Safety surveillance of bevacizumab biosimilar (Bevax) in Argentina

Benefit-risk evaluations are mandatory throughout the life cycle of a therapeutic agent, to guarantee efficacy for the authorized indications without an unacceptable incidence of adverse effects. This monitoring can be carried out using pharmacovigilance (PhV) procedures, which are vital in the identification and prevention of adverse drug reactions (ADRs). Due to the inherent variability of bioproduction, this is of paramount importance for biological products, including biosimilars.

The original bevacizumab product (Avastin, Roche) was approved in 2004 in the US and in 2005 in Europe as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. It has since been approved for the treatment of other cancers in combination with other chemotherapy agents. The patents on Avastin will expire in the US in July 2019 and in Europe in January 2022. There are estimated to be around 15 biosimilars of bevacizumab at various stages of development [1]. These include Mvasi, produced by Amgen and Allergan, which was approved by the US Food and Drug Administration (FDA) in September 2017 [2] and by the European Commission in January 2018 [3], and Pfizer’s Zirabev, which the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorization in December 2018 [4].

Bevax, a biosimilar of Avastin, was first launched in Argentina in November 2016 following authorization in June 2016. Post-marketing use of Bevax has been monitored through an active PhV programme as part of a risk management plan. This programme is designed to establish its safety profile by assessing the incidence of ADRs. As an initial phase, a Treatment Registry (TR) surveillance database was established to collect data from patients treated with Bevax.

The aim of this descriptive study conducted by Fernández et al. [5] was to summarize and analyse data recorded in the TR database related to the post-marketing use of Bevax, including indications and associated ADRs. Data were collected in Argentina between November 2016 and May 2018. ADRs were coded using preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA, version 21.0) and grouped using the System Organ Classes (SOCs) classifications of MedDRA. ADRs were classified as either ‘serious’ or ‘non-serious’. Serious ADRs generally refer to any medical occurrence that 1) results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization; 2) results in persistent or significant disability/incapacity; or 3) results in a congenital anomaly/birth defect or any other important medical event.

In total, 818 notification forms were registered in the TR database for patients who started treatment with Bevax during the study period, and follow-up information was available for 416 patients. In most patients, Bevax was used for approved indications (n = 805, 98.4%). During the study period, 44 individual case safety reports (ICSRs) were received, 23 of which were considered serious events. These ICSRs were associated with a total of 51 ADRs, 26 of which were considered serious events. The most commonly reported ADRs were related to disease progression (15 occurrences), off-label use (11 occurrences) and hypertension (5 occurrences). Other ADRs with more than one report were sepsis, neutropenia and epistaxis (two occurrences each); all other ADRs were reported as single occurrences without any specific reporting pattern. The most commonly identified SOCs were related to administration site conditions and general disorders (including the ADR of disease progression) in addition to poisoning, injury and procedural complications (including the ADR for off-label use). While SOCs for vascular disorders (including events of hypertension) and skin and subcutaneous tissue disorders were also identified, these occurred at much lower frequencies.

The ADRs identified in this database are generally consistent with those of the reference product Avastin, supporting the clinical use of Bevax for the authorized indications. Reports were generally in agreement with the established safety profile of bevacizumab, and there was no evidence of specific patterns. However, the relatively low number of ICSRs analysed precludes the establishment of a reliable safety profile for Bevax in this context.

The authors highlight the need to further develop and implement effective PhV programmes to increase knowledge of biosimilar safety and to promote their rational use.

Editor’s comment
Readers interested to learn more about the regulation of biosimilars in Latin America are invited to visit www.gabi-journal.net to view the following manuscript published in GaBI Journal:

Recommendations for the regulation of biosimilars and their implementation in Latin America

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References
1. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of bevacizumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 15]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-of-bevacizumab
2. GaBI Online - Generics and Biosimilars Initiative. FDA approves bevacizumab biosimilar Mvasi [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb15]. Available from: www.gabionline.net/Biosimilars/News/FDA-approves-bevacizumab-biosimilar-Mvasi
3. GaBI Online - Generics and Biosimilars Initiative. EC approval for bevacizumab biosimilar Mvasi [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 15]. Available from: www.gabionline.net/Biosimilars/News/EC-approval-for-bevacizumab-biosimilar-Mvasi
4. GaBI Online - Generics and Biosimilars Initiative. EMA approval for bevacizumab biosimilar Zirabev [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 15]]. Available from: www.gabionline.net/Biosimilars/News/EMA-approval-for-bevacizumab-biosimilar-Zirabev
5. Fernández F, Deprati M, Acedo PR, Spitzer E, Romera A, Español N. Implementing a treatment registry for a biosimilar: continuous safety surveillance of the biosimilar Bevax® (bevacizumab) in Argentina. Generics and Biosimilars Initiative Journal (GaBI Journal). 2018;7(3):111-20. doi:10.5639/gabij.2018.0703.023

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