Clinical and Regulatory Concerns of Biosimilars: A Review of Literature

Although biosimilars have been part of clinical practice for more than a decade, healthcare professionals (HCPs) do not fully accept them. This is because of the perception that biosimilars may not be like their originators in terms of quality, safety, and efficacy. This study aims to evaluate the current knowledge and attitudes of healthcare professionals toward biosimilar prescription, and to elaborate on their concerns. We reviewed the literature using PubMed, Cochrane Library, and Science Direct electronic databases in the period from 2018 to 2020. The knowledge and confidence of healthcare professionals vary between countries, between clinical profiles and between studies. Although most of the healthcare professionals had a positive attitude to prescribing biosimilars, they would still prefer to prescribe them in initial treatment. Generally, HCPs were against multiple switches and substitution of biosimilars at the pharmacy level. HCP’s key concern was interchangeability, with eventual consequences on the clinical outcome of patients. HCPs still approach biosimilars with caution and stigma. HCPs need to have an unbiased coherent understanding of biosimilars at clinical, molecular and regulatory levels. It was also observed that most of their concerns are more theoretical than science-based. Physicians are in an excellent position to accept biosimilars, but they need the additional support of regulatory authorities to approve and take into consideration the available scientific data regarding biosimilars.


Introduction
Biological medicines or biologics have shaped modern medicine by drastically changing the prognosis for many severe and life-threatening diseases such as cancers, diabetes and autoimmune diseases (rheumatoid arthritis, Morbus Crohn, multiple sclerosis, severe psoriasis) and rare diseases [1,2]. Biologics are fundamentally distinct from conventional medicines in terms of nature or origin, structural complexity and variability, manufacturing process, side effects (immunogenicity), formulation, sensitivity, and regulatory aspects [1]. But the crucial obstacle for accessing biologic medicines is their high cost, due to their lengthy and risky development process [1,2]. Originator biologics are novel medicines that consist of active substances made from living cells or organisms and are manufactured through biotechnology, using complex system cells and recombinant DNA technology [1].

Search Strategy
To conduct and explore this review, we mainly followed the PRISMA guidelines for systematic reviews [18], although "state of the art" methodology was also used. To identify relevant studies, we used the following database: PubMed, Cochrane Library and Science Direct between 2018-2020. To explore biosimilars in clinical practice, we used the following keywords: "biosimilar", "biologics", "biosimilars", "follow on biologics", "biologics, subsequent entry", "subsequent entry biologics", 3 of 17 "knowledge", "practice", "perception", "awareness", "questionnaire", "survey". We combined keywords with Boolean connectors and the search model was adapted according to each database software. For our second aim, we used reliable regulatory information retrieved from the European Medicines Agency (EMA) [19], the Food and Drug Administration (FDA) [11], and the World Health Organization (WHO) [20]. Several peer-reviewed articles , retrieved following the snowball citation, were also included.

Study Selection
The initial studies retrieved from the databases were first selected, and studies that met the eligibility criteria, were reviewed and analyzed. Inclusion and exclusion criteria are given in Table 1. By applying these criteria, from 407 studies, 16 were included in the analysis (Figure 1). No studies were excluded because of poor quality. Although we analyzed studies between 2018-2020, two systematic reviews were included which were conducted between 2014-2020.

Category Criteria
Year of publication 2018-2020

Geography
No study was excluded because of geography; Studies from Europe, United States, Asia, Australia, UK, Africa.

Language English and Spanish
Sources Only peer-reviewed literature

Study design
First objective: surveys, interviews and systematic reviews concerning healthcare professionals such as clinicians, pharmacists, nurses, consultants. Narrative reviews, commentaries, editorials, and protocols were excluded. Second objective: Reliable information from regulatory agencies such as European Medicines Agency (EMA), Food and Drug Administration (FDA) and World Health Organization (WHO); peer-reviewed articles following snowball citation .
Study design professionals such as clinicians, pharmacists, nurses, consultants. Narrative reviews, commentaries, editorials, and protocols were excluded. Second objective: Reliable information from regulatory agencies such as European Medicines Agency (EMA), Food and Drug Administration (FDA) and World Health Organization (WHO); peer-reviewed articles following snowball citation .

Data Collection Process
Each study that met the inclusion criteria was analyzed from several aspects such as authors, date of publication, time when the study was conducted, study design, objectives, results, and limitations.

Current Knowledge and Attitudes of Healthcare Professionals toward Biosimilar Prescription
In seven studies [21,22,27,29,31,33,34], we found that healthcare professionals had a good knowledge of biosimilars, and at least know the basic concepts of them. However, healthcare professionals were not satisfactorily familiar with concepts and the processes of interchangeability, extrapolation and pharmacovigilance. Nevertheless, the knowledge and awareness of healthcare professionals vary between countries, studies, and clinical profiles. For instance, in Aladul et al.'s study, consultants, nurses and pharmacists had good knowledge of biosimilars and were keen to use them in initial treatment [21]. Giuliani  their general knowledge of biosimilars as average to high, only 36.3% of them correctly selected the questions regarding interchangeability [22]. By systematically analyzing 17 studies from Europe and three from the US, Leonard et al. found an overall lack of biosimilar knowledge and low prescribing comfort [23]. The study from Latin America reports a lack of awareness among rheumatologists about the availability of biosimilars, automatic substitution and the understanding of the nomenclature of biosimilars [24]. The Russian study found that only 20% of clinicians considered that biosimilars are not equal to generics [25]. However, Teeple et al. reported that 88% of rheumatologists, dermatologists and gastroenterologists knew what biosimilars are [27]. The study from Spain found that only 27% of primary care physicians know the difference between generics and biosimilars, and 84% of them do not understand biosimilar clinical development [28]. In Aladul et al.'s survey of 2019, 6% of healthcare professionals (mainly nurses) had never heard of biosimilars [29]. 80% of respondents lacked understanding of the differences between biosimilars and generics. 67% supported prescribing biologics by distinguishable names. 20% of respondents twice confirmed that biosimilars were different from generics and that they were not identical copies of the originator. 53% were against automatic substitution.
Study findings are related to local biosimilars in Russia, and does not reflect the opinion of clinicians for international biosimilars. Gaps in knowledge, and harmonization between regulation and science.

Russia
Questions regarding the understanding of biosimilars were not clearly formulated by authors. Table 3. Major clinical and regulatory concerns of healthcare professionals related to biosimilars.

Clinical and Regulatory Concerns Definitions
Interchangeability concepts Europe: Interchangeability: switching and substitution describes the process of transitioning from the originator to biosimilar and back and forth or between two biosimilars. Interchangeability comprises switching (a transition implemented by the clinician) and automatic substitution (a transition implemented by the pharmacist without consulting the clinician). United States: Switching describes the process of transitioning from the originator to biosimilar and back and forth or between two biosimilars at the pharmacy level.

Extrapolation concept
A scientific rationale used to describe transferring of the safety and efficacy data from one indication to others, without the need to conduct clinical trials for each indication.

Pharmacovigilance reports
Crucial for the identification of adverse events. Using trade name, international nonproprietary name (INN), and batch number is critical, considering that no two biologics even with the same active substance and from the same batch are identical.
Cook et al. reported that 74% of academic oncology clinicians did not know the basic definition of biosimilars and 40.3% of them considered biosimilars and generics as the same molecules [30]. In Park et al.'s survey, 66.2% of Asian gastroenterologists knew the basic concepts of biosimilars, but only 6% of them felt confident to use biosimilar monoclonal antibodies [31]. After receiving printed educational material, the survey of Ismailov and Khasanova found that over 90% of oncology/hematology nurses, nurse practitioners, medical assistants, and patient navigators identified correct answers about the definition, regulation, interchangeability and safety of biosimilars [31]. Sarnola et al. found that 49%-76% of healthcare professionals were familiar with biosimilars, while 2%-25% did not know what biosimilars were [35].

Interchangeability
Most healthcare professionals were not very keen on interchangeability, especially in multiple switches and in automatic substitution. They would prefer to use biosimilars as an initiative therapy rather than switching patients who are already using the originator or switching by the pharmacist without consulting the clinician. HCPs were reluctant about interchangeability because of the possibilities of emerging new adverse events or an increase of prevalence of these. The dominant safety concerns that inhibit healthcare professionals from implementing interchangeability are immunogenicity and allergic reactions. Several healthcare professionals believe that biosimilars do not have the same efficacy profile as their originators. They were also concerned that some biosimilars are not available in the same pharmaceutical dosage as their originators. One barrier that healthcare professionals reported is the use of unique administration devices for biosimilars. Some healthcare professionals would prescribe biosimilars with a trade name, to make sure that the pharmacist would not switch them. To implement interchangeability, most HCPs realized that they need a robust monitoring system and correct engagement in pharmacovigilance records. Even though in some studies healthcare professionals identified the definition of extrapolation, they still lack comprehension of the principles of this scientific rationale.
It is interesting to note that the vast majority of healthcare professionals in rheumatology and diabetology believe that if the cost was equivalent between originator and biosimilar, they would choose the originator biologic over the biosimilar [21]. The survey of Greene et al. that listed 16 strategies for overcoming key barriers to biosimilar adoption found that 84% of managed care and specialty pharmacists agree or strongly agree that US biosimilars are safe and effective for patients when switching [26]. Still, 61% of them had concerns about the safety and efficacy of biosimilars [26].
If the FDA designated the biosimilar as an interchangeable medicine, 94.8% of academic oncology clinicians in Cook et al.'s study would prescribe a biosimilar interchangeably with its originator [30]. In Park et al., 86.7% of Asian gastroenterologists were against automatic substitution at the pharmacy level [31]. In the Polish study, 88% of hospital pharmacists reported concerns that biosimilars are not identical with the originators, 48% with concerns about their immunogenicity and 44% with concerns about other pharmacokinetic properties [33]. In the systematic review of Sarnola et al., 64%-95% of physicians were against the substitution of biosimilars at the pharmacy level [35]. Meanwhile, the Bangladesh study reports that 74% of academicians, 41% of clinicians and 61% of industry experts are positive about interchangeability [36].

Discussion
The advancement of biotechnology and the recent entry of many novel biologics, biosimilars, bio-betters, and biomimetics may be contributing factors as to why clinicians nowadays don't approach biosimilars with acuteness. Most clinicians receive continuous education about biologic therapies from professional associations, peer-reviewed articles, conferences, brochures, guidelines from regulatory authorities, pharmaceutical companies, and information from their colleague pharmacists. We still cannot judge whether HCPs receive biased information, but some healthcare professionals perceive biosimilars as therapies with low safety and efficacy.
To provide reliable regulatory and scientific information for healthcare professionals, the European Medicines Agency, jointly with the European Commission and other scientific experts, has established an information guide for healthcare professionals available in 23 languages of the European Union [1]. As patients also need to be considered as part of clinical decisions, and need to know the therapies to which they might have access, the European Medicines Agency together with other experts from relevant fields has established a consensus information leaflet for patients who want to understand biosimilars [37].
So far, all of these regulatory and clinical concerns of HCPs are more theoretical than science-based [38][39][40][41][42][43][44][45][46][47]. Perhaps when biosimilars were introduced, they should have been presented together with their originators, explaining that concerns could not only emerge from biosimilars, but also from their originators among batches. However, despite the education of healthcare professionals, regulatory authorities across countries need to converge guidelines for developing and approving biosimilars [48]. Regardless of the results, the studies had limitations, and some of them did not have a representative power size and response rate, therefore we cannot know exactly if these are the actual views of healthcare professionals regarding biosimilars. Although the studies have been published in the last two years, we must take into consideration that some of them have been conducted earlier. Therefore, these do not necessarily represent the exact reflection of current acquaintance with biosimilars among healthcare professionals.

Biosimilars from a Regulatory Perspective: What Should Healthcare Professionals Know?
Inherent structural variability and the non-identical issue were present in biologics before the existence of their copies known as biosimilars [1,6,49]. This is because of the inability to replicate biological molecules [49]. Therefore, clinicians should take into consideration that no two biologics even with the same active substance and produced by the same manufacturer are identical and perhaps each biologic is different in itself [50].
Moreover, comparability studies of the biosimilar development paradigm and extrapolation are not novel concepts; they have been in existence for some time and they continue to be implemented in originator biologics when there is any change during the manufacturing process [51]. Therefore, originator biologic manufacturers need to demonstrate that the proposed change is not clinically meaningful and does not alter the clinical outcome [51]. Nevertheless, the manufacturer of the proposed biosimilar is not as familiar with the manufacturing process as is the manufacturer of the originator biologic, thus creating intentional copies by trying to reverse the manufacturing process of the originator [50]. Therefore, before developing a new biosimilar, it is crucial to fully comprehend the physical, chemical, biological and microbiological attributes of the originator biologic [1,6,52]. The major responsibility of regulatory authorities and manufacturers is to avoid any clinically meaningful structural difference that might affect negatively the efficacy and safety of the proposed biosimilar [1,6,12]. This is accomplished by assessing and respectively demonstrating a high scale of structural and functional similarities between both [1,10,11]. The biosimilar investigational pathway aims to demonstrate neither superiority nor inferiority between the biosimilar candidate and the originator, but to demonstrate that the biosimilar does not have a decreased or increased safety and efficacy profile compared to the originator [53]. This pathway is distinct from the pathway established for originator biologics and even more distinct from generics [54,55]. Therefore, healthcare professionals should not equate biosimilars with generics (Table 4) [1,6,54,55]. The investigation of biosimilars begins with analytical and functional studies of the biosimilar candidate itself and then with the originator [1,6]. The outcomes from the results of this crucial phase determine the need for additional specific studies in non-human and human primates [1,12,52]. The investigational clinical pathway starts with phase one pharmacokinetics and pharmacodynamics studies (if relevant markers exist) in healthy participants and phase three confirmatory clinical trials between the biosimilar candidate and originator [55,56]. Moreover, at least one immunogenicity clinical trial is required to compare immunogenicity aspects between biosimilar and originator biologic [55,56]. Since clinical trials have already been established for originator biologics, the aim of biosimilar clinical investigation is not to establish the clinical benefit, but to demonstrate the clinical equivalence with the originator biologic [56].

Interchangeability: Switching and Substitution
Currently, interchangeability falls within the scope of clinical practice and it is used to describe the process of transitioning from the originator to the biosimilar and back and forth or between two biosimilars [1,55]. Interchangeability is assessed after the biosimilar gets approval from the regulatory authorities, not simultaneously during the approval [52]. Until now, no biosimilar has been approved to be used interchangeably with its originator biologic, although some biosimilars with low molecular weight like insulins are favorable candidates to obtain interchangeability status soon, and when that happens these therapies will get one year of market exclusivity [57,58]. The EMA does not take responsibility for interchangeability and they leave this with the EU member states [1,55]. Moreover, the FDA requires additional clinical trials which include at least three switches between the biosimilar candidate and the originator biologic [57]. In European countries, several national regulatory authorities support switching during the initiative treatment or with the decision of the prescribing clinician, while substitution is not linearly supported between European states [55,56]. In this scenario, the substitution is automatically implemented by the dispensing pharmacist without consulting the clinician [1,55]. In the US, when the biosimilar is designated to be used interchangeably with the originator biologic through additional clinical studies, the pharmacist can dispense and can authorize the automatic substitution [55,57]. Therefore, the FDA's concept of interchangeability corresponds to the EU's concept of substitution.
The main theoretical dilemma of clinicians regarding interchangeability, especially in multiple switches and at the pharmacy level, is the fear of the eventual inducement of immune reaction responses (immunogenicity) and their potential consequences in terms of safety and efficacy [59]. However, it is important to note that immunogenicity might be a consequence of several factors like underlying disease, genetic background, age, immune status, including immunomodulating therapy, dosing schedule and structural and manufacturing structural homology, post-translational modifications, modification of the native protein, formulation, and impurities [1,59,60]. Not just biosimilars but also biologics could have immunogenic properties [59,60]. Many researchers and governments have tried to explore interchangeability, either by inducing comparative clinical studies or literature reviews of all the available clinical studies, and several conclusions have been generated either supporting interchangeability or otherwise [55,56]. Still, confirmatory clinical trials are needed to produce significant results. However, together with clinical trials, we need support from regulatory agencies to achieve clarity in physicians' view of biosimilars.

Extrapolation
Extrapolation is a rationale scientific principle used to describe the process when the proposed biosimilar receives all the approved indications of the originator, while performing comparative clinical studies of just one or two indications [60,61]. This rationale is acquired in phase three confirmatory clinical trials, although the results from each investigational phase impact the extrapolation of indications [61]. Still, limitations exist if particular indications are under patent protection [61,62]. The integral key to comprehending extrapolation lies in the fact that the structure determines the clinical performance of the medicine [61]. Currently, this concept of transferring the safety and efficacy data from one indication to the other is not very clear to regulators and clinicians. Whether the proposed biosimilar will be able to receive all the other indications from the originator, while performing a clinical trial for one indication, depends on several factors: mechanism of action, posology, pharmacokinetics, and population type [61,62].

Post-Approval Surveillance of Biosimilars
The clinical studies required for the approval of biosimilars are often conducted in a small study population, hence these trials are unable to reveal all potential adverse events, particularly rare and delayed ones [1,62]. Therefore, robust post-approval surveillance remains the crucial part of identification, evaluation and prohibiting adverse effects and other questionable concerns, such as elucidating interchangeability [1,63]. The use of distinguishable names for biosimilars is controversial as to whether it would benefit pharmacovigilance would decrease the confidence of clinicians in thinking that the biosimilar has a different clinical profile compared with the originator biologic [62][63][64][65]. The correct engagement of health care professionals in surveillance records and reports can also be considered an important contribution to safety and other related problems considering biosimilars [63,64]. Serialization of biosimilars is also imperative, detecting eventual safety and quality concerns in each package within the same batch, having regard also to the fact that biosimilars and originator biologics are very sensitive to light, high temperature, and could be easily prone to microbial and viral contamination [1,63]. Even a minor change in the manufacturing process or equipment, product handling and container closure, such as regarding the syringe and needle, could impact the quality, efficacy and safety of biologic medicines [6,52,64].

Conclusions
This study suggests that efforts and incentives should be made to create evidence-based continuing educational programs for biologic therapies. This would help improve understanding of biosimilars not only at the clinical level but also at molecular and regulatory levels. Regardless of government incentives for implementing prescription quotas for clinicians, central regulatory authorities formally responsible for their quality, safety and efficacy should also take several positions. These include the following: (1) to shift the biosimilar development paradigm in order to demonstrate interchangeability when applying for approval; (2) interchangeability should be granted automatically upon approval; (3) to release a position statement strongly supporting strongly interchangeability as a first-course initiative; (4) to harmonize the basic concepts of interchangeability, switching and substitution. Even though it is within the responsibility of regulatory authorities to create a balanced environment between innovation and research (originator biologic) and access to biologics and market competition (biosimilars), its position is imperative in accepting biosimilars in clinical practice. Biosimilars will continue competing with biologics, but without adjustment of these positions we will not be able to realize the full benefits of biosimilars.