Oncology biosimilars: New developments and future directions

Abstract Biologicals have become an integral part of cancer treatment both as therapeutic agents and as supportive care agents. It is important to know that biologics are large, complex molecular entities requiring extensive immunogenicity testing and pharmacovigilance strategies to ensure no immune response is evoked in the body. Oncology's pharmacological market is dominated by biologics; however, their high development and manufacturing costs are burdensome to health care systems. Biologics being the most expensive prescription drugs on the market limit the accessibility for necessary treatment in the case of many patients. As biologics patents expire, the development of biosimilars is underway in an effort to lower costs and enable patients to access new cancer therapies. Regulatory guidelines for biosimilars have now been established and are constantly being revised to address any issues, facilitating their robust development. Moreover, many scientific societies offer guidance to help stakeholders better understand current regulations and biosimilar's safety. Despite the potential cost benefits, lack of knowledge about biosimilars, and the possibility of immunogenicity have created an uncertain environment for healthcare professionals and patients. In this review, we provide an overview of relevant legislation and regulations, pharmacoeconomics, and stakeholder perceptions regarding biosimilars. The article also describes biosimilars in development, as well as the ones currently available on the market.

pharmacological market is dominated by biologics; however, their high development and manufacturing costs are burdensome to health care systems. Biologics being the most expensive prescription drugs on the market limit the accessibility for necessary treatment in the case of many patients. As biologics patents expire, the development of biosimilars is underway in an effort to lower costs and enable patients to access new cancer therapies. Regulatory guidelines for biosimilars have now been established and are constantly being revised to address any issues, facilitating their robust development. Moreover, many scientific societies offer guidance to help stakeholders better understand current regulations and biosimilar's safety. Despite the potential cost benefits, lack of knowledge about biosimilars, and the possibility of immunogenicity have created an uncertain environment for healthcare professionals and patients. In this review, we provide an overview of relevant legislation and regulations, pharmacoeconomics, and stakeholder perceptions regarding biosimilars. The article also describes biosimilars in development, as well as the ones currently available on the market. Biologics are generally large complex molecules produced through biotechnology in a living system such as microorganism, plant cell, or animal cell. These products are used to diagnose, prevent, treat, and cure medical conditions. 1 Biosimilars are biological drugs that are designed to be highly similar to the existing marketed biologics. 2 The high level of similarity to the originator biologic is defined in terms of physicochemical characteristics, efficacy, and safety as outlined by the respective regulatory authorities. 3,4 A generic drug is a medication that has the same active ingredients and provides the same clinical benefits as that of a brand name drug. It is created to have an identical dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. 1 However, biosimilars are not a generic version of biologics, as it is not possible to develop an identical biochemical entity. This is mainly due to the inherent complexity of the proteins and their associated manufacturing processes. 5 Inherent variation is common within each lot and between lots during the manufacturing of biologics as well as biosimilars. Both Biosimilars and generics are approved through different abbreviated pathways that do not require extensive clinical studies. 6 So far, 29 biosimilars for various indications have been approved in the United States 7 whereas 64 biosimilars were approved in Europe. 8 The European Medical Agency (EMA) was the first to approve a biosimilar in 2006 and to provide guidance for biosimilar development and approval. 9 However, the pathway for marketing biosimilars in the United States has had several barriers. 10 Even though the patent protection of several originator biologics was close to the expiration date, the market competition that was seen with chemical drugs through generics did not occur with biosimilars. 11 Generics have been able to be marketed in the United States since 1984 due to the established abbreviated pathway through the Hatch-Waxmann Act. 12 However, with biologics the FDA lacked a clear regulatory pathway for the approval of biosimilars until 2010. This was one of the main reasons for the slow adoption of biosimilars in the US when compared to Europe. 13 Moreover, the marketing launch of biosimilars in the US is delayed by patent infringement lawsuits, exclusionary contracts, and anticompetitive tactics of brand name manufacturers. 14

| THE NEED FOR BIOSIMILARS IN CANCER
Cancer is among the leading causes of death worldwide. Globally, cancer accounts for about one in every six deaths, which is more than HIV, tuberculosis, and malaria combined. 15 In 2020, there were about 19.3 million estimated new cases and 10 million cancer-related deaths worldwide. Among these deaths, one-quarter of the cases occur in low-and medium-Human Development Index countries, which lack resources and medical systems to address the disease burden. 16 By 2040, the global cancer burden is expected to increase to an estimated 27.5 million cases and 16.3 million deaths based on the aging and growth of the population. 17 The National Cancer Institute estimates the direct medical costs related to cancer treatment in the United States were $183 billion in 2015 and are expected to increase to $246 billion by 2030, a 34% raise. 18 However, owing to the advances in personalized treatments and inflation, this increase is likely to be an underestimation. 19,20 With the advent of biosimilars, market competition is on the rise which can help in increasing the accessibility and decreasing the cost burden to cancer patients.

| Stake holders' perceptions on biosimilars/ barriers to implementation
There are numerous obstacles to the integration of biosimilars into oncology treatment. One major barrier is the patient and prescriber perception of biosimilars. Survey responses collected from 1201 US physicians across specialties by the biosimilars Forum through SERMO (global social media/network organization for physicians) indicated knowledge gaps among physicians. Lack of awareness about biologics, biosimilars, the approval process for biosimilars, safety & immunogenicity, interchangeability, and substitution of biosimilars was observed. 21 Another survey involving 500 US-based hematologists and oncologists also indicated critical education gaps. Almost 49% of the respondents were not familiar with the concept of extrapolation and 81% of respondents were hesitant to prescribe biosimilars until an average sales price (ASP) was established. However, 77% of respondents were receptive to receiving communications about biosimilars from professional organizations like ASCO. 22 Moreover, there is a growing concern that regulatory guidelines of generics may be applied to biologics, which has led several states to amend older laws to address the complex molecular characteristics of biologic products and biosimilars. 23 Given the novelty of biosimilars and their reduced emphasis on clinical testing, there is a great need for education among prescribers and patients. 24 American Society of Clinical Oncology (ASCO) provides information and guidance to the oncology community on the use of biosimilars, their safety & efficacy, interchangeability, substitution, regulatory considerations, and prescriber & patient education.
CancerLinQ, an integrated real-time data resource also provides valuable information on the use of biosimilars and their effectiveness. 23 The FDA also offers educational webinars and presentations to help clinicians better understand current regulations and biosimilar's safety. 25 28 In the case of patients, the primary education source is the treating physician. 29 Several patient advocacy groups including CancerCare, 30 Susan G. Komen, 31 Global Colon Cancer Association, 32 and so forth, also provide a broad range of educational materials tailored for patient use to facilitate their understanding and acceptance of biosimilars.

| Overview of biosimilar legislation and regulation
Historically in the United States, biologics were regulated by the Public Health Hygienic Laboratory, a precursor of NIH, which was then transferred to the Bureau of Biologics at the FDA in 1972. 33 After a decade later, the Bureau of Drugs and Bureau of Biologics were merged into a single entity to form National Center for Drugs and Biologics (NCDB). 34 However, in 1987 the Center for Drugs and Biologics was divided back into the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). 35 The jurisdictional responsibilities of the two centers were assigned through the Intercenter Agreement issued by the FDA in 1991. 36 Traditional biologics including vaccines, blood, blood products, allergenic extracts, certain devices, and test kits are regulated by CBER. The center also regulates gene & cellular therapy products and tissue transplants from human and non-human sources. 37 42 The BPCIA has also set periods of regulatory exclusivity for brand name biologics and biosimilars as well as laid procedures for resolving patent disputes. 11 Biologics are offered 12 years of exclusivity during which the FDA cannot approve any biosimilar or interchangeable product referencing the brand name biologic. However, a BLA (Biologics License Application) of a biosimilar or interchangeable product can be submitted after 4 years from the date on which the reference product was first licensed. 43 A BLA can be submitted directly by an applicant or through a legal entity involved in the manufacturing, who is responsible for product  45 Over the years, the FDA has released additional guidance on a variety of other areas related to biosimilars and all of these documents can be accessed through the FDA website. 42 The agency's database "Purple Book" contains information about all FDA-licensed biologics regulated by the CDER including their biosimilars and interchangeable products. In-depth information about the date on which the biological product was licensed, if the biological product has proven to be a biosimilar or interchangeable to an already licensed biological drug, and the expiration dates of applicable exclusivities of the reference biologics can be obtained. Also, the database provides information about licensed products regulated by the CBER. 46 On the other hand, guidelines for the regulation of medicines in the European Union (EU) are very well established. A dedicated pathway for the development and approval of biosimilars was introduced in 2004. 47 General guidelines on biosimilars were issued by EMA to introduce the concept and to provide biosimilar manufacturers with a user guide containing relevant scientific information. 48 In the EU, biologics are offered 8 years of exclusivity during which a biosimilar referencing the brand name biologic cannot be marketed. 4 Biotechnology products including biosimilars are approved by the EMA through a marketing authorization application (MAA) following a centralized procedure. 47  ing Party) and biosimilars (Biosimilar Working Party). 47 The scientific opinion obtained after the EMA's evaluation is recommended to the European Commission, which ultimately decides if an EU-wide marketing authorization must be granted. Once approved, the decision of the commission is published in the Community Register of medicinal products for human use. In addition, the EMA also publishes a European public assessment report (EPAR) for each application that has been granted/refused a marketing authorization. 49 The complete list of centrally authorized biosimilars approved to date can be accessed from the EMA's website. 8

| Biosimilars in oncology
Currently, there are only a few biosimilars approved for cancer treatment and supportive care. Biosimilars are available for monoclonal antibodies (mAb) including Rituximab, Trastuzumab & Bevacizumab, F I G U R E 2 Pegfilgrastim, filgrastim and their biosimilars' mechanism of action. Once bound to the granulocyte colony stimulating factor receptor, the JAK-STAT signaling pathway is activated, leading to neutrophil survival, proliferation, and differentiation.
F I G U R E 3 Epogen/Procrit and its biosimilars' mechanism of action. Once bound to the erythropoietin receptor, the JAK-STAT signaling pathway is activated, leading to red blood cell survival, proliferation, and differentiation. and supportive agents including filgrastim, pegfilgrastim, epoetin α & epoetin ζ. 50

Filgrastim and pegfilgrastim
The first-ever biosimilar product to be marketed in the United States was Zarxio ® (filgrastim-sndz) and was approved by FDA Y.T.T March 2015. 51 Later in 2018, Nivestym ® (filgrastim-aafi) was approved, both of these biosimilars can be used for the same indications as the reference drug, Neupogen ® (Filgrastim). 52 Filgrastim is a recombinant granulocyte colony-stimulating factor (G-CSF) that regulates neutrophil production from bone marrow. Filgrastim is used to reduce febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anticancer agents or myeloablative chemotherapy followed by bone marrow transplantation. It is also used in patients with acute myeloid leukemia receiving induction or consolidation chemotherapy for reducing the time of neutrophil recovery and the duration of fever. 53 In Europe, nine biosimilars of Filgrastim are approved by the EMA including Accofil ® , 54 Biograstim ®55 Filgrastim Hexal ® , 56 Filgrastim Ratiopharm ® , 57 Grastofil ® , 58 Nivestim ® , 59 Ratiograstim ® , 60 Tevegrastim ®61 and Zarzio ® . 62 However, the marketing of Biograstim ® and Filgrastim Ratiopharm ® was withdrawn by the EMA at the request of their respective marketing authorization holders. 55,57 Two other G-CSFs that are commonly used for treating chemotherapy-induced neutropenia (CIN) include pegfilgrastim and lenograstim. Filgrastim and lenograstim are short-acting G-CSFs that are injected daily during chemotherapy while pegfilgrastim is a long-acting G-CSF, administered once per chemotherapy cycle. 63 Pegfilgrastim has an additional polyethylene glycol unit, which causes an increase in the size of the molecule, thereby prolonging the half-life of the drug. 64 Once bound to G-CSF receptors, filgrastim, pegfilgrastim, lenograstim, and all biosimilars act to increase the proliferation and maturation of neutrophils thereby decreasing the risk for neutropenia as seen in Figure 1. The JAK-STAT signaling pathway is activated and results in the translocation of JAK3 to the nucleus. Once in the nucleus, JAK3 binds to DNA and activates transcription linked to neutrophil proliferation 65 as seen in Figure 2.

Epoetins
Epoetins are used for treating chemotherapy-induced anemia (CIA), reducing the need for blood transfusions thereby improving the quality of life. These are similar to erythropoietin hormone, secreted by the kidneys that stimulate red blood cell production (erythropoiesis) in the bone marrow and are also referred to as erythropoiesis-stimulating agents (ESAs). 78

| Pharmacoeconomics of biosimilars in oncology
For bevacizumab, the percentage savings with biosimilars ranged from 15% to 23%. Among bevacizumab biosimilars, the savings were significantly higher with Zirabev ® when compared to the originator product, Avastin due to legal issues. 190 Shanghai Henlius Biotech withdrew its rituximab biosimilar candidate HLX01 from phase 3 studies due to strategic reasons. The study was intended to evaluate the candidate safety and efficacy in patients with low tumor burden follicular lymphoma. 194 For the same reasons, Jiangsu-Hengrui-Medicine also withdrew its bevacizumab candidate BP-102, from a phase 2 evaluation in patients with mCRC. 195

| CONCLUSIONS AND FUTURE PERSPECTIVES
The use of biosimilars is rapidly evolving and will continue to play an important role in the future care of cancer patients. 196 Many biosimilars are expected to be available in the coming years and their use will largely depend on patient and provider acceptance, which is in turn based on an adequate understanding of the safety and efficacy of these agents in cancer treatment. 23  Foundation.

CONFLICT OF INTEREST
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

ETHICS STATEMENT
This review did not require any ethical clearance. However, all participants practiced highest ethical standards as mandated by National Institute of Health throughout the preparation of this manuscript.

DATA AVAILABILITY STATEMENT
Not applicable.