ABSTRACT
Background
Professional associations publish guidance advising gastroenterologists on prescribing biosimilars; however, guidelines differ between countries and change over time. This study aimed to map the presence and content of guidance from European gastroenterology associations on TNFα inhibitor biosimilar use and its development over time.
Research design and methods
Guidelines on biosimilar prescribing from national gastroenterology associations in the European Economic Area (EEA) partnered with the European Crohn’s and Colitis Organization (ECCO) were collected. Treatment guidelines and biosimilar position papers from 2010 to 2022 were included. Data were extracted using a template.
Results
26 of 30 EEA countries have an ECCO-partnered gastroenterology association, of which 14 (53.8%) had national guidelines addressing biosimilars, four (15.4%) followed ECCO’s position, and three (11.6%) had treatment guidelines without mentioning biosimilars. From five countries (19.2%) no guidelines were retrieved. Among 18 countries with guidance, 14 (77.8%) associations endorsed initiating biological treatment with biosimilars, and 13 (72.2%) endorsed transitioning from originator to biosimilar. Nine associations published multiple guidelines over time addressing biosimilars; overall, their positions became more encouraging.
Conclusions
The majority of gastroenterology associations endorsed biosimilar use. The lack of (up-to-date) guidelines for some associations indicates an area of improvement to support biosimilar use in clinical practice.
1. Introduction
Tumor necrosis factor (TNF)α inhibitors have significantly improved the pharmacological treatment of inflammatory bowel disease (IBD), including Crohn’s Disease (CD) and ulcerative colitis (UC). These agents make clinical and endoscopic remission realistic targets for patients who do not respond sufficiently to first-line conventional therapy, such as aminosalicylates or immunomodulators, sometimes combined with (short-term) corticosteroids [Citation1]. TNF is a central cytokine in the pathogenesis of IBD, causing inflammation located in the gut (UC), or affecting the whole gastrointestinal tract (CD) [Citation2]. TNFα inhibitors neutralize TNF and consequently reduce inflammation [Citation3]. However, TNFα inhibitors, like most biological medicines, were substantially more expensive than conventional small-molecule medicines, which has stressed healthcare budgets [Citation4]and sometimes limited patients’ access to these treatments.
The patent and regulatory exclusivities expired several years ago for the infliximab (Remicade®) and adalimumab (Humira®) brand products, the two most used TNFα inhibitors in IBD [Citation4]. This allowed the introduction of biosimilars as lower-cost versions of these medicines [Citation4]. A biosimilar is defined by the European Medicines Agency (EMA) as ‘a biological medicinal product that contains a similar version of the active substance of an already authorized biological medicinal product (also called the reference product or originator)’ [Citation5]. For a biosimilar to be authorized in the European Union (EU), it undergoes an extensive comparability exercise with the originator biological to assess its biosimilarity, both in vitro and in vivo [Citation6]. Until October 2022, four biosimilars for infliximab and 11 for adalimumab had been approved for IBD in the EU [Citation7]. Introducing these biosimilars in many countries has led to price competition, resulting in lower healthcare costs and, in some cases, improved patient access to biological therapy [Citation8].
With the introduction of biosimilars, it became possible to start new patients with a biosimilar instead of an originator and to switch patients currently under treatment with an originator to the biosimilar. The latter process is also referred to as ‘transitioning.’ The use and clinical acceptance of biosimilars have been heavily debated among physicians, with positions changing over time. For example, in their 2013 position paper on biosimilars, the European Crohn’s and Colitis Organization (ECCO) stated that more research, specifically in IBD patients, was needed to ensure that biosimilars are effective and safe before prescribing them. Furthermore, the 2013 guideline did not mention transitioning [Citation9]. However, ECCO’s updated position in 2017 was much more supportive of biosimilar use; it stated that both starting new patients on a biosimilar and transitioning patients from originator to biosimilar are acceptable as they do not affect efficacy or safety [Citation10].
Clear guidance on implementing biosimilars in clinical practice is essential to support gastroenterologists in prescribing biosimilars with confidence. In general, gastroenterologists have two important sources for guidance on prescribing biosimilars: guidelines issued by ECCO and guidelines issued by their national gastroenterology association. The availability and content of these national gastroenterology guidelines might differ between countries, so comparing guidelines highlights the similarities and differences in the national positions by gastroenterologists on biosimilars. Currently, an overview of clinical guidelines regarding the use of biosimilars in clinical practice is not available for EEA countries. Therefore, little is known about the resemblance or divergence between clinical guidelines from gastroenterology associations on biosimilar use on the European level.
This study aimed to map the presence and content of guidance from gastroenterology associations in countries of the EEA on the use of biosimilars in clinical practice, including the development of guidance on biosimilar prescribing over time.
2. Patients and methods
2.1. Systematic search and inclusion of guidelines
Guidelines were retrieved from national gastroenterology associations of EEA member countries (hence the 27 EU Member States, plus Norway, Liechtenstein, and Iceland) and countries listed as partners of ECCO (n = 26) () [Citation11,Citation12]. Inclusion was limited to those countries within the EEA, since biosimilars in these countries are subject to the regulations for biosimilar regulatory approval of the EMA. The list of ECCO partner organizations was verified to be up to date by e-mail contact with ECCO [Citation12].
Guidelines were manually searched from the websites of the national gastroenterology associations and from PubMed between February 2022 and May 2022. To validate the manual search, each national gastroenterology association was contacted via e-mail (and two reminder e-mails) and asked to provide their guidelines. If no response was received, guidelines found on the gastroenterology associations’ website were eligible for inclusion. Guidelines were included if they addressed the treatment of Crohn’s disease, ulcerative colitis, or IBD in general or the treatment of IBD with biologicals because these potentially contain guidance on biosimilars. Position papers specifically addressing biosimilars were also included. Guidelines published between 2010 and May 2022 were included because the EMA authorized the first biosimilar with a gastroenterological indication in 2013 [Citation13]. If no guidelines were found on the association’s website, and the association did not respond to the e-mails, the guidelines could not be retrieved and were excluded or were considered non-existent.
If no guidelines were available, but the national gastroenterology association explicitly referred to a guideline from another medical association, either on the website or in response to the emailed request from the authors, that guideline was included in this study. For example, a guideline from an overarching non-disease-specific association for medical specialists would be included. Only guidelines from medical associations were included; thus, guidelines from regulatory authorities were excluded.
If national associations had published multiple versions of their guidelines over the study period, all versions were included from 2010 until May 2022 to review the evolving landscape of biosimilar guidance over time. In case a gastroenterology association had published multiple guidelines, all were included, and discrepancies between the guidelines were analyzed and reported. If the national gastroenterology association that was listed as a partner of ECCO had no guidelines available, and ECCO’s website had another gastroenterology association from that country listed (as ‘other organization’), that association was checked for guidelines, which were included if present.
2.2. Data extraction
The primary outcome of this study was to assess gastroenterology associations’ guidelines for recommendations on starting new patients on a biosimilar and on transitioning patients from an originator to a biosimilar. In addition, guidance related to transitioning, such as informing and monitoring patients, was also assessed. Information on these outcomes was extracted from the included guidelines.
First, a standardized data collection template was designed, discussed among the authors, and adjusted until a consensus was reached. The standardized template contained detailed questions on the guidelines for prescribing biosimilars. The template was based on the 2017 ECCO guideline on biosimilars [Citation10] and the authors’ expertise. The template included characteristics of the guidelines themselves, such as the type of document, the year the guidelines were published, recommendations on starting treatment with a biosimilar, transitioning patients from originator to biosimilar, which patients were eligible for biosimilar treatment (for starting or transitioning), recommendations on informing and monitoring patients during transitioning, and recommendations on cross-transitioning (biosimilar to biosimilar) and retransitioning (biosimilar to originator). See for the template and a more detailed description.
Data was extracted from the guidelines by RWM in a standardized form in Microsoft Excel. The coauthors (LB, LCD, KS, and HMT) validated data extraction from the guidelines by cross-checking for eight countries if they had guidelines available, and crosschecking data extraction from the guidelines from all countries that had national guidelines available and from the ECCO position paper on biosimilars (). Data were discussed in a group meeting, and discrepancies or disagreements were discussed until a consensus was reached. Data extraction was done as much as possible in the original language of the guideline, but if the understanding of the original language was insufficient, Google translate was used for translation to English.
For the national gastroenterology associations with multiple versions of guidelines, including biosimilars, data was extracted from each guideline document and compared to identify potential development over time.
2.3. Data analysis
The availability of guidelines was visually depicted. Baseline characteristics (type of document and year of publication) and recommendations on starting and transitioning were summarized by country and listed as the number of associations, and the percentage from the total number of national gastroenterology associations with guidance available was provided. The development of guidance over time was graphically presented and separated into a chart that lists the recommendations for starting patients on a biosimilar and transitioning patients from originator to biosimilar.
3. Results
3.1. Baseline characteristics
Of the 30 EEA countries, four countries were excluded because they did not have a gastroenterology association partnered with ECCO. Of the remaining 26 countries, gastroenterology associations from 14 countries (53.8%) had a national guideline that addressed biosimilars, gastroenterology associations from four countries (15.4%) followed the position of ECCO, associations from three countries (11.6%) had guidelines that did not mention biosimilars, and, from five associations (19.2%), no guidelines were retrieved (). In total, 40 guidelines (including guidelines without mention of biosimilars and guidelines with multiple versions) were retrieved. One guideline version was retrieved from six national gastroenterology associations, and a further four national associations and ECCO’s position paper on biosimilars yielded two versions. Four associations yielded three versions and tree associations yielded four.
Figure 1. Availability of guidelines on the use of biosimilars in clinical practice from national gastroenterology associations (n countries included = 30).
In total, 18 countries, including 28 guidelines, had guidance on biosimilars. National gastroenterology associations from nine countries had multiple versions of their guidelines available that included biosimilars. All included guidelines were publicly available on the national gastroenterology association’s website or via PubMed.
As depicted in , 18 national gastroenterology associations had their own guidelines that included recommendations on biosimilars or followed ECCO guidelines. Of these, 13 (72.2%) were a position paper specifically on biosimilars. Four (22.2%) were a section or paragraph on biosimilars in another type of guideline, such as a guideline on the use of biologicals in IBD, and Germany (5.6%) had both a position document on biosimilars and a section in their clinical treatment guidelines for Crohn’s disease and ulcerative colitis. The most recent versions of the guidelines were published between 2014 and 2022, with the majority published between 2017 and 2019.
Table 1. Guidelines on the use of biosimilars from national gastroenterology associations (only information on the most recent guideline is provided).
3.2. Initiating TNFα inhibitor treatment with a biosimilar
summarizes recommendations from gastroenterology associations’ most recent guidelines regarding initiating TNFα inhibitor treatment using biosimilars. For the majority of the 18 national gastroenterology associations (n = 14 [10 with national guidelines and 4 that follow ECCO], 77.8%), no extra recommendations were provided when initiating treatment with a biosimilar in treatment-naïve patients compared with starting TNFα inhibitor treatment with the originator (). National gastroenterology associations from Croatia and Slovenia (11.1%) did not accept initiating treatment with a biosimilar because they did not support the concept of extrapolation of indications. The association from Romania did not include guidance on initiating patients on biosimilars but only transitioning from originator to biosimilar. The guideline from the Danish gastroenterology association does not distinguish between biosimilar medicines as they are considered equivalent and substitutable, without further explicit recommendations on the use of biosimilars. Most national gastroenterology associations (n = 12, 66.7%) reported no extra recommendations regarding which patients could initiate TNFα inhibitor treatment with a biosimilar. The gastroenterology associations from Austria and Croatia restricted starting a biosimilar only to patients with indications in which the biosimilar was tested; the other countries did not mention which patients can initiate biosimilar treatment.
Figure 2. (a). Development on guidance on starting TNFα inhibitor treatment with a biosimilar over time. The black line indicates a new guideline version (end of follow-up May 2022). *Finland had national guidelines in 2013, but changed to following ECCO’s guidance in 2017. (b). Development on guidance on transitioning patients from an originator TNFα inhibitor to a biosimilar over time. The black line indicates a new guideline version (end of follow-up May 2022). *Finland had national guidelines in 2013, but changed to following ECCO’s guidance in 2017.
3.3. Transitioning patients from TNFα inhibitor originator to biosimilar
The majority (n = 13, 72.2%) of the national gastroenterology associations accepted transitioning patients from originator to biosimilar (, ) in the most recent version of their guidelines. These associations were approximately the same as the associations that endorsed treatment-naïve patients to initiate TNFα inhibitor treatment with a biosimilar, except for the Austrian association that only allowed naïve patients to initiate biosimilar treatment. Transitioning to a biosimilar was not acceptable for gastroenterology associations from Austria, Romania, Croatia and Slovenia (22.2%). The latter two associations also did not endorse naïve patients initiating TNFα inhibitor treatment with a biosimilar. Gastroenterology associations from Romania and Croatia did not endorse transitioning patients from an originator to a biosimilar, but retrieving informed consent was recommended for the patients who were transitioned. The guideline from the Danish association made no recommendations, but only stated that they do not distinguish between biosimilars as they are considered equivalent and substitutable.
Out of the 13 associations that endorsed transitioning to a biosimilar, seven reported that all patients are eligible for transitioning, Belgium restricted eligibility to patients in remission, and Portugal to patients treated with originator for a specific time. The type of patients eligible for transitioning was not specified by four national gastroenterology associations that endorsed transitioning.
Fourteen national associations recommended informing patients about transitioning, with six countries additionally stating that patients should consent to transitioning, and Belgium stating that patients should be informed to mitigate from the nocebo effect.
National gastroenterology associations of eight countries had recommendations on monitoring patients after transitioning. The recommendations were diverse. The French and Dutch associations’ guidelines recommended extra monitoring of clinical parameters, the Belgian associations’ guideline mentioned monitoring for pharmacovigilance (without further specifying what is meant), and the Croatian and Slovenian mentioned monitoring for adverse events. The Polish guideline recommended monitoring of immunogenicity. The associations from Portugal and Sweden mentioned that patients could be monitored in routine clinical care.
3.4. Cross-transitioning and retransitioning
Recommendations on cross-transitioning (i.e. transitioning from one biosimilar to another biosimilar of the same originator) varied. The gastroenterology association from the Netherlands found it acceptable to transition patients once, either from originator to biosimilar, or from biosimilar to another biosimilar, and the association from Sweden recommended cross-transitioning in a study context. However, gastroenterology associations from eight countries, including the four associations following the ECCO guidelines, did explicitly not support cross-transitioning. For seven associations, specific guidance on cross-transitioning was not provided, or a stance on cross-transitioning was not applicable because the association did not endorse transitioning. The different guidelines from Germany varied on cross-transitioning; crosstransitioning was not endorsed by the German clinical guidelines, as they noted that data on this topic was scarce. However, the German position paper found cross-transitioning acceptable.
Retransitioning (i.e. transitioning from biosimilar back to the originator, after an initial transition from originator to biosimilar) was explicitly not accepted by the four associations following the ECCO guidelines because, according to the ECCO guideline, evidence of effectiveness and/ or safety is lacking (); retransitioning was not mentioned in the other guidelines. The German clinical guidelines did not endorse retransitioning but was not mentioned in the German position paper.
3.5. Development of guidance over time
Fourteen national gastroenterology associations had multiple versions over time of their guidelines available ( and ). Guidelines published between 2010 and 2013 did not include recommendations on the use of biosimilars (). Guidelines published in 2013 and 2014 did not accept initiating TNFα inhibitor treatment with a biosimilar and transitioning patients from originator TNFα inhibitor to a biosimilar. In 2015, this pattern first changed with guidelines that accepted initiating TNFα inhibitor treatment with a biosimilar until, eventually, all national gastroenterology associations that had updated their guidelines indicated acceptance of transitioning from originator to biosimilar ().
Table 2. Development of guidance on biosimilars over time.
4. Discussion
This study aimed to provide an overview of guidance from gastroenterology associations on starting IBD patients on a biosimilar and transitioning IBD patients to a biosimilar in EEA countries. In most countries (n = 18 of 26 included EEA countries, 69.2%), gastroenterology associations had guidance available on prescribing biosimilars in the form of a national guideline, position paper, or statement referring to an ECCO guideline. From the gastroenterology associations of eight countries (30.8%) no guidelines on biosimilar use were retrieved.
The majority of the associations from the 18 countries endorsed initiating TNFα inhibitor treatment with a biosimilar (n = 14) and transitioning current patients from originator to biosimilar (n = 13). However, there was varied guidance on the presence and content of recommendations regarding informing and monitoring patients while transitioning, cross-transitioning, and retransitioning. The gastroenterology associations of nine countries had multiple versions of their guidelines available that indicated the development of their positions on biosimilars over time, specifically showing a development toward broader support of biosimilars.
In this study, eight of the 26 countries with an ECCO-partnered gastroenterology association had no guidance regarding the use of biosimilars in clinical practice available, either because no guidelines were retrieved (Cyprus, Estonia, Greece, Hungary and Malta), or because the national guidelines did not include recommendations on biosimilars (Bulgaria, Slovakia and Spain). Professional guidelines, such as guidelines from their association, are an essential source of information on biosimilars for gastroenterologists [Citation14]. Gastroenterologists, as well as other physicians, have typically had reservations about biosimilars. A recent systematic literature review showed that around three out of four European gastroenterologists were reluctant regarding the practice of transitioning patients from originator to biosimilars due to insufficient knowledge of biosimilars [Citation14]. Moreover, other factors, such as the paucity of a structured transitioning strategy, limit physicians from transitioning their patients [Citation15]. A previous study demonstrated that incentive policies, such as guidelines on biosimilar use, are positively associated with biosimilar uptake [Citation16]. Although many other factors contribute to a country’s biosimilar uptake, for countries that had no guidance, the uptake of biosimilars was low. For example, Slovakia, that did not include any mentioning of biosimilars in their clinical guidelines, has a biosimilar market share of 12%, which is well below the EU average of 41% [Citation8]. Moreover, in Spain, the prescriber initiates transitioning patients from the originator TNFα inhibitor to a biosimilar. However, recommendations on the use of biosimilars in treatment guidelines are lacking in the gastroenterology field, which could temper gastroenterologists in prescribing biosimilars [Citation17]. Thus, clinical guidelines are vital to facilitate evidence-based use of biosimilars in clinical practice, and countries that had no gastroenterology guideline on biosimilars available, are urged to construct guidelines and/ or to make them (publicly) accessible.
The most recent version of national gastroenterology guidelines from seven countries, and those from ECCO, were published at least five years ago. In three countries, the timespan between guideline versions was five years or longer, a lengthy period considering the increased knowledge of and experience with biosimilars. This gap in time could delay the adoption of revised gastroenterology guidelines that utilize new knowledge of biosimilars and may postpone clinicians and patients benefitting from this knowledge [Citation18].
In almost all guidelines that include recommendations on biosimilars, the position on the use of biosimilars in clinical practice (yes or no) was evident. The most recent versions of the guidelines that included explicit recommendations on biosimilars (n = 17) indicated their positions on the use of biosimilars in clinical practice. Many also provided physicians with recommendations for transitioning patients from an originator to a biosimilar. Three quarters of guidelines (n = 14) indicated that patients should be informed regarding transitioning to a biosimilar. This recommendation aligns with studies on patients’ wishes during transitioning from an originator to a biosimilar; patients have expressed the need for quality information to make them comfortable with transitioning to a biosimilar [Citation19,Citation20].
Additionally, one-third of the guidelines provided recommendations on extra monitoring of patients during transitioning. However, the type of parameters to monitor varied significantly between guidelines (e.g. monitoring of adverse events, clinical parameters, or for pharmacovigilance). However, details on what to monitor and when were lacking. Moreover, based on the principle of similarity between the biosimilar and the originator, monitoring patients in routine clinical care could be sufficient.
Cross-transitioning and retransitioning are generally not endorsed (including by ECCO) and might not be addressed sufficiently in current guidance for clinicians to navigate these situations. More biosimilars for an originator are becoming available in clinical practice, and cross-transitioning is increasingly studied [Citation21–23]. These developments could potentially decrease healthcare spending, similar to originator-to-biosimilar transitioning. Retransitioning is reported to occur in about 7% of IBD patients who transitioned from originator to biosimilar and is caused by a (perceived) loss of effect or experience of adverse events [Citation24]. As this occasionally occurs, despite not being endorsed in guidelines, recommendations on this topic are important to inform and support clinicians with retransitioning patients. Although retransitioning might not be in line with current scientific evidence, from the perspective of patients who experienced (perceived) unwanted effects after transitioning (i.e. the nocebo effect), retransitioning might be desirable [Citation25].
While this study focused on the availability, similarities, and differences between national gastroenterology associations’ positions on biosimilar use, earlier studies have mapped the guidance and positions on the use of biosimilars provided by health authorities, such as regulatory agencies, health technology assessment (HTA) bodies or ministries of health across Europe. Of the 19 countries included in this study and studies on health authorities’ positions on the use of biosimilars, positions were aligned between gastroenterology associations and health authorities in most countries (Belgium, Croatia, Czech, Finland, France, Germany, Italy, Latvia, the Netherlands, Norway, Portugal, and Slovakia) [Citation26–29].
However, positions differed between gastroenterology associations and their national health authorities in Austria, Ireland, and Romania. Austrian health insurance policies endorse prescribing the most economical medicine and thus may endorse transitioning from originator to biosimilar; conversely, the country’s gastroenterology association discourages transitioning [Citation27,Citation28]. The Irish gastroenterology association and the governmental prescribing guidelines differ regarding which patients are eligible for transitioning. The gastroenterology association follows ECCO’s recommendation that all patients are eligible. In contrast, the governmental prescribing guidelines advised transitioning only stable, well-supervised patients [Citation28]. The Romanian gastroenterology association discouraged transitioning from originator to biosimilar. However, the insurance coverage of the originator is restricted, which could lead to financial uncertainty for patients [Citation27]. To a lesser extent, the Swedish gastroenterology association had a more favorable position on the cross-transitioning of patients compared to their regulatory authority [Citation26]. Furthermore, Spanish gastroenterology guidelines do not guide biosimilar use, but Spanish health authorities recommend transitioning patients from originator to biosimilar [Citation28].
Gastroenterologists probably have to prioritize adhering to governmental policies or laws, or the outcomes of (national or regional) price negotiations over their associations’ recommendations, in case of discrepancies, which limits the impact of gastroenterology associations’ guidance. For countries in which recommendations and regulations on biosimilars are not aligned, guidance could be improved by collaborating to harmonize them across gastroenterology associations, health authorities other involved parties within the country. Of note, some health authorities might receive direct financial benefits from patients transitioning from originator to biosimilar, whereas the direct incentives for gastroenterology associations are often limited.
Besides national regulatory agencies’ positions, EMA and the Heads of Medicines Agencies (HMA) recently published a joint position on biosimilar interchangeability, stating that biosimilars approved in the EU are interchangeable. In other words, a biosimilar can be used instead of its originator (or vice versa) or another biosimilar corresponding to the same originator, and the clinical effect will be the same [Citation30]. This statement aligns with ECCO’s statement on transitioning patients from originator to biosimilar, but, in contrast to ECCO’s position, it also facilitates cross-transitioning from one biosimilar to another of the same originator.
The national gastroenterology associations with multiple versions of guidance all showed a trend of becoming more encouraging toward using biosimilars in clinical practice. This pattern is similar to the evolution of ECCO’s position, which was primarily motivated by the results of the NOR-SWITCH trial [Citation10]. The NOR-SWITCH study demonstrated no difference in disease worsening between patients who remained on originator infliximab compared with patients who transitioned from originator infliximab to a biosimilar [Citation31]. The NOR-SWITCH study’s results and the subsequent changes to ECCO’s position on biosimilars might explain the development of gastroenterology guidance toward more supportive recommendations regarding biosimilars at the national level of EEA countries.
It could be hypothesized that favorable guidance from national gastroenterology associations on biosimilar use is associated with higher usage of TNFα inhibitor biosimilars. However, many more factors influence the use of biosimilars. This finding is evidenced by the Romanian and Slovenian associations’ restrictive guidelines on prescribing biosimilars in gastroenterology, while the TNFα inhibitor biosimilar market share is 28% in Romania but 49% in Slovenia. By contrast, in Belgium, guidelines encourage biosimilar use in gastroenterology, but the biosimilar market share for TNFα inhibitors is ‘only’ 33% [Citation8]. These numbers underline that clinical guidelines on prescribing biosimilars are only one of several factors that contribute to the uptake of biosimilars.
Furthermore, countries differ in terms of regulating the use of biosimilars. For example, Denmark and Norway have national tendering systems, thus the use of biosimilars for multiple indications is decided on a national level. The transition from originator to biosimilar in Denmark was mandatory, both for patients and for clinicians. Thus, gastroenterology associations’ recommendations on the uptake of biosimilars would contribute little to their, almost total, biosimilar uptake [Citation32,Citation33]. In Belgium, the decision to prescribe a biosimilar differs based on the active substance. For infliximab, the decision is determined by the tender outcomes, but for adalimumab, it depends generally on the individual gastroenterologist [Citation34]. Since TNFα inhibitor biosimilars are also prescribed for indications other than for IBD, other guidelines on biosimilars may affect biosimilar uptake. The goal of biosimilars is to create price competition between the originator and the corresponding biosimilars, which also can result in a lower-priced originator. Therefore, countries should not strive to achieve the highest uptake of biosimilars, but for the usage of the best-value biologicals, which can either be the originator or a biosimilar [Citation35] .
4.1. Strengths and limitations
The present study provides a comprehensive overview of the positions of the national gastroenterology associations in the EEA countries of biosimilar use. A significant strength of this study includes the substantial efforts to ensure comprehensive data collection, including a manual search of guidelines from all national gastroenterology associations that are ECCO members and contacting these associations to obtain their guidelines and validation purposes. Further, the data extraction process was validated via cross-checks on seventeen countries, including all national guidelines and group discussions to overcome differences in interpretation of recommendations.
However, the present study also contains some limitations. First, despite a thorough search and three e-mails to each national gastroenterology association, no treatment guidelines were found for five countries. This could mean that no national guidelines exist in these countries, or that these guidelines were not retrieved in this study. Twelve associations responded to the e-mail requests for guidelines (), thus possibly some guidelines that were not publicly available were not retrieved.
Second, gastroenterologists might adhere to guidelines for prescribing biosimilars other than those from national gastroenterology associations, such as regional, or hospital guidelines, but those types of guidance documents were not included in this study. In general, adherence to guidelines was not studied; thus if gastroenterologists prescribe according to the guidelines and the actual impact of guidelines on prescribing behaviors are unknown.
Third, gastroenterology associations from several countries had guidelines available in their national language, including some languages not (sufficiently) understood by the authors. Automatic translation by Google Translate was used in these cases. However, some information might be difficult to interpret with automatic translation. Moreover, despite of limitations in language, the authors had various interpretations of some recommendations, possibly indicating that clinicians might have multiple interpretations of these recommendations as well.
5. Conclusions
Almost three-quarters of national gastroenterology associations in EEA countries with an ECCO affiliation had guidance on biosimilar prescribing, either in the form of a national association guideline, a position paper, or an endorsement of ECCO guidelines. Associations in most countries endorsed initiating TNFα inhibitor treatment with a biosimilar (n = 14) and transitioning from an originator to a biosimilar (n = 13). In general, positions became more supportive of biosimilar use over time. Guidance on how to monitor patients and on multiple transitions was scarcer and more varied between countries. There are still countries where the national gastroenterology association lacks guidelines, possesses outdated guidelines, or utilizes guidelines that are inconsistent with current best practices; accordingly, there is room to improve guidance on biosimilar prescribing by medical associations. Clear guidance can support gastroenterologists in confidently prescribing biosimilars to treatment-naïve patients and to patients transitioning from an originator to a biosimilar.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
RW Meijboom, L Barbier, LC Druedahl, K Sarnola, HM Tolonen, H Gardarsdottir, ACG Egberts, TJ Giezen contributed to the study design. RW Meijboom, L Barbier, LC Druedahl, K Sarnola, HM Tolonen contributed to the data collection and analysis. RW Meijboom wrote the first draft of the manuscript. All authors critically revised the manuscript. All authors approved the final version of the manuscript.
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Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2023.2189008
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Appendix
Table A1. Overview of the EEA member states [12] and the included gastroenterology association from that country and the reference to their guidelines.
Table A2. Template for data extraction. The data collection template consisted of three parts. First, general information on presence of guidelines and, if applicable, characteristics of guideline itself were collected. The type of guideline was categorized into the clinical disease treatment guideline, other clinical treatment guidelines, e.g. guidelines on biologicals in IBD, or position papers (i.e. consensus statements, position documents, etc.) Second, information on the content of the guideline was collected. This included guidance on starting naïve patients on a biosimilar; whether starting IBD patients on a biosimilar was accepted and which patients were eligible for starting with a biosimilar. And it included information on guidance on transitioning IBD patients from an originator to a biosimilar; data was collected on the acceptance of transitioning patients, which patients were eligible for transitioning, guidance on informing patients about the transition and if and how patients should be monitored during transitioning, and if cross-transitioning (biosimilar to biosimilar) and retransitioning (originator to biosimilar) was accepted. Part 1: General information.
Part 2: Content of the guideline
Table A3. List of crosschecked country data.