What do oncologists need to know about biosimilar products?
© The Author(s) 2016
Received: 24 August 2015
Accepted: 29 August 2016
Published: 13 October 2016
Many biologic products have improved the outcomes of cancer patients, but the costs can substantially burden healthcare systems. Biosimilar products can potentially reduce drug costs and increase patient access to beneficial treatments. Approval of a biosimilar product relies on the demonstration of “comparability” or “no clinically meaningful differences” as compared to its reference biologic product. Biosimilar products for erythropoietin, granulocyte colony-stimulating factor, trastuzumab, and rituximab are already available, and the regulatory processes in various countries are constantly evolving. It is important that oncologists be familiar with the potential issues surrounding the clinical use of biosimilar products. In this review article, we provide background information about biosimilar products and their regulatory approval processes, followed by a discussion of individual biosimilar drugs.
KeywordsBiosimilar products Biologic products Regulation Oncology
Key oncological biologics whose patents either have expired or will expire soon
Biologic (brand name)
Estimated patent expiry (month and year)
Epoetin alfa (Emprex/Epogen/Procrit)
Darbepoetin alfa (Aranesp)
“Biosimilar”, as the name implies, is a biologic that is similar to the licensed “reference” drug. Before a biosimilar is incorporated into the clinical management of patients, clinicians should determine whether, based on efficacy and safety, the biosimilar can be used “instead of” or “interchangeably with” the reference biologic. Regulatory authorities play an important role in the development of biosimilars, and medical societies help guide clinicians on the use of biosimilars [2–5]. Currently available and of most interest in the field of oncology are biosimilars of the supportive agents filgrastim and erythropoietin and the mAbs trastuzumab and rituximab. Bevacizumab and cetuximab are innovator drugs in oncology whose patents will expire in the next few years . Recent surveys conducted in America, Europe, and Asia showed that most clinicians are not very familiar with biosimilars [5, 7, 8]. In this review, we provide information that oncologists need to know about this new category of medicine.
What is a biosimilar?
Comparisons between biosimilars and generics
US FDA A biosimilar is a biological product that is highly similar to a licensed reference biological product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product
US FDA A generic drug is identical to a brand name drug in dosage, safety, strength, route of administration, quality, performance, and intended use
EU EMA A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product (reference medicinal product). Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise need to be established
EU EMA A generic medicine is a medicine that is developed to be the same as a medicine that has already been authorized (the “reference medicine”). It contains the same active substance(s) as the reference medicine, and it is used at the same dose(s) to treat the same disease(s) as the reference medicine
Complex, as they are derived from living cells or organisms, sensitive to manufacturing changes
Simple, as produced by chemical synthesis
Compared with original counterparts
Similar but not identical
Need to demonstrate comparability (i.e., no clinically meaningful differences) to its comparator (the reference drug)
Automatic substitution not recommended (some biosimilars might not carry all the same indications, especially if the reference biologics have multiple mechanisms of action)
Allow automatic substitution
Biosimilar regulatory approval
The European Medicines Agency (EMA) is the body responsible for approving biosimilars in the European Union (EU), and it established the first legislative pathway for doing so. In 2005, it published guidelines governing the development of biosimilars; since then, it has developed individual guidelines for the biosimilars of granulocyte colony-stimulating factor (G-CSF), erythropoietin, and various mAbs . The EMA defines biosimilars as “a biological medicinal product that contains a version of the active substance of an already authorized reference medicinal product and similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established” . The concept of “comparability” in reference to the original biologic is considered fundamental to the approval of a biosimilar. Comprehensive comparability studies should demonstrate similarity in physiochemical, biological, and immunological characteristics and in efficacy and safety. Immunogenicity has been a safety concern for biosimilars; thus, a robust pharmacovigilance system and risk management procedures should be in place to ensure long-term safety.
Global regulations for the evaluation and approval of biosimilars
Own biosimilar guideline issued?
South Korea—MFDS, 2010
Canada—Health Canada, 2010
India—Ministry of Science and Technology and Ministry of Health and Family Welfare, 2012
New Zealand—Medsafe (but refers to both EU and US guidelines)
China—CFDA (follows a simplified new product approval pathway)
Reference product must be registered in the region/country?
Malaysia (products registered in the reference countries Australia, Canada, EU, United Kingdom, France, Japan, Sweden, Switzerland, and US are considered acceptable)
Singapore and Malaysia (allow if both biosimilar and reference product approved for the same indication but cannot be substituted with one another during a treatment period)
Extrapolation from one indication to another?
India (allow for extrapolation of therapeutic similarity across indications in certain cases, depending on clinical experience, available literature data, and whether the same mechanisms of action or the same receptor(s) are involved in all indications)
Pharmacovigilance of biosimilars
Pharmacovigilance is “the science and activities relating to the detection, assessment, understand and prevention of adverse effects or any other drug related problem” . Pharmacovigilance is particularly important when dealing with biologics because safety data from pre-authorization clinical studies only identify some potential risks and are insufficient to detect rare adverse events. Immunogenicity can be related to the route of administration, dosing regimen, patient-related factors, and disease-related factors, and it is an ongoing safety concern . The case of erythropoietin antibody-mediated pure red cell aplasia (PRCA) is a good example of immunogenicity being identified by post-marketing surveillance, when a small change in the formulation of the biologic led to an adverse immune response . In addition to immunogenicity, other safety concerns, such as the administration of hematopoietic colony-stimulating factors to healthy donors, which led to the development of hematologic malignancies, have been observed with biologics . To ensure long-term safety, biosimilars are required to follow the same pharmacovigilance regulations as their reference counterparts. Required as part of the marketing application are a risk management plan describing the safety profile of the drug as well as proposed pharmacovigilance and risk minimization measures. After biosimilars are approved, companies are required to submit periodic safety reports. Prescribers should report any suspected serious adverse reactions associated with the use of biosimilars, and ensuring traceability of the biosimilars associated with adverse events is essential. To date, no specific safety concerns regarding approved and marketed biosimilars have been identified.
Interchangeability between a biologic and its biosimilar
Generic medications can be used interchangeably with their branded originators since they are considered therapeutically equivalent; often, pharmacists may substitute a prescribed drug for a generic medication without the prior consent of the treating physician (known as “automatic substitution”) . Interchangeability refers to switching back and forth between two medicinal products without any observed changes in efficacy or safety risk. Biosimilarity does not imply interchangeability, and interchangeability does not always imply substitutability.
Some biosimilars might not have all the same indications that the reference biologics are approved for, especially if the reference biologics have multiple mechanisms of action. Even if a biosimilar is approved for the same indication as the reference originator, it is generally recommended that automatic substitution not be allowed because the clinician should be fully aware of which drug is given to the patient. If, during a treatment period, alternation or switching between the biosimilar and the branded biologic cannot be avoided, this must be recorded accurately; maintaining pharmacovigilance by clearly delineating between biosimilars and branded originators is important.
The USA allows an “interchangeable” designation for biosimilars, provided that, in any given patient, the biosimilar can be expected to produce the same clinical results as the reference product and that the safety and efficacy observed when alternating or switching between the two remain the same . Other countries, such as Australia and Canada, do not provide recommendations on whether a biosimilar can be used interchangeably with its reference medicine, and they have officially prohibited the automatic substitution of biologics [10, 14]. The EMA also does not provide an interchangeable recommendation when approving a biosimilar . Individual EU countries must decide on the interchangeability between a biologic and its biosimilar .
Erythropoiesis-stimulating agents (ESAs), such as epoetin alfa (Eprex, Erypro), epoetin beta (NeoRecormon), and darbepoetin alfa (Aranesp), are approved for cancer patients with chemotherapy-induced anemia [28, 29]. They are considered equivalent in terms of efficacy and safety. In 2010, concerns about an increased risk of venous thromboembolism and an increased mortality risk associated with the use of ESAs by cancer patients led the European Society for Medical Oncology and the American Society of Clinical Oncology/American Society of Hematology to issue revised guidelines . These guidelines recommended against the use of ESAs for the treatment of malignancy-associated anemia in patients not receiving concurrent myelosuppressive chemotherapy; they also recommended against the use of ESAs for patients receiving chemotherapy for curative intent, until further safety data are collected. However, the EMA’s Committee for Medicinal Products for Human Use stated that the benefits of using ESAs for approved indications (hemoglobin target range of 10–12 g/dL in chemotherapy-induced anemia) continue to outweigh the associated risks, including increased risk of tumor progression and venous thromboembolism and reduced survival, except for those cancer patients with a reasonably long life expectancy whose anemia should be treated by blood transfusions .
List of currently approved erythropoietin biosimilars
Active substance (laboratory code)
Brand name (pharmaceutical company)
Indications in oncology
Epoetin alfa (HX575)
Treatment of anemia and reduction of transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, and at risk of transfusion as assessed by the patient’s general status (e.g., cardiovascular status, pre-existing anemia at the start of chemotherapy)
Abseamed (Medice Arzneimittel)
Epoetin alfa Hexal (Hexal)
Epoetin zeta (SB309)
Silapo (Stada Arzneimittel)
Treatment of anemia in patients with non-myeloid malignancies where anemia develops as a result of concomitantly administered chemotherapy and where blood transfusion is not considered appropriate
Epoetin alpha (HX575)
Treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy
List of currently approved granulocyte colony-stimulating factor biosimilars
Brand name (pharmaceutical company)
Indications in oncology
Reduction in the duration of chemotherapy-induced neutropenia and the incidence of febrile neutropenia (except for chronic myeloid leukemia and myelodysplastic syndromes)
Reduction in the duration of neutropenia caused by myeloablative therapy followed by bone marrow transplant
Mobilization of peripheral blood progenitor cells
Filgrastim Hexal (Hexal)
Zarxio/(Sandoz) [Placeholder non-proprietary name: filgrastim-sndz]
Decrease in the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever
Reduction in the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia
Reduction in the duration of neutropenia and neutropenia related clinical sequelae (e.g., febrile neutropenia) in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation
Mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
Decrease in the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs in doses not usually requiring bone marrow transplantation;
Reduction in duration of neutropenia and clinical sequelae in patients undergoing induction and consolidation chemotherapy for acute myeloid leukemia;
Mobilization of autologous peripheral blood progenitor cells alone, or following myelosuppressive chemotherapy, to accelerate neutrophil and platelet recovery by infusion of such cells after myeloablative or myelosuppressive therapy in patients with non-myeloid malignancies;
Mobilization of peripheral blood progenitor cells in normal volunteers; for use in allogeneic peripheral blood progenitor cell transplantation;
Treatment of patients receiving myeloablative chemotherapy, for reducing the duration of neutropenia and clinical sequelae following autologous or allogeneic bone marrow transplantation
Tevagrastim (Aspen Pharmacare)
Mobilization of autologous peripheral blood progenitor cells alone, or following myelosuppressive chemotherapy and the mobilization of peripheral blood progenitor cells in normal donors [allogeneic peripheral blood progenitor cell (PBPC)]
Reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes) and for the reduction in the duration of neutropenia and its clinical sequelae in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia
Reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes)
Reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia
Filgrastim BS (Mochida/Fuji)
Treatment in neutropenia induced by anti-cancer chemotherapy
Filgrastim BS (Nippon Kayaku/Teva)
Filgrastim BS (Sandoz)
Key studies of biosimilar filgrastim that demonstrated clinical equivalence to the reference drug
Key studies of biosimilar filgrastim demonstrating clinical equivalence to reference drug
Multinational, multicenter, randomized, controlled phase III study; breast cancer patients receiving docetaxel/doxorubicin chemotherapy (n = 348)
Reference drug, Neupogen 
Multinational, multicenter, randomized, controlled phase III study; lung cancer patients receiving platinum based chemotherapy (n = 240)
Reference drug, Neupogen 
Multinational, multicenter, randomized, controlled phase III study; patients with non-Hodgkin lymphoma receiving chemotherapy (n = 92)
Reference drug, Neupogen 
Multinational, multicenter, randomized, controlled phase III study in chemo-naïve breast cancer patients receiving neoadjuvant/adjuvant docetaxel, doxorubicin, and cyclophosphamide chemotherapy (n = 218)
Reference product, Neupogen 
Multicenter, randomized, controlled phase III study; breast cancer patients treated with doxorubicin and docetaxel in neoadjuvant/adjuvant or first-line metastatic setting (n = 279)
Reference drug, Neupogen 
Enhanced by a 20-kDa polyethylene glycol molecule compared with filgrastim, pegfilgrastim has a longer half-life and is administered less frequently . Pegfilgrastim has been approved by the US FDA and the EMA since 2002 and is indicated in non-myeloid cancer patients undergoing chemotherapy to decrease the incidence of febrile neutropenia [54, 55]. Unlike filgrastim, pegfilgrastim is not approved for hematopoietic progenitor cell mobilization. Since 2007, four pegfilgrastim biosimilars have been approved in India . In December 2014, Apotex, in conjunction with Intas Pharmaceuticals, successfully filed its biosimilar pegylated apofilgrastim with the US FDA. Another biosimilar pegfilgrastim, LA-EP2006, developed by Sandoz, is being compared with its reference product Neulasta in three phase III studies; the results will be used to support the company’s registration application in the USA and the EU. The US patent for pegfilgrastim expired in October 2015; the EU patent is expected to expire in August 2017.
List of currently approved biosimilar monoclonal antibodies in oncology
Brand name (pharmaceutical company)
Approved indications in oncology
CANmab (Biocon)/Hertraz (Mylan)
HER2-positive breast cancer
HER2-positive breast cancer
Advanced (metastatic) gastric cancer
AcellBia (CSJC biocad)
CD20-positive non-Hodgkin’s B-cell lymphoma
Rituximab is an mAb that acts against CD20 to treat non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia. Marketed by Roche as Rituxan and MabThera, rituximab was originally approved for use in 1997 in the USA  and in 1998 in the EU . In November 2013, the patent for rituximab expired in the EU; in September 2016, it will expire in the USA. In 2007, Dr. Reddy’s Laboratories marketed Reditux in India as a biosimilar of rituximab to treat diffuse large B cell lymphoma . However, Reditux is not a true biosimilar because it has not been studied head to head against its reference product. In May 2014, Biocad’s Acellbia (also known as BCD020), a biosimilar of rituximab, was approved in Russia for the treatment of NHL  (Table 6). The approval was based on the results of a randomized, open-labelled study, involving over 30 centers in Ukraine, Russia, and India, which showed that the drug’s pharmacokinetics, pharmacodynamics, efficacy, and safety were similar to rituximab .
The rationale for the development of biosimilar products is to improve patient access to biological therapies in a safe and cost-effective way. As the technology advances and evolves, so too do regulations governing the development of biosimilars. Oncologists should be aware that biosimilars are not generics of biological medicines, but they do have comparable efficacy and safety to the originators. Pharmacovigilance is critical to ensuring the long-term quality and safety of biosimilars. With biosimilars, it is important to be mindful of concerns about drug substitutions and extrapolation across indications.
LKSL, KM, and CL drafted the manuscript. LKSL and SLC revised this paper. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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