Introduction

This work represents a needed update on the Expert Group Position Statement published in 2014, concerning the safety of monoclonal antibodies and fusion proteins treatment [1]. The need for an update is a result of the rapid developments in this field as well as new patient experiences with treatments accumulated in recent years [2].

One of biggest hurdles associated with biological treatment, particularly with monoclonal antibodies and fusion proteins, is the high cost. In the case of bio-originators, this high cost is due to the specificity of the manufacturing technology as well as the need to conduct appropriate clinical trials [3,4]. In Poland, biologic therapies are conducted through specific drug programs. As of now (1.04.2019) there are 101 drug programs (62 of them non-oncology related) with over 120,000 patients enrolled. Since the previous statement was published, numerous new biological therapies have been introduced, including natalizumab (multiple sclerosis), secukinumab (plaque psoriasis), vedolizumab (ulcerative colitis), aflibercept (age-related macular degeneration-AMD), anakinra (autoinflammatory syndromes), eculizumab (paroxysmal nocturnal hemoglobinuria), alirocumab (heterozygous familial hypercholesterolemia), rituximab (granulomatosis with polyangiitis, microscopic polyangiitis, pemphigus). The cost of these therapies affects the patient inclusion criteria in drug programs. Fewer patients meet inclusion criteria and those patients who qualify have diseases that are more advanced or severe.

The considerable cost of biological treatment is an issue in every country where such treatment is available. The proposed solution to reduce economic impact without affecting treatment efficacy and safety is introducing biosimilars - products highly similar to bio-originator drugs with expired patents.

Since the Expert Group Position Statement was published in 2014, biosimilars have been introduced in clinical settings with approval by the European Medicines Agency (EMA), which requires extensive analytical and clinical studies to confirm that there are no clinically significant differences between biosimilars and bio-originators [4-14]. In addition, observational studies and Real World Evidence (RWE) results have been published as well as meta-analyses regarding switching between bio-originators and biosimilars [15-25]. Recommendations regarding using biosimilars in some medical fields have been developed [26].

Despite the positive evidence for switching to biosimilars, the safety of switching is still a major concern for physicians and patients, discussed even on social media platforms [27-30].

OBJECTIVE

This study aims to provide a consensus from Polish experts in numerous medical fields on the topic of biological treatment, with Polish systemic health care solutions taken into account. The presented position is based on data from references and on experts’ own experience.

METHODS

Expert Group

The position statement was developed in collaboration with national consultants (or their delegates). experts in different fields of medicine (rheumatology, allergology, gastroenterology, oncology, dermatology, ophthalmology, clinical immunology, paediatrics, and haematology) who deal with the issues of biological therapy. Ten invited panelists participated in a study.

A modified Delphi process was implemented in order to develop the position statements [31]. This particular method is used in cases where clinical data is scarce or controversial.

The first two phases consisted of online voting, where experts anonymously rated discussed issues using the VAS (Visual Analogue Scale) from 1 (I completely disagree with the presented opinion) to 10 (I fully support the presented view). During these phases, it was also possible to make comments. The third phase was a face to face meeting, where controversial issues were discussed, and the conclusions presented in this paper were made.

Based on available data, the following issues were selected to discuss: the possible benefits of introducing biosimilars, their registry process, and the extrapolation of indications; switching from biologics to biosimilars, including non-medical indications to do so; safety monitoring of biological therapies; and the cost and legal aspects of biological therapies.

Preliminary statements can be found in the supplementary materials.

Results

Ultimately, 9 statements achieved at least 80% consensus from the expert panel. The summary of results is presented in Table 1.

Table 1. The Polish Expert Group Position Statement on the safety of biological treatment with monoclonal antibodies and fusion proteins: results of the Delphi method. 

During the discussion, no consensus was reached regarding patient consent, however 70% of experts thought that the patient should be informed before switching the bio-originator to a biosimilar (VAS 8.2). Similarly, 70% of experts were against automatic substitution at the pharmacy level (VAS 2.6).

Participants deemed safety data regarding multiple switching to be insufficient for this kind of practice to be encouraged as of now, although it may change in the future (70%, VAS 8.4).

During the discussion, the current state of pharmacovigilance in Poland was a controversial topic. More specifically, two experts deemed it sufficient, three had no opinion, and five participants considered it insufficient.

The experts chose not to make any statements about drug-tendering procedures or legal issues regarding biological treatment since they considered those to be outside their areas of expertise.

Discussion

The presented position statements encompass different issues associated with biological drug therapies. Biologics are one of the most rapidly developing branches of modern medicine, including both reference drugs and biosimilar drugs i.e. analogues of innovative drugs with expired patents [1]. This publication responds to the growing need of Polish physicians involved in biological therapies, most of them via drug programs, for resources to aid in decision-making related to biologics.

A significant part of the updated consensus is the experts’ attitude towards biosimilars and drug switching. It is believed that the introduction of biosimilars is associated with benefits such as reduced costs and increased availability of the treatment, which was confirmed by budget impact analyses conducted in various European countries [32-36].

There are, however, some concerns associated with the slow implementation of changes in drug programs despite cost reductions achieved by using biosimilars. For example, although there was a switch from infliximab to a biosimilar drug in a Crohn’s disease/ulcerative colitis drug  program in 2014, the change to the length of the therapy was delayed until 2016. Furthermore, the inclusion criteria for patients with  Crohn’s disease in drug programs have yet to be changed.

In comparison to 2014, studies have indicated biosimilars are safe by extrapolation from clinical indications as well as safe when single switching from a reference drug to a biosimilar drug [26]. The results of the NOR-SWITCH study, which has proven that switching from infliximab to a biosimilar (CT-P13) is not associated with a decrease in efficacy (prespecified non-inferiority margin of 15%), is a strong argument in favour of switching. The year-long study was carried out in patients in stable condition who suffered from Crohn’s disease, ulcerative colitis, spondyloarthropathy, rheumatoid arthritis, psoriatic arthropathy, and psoriasis [22]. The study was not designed to assess switching for a single indication. Data from 2 observational studies regarding inflammatory bowel disease patients confirm the results from the NOR-SWITCH study [37].

In the experts’ opinion, the data on the safety of multiple switching is still insufficient, although there are two promising studies conducted among psoriasis patients, who were treated with either the biosimilar etanercept [38] or the biosimilar adalimumab [39]. Currently, it is strongly recommended to carefully consider each case of implementing such therapy. Experts agree that multiple switching should be defined more precisely and assessed not only in randomised studies, but also in observational studies, and by using data from medical registries that are soon expected to be implemented [26].

The experts emphasised that any potential reduction in treatment costs must not overshadow the safety of the therapy [1]. Patient groups who should be observed especially carefully are the ones who had adverse reactions in the past and the ones with refractory disease failed two or more biological courses [40]. In those cases, issues that are particularly relevant are immunogenicity and the physician independence in choosing a particular drug.

Pharmacovigilance of biological therapies is still considered a significant issue in Poland. On the one hand, those therapies are mostly conducted through drug programs that require a very careful and thorough assessment of efficacy and safety during the treatment period. On the other hand, follow-up periods of patients who finish the program are too short to effectively monitor long-term adverse reactions such as cardiovascular complications or malignancy. In other countries this data is collected mostly through medical registries [41,42].

In the process of creating this expert consensus, the importance of nocebo effect was emphasized. This effect, while being difficult to objectively assess, is a significant reason to terminate biological treatment in cases of switching to a biosimilar drug for non-medical causes [43,44]. It is recommended that both patients and health care providers are educated on the current evidence on biosimilars, and that the patients should be educated in an understandable way.

In summary, the presented consensus should serve as a guide for physicians involved in biological therapies. Its significant advantage is the multi-disciplinary scope of the experts involved as well as their experience in creating and conducting drug programs in Poland. The consensus was reached through a multi-step discussion process that also involved a face to face meeting of experts. In order to achieve a statement validity, at least 80% of experts must have agreed on it. The findings in this study can serve as the basis for introducing biosimilar therapies in a safe and thoughtful manner as well as making those therapies more accessible in Poland.

Acknowledgements

Position Statement authors would like to express gratitude to following participants for their input and substantive discussion on the issues of biological and biosimilar medicines during Policy debate, organized in the „Polityka” editorial office by Unique Work on January 10, 2019:

Marcin Czech (Ministry of Health - Undersecretary of State), Andrzej Czesławski (URLIPB), Jakub Gierczyński (Lazarski University), Krzysztof Kopeć (Polish Association of Pharmaceutical Industry Employers), Maciej Niewada (ISPOR Poland Chapter), Katarzyna Połujan (Infarma), Irena Rej (Chamber of Commerce Pharmaceutical Poland).

Corresponding Author: Ewa Więsik-Szewczyk, ewa.w.szewczyk@gmail.com