The number of biological medicines used in clinical practice has increased significantly in recent years. Despite no biological medicines appearing on the 2015 list of top ten drugs by prescription counts, six biological medicines occupy places in the top ten drugs by cost to the Pharmaceutical Benefits Scheme (PBS). The high cost of these new therapies has generated a lot of interest in the use of biosimilars.
The Therapeutic Goods Administration (TGA) defines a biosimilar as a version of an already registered biological medicine that has similar physical, biological, and immunological characteristics, and similar efficacy and safety as demonstrated by comprehensive comparability studies. However, a biosimilar cannot simply be thought of as a generic medication. Small molecule drugs have relatively simple chemical structures that can be reproduced identically. In contrast, biological medicines are large molecules with complex structures presented as microheterogeneous mixtures of isoforms. These medicines are produced in genetically engineered cell lines which are inherently variable. Some variation in biological medicines, including between batches of the same brand, is therefore inevitable. However, these variations must be minor and relate to clinically inactive elements of the drug in order to be considered a biosimilar.
The range of accepted variability for a biosimilar is the same as what is allowed between batches of the originator. The TGA addresses the issue of variability by placing all newly registered biological medicines, including biosimilars, on a batch release program. Samples from each batch must be submitted to the TGA until batch consistency is demonstrated. Changes in manufacturing processes, such as upscaling production or changing the production site, can also produce variations in a biological medicine and may require additional studies.
The TGA draws on international experience and has adopted guidelines developed by the European Medicines Agency (EMA) for the approval of biosimilar medicines. The EMA has pioneered the regulation of biosimilars since issuing its first approval for a biosimilar in 2006. In the ensuing ten years, a further 27 biosimilars have been approved. The evidence acquired over this time demonstrates that biosimilars can be used as safely and effectively as the originator medicine. An information guide recently released by the EMA notes that monitoring systems have not identified any relevant differences in the nature, severity, or frequency of adverse effects between biosimilars and the originator medicines.
Infliximab is a biological medicine available in Australia under the brand name, Remicade®. Following expiration of the Remicade® patent, Inflectra® became the first biosimilar monoclonal antibody to be registered in Australia in 2015. Appraisal of clinical trial data by the Pharmaceutical Benefits Advisory Committee (PBAC) led to Inflectra® receiving ‘a’ flag designation with Remicade®. An ‘a’ flag indicates that different pharmaceutical benefit items are equivalent and can be interchanged without differences in clinical effect. However, switching patients who are stable on the originator brand of a biological medicine has remained a somewhat controversial issue.
Infliximab is a monoclonal antibody that binds to human tumour necrosis factor alpha (TNFα). TNFα is a proinflammatory and immunoregulatory cytokine important in the pathogenesis of many chronic inflammatory conditions. Infliximab neutralises the biological effects of TNFα by preventing interaction with its receptors. Infliximab is approved for use in the following indications:
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriatic arthritis, psoriasis
- Crohn’s disease
- Refractory fistulising Crohn’s disease, and
- Ulcerative colitis.
While the approved indications for Inflectra® are the same as Remicade®, pivotal trials used to support the listing of Inflectra® were conducted in ankylosing spondylitis and rheumatoid arthritis only. Extrapolation of clinical efficacy is well-established in the evaluation of biological medicines. This scientific principle has been utilised with originator medicines to avoid unnecessary repetition of clinical trials following manufacturing and formulation changes. In the context of biosimilars, extrapolation may be considered when the biosimilar exhibits a high degree of similarity in terms of structure, biological activity and efficacy, safety, and immunogenicity. Comparable safety and efficacy in one indication may then be extrapolated to other indications already approved for the originator medicine. However, safety and efficacy in subpopulations is important, particularly for medications that have more than one active site or interact with many receptors. The decision to extrapolate clinical indications must, therefore, be scientifically justified and take into account the overall clinical experience and available literature data.
The recently published NOR-SWITCH study adds to the available infliximab data by including patients from all six approved indications. This randomised, non-inferiority, double-blind study investigates the safety, efficacy, and immunogenicity of switching patients stabilised on Remicade® to the biosimilar CT-P13, registered as Inflectra® in Australia. The primary endpoint was disease worsening across the different disease groups with a non-inferiority margin of 15%.
The results of the NOR-SWITCH study demonstrate that a single switch from infliximab originator to the biosimilar is not inferior to continuing treatment with the originator. Disease worsening was noted to occur in 26% of patients in the originator group compared to 30% of the biosimilar group. Remission rates were identical in each group at 61%, and immunogenicity was also similar. Of the patients tested for the presence of anti-drug antibodies, positive results were discovered in 7% of the originator group compared to 8% of the biosimilar group.
While the NOR-SWITCH study provides valuable data on the safety and efficacy of biosimilar infliximab, it has some limitations. Although non-inferiority was demonstrated across the six diagnostic groups, the study was not sufficiently powered to demonstrate non-inferiority within each group. Exploratory analyses suggest non-inferiority of the biosimilar for the treatment of spondyloarthritis, while the confidence interval for Crohn’s disease approached inferiority. The study also only examines the effects of a single switch from the originator to biosimilar infliximab. There is currently insufficient evidence to support multiple switches between infliximab brands.
The positive results of this study add to the growing evidence to support the safety and efficacy of biosimilar infliximab. The Australian Government supports the appropriate use of biosimilars as a means of increasing competition and, therefore, affordability. Financial analyses project potential savings of up to $880 million between 2015 and 2020 from a greater uptake of biosimilars. This forms an important part of pharmaceutical reforms designed to improve the long-term sustainability of the PBS. The Biosimilar Awareness Initiative, published by the Department of Health, can be consulted for further information on the appropriate use of biosimilars.
- Department of Health. Biosimilar Awareness Initiative: Project Management Plan. Canberra: Australian Government; 2016.
- European Medicines Agency and the European Commission. Biosimilars in the EU: Information guide for healthcare professionals. London: EMA; 2017.
- Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. The Lancet 2017.
- Mabbott V, Storey P. Australian Statistics on Medicines 2015. Canberra: Commonwealth of Australia, 2016.
- Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013; 72(10): 1605-12.
- Remicade® (infliximab) Australian approved product information. Macquarie Park: Janssen Cilag. Approved 2017.
- Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk S, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013; 72(10): 1613-20.