The level of evidence and the grade of recommendations were evaluated based on the 2014 European Alliance of Associations for Rheumatology (EULAR) standard operating procedures [35].

4.1 Overarching Principles A.

Rheumatologists, patients, and other stakeholders can benefit from awareness campaigns that educate and update them on the nature, approval processes, safety, and efficacy of biosimilars in comparison to reference products.

It is critical that rheumatologists, patients, and other stakeholders be made aware of the rigorous evaluation and approval processes of biosimilars in order to understand the similarities and differences in the nature, safety, and efficacy in comparison to reference products [20, 36]. Targeted awareness campaigns and educational initiatives aimed at healthcare professionals and the public can be used to regularly convey information and updates on biosimilars in order to strengthen the familiarity, augment the understanding, and promote the acceptance of biosimilars as safe and effective treatment options for rheumatic disease [25, 37]. Awareness campaigns have been sporadically carried out in the Gulf region, primarily instigated by pharmaceutical companies, with occasional involvement from health organizations like Abu Dhabi Health Services Company (SEHA) in the UAE and other non-profit rheumatological societies. Raising awareness about the benefits of biosimilars among various stakeholders besides rheumatologists and patients, such as regulatory bodies, healthcare administrators, pharmacists, policymakers, and those in charge of coverage decisions in the private and public sectors, is vital to facilitate the development of standardized policies for the adoption, prescription, and reimbursement of biosimilars. In the Gulf region, the number of biosimilar conferences has been on the rise, with the 2023 International Biosimilars Congress held in Dubai serving as a notable example, where rheumatologists, gastroenterologists, hematologists, dermatologists, oncologists, pharmacists, and charitable organizations were invited as speakers.

B.

A better understanding of biosimilars can help rheumatologists communicate the benefits of biosimilars more efficiently with patients, thereby reinforcing positive perceptions towards biosimilars and improving adherence.

A reluctance to prescribe biosimilars among clinicians in the Middle East has been observed as a result of a limited understanding of biosimilars and a lack of confidence in its efficacy and safety [13, 20]. Furthermore, some surveys found that pharmacists lacked adequate information about biosimilars in order to advise patients appropriately [38, 39]. Moreover, negative perceptions towards biosimilars can occur among patients because of the misconception that the lower cost of biosimilars is associated with inferior quality and poorer outcomes compared with reference products [40]. This can potentially lead to the development of nocebo effects among patients, resulting in increased non-adherence to biosimilars [13, 36, 40]. The negative perceptions and unrealistic expectations of patients towards newer therapies or changes to current therapy subsequently lead to poorer outcomes or failure of therapy [37, 41].

The approval of biosimilars is based on the totality of the evidence that demonstrates a high degree of similarity with the reference product following a rigorous comparative testing process [13, 26, 42]. Therefore, rheumatologists must understand the available evidence in order to confidently counsel patients regarding biosimilars as a viable and more affordable treatment option for rheumatic diseases [12]. This will enforce positive patient perceptions towards biosimilars and mitigate the impact of nocebo effects. The needs, perspectives, apprehensions, misconceptions, and expectations of patients must be considered and discussed during treatment planning.

C.

Rheumatic disease treatment decisions should be made collaboratively by the patient and their rheumatologists (shared decision making) and must be based on available clinical evidence and local healthcare regulatory guidelines/recommendations.

Shared decision making empowers patients to take control of their health and has been shown to improve patient satisfaction [12, 36, 37, 41]. Rheumatologists are obligated to provide patients with the necessary information that can improve the patient’s understanding of the disease, available treatment options, and the risks and benefits of each, including biosimilars [12]. This can create a positive perception towards biosimilars, thereby enabling patients to make informed decisions regarding their treatment preferences and goals, ultimately resulting in increased acceptance of biosimilars, better adherence to prescriptions, and improved treatment outcomes [31, 36, 37, 41, 43].

D.

Standardized protocols for collecting real-world data on both biosimilars and reference products must be established across the region.

The approval processes for biosimilars mandate a high level of similarity in the physiochemical characterization and clinical outcomes to that of reference products [12, 13, 42]. Although biosimilars are expected to remain highly comparable to their reference products over time, it is critical to gather real-world post-marketing efficacy and safety data in order to track clinical outcomes [12, 31, 44]. This is a common post-marketing requirement for all drugs, including biosimilars [12, 26, 45], and is particularly important in the Gulf region because of the dearth of regional real-world data, which can be useful in generating evidence demonstrating their comparability to reference products [45]. In the regional and local settings, this may be valuable in instilling confidence in biosimilars among clinicians.

E.

Biosimilars must be made available to all patients at significantly lower acquisition costs in order to widen access to treatment by providing more affordable treatment options.

Given the high degree of comparability in the efficacy and safety of biosimilars and reference products, cost can become a major determinant when selecting one treatment option over the other [12, 17]. Biosimilars have been shown to be lower cost alternatives to reference products, with an estimated treatment cost saving between 44 and 69% compared with reference products [17, 46]. For instance, a study reported that patients taking the infliximab biosimilar paid 12% less than the reference product [17, 47].The lower market price of biosimilars can potentially result in a significantly higher absolute cost saving compared with reference products [48]. In Europe, the cumulative savings resulting from biosimilar competition has been estimated to have surpassed €30 billion in 2022, which can be attributed to price reductions in the markets [16]. Additionally, the lower prices of a biosimilar could lead to a competitive domino effect in price reductions for other biosimilars [17, 49]. This can be observed in counties like Denmark and Norway that follow a tender system for controlling drug prices [17]. This is likely to widen the access to affordable treatment options for all patients. Switching patients with RA from infliximab to its biosimilar in the UK, France, and Germany was estimated to generate savings between 20% and 30% over 5 years, which could facilitate the treatment of over 7500 additional patients with RA with biosimilars [17, 50]. However, despite an increase in access to biosimilars, there is a disparity in their uptake across Europe [16].

4.2 Consensus Recommendations

Recommendation 1. Biosimilars are comparable to their respective reference products in terms of efficacy, safety, and immunogenicity profiles and can be considered a treatment alternative.

As mentioned earlier, the comparative pharmacokinetic, pharmacodynamic, efficacy, safety, and immunogenicity data are stringently reviewed and approved by regulatory agencies [12,13,14]. Since the approval of the first biosimilar in 2006, evidence from both clinical studies and real-world experience have validated the comparability between biosimilars and reference products and have shown no significant differences in physiochemical properties and post-translational modifications or impurities [12, 14, 51,52,53]. Therefore, approved biosimilars can be utilized as a more affordable treatment alternative to their respective reference products [12, 26, 36]. However, it is important that factors such as the need and preferences of the patient and access to the biosimilar be taken into account when considering treatment with biosimilars [26].

Recommendation 2. The formation of antidrug antibodies is not significantly different between biosimilars and reference products and therefore does not need to be routinely measured in clinical practice.

Monoclonal antibodies induce an immune response in some patients by triggering the production of antidrug antibodies, which may result in lowered trough drug concentrations and subsequently, decreased efficacy in some patients [12]. Neutralizing antibodies are typically detected within 6 months of exposure to a biologic agent and can negate drug efficacy. Over the past 17 years since the first approval of a biosimilar, studies have demonstrated no clinically significant differences in the formation of antibodies between biosimilars and reference products [14, 53, 54]. Therefore, antidrug antibodies to biosimilars do not need to be routinely measured in clinical practice [12].

Recommendation 3. Rheumatologists must be well informed about the safety, efficacy, and immunogenicity profiles of biosimilars to effectively explain treatment options to patients. This knowledge will help mitigate challenges related to retention rates, nocebo effects, and patient misconceptions regarding biosimilars.

Despite the rigorous clinical studies demonstrating the comparability of biosimilars and reference products, higher drug discontinuation rates have been observed among patients who were switched from reference products to biosimilars in clinical studies [41, 55]. The poorer retention rates because of adverse events that could not be attributed to the treatment’s effects have raised suspicions of potential nocebo effects [41, 56]. This can lead to intentional non-adherence and result in poorer treatment outcomes among patients taking biosimilars [55]. Studies have demonstrated significant improvements in retention rates of biosimilars when structured communication strategies were used, resulting in comparable discontinuation rates among patients taking biosimilars and reference products [41, 57]. Therefore, it is necessary for rheumatologists, pharmacists, nurses, and other allied healthcare professionals who interact with patients to be well informed about the various aspects of biosimilars in order to be an effective resource of information to patients [41, 58]. All relevant stakeholders, including healthcare personnel such as rheumatologists, pharmacists, and nurses, should be trained to ensure a standardized and unified approach to patient communication regarding biosimilars [43, 59]. This ‘One Voice’ approach can help clarify patient queries regarding biosimilars, clarify misconceptions and misinformation in a coherent and univocal manner, and as a result, reduce the occurrence of nocebo effects and improve retention rates among patients. Such a strategy has been associated with higher acceptance rates and better treatment outcomes with biosimilars among patients [43, 55]. It is important to note that patient characteristics such as age, level of education, perceived hypersensitivity to drugs, and the level of trust on the rheumatologist and the medication can influence the patient’s perceptions [40].

Recommendation 4. Switching/transitioning from a reference product to an approved biosimilar should be considered in clinical practice due to the comparable efficacy, immunogenicity, and long-term safety outcomes.

Non-medical switching is the changing of the medication of a stable patient from a reference drug to another clinically similar medication for reasons other than clinical ineffectiveness, tolerability, or adherence [20, 56, 60]. Non-medical switching is commonly associated with drug availability, formulary changes, or costs [56, 60]. However, because of limited regional guidelines on switching patients from a reference product to its biosimilar, clinicians in the Middle East are reluctant to initiate such a switch/transition [20,