guardian. Participants were provided a copy of the informed consent form for the study and were allowed time to consider whether they wanted to participate. Participant names were not included on the video, and all data were stored under protected computer systems that were only available to the usability vendor project team. The study protocol and supporting materials were reviewed and approved on 21 June 2019, by Core Human Factors, an independent Institutional Review Board located in Philadelphia, PA, USA, prior to collecting data from participants.

This summative usability evaluation study was performed among participants representative of intended YLB113 etanercept AI users that included patients, caregivers and healthcare providers (HCPs). Patients were included if they were diagnosed with a condition as described in the therapeutic indications section of the Enbrel summary of product characteristics [1] or, as few as possible children who had used any AI, e.g. epinephrine. Patients were divided into age groups of 12 to 17, 18 to 64, and 65 years and older. Caregivers (non-professionals) were included if they routinely helped someone ad-minister their medications. HCPs were included if they were a licensed nurse practitioner or registered nurse who administers or trains patients to administer medications using an AI, regardless of the patient diagnosis.

Figure 3

Intended YLB113 etanercept AI users may or may not have experience with AIs, therefore, half of the patient and caregiver groups were naïve to AI use and half had prior experience with AIs. Testing was conducted at multiple independent research facilities in the UK by a usability vendor. The study was conducted in a simulated home-use environment in which a moderator, following a script, interacted 1-on-1 (moderator to participant) or 1-on-2 (moderator to adolescent and their parent or guardian) to observe participants interacting with the user interface to simulate dose administration in accordance with a predefined task. The environmental conditions included standard room lighting, minimal noise distraction, and low-level background noise. The YLB113 etanercept AIs were presented in a carton representative of the shape and design of the commercial packaging. The labelling used in this study represented the Australian product as European labelling was still in development, see Figure 3 and Figure 4. The samples used in the study were not suitable for human injection and were intended only for simulated injection into a foam pad on the table. The foam pad had a hard plastic base to minimize the risk for accidental needle-stick injury. Supplies were presented to the participants or were available in the testing room for each session, and included a carton with four AIs, instructions for use, foam injection pad, hand sanitizer and paper towels, alcohol swabs, adhesive bandages, sharps bin, first aid kit, portable eye wash kit, and telephone. In addition, the testing room was equipped with cameras to enable a wide view of the moderator and participant, as well as a close-up view of the participant completing the task, to allow the project team to re-watch the session to aid in any root cause analysis.

Figure 4

As intended for all YLB113 etanercept AI users, participants received training on the usage of the commercially equivalent, single-use disposable AI according to a training guide one day before usability testing. A minimum of 18 hours with only one overnight between training and testing sessions was required to represent a reasonable time for knowledge decay from the time of receiving a prescription to administration of the first dose. During the testing session, participants were asked to simulate delivering a dose of medication into a foam pad twice in a row. Participants were given an opportunity to use the system independently and in as realistic a manner as possible, without guidance, coaching, or critique. Additional tasks and knowledge-based questions were used for further demonstration of safe and effective use. At the end of the task, a post-task interview was conducted to investigate the root cause of any use errors or close calls through open-ended questions and to record the participant’s perspective of their interaction with the user interface. In addition, a dynamometer was used to assess grip strength. The highest of three measurements from the dynamometer was taken from each participant and was averaged to calculate the mean maximum grip strength for each user group. A pinch gauge was also used to assess pinch strength. The highest of three measurements from the pinch gauge was taken from each participant and was averaged to calculate the mean maximum pinch strength for each user group.

Results

A total of 79 participants were included in this summative usability evaluation study. All the HCP participants in this study were female (n = 15). Across all other user groups, 63% were female. Demographic information, including gender, dominant hand, mean maximum grip strength, and mean maximum pinch strength are shown in Table 1.

Table 1

The task and knowledge question outcome summary across all groups is shown in Table 2a and Table 2b. All (100%) participants successfully delivered both simulated doses from the YLB113 etanercept AI into the foam pad and answered knowledge questions on where to store the pens, what the liquid should look like, where to look to see the liquid, injecting at 90°, initiating the injection, removing the pen from the injection site, and performing the injection without injury. Some participants experienced use errors, use difficulties, or close calls while performing tasks or answering knowledge questions. Success was recorded when no use errors, usability issues, close calls, or issues necessitating assistance were observed, see Table 3. Success rates for the tasks and knowledge questions were: removing the pen from carton (92%), knowing to let the pen reach room temperature (97%), reporting the expiry date (99%), knowing when a full dose has been taken (99%), washing their hands (94%), knowing the correct injection site (97%), cleaning the injection site (99%), removing the safety cap (96%), disposing of the cap in a sharps container (98%), stretching the skin (88%), holding the AI down for 15 seconds after the second click (98%), and disposing of the pen in the sharps container (96%). A total of 11 use errors occurred on critical tasks over 158 simulated injections. The root cause analyses of these use errors are shown in Table 4. Use difficulties only occurred when removing the pen from the carton (n = 11) and stretching the skin at the injection site (n = 1)

Table 2a

Table 2b

Table 3

Discussion

In this summative usability evaluation study conducted at multiple independent research facilities in the United Kingdom, patients across all age groups, caregivers, and HCPs demonstrated a high rate of injection success using the YLB113 etanercept AI. All participants were able to successfully deliver two simulated injections into a foam pad, including patients and caregivers with or without prior AI experience. In addition, all participants indicated they knew where to store the pens, what the liquid should look like, and where to look to see the liquid. All participants also demonstrated success with injecting at 90°, initiating the injection, removing the pen from the site, and performing the injection without injury. Although the vast majority of participants demonstrated success across all other success criteria, some participants experienced use errors, use difficulties, or close calls while performing tasks or answering knowledge questions, see Table 4.

Table 4

Table 4

Limitations

A limitation of this study is that injections were simulated into a foam pad at a research facility as opposed to using the AI in a clinical or home-use setting. However, it is important to note that simulated-use testing, as employed in this study, is sufficient to assess the adequacy of the user interface for most combination products, according to health authority guidance [5-7]. In addition, it is anticipated that patients being prescribed the YLB113 etanercept AI will receive training, however, the training of all participants prior to simulating an injection limits the generalizability of these findings to those who have not received such training.

Conclusions

Patients across all age ranges, grips strengths, and pinch strengths; caregivers and HCPs were able to successfully deliver two doses of etanercept into a foam pad to demonstrate safe and effective use of the AI. The results from this study support the demonstration of safe and effective use of the YLB113 etanercept AI as a substitutable biosimilar product to Enbrel.

For patients

Antitumour necrosis factor inhibitors, such as etanercept, are indicated for use in patients suffering from inflammatory conditions in the form of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, axial spondyloarthritis, and adult and paediatric psoriasis. Patients suffering from these conditions may receive benefits from the use of self-administered injectable medications, such as improved compliance, ease of use, dosing accuracy, and fewer injection-site reactions. Research indicates patients prefer autoinjectors (AI) to traditional injections, however, inflammatory diseases commonly present with clinical manifestations that limit dexterity and ability to manoeuvre AI devices. The YLB113 etanercept AI may be a substitutable biosimilar product to Enbrel®, and this manuscript reviews the summative usability studies of YLB113 etanercept AI among intended users. The findings confirm that intended users across all age ranges, and grip and pinch strengths, including patients, caregivers and healthcare professionals, were able to demonstrate safe and effective use of the device. The results from this study support the demonstration of safe and effective use of the YLB113 etanercept AI as a biosimilar substitute product to Enbrel®.

Declarations

Compliance with ethics guidelines

The study was conducted in accordance with the principles of Good Clinical Practice and the provisions of the Declaration of Helsinki of 1964 and its later amendments. Participants eligible for study recruitment had the nature, purpose, and risks of the study explained to them by the moderator. Informed consent was given by all participants and those aged younger than 18 years completed assent forms and were accompanied by a parent or guardian. Participants were provided a copy of the informed consent form for the study and were allowed time to consider whether they wanted to participate. Participant names were not included on the video, and all data were stored under protected computer systems that were only available to the usability vendor project team. The study protocol and supporting materials were reviewed and approved on 21 June 2019 by Core Human Factors, an independent Institutional Review Board located in Philadelphia, PA (USA), prior to collecting data from participants.

Author contributions

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. The authors made all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. All authors had final approval of the manuscript and are accountable for all aspects of the work in ensuring the accuracy and integrity of this manuscript. Authors have full control of all primary data and agree to allow the journal to review the data if requested.

Competing interests: KC and CN are employee and shareholder of Mylan.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Kelly Canham1, BSc Hons
Senior Device Development Manager and Human Factors Lead
Claire Newcomb2, MSc

1Viatris/Mylan Pharma UK Ltd (formerly Mylan Pharma UK Ltd), Suite 13 Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK
2Viatris/Mylan Pharma UK Ltd (formerly Mylan Pharma UK Ltd), Floor 3, Discovery Park House, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, UK

References
1. Enbrel® (INN-etanercept) [summary of product characteristics]. Puurs, Belgium: Pfizer Manufacturing; 2019.
2. Weinhold T, Del Zotto M, Rochat J, Schiro J, Pelayo S, Marcilly R. Improving the safety of disposable auto-injection devices: a systematic review of use errors. AAPS Open. 2018;4:7.
3. Vermeire S, D’heygere F, Nakad A, Franchimont D, Fontaine F, Louis E, et al. Preference for a prefilled syringe or an auto-injection device for delivering golimumab in patients with moderate-to-severe ulcerative colitis: a randomized crossover study. Patient Prefer Adherence. 2018;12:1193-202.
4. Gandell DL, Bienen EJ, Gudeman J. Mode of injection and treatment adherence: results of a survey characterizing the perspectives of health care providers and US women 18-45 years old. Patient Prefer Adherence. 2019;13:351-61.
5. EN 62366:2015 Medical devices – Part 1: Application of usability engineering to medical devices.
6. Medical & Healthcare Products Regulatory Agency. Human factors and usability engineering – Guidance for medical devices including drug-device combination products. 2021 [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/645862/HumanFactors_Medical-Devices_v1.0.pdf
7. U.S. Food and Drug Administration. Human factors studies and related clinical study considerations in combination product design and development. Draft guidance for industry and FDA staff. 2016. [homepage on the Internet]. [cited 2021 Feb 11]. Available from: https://www.fda.gov/media/96018/download

Author for correspondence: Kelly Canham, BSc Hons, Senior Device Development Manager and Human Factors Lead, Viatris/Mylan Pharma UK Ltd (formerly Mylan Pharma UK Ltd), Suite 13 Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK

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.


Last update: 19/01/2022

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