The role of healthcare providers in accompanying biosimilars in inflammatory bowel diseases

KEYWORDS:

• Anti-TNF
• biological therapy
• biosimilar
• inflammatory bowel disease
• infliximab

1. Introduction

Biological therapies such as the inhibitors of tumor necrosis factor alpha (anti-TNFs) are well recognized as effective treatment for inflammatory bowel diseases (IBD). Infliximab and adalimumab have been widely used in the last two decades and in Europe their patents are both recently expired (infliximab in 2015 and adalimumab in mid-October 2018); infliximab patent expired also in the US. Consequently, other pharmaceutical companies have been authorized to produce ‘biosimilars’ of anti-TNFs and, in particular, infliximab biosimilars (i.e. CT-P13 and SB2) have been already available for use in clinical practice during the last 3 years. The main advantage of biosimilars is the lower cost in comparison with the originator, improving patient access to these treatments, and countries with a public health system may impose their prescription on clinicians to optimize cost savings. However, switching from the reference drug to biosimilars represents a challenge for health-care providers, given the possible concerns that patients may have in changing an effective treatment. In this context, the relationship between patients and IBD specialists (including both doctors and nurses) becomes fundamental to guarantee the best outcome in terms of patient compliance, drug persistence, safety profile, and cost-effectiveness.

2. Definition of biosimilars

The production of biological agents is a complex and peculiar process, involving living cells systems: this is the reason why it is impossible to obtain biological drugs completely identical [1]. Biosimilars have the same amino acid sequence of the reference drug, but may be different in the level of glycosylation, the composition of excipients, or in other post-transcriptional protein characteristics. Before marketing approval, regulatory authorities require that biosimilars perform comprehensive comparability exercises in order to assure similarity with the reference product in non-clinical analyses first (in vitro physicochemical, structural and functional analysis). Then, clinical data must be presented to demonstrate pharmacokinetic and pharmacodynamic equivalence to the originator compound, and clinical efficacy equivalence in one of the licensed indications. Interestingly, once approved, further studies across indications are not mandatory and biosimilars may be used for all clinical applications of the reference drug (i.e. ‘extrapolation’). Post-approval surveillance then represents the best control for efficacy/effectiveness and safety of biosimilars in clinical practice [1].

3. Infliximab biosimilars in IBD: the evidence

CT-P13 is the first biosimilar of infliximab approved by the European Medicines Agency in 2013, after two randomized controlled trials comparing it with infliximab originator (Remicade®) in patients with ankylosing spondylitis and rheumatoid arthritis: in both these studies, CT-P13 was equivalent to infliximab in terms of pharmacokinetic, immunogenicity, efficacy and safety [2,3]. Although there are no published controlled studies comparing them for induction and maintenance therapy in anti-TNF naïve IBD patients, recommendations for regulatory approval of biosimilars allow the extrapolation of indications and CT-P13 was then approved also in this specific clinical setting. In a recent meta-analysis [4], seven studies (four prospective and three retrospective) including data on induction and maintenance outcomes with CT-P13 in IBD were found, showing high rates of clinical benefit. Initially, the prescription of infliximab biosimilar was reserved to ‘originator naïve’ patients. Later, the NOR-SWITCH trial [5] investigated the rate of disease worsening in patients with different immune-mediated conditions, including IBD (n = 248), who switched to CT-P13 after being in stable clinical remission for at least 6 months under treatment with infliximab originator. The design of the study was randomized and double-blind, with a duration of 52 weeks. The results showed non-inferiority of CT-P13 in comparison with the reference drug in the overall study population (n = 482), although the analysis of each disease sub-group is not reliable due to underpower. Such reassuring findings have been confirmed in a large prospective cohort of IBD patients treated with CT-P13: in particular, among all subjects included in this study (n = 810), 155 were switched from infliximab originator to the biosimilar, with no increase of adverse events and without affecting persistence of therapy [6]. The SECURE trial [7] analyzed as primary endpoint the serum drug level of CT-P13 16 weeks after switching from the originator in patients with IBD in clinical remission: results showed no differences in the pharmacokinetics and confirmed comparable outcomes in terms of efficacy and safety.

Several further observational real-life studies have been published so far, confirming equivalence of infliximab biosimilars compared to the originator in terms of efficacy and safety, but some of them presenting important limitations such as small sample size, the absence of a control group, and a short period of follow-up [8].

4. Infliximab biosimilars in IBD: cost-effectiveness

Cost saving for the health system represents the main incentive for biosimilar prescription. An economic model to assess the impact of biosimilars over 5 years after their introduction showed a potential cost saving of €493 millions in the Netherlands [9]. Furthermore, the establishment of gain-share agreements should be promoted to re-invest the saved money in the development of managed switching programs dedicated to patients transitioning to biosimilars and also in the improvement of IBD services [10]. For example, in the UK a managed switching program was recently experimented to guide the transition of IBD patients to infliximab biosimilar and was funded by a gain-share agreement between the hospital and a local clinical commissioning group: 143 patients accepted to enter the switching program, showing no change in clinical outcomes and laboratory values before and after the switch, drug persistence comparable with a control cohort treated with infliximab originator and no safety concerns [11]. Furthermore, a reduction of costs between £40,000 and £60,000 per month was reported, with the possibility to fund the nurse-led IBD biologics service for both outpatients and inpatients [11].

5. Infliximab biosimilars in IBD: patient concerns

Peyrin-Biroulet and coauthors recently performed a survey using a questionnaire developed by the European Federation of Crohn’s and Ulcerative Colitis Associations to investigate the patient perspectives on the use of biosimilars in IBD [12]. Only a minority of patients who accepted to participate in the survey were familiar with biosimilars (38% of 1059 IBD patients); interestingly, most of them expressed concerns regarding efficacy (40.3%) and safety (47%) of biosimilars and would like to be clearly informed before drug administration. Such findings confirmed the results of a previous international survey in Europe and in the US, involving patients with diseases susceptible to biosimilar therapies (both immune-mediated and oncologic), caregivers, patient support groups and the general population: 3198 subjects responded to the survey and the awareness about biosimilars oscillated between a minimum of 6% in the general population and a maximum of 30% in European patient advocacy groups [13].

Given the low level of awareness, proper communication strategies to inform and educate patients about biosimilars are fundamental to avoid misunderstandings and to reduce the subsequent risk of lack of adherence and worse clinical outcomes. At this regard, the ‘nocebo’ effect is an emerging clinical issue for patients eligible to receive biosimilars: it is defined as an unexplained detrimental reaction to pharmacological or non-pharmacological treatment, driven by the negative expectations of the patient [14]. A recent study, in particular, documented a nocebo rate of 12.8% in patients switched to infliximab biosimilar, which completely resolved after the re-initiation of the originator [15]. Also in the rheumatologic setting, a recent study showed a high percentage of discontinuation from CT-P13 during the first six months after switching (24%), mainly due to subjective complaints and without changes in the objective measures of articular inflammation [16].

6. Expert opinion

Two main typologies of IBD patients may approach to biological biosimilars: naïve and non-naïve to the reference drug. In the first case, the main concerns of patients are typically related to the efficacy and safety of biosimilars. In case of a switch, patients in stable clinical remission may be worried to lose the clinical benefit with difficulty gained. In both cases, the transition to biosimilars should be driven by IBD specialists, including doctors and nurses with expertise in the management of biological therapies and specifically trained on biosimilars, and should provide correct patient education. To reduce the possible nocebo effect, which is a raising issue for these patients, the given information should be structured in a ‘positive framing’, underlying all similarities between the drugs and reassuring about immunogenicity, safety, and efficacy [14]. In fact, despite the regulatory process for the approval of biosimilars is easier and quicker than that required for the reference drug, the evidence available so far did not show any specific clinical concern.

Apart from verbal communication, also written leaflet or other support material (i.e. web-based educational courses or social media updates) may be used to make easier the comprehension of scientific data [1]. Moreover, the involvement of patient support groups may offer a valid help in reassuring the patients, through the sharing of communal positive experiences.

Cost saving represents the main incentive for biosimilar prescription for the health system, improving the affordability of biological therapies, especially in naïve patients and in countries with a cost-based restriction on medical prescriptions. Also, the establishment of gain-share agreements may represent a valid strategy to re-invest the saved money in the development of managed switching programs dedicated to patients transitioning to biosimilars and also in the improvement of IBD services: The British example is a valid starting point [10]. However, such initiatives are unlikely to be realized in healthy systems based on insurance companies.

In conclusion, the use of biosimilars is destined to significantly increase in the next future, not just for infliximab but also for other biological therapies, given the reduction of health costs and the possibility to increase patient access to these drugs. Education and active involvement of patients in the decision-making process is fundamental to guarantee the best clinical outcomes during this transition process.

Declaration of interest

C Felice: consultancy or advisory board member for AbbVie and MSD. D Pugliese: consultancy or lectur fee from Abbvie, Takeda, MSD. A Armuzzi: consultant for AbbVie, Allergan, Amgen, Biogen, Celgene, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Mylan, Pfizer, Samsung Bioepis, Sandoz, Sofar, Takeda. Lecture fees: AbbVie, Amgen, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, Medtronic, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Otsuka, Pfizer, Samsung Bioepis, Takeda, Tigenix, Zambon. Research grants: MSD, Takeda, Pfizer. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.