## Abstract

Biologics are significant drivers of globally escalating healthcare costs. Biosimilars have potential to offer cost savings with comparable efficacy and safety to innovator products and increase the access of treatment to more patients. This study aimed to increase understanding and perception of biosimilars concept. It also described the pharmacoeconomic impact of biosimilar in oncology and formulary consideration of oncology biosimilars substituting with their originators in major oncology centers in the Saudi Arabia. A biosimilar is a biological product that is similar to a reference biopharmaceutical product. As the manufacturing process hinders the ability to identically replicate the structure of the original product, biosimilar cannot be described as an absolute equivalent of the original medication. Different regulatory agencies such as United States Food and Drug Administration, European Medicines Agency, and Saudi Food and Drug Authority have approved several biosimilars of oncology biologics. The experience of biosimilar use in Europe and USA provides valuable insights into the use of biosimilars. The widespread use of biosimilars has the potential to reduce healthcare expenditure, as well as improving access without compromising patient outcomes. There is a need for increasing awareness about biosimilars to improve acceptance rates. The use of biosimilar filgrastim in Ministry of National Guard Health Affairs, Saudi Arabia, has resulted in a significant cost saving annually. It was proposed that further substitution and switching to biosimilars in oncology would lead to major savings in resources.

## Introduction

Biosimilars are biological medicines that contain a highly similar version of the active substance of an approved biologic reference product. The availability of biosimilars might provide an opportunity to lower healthcare expenditures as a result of the inherent price competition with their reference product. Understanding how biosimilar cancer drugs are regulated, approved, and paid for, as well as their impact in a value-based care environment is essential for physicians and other stakeholders in oncology.[1]

A biosimilar is a biologic product that is similar to a reference biopharmaceutical product. The manufacturing process of biosimilar hinders the ability to identically replicate the structure of the original product, and therefore, it cannot be described as an absolute equivalent of the original medication. The currently available technology does not allow accurate copy of complex molecules, but it does allow the replication of similar molecules with the same activity.[2]

New agents for the treatment and supportive care of cancer have markedly improved therapeutic options and outcome for many malignancies. Biologics include monoclonal antibodies targeted to critical pathways involved in cancer pathogenesis and growth factors to reduce or ameliorate treatment-related hematological toxicity. Unfortunately, access to potentially lifesaving biologics is limited in many areas of the world.[35] As the patent expiry of several drugs approaches, there has been intense interest in developing biosimilar agents to introduce cost savings for health-care systems and to widen global access to key biological therapies.[3,4,6] A biosimilar drug is a biological product that is highly similar, but not identical, to a licensed biological product (the reference or originator product).[79] Unlike small-molecule generic drugs that are typically chemically synthesized and easy to replicate, it is impossible to make exact copies of reference products because biosimilars (as biologics) are large and highly complex molecules produced in living cells. Structural differences to the reference product may arise because of variations in post-translational modification (such as glycosylation patterns), which could have impact on drug efficacy or safety.[79] The development of biosimilars, therefore, involves extensive evaluation and a detailed, comprehensive manufacturing process to ensure that there are no clinically meaningful differences in purity, safety, or potency.[79] As is the case for any new therapeutic agent, the evaluation process and approval requirements for a proposed biosimilar may differ between regulatory agencies, leading to differential access based on geographic location.

Extrapolation is the approval of a biosimilar for use in an indication held by the originator biologic not directly studied in a comparative clinical trial with the biosimilar. Extrapolation is a scientific rationale that bridges all the data collected (i.e., totality of the evidence) from one indication for the biosimilar product to all the indications originally approved for the originator.[10] United States (US) Food and Drug Administration (FDA) and the current World Health Organization (WHO) guidance allow the use of clinical efficacy and safety data for one indication to be extrapolated to other indications for the reference biologic. In general, guidelines suggest that extrapolation of data may be allowed for biosimilars as long as sufficient justification can be provided for the new indication (e.g., similar anticipated mechanism of action for the biosimilar) and a rationale for similar pharmacokinetics, efficacy, safety, and immunogenicity can be provided for the new indication target population. This is similar to the existing WHO guidance on extrapolation of clinical data. Examples from the European experience have shown that data for one indication of an innovator may be reasonably extrapolated to another.[11]

Different regulatory agencies such as US FDA, European Medicines Agency (EMA), and Saudi Food and Drug Authority (SFDA) have approved several biosimilars of oncology biologics and more are expected to be approved in near future. As of now EMA has approved 31 biosimilars, US FDA has approved 13 biosimilars and SFDA has approved 4 biosimilars of oncology biologicals. SFDA-listed prices of biosimilars are significantly less than the prices of their originators. It is anticipated that SFDA will approve biosimilar of trastuzumab, rituximab, and bevacizumab in near future. Below mentioned are the lists of the oncology biosimilars approved by EMA [Table 1], US FDA [Table 2], and SFDA [Table 3].[1214]

Table 1:

List of EMA-approved oncology biosimilars[12]

Table 2:

List of US FDA-approved oncology biosimilars, purple book[13]

Table 3:

List of SFDA-approved oncology biosimilar agents[14]

This study describes the pharmacoeconomic impact of biosimilar in oncology and formulary consideration of oncology biosimilars substituting with their originators in major oncology centers in Kingdom of Saudi Arabia (KSA). It also delineates challenges faced by biosimilars because of the approval of second-generation biologicals and how to address these challenges. This study also emphasizes on the need to have a rigorous pharmacovigilance efforts and naming strategies. The Ministry of National Guard Health Affairs (MNGHA) has recommended specific naming strategies of the biosimilars for effective pharmacovigilance monitoring of biologics and biosimilars.

## Pharmacovigilance of Biosimilars in Oncology

There are still some concerns regarding the long-term evaluation of biosimilars, particularly, the limited experience with these products in terms of efficacy, safety, and immunogenicity at the time of approval. For this reason, pharmacovigilance should be rigorous and is important as a public health concern. Ultimately, only clinical trials and effective post-marketing pharmacovigilance will provide definitive evidence that a biosimilar is comparable with the reference product in term of efficacy and safety. The aim of clinical trials with trastuzumab biosimilars was to show equivalence, and not patient benefit, as this was shown with brand trastuzumab.[15] Now biosimilars of trastuzumab, rituximab, and bevacizumab have been approved and we have several challenging issues that need to be addressed, such as maintaining appropriate pharmacovigilance, extrapolating across indications and automatic substitution, and switching. No consensus has yet been reached in any of these areas.

Clinical testing preapproval may not identify all possible adverse events (AEs) with most biologics, including biosimilars. An evaluation of clinical safety therefore is continued in the post-marketing setting. WHO guidance provides recommendations for post-marketing safety reports for product tolerability, and such reports include a scientific evaluation of frequency/causality of AEs. WHO also recommends that following approval, the manufacturers have a system in place to detect and assess, understand, and prevent any potentially drug-related AEs. This system, referred to as pharmacovigilance, also provides for notification regarding the occurrence of such AEs in whatever countries the product may be marketed. The goal of a post approval pharmacovigilance plan is to identify and understand, as fully as possible, the frequency and nature of AEs associated with a specific product, including potential risk factors for such AEs.[11]

To address safety considerations, the EMA mandates post approval monitoring, as well as pharmacovigilance plans for biologic drugs, including biosimilars.[16] In addition, WHO and EMA recommend that if, based on clinical experience, any additional specific safety monitoring or pharmacovigilance plan has been required for the reference biologic, or its specific product class (e.g., erythropoietin stimulating agents), the same plan should be applied to the biosimilar. Likewise, if additional concerns (e.g., increased immunogenicity of the biosimilar) have arisen during the evaluation of the biosimilar product, these also may be evaluated through appropriate safety monitoring.[12]

US FDA guidance on Good Pharmacovigilance Practice considers routine spontaneous AEs reporting to be sufficient post-marketing surveillance for products where no safety risks have been identified pre- or postapproval, and if used in adequately studied populations. US FDA considers a specific pharmacovigilance plan as appropriate; however, in the event the at-risk population needs additional study, or if safety risks have been identified either pre- or postapproval. As defined by existing US FDA guidance, such a pharmacovigilance plan could include additional measures beyond routine reporting, such as expedited reporting of serious AEs, active surveillance for specific AEs, creation of product registries, pharmacoepidemiologic studies, or additional clinical trials.[20]

Nomenclature and Product Labeling Considerations Naming is an important consideration when developing regulatory policies for biosimilars because of its potential impact on physician prescribing or patient bias, interchangeability, as well as pharmacovigilance. It is important that biosimilars have names that make them readily distinguishable from the innovator biologic (as well as other biosimilar products).[17,18] This is necessary to make certain that AEs that occur in the post-market setting can be readily and correctly matched to a specific product.[17,19] US FDA has published Nonproprietary Naming of Biological Products guidance for industry in January 2017. With the introduction of more biological products, US FDA believes it is important to encourage routine use of designated suffixes in ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices for biological products, irrespective of their licensure pathway and date of licensure. The designated suffix will provide a consistent, readily available, and recognizable mechanism for patients and healthcare professionals, including providers and pharmacists, to correctly identify these products. US FDA believes it is likely that US FDA-designated suffixes will be used routinely when identifying, describing, and recording use of biological products if such suffixes are present in the proper names of all biological products licensed under the Public Health Service (PHS) Act.[20]

Some position statements suggest the International Nonproprietary Name (INN) system should not be used to prescribe biologic drugs.[21] One of the reasons for this is that INN nomenclature with biosimilars can lead to problems, for example, if some countries allow pharmacists to auto-substitute a less-expensive drug having the same INN as its reference product.[22] Instead, naming according to product brand has been recommended to enable better pharmacovigilance of biosimilars, so specific events can be associated with the correct product and manufacturer.[19,21]

Corporate Pharmacy and Therapeutic committee at MNGHA has approved a naming strategies policy for biosimilars in MNGHA formulary. It has recommended to use brand names to be included in computerized prescribing order entry in Health Information System in addition to the generic name (INN) of the drug to allow tracking for pharmacovigilance monitoring. The biosimilar product is identified as a “biosimilar” in the order entry screen by adding the term (Biosimilar) to the product's name. Biosimilars have a different formulary codes than the reference product. Other hospitals in the country can also use the same naming strategy for effective pharmacovigilance monitoring.

Healthcare practitioners in KSA should be encouraged to engage effectively in pharmacovigilance efforts and monitor and report AEs, efficacy concerns, immunogenicity concerns, and medication errors associated with biosimilars to SFDA. Healthcare practitioners should document correct attribution of safety event, for example, what was ordered vs. what did the patient receive in maintenance of electronic medical record, bar code administration, and medication reconciliation (during transition of care).

### Challenges faced with biosimilars due to approval of second-generation biologicals

The emergence of second-generation biologics (or biologics that make improvements on existing biologics through pegylation, alternative formulations, or other means) may affect the value of not only first-generation reference biologics, but also their biosimilars. As research and development of biologics in the oncology setting continues, newer, second-generation biologic drugs may offer different clinical properties compared with currently approved reference biologics.[23,29] They may include new formulations, different efficacy profiles and/or dosing regimens, or reduced immunogenicity. A second-generation biologic may have an improved efficacy and/or safety profile, but if the efficacy and safety of a given second-generation drug is comparable to the first-generation drug or its biosimilar, a CMA could be performed to identify the most economical solution for patients and payers. In contrast, cost-effectiveness comparison analyses could be performed with novel biologics that have different efficacy and/or safety profiles relative to first-generation products or their biosimilars. The results of pharmacoeconomic analyses that incorporate second-generation biologic drugs may affect the value that biosimilars of first-generation reference biologic drugs offer patients with cancer and healthcare providers. This may include the extent of financial and opportunity costs offset by the emergence of these therapies. For example, if a second-generation biologic has improved efficacy, the opportunity for the patient to have a better outcome would possibly negate its higher cost. In addition, the emergence of second-generation biologic drugs may affect the drug acquisition prices for first-generation reference biologic drugs and their biosimilars.[23] Manufacturers of second-generation biologics have extended their patency for another 15–20 years.

## Summary and Conclusion

Biosimilar is a biologic product that is highly similar to the reference product, notwithstanding minor differences in clinically inactive components. There are no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency.

Corporate Pharmacy and Therapeutic committee at MNGHA has approved a naming strategies policy for biosimilars in MNGHA formulary. It has recommended to use brand names to be included in computerized prescribing order entry in Health Information System in addition to the generic name (INN) of the drug to allow tracking for pharmacovigilance monitoring. Other hospitals in the country can also use the same naming strategy for effective pharmacovigilance monitoring. Healthcare practitioners in KSA should be encouraged to engage effectively in pharmacovigilance efforts when using biologicals including the biosimilars and monitor and report AEs, efficacy concerns, immunogenicity concerns, and medication errors to SFDA.

Biologics are significant drivers of globally escalating healthcare costs. Biosimilars have potential to offer cost savings with comparable efficacy and safety to innovator products and increase the access of treatment to more patients. Substitution of filgrastim (neupogen brand) with biosimilar filgrastim has resulted in significant cost saving when biosimilar filgrastim was used for prophylaxis and management of FN as well as for mobilization of stem cells in MNGHA. Moreover, substitution of three commonly used monoclonal antibodies such as rituximab, trastuzumab, and bevacizumab with their approved biosimilars will have significant cost saving in different oncology hospitals of the KSA.

Second-generation biologics may have improved, efficacy, tolerability, and convenient administration pattern saving infusion center time. In our opinion, it seems difficult to substitute SC rituximab with biosimilar rituximab because of convenient administration pattern saving infusion center time. However, IV and SC trastuzumab can be substituted with IV biosimilar trastuzumab because the difference in the administration time between IV and SC trastuzumab dosage form is not significant and this substitution will have huge impact on cost saving. Similarly, IV bevacizumab can be substituted with its biosimilar bevacizumab resulting in significant cost saving.

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