Is there a difference in health outcomes between the biosimilar medicine and the reference biological medicine?

Page last updated: 23 March 2017

A biosimilar medicine has been tested and shown to be as safe and effective as the reference biological medicine:

  • The minor differences between reference and biosimilar medicines do not affect the safety or effectiveness of the biosimilar medicine.
  • The medicines have been assessed to have no clinically meaningful differences and are therapeutically equivalent.
  • The manufacturing process for a biosimilar medicine must comply with the same quality requirements for any biological medicine and thus must demonstrate that the production process can consistently produce a high-quality product.
  • A recently published analysis supports the high pharmaceutical–quality of biosimilar medicines licensed in the European Union.[1]

[1] Brinks V, Hawe A, Basmeleh AHH, et al. (2011). Quality of original and biosimilar epoetin products. Pharmaceutical Research 28(2):386–393.

A comprehensive literature review, conducted by the School of Pharmacy and Medical Sciences at the University of South Australia on behalf of the Australian Government Department of Health, first conducted in June 2016 and updated in September 2016, found that the international postmarket experience of biosimilar medicines showed that they were as safe and effective as the reference biological medicines, and of the same quality. The review did not find any studies that had identified significant issues or differences in safety, effectiveness or quality between biosimilar medicines and reference biological medicines.

The review investigated all studies that covered large-scale, multicentre use of biosimilar medicines (Table 3), and numerous other small-centre studies of biosimilar medicines that have recently been published.

Table 3 Published studies of large-scale, multicentre use of biosimilar medicines

Published study

Results

Bongiovanni A, Monti M, Foca F, Recine F, Riva N, Di Iorio V, et al. (2016). Recombinant granulocyte colony-stimulating factor (rG-CSF) in the management of neutropenia induced by anthracyclines and ifosfamide in patients with soft tissue sarcomas (NEUSAR). Supportive Care in Cancer 27:27.

The study found that there were no statistically significant differences in the incidence of febrile neutropoenia or in adverse events between three groups treated with biosimilar filgrastim, originator filgrastim or Ienograstim. Biosimilar filgrastim was associated with a cost saving of €225.25 per patient compared with the originator filgrastim.

Farkas K, Rutka M, Golovics PA, Vegh Z, Lovasz BD, Nyari T, et al. (2016) Efficacy of infliximab biosimilar CT-P13 induction therapy on mucosal healing in ulcerative colitis. Journal of Crohn’s and Colitis 10(11):1273–1278.

The authors concluded that ‘infliximab biosimilar CT-P13 represents a promising treatment option for patients with UC [ulcerative colitis] not only regarding clinical activity, but also in achieving mucosal healing’.

Gascon P, Aapro M, Ludwig H, Bokemeyer C, Boccadoro M, Turner M, et al. (2016). Treatment patterns and outcomes in the prophylaxis of chemotherapy-induced (febrile) neutropenia with biosimilar filgrastim (the MONITOR-GCSF study). Supportive Care in Cancer 24(2):911–925.

The rates of chemotherapy-induced neutropoenia and febrile neutropoenia episodes, associated hospitalisations, chemotherapy disturbances, and adverse events and reactions were considered to be ‘statistically within the range of rates reported historically’. The authors concluded that ‘the effectiveness and safety results of this study should address prescribers’ concerns about biosimilars’.

Gecse KB, Lovasz BD, Farkas K, Banai J, Bene L, Gasztonyi B, et al. (2016). Efficacy and safety of the biosimilar Infliximab CT-P13 treatment in inflammatory bowel diseases: a prospective, multicentre, nationwide cohort. Journal of Crohn’s and Colitis 10(2):133–140.

The authors concluded that ‘this prospective multicentre cohort shows that CT-P13 is effective and safe in the induction of clinical remission and response in both CD [Crohn’s disease] and UC [ulcerative colitis]’ and that the ‘efficacy and safety of CT-P13 reported herein is comparable to those of observational studies of the originator compound’.

Horbrand F, Bramlage P, Fischaleck J, Hasford J, Brunkhorst R (2013). A population-based study comparing biosimilar versus originator erythropoiesis-stimulating agent consumption in 6117 patients with renal anaemia. European Journal of Clinical Pharmacology 69(4):929–936.

The study found that the prescribed daily dose (PDD) was ‘comparable’ for biosimilar and originator epoetin and did not increase in patients who switched from originator to biosimilar epoetin. The absence of a difference in PDD is consistent with attaining equivalent clinical outcomes.

Michallet M, Luporsi E, Soubeyran P, Amar NA, Boulanger V, Carreiro M, et al. (2014). Biosimilars in the management of anaemia secondary to chemotherapy in haematology and oncology: results of the ORHEO observational study. BMC Cancer 14:720.

The study found that the rate of adverse effects was considered ‘similar’ to that previously reported for epoetin zeta with only 1.9% of patients stopping treatment because of an adverse effect and thromboembolic events (3.55%) were ‘lower than reported previously’ for epoetin zeta (4.2%) and epoetin alfa (4.0%).

Nahon S, Rastkhah M, Ben Abdelghani M, Soumoudronga RF, Gasnereau I, Labourey JL (2016). Zarzio®, biosimilar of filgrastim, in prophylaxis of chemotherapy-induced neutropenia in routine practice: a French prospective multicentric study. Supportive Care in Cancer 24(5):1991–1998.

The authors concluded that ‘the results obtained in real-life conditions of this study confirm that Zarzio is efficient and well tolerated in cancer patients’.

Park SH, Kim YH, Lee JH, Kwon HJ, Lee SH, Park DI, et al. (2015). Post-marketing study of biosimilar infliximab (CT-P13) to evaluate its safety and efficacy in Korea. Expert Review of Gastroenterology and Hepatology 9:S35–S44.

The authors concluded that ‘the tolerability profile observed with CT-P13 in IBD [inflammatory bowel disease] appears to be at least in line with what has previously been reported with RMP [originator]’, and that ‘clinical outcomes such as safety and efficacy are comparable for CT-P13 and RMP [originator]’.

Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Urena S, et al. (2017). Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Annals of the Rheumatic Diseases 76(2):346–354.

The study found that the proportion of ADA [anti-drug-antibody] positive patients were similar between the treatment groups and the proportions with a sustained ADA response were similar. Notably, the ADA incidence within the switching group did not increase after the switch occurred.

Tesch H, Ulshofer T, Vehling-Kaiser U, Ottillinger B, Bulenda D, Turner M (2015). Prevention and treatment of chemotherapy-induced neutropenia with the biosimilar filgrastim: a non-interventional observational study of clinical practice patterns. Oncology Research and Treatment 38(4):146–152.

The authors concluded that the safety profile of the biosimilar filgrastim was ‘generally in line with that reported in the phase III clinical trial and in clinical studies of the originator filgrastim’ and that their study ‘provides further reassurance that the efficacy of this biosimilar observed in the clinical trial setting is maintained in clinical practice.’

Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. (2016). Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Annals of the Rheumatic Diseases 76(2):355–363.

The study found no differences in the proportion of patients experiencing treatment-emergent adverse events (53.5% vs. 53.8% for the maintenance and switch groups, respectively).

Rugo HS, Barve A, Waller CF, et al. (2017). Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial. JAMA 317(1):37–47.

The study found an equivalent overall response rate (defined as complete or partial response) after 24 weeks of treatment (70% biosimilar trastuzumab and 64% reference trastuzumab) among 500 women with ERBB2-positive metastatic breast cancer.

The incidence of adverse effects or side effects is not higher for biosimilar medicines than for the reference biological medicines. For a biosimilar medicine to be approved for use in Australia, the sponsor must have demonstrated to the TGA that the medicine has the same safety profile, including the same incidence and severity of adverse effects and side effects.

In the European Union, there have not been any significant problems discovered with biosimilar medicines since their introduction in 2006.[1] For example, a recent study, which used all the available safety evidence for two approved biosimilar erythropoietins in Europe, found that both had similar safety profiles with neither being more nor less safe. They found that the incidence of known adverse effects for the two biosimilar medicines was not statistically higher than what is known about erythropoietins in general.[2]

A report by the European Commission in 2013[3] found that no specific safety concerns had been identified for approved and marketed biosimilar medicines by the Committee for Medicinal Products for Human Use (CHMP) and the CHMP Pharmacovigilance Working Party of the European Medicines Agency.


[1] Pasina L, et al (2016) Biological agents and biosimilars: Essential information for the internist. European Journal of Internal Medicine 33:28-35

[2] Abraham I, MacDonald K (2012). Clinical safety of biosimilar recombinant human erythropoietins. Expert Opinion on Drug Safety 11:819–840.

[3] European Commission (2013). What you need to know about biosimilar medicinal products; a consensus information document, European Commission.

The incidence of immunogenicity for biosimilar medicines is not higher than for the reference biological medicines.

All medicines may have the potential to induce an immune response in the body. Although synthetic chemical medicines may cause immune responses, this tends to be rare. Biological medicines, including biosimilar medicines, have a higher potential to cause an immune response because they are derived from living cells or organisms. The ability to cause an immune response is called immunogenicity.

Immunogenicity is assessed during the development and registration of all biological medicines, including biosimilar medicines. Human immunogenicity data are always required for the licensing of biological medicines, including biosimilar medicines.

Concerns have been expressed that the minor differences between the biosimilar medicine and its reference biological medicine will increase the likelihood of immunogenicity. However, it is important to note that there are already minor differences between batches of the same reference biological medicines. This is because the inherent variability of the biological systems used in the manufacturing process means that the resulting product are also variable.

Indeed, changes to manufacturing processes for reference biological medicines can also increase the likelihood of immunogenicity. For example, in the case of Eprex®, an increase in antibody-induced pure red cell aplasia in the early 2000s was found to be because of a change in the manufacturing process used for the biological medicine epoetin, and not because of a biosimilar medicine.[1]


[1] McKoy JM, Stonecash RE, Cournoyer D, et al. (2008). Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transfusion 48(8):1754–1762.

Indication extrapolation is defined as therapeutic indications for which no specific clinical trials with the biosimilar have been performed, and that have been registered based on extrapolation of efficacy and safety data from other studied indications.

Extrapolation of data is not a new concept and is based on sound scientific principles. In Australia, decisions about indication extrapolation for biosimilar medicines are made by the Therapeutic Goods Administration. A strong scientific justification for indication extrapolation is required, which includes that:[1]

  • similarity with the reference biological medicine must be convincingly demonstrated, based on the totality of the evidence from the comparability exercise
  • if clinical similarity can be shown in a key indication, extrapolation of efficacy and safety data to other indications of the reference biological medicine may be possible (e.g. if the relevant mechanism of action and/or the receptors involved in the extrapolated indications are the same). If the mechanism of action is different or unknown, additional convincing data are necessary to provide further reassurance that the biosimilar will behave the same as the reference biological medicine
  • the safety profile of the biosimilar must have been properly characterised, and unacceptable immunogenicity excluded.

The guidelines used by the TGA to assess extrapolated indications were published by the European Medicines Agency.

Internationally, indication extrapolation is allowed in all regions that have adopted biosimilar regulations. For example, in the European Union, filgrastim data were extrapolated to stem cell mobilisation and collection in healthy donors, which had not been clinically tested in the biosimilar medicine. Despite concern from some health care professionals, postmarket studies confirmed the safety and effectiveness of the biosimilar filgrastim in all the approved indications.[2]


[1] Weise W, Bielsky M-C, De Smet K, Ehmann F, Ekman N, Giezen TJ, Gravanis J, Heim H-K, Heinonen E, Ho K, Moreau A, Narayanan G, Kruse NA, Reichmann G, Thorpe R, van Aerts L, Vleminckx C, Wadhwa M, Schneider CK (2012). Biosimilars: what clinicians should know. Blood 120(26): 3191–3196.

[2] Weise M, Kurki P, Wolff-Holz E, Bielsky M-C, Schneider CK (2014). Biosimilars: the science of extrapolation. Blood 124(22); 3191–3196.

Published international postmarket experience of biosimilar medicines has demonstrated no difference in the safety or health outcomes of patients who have switched from the reference to the biosimilar agent, compared with remaining on the reference biological medicine.

For further details on the available published literature, refer to the literature reviews conducted by the University of South Australia.

An open-label extension study[1] investigated the efficacy and safety of switching from the infliximab reference biological medicine to the biosimilar infliximab in patients with rheumatoid arthritis, and to provide data on extended duration (102 weeks) treatment with only the biosimilar medicine. The study demonstrated comparable efficacy and safety between those continuing biosimilar treatment and those who switched. Efficacy endpoints assessed the American College of Rheumatology 20% (ACR20) response, ACR50 and ACR70, with response rates comparable between the maintenance and switching groups. The study found no differences in the proportion of patients experiencing treatment-emergent adverse events (53.5% vs 53.8% for the maintenance and switch groups, respectively).

Another open-label extension study[2] examined the long-term safety and efficacy of CT-P13 in 174 patients with ankylosing spondylitis, which included a treatment arm of patients switching from the reference infliximab to the CT-P13 biosimilar. The study demonstrated comparable efficacy and safety between those continuing biosimilar treatment and those who switched. Efficacy was determined according to the Assessment of SpondyloArthritis International Society (ASAS)20, ASAS40 and ASAS partial remission. End-of-study response rates were comparable between maintenance and switching groups ACR20 (71.7% vs 71.8%, respectively), ACR50 (48.0% vs 51.4%, respectively) and ACR70 (24.3% vs 26.1%, respectively). With regards to the formation of antidrug antibodies (ADA), 40.3% of maintenance group patients and 44.8% of switch group patients were ADA positive at study conclusion (P = 0.48). The proportion of patients with at least one positive ADA result during the extension study were similar between the treatment groups (57.2% for the maintenance groups vs 64.3% for the switch group) and there were no differences in the number of patients with sustained ADA responses. The study also found that the proportion of ADA-positive patients was similar between the treatment groups, and the proportions with a sustained ADA response were similar. Notably, the ADA incidence within the switching group did not increase after the switch occurred.

Preliminary data recently released from an independent Norwegian study called NOR-SWITCH[3] provide additional support for the similarity of biosimilar medicines. This was a 52-week, randomised, double-blind, comparative study to evaluate the efficacy, safety and immunogenicity of switching adult patients to an infliximab biosimilar. The study was of 481 consumers aged 18 years or over who were diagnosed with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn’s disease or chronic plaque psoriasis. Patients who had been receiving the reference biological medicine (Remicade®) for the previous 6 months were randomised to either continue treatment with Remicade® or be switched to the biosimilar medicine (Remsima®) at the same dose and frequency. The primary endpoint was worsening of the disease during follow-up, determined by disease-specific composite measures and/or consensus between the patient and physician leading to a major change in treatment. Disease-worsening occurred in 53 (26.2%) patients in the Remicade® arm and 61 (29.6%) patients in the RemsimaTM arm. The incidence of ADA detected was 17 (7.1%) in patients taking Remicade® and 19 (7.9%) in those taking RemsimaTM. Patients experienced similar frequencies of adverse events, including infusion reactions, in both arms of the study.


[1] Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. (2017). Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Annals of the Rheumatic Diseases 76(2):355–363.

[2] Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Urena S, et al. (2016). Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Annals of the Rheumatic Diseases 76(2):346–354.

[3] Jørgensen K, et al (2016). Biosimilar infliximab (ct-p13) is not inferior to originator infliximab: results from the 52-week randomized NOR-SWITCH trial. United European Gastroenterology Week.

In this section