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. 2023 Jul 19;15(14):3680. doi: 10.3390/cancers15143680

Comparative Safety Profiles of Oncology Biosimilars vs. Originators in Europe: An Analysis of the EudraVigilance Database

Victoria Nikitina 1, Greta Santi Laurini 1, Nicola Montanaro 2, Domenico Motola 1,*
Editor: Thomas Mürdter
PMCID: PMC10377930  PMID: 37509341

Abstract

Simple Summary

Nowadays, biosimilar drugs are numerous and widely used in many clinical fields, including oncology. However, skepticism remains towards these products among doctors and patients, particularly regarding their safety profile compared to the reference products. This prompted this comparative pharmacovigilance study using real-world clinical data. Consistent with the expected similarity in safety, our results reaffirm that biosimilars are comparable to the reference products in the real-world setting. This should further reassure and encourage their even greater use which, on the one hand, allows for all patients to be treated with the best available treatments and, on the other, frees up healthcare resources for innovative and more expensive drugs.

Abstract

In the last decades, the clinical management of oncology patients has been transformed by the introduction of biologics. The high costs associated with the development and production of biologics limit patient access to these therapies. The expiration of exclusive patents for biologics has led to the development and market introduction of biosimilars, offering the reduction of costs for cancer treatments. Biosimilars are highly similar to the reference products in terms of structure, biological activity, efficacy, safety, and immunogenicity. Therefore, the monitoring of biosimilars’ safety in real-world clinical practice though pharmacovigilance is essential. This study aimed to analyze the post-marketing pharmacovigilance data of biosimilar monoclonal antibodies used in oncology and compare them with respective reference products. Data of a 2-year period (1 January 2021–31 December 2022) were retrieved from EudraVigilance, and descriptive and comparative analysis were performed using the Reporting Odds Ratio to evaluate the distribution of medicine-reaction pairs related to biosimilars of three antitumor biological products and their corresponding reference products: bevacizumab, rituximab, and trastuzumab. The results showed that most frequently reported ADRs for biosimilars were non-serious and consistent with the safety profiles of reference products. These findings provide reassurance regarding safety equivalence of biosimilars and support their use as valid alternatives to originator biologics.

Keywords: bevacizumab, biosimilars, monoclonal antibodies, oncologic biosimilars, oncology, pharmacovigilance, rituximab, trastuzumab

1. Introduction

In the last decades, the clinical management of oncologic patients has undergone substantial changes due to the introduction of biologic medicines, which may contribute to a positive clinical outcome. Since biologics presents a complex structure and are produced in living system under strictly controlled conditions, their development and manufacture require very high costs, and consequently, these high prices are hardly affordable by the health service structures. Following the expiry of the exclusive patents for these biologic medicines, several biopharmaceutical industries have developed and introduced into the market similar biologic products, named biosimilars, allowing for a significant price lowering with a cut costs for cancer treatments.

Biosimilar is defined by the European Medicines Agency (EMA) as “a biological medicine highly similar to another already approved biological medicine (the ‘reference medicine’). Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines” [1]. Other definitions of biosimilars according to major international regulatory organizations are reported in Table 1. The EMA also specifies that biosimilar agents are highly similar to the reference product in terms of structure, biological activity and efficacy, safety, and immunogenicity profile [1]. EMA like other regulatory agencies has delineated specific comparability pathways to ascertain the similarity between a biosimilar candidate and its reference product (RP) [2,3,4]. Biosimilars differ from the generic form of the chemical products, because in this case it is not possible to develop molecules identical to their reference products due to biologic natural variation and their heterogenic product process [5]. Therefore, it is fundamental that the safety profiles of biosimilars are similar to those of the original biologics. Rituximab, bevacizumab, and trastuzumab are monoclonal antibodies (mAbs) used in first- and second-line treatment regimens in combination with other anti-cancer therapies for a number of common malignant diseases [6,7,8]. A growing number of biosimilar versions of these agents are available on the market, and many others are in development. In these circumstances, as with any medication, the evaluation of the adverse drug reaction (ADR) profiles of biologics and biosimilars through post-marketing surveillance is essential.

Table 1.

Definition of biosimilars according to international regulatory organizations.

Regulatory Authority Definition Reference
The European Medicines Agency (EMA) A biosimilar is a biological medicine highly similar to another already approved biological medicine (the “reference medicine”). Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines. The European Medicines Agency. Biosimilar Medicines: overview [1]
Food and Drug Administration (FDA) A biosimilar is a biologic medication that is highly similar to and has no clinically meaningful differences from an existing FDA-approved biologic, called a reference product. Food and Drug Administration. Biosimilars [9]
The World Health Organization (WHO) A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product. The World Health Organization. Biosimilars [10]

The aim of this study was to analyze the post-marketing pharmacovigilance data of biosimilar mAbs used in oncology and compare their safety information with the respective reference products.

2. Materials and Methods

Data were retrieved from the European Union’s post-marketing surveillance database EudraVigilance (EV), using the online interface adrreports.eu [11]. EV is a public spontaneous reporting system maintained by the European Medicines Agency on behalf of the European Union (EU), which receives Individual Case Safety Reports (ICSRs) of suspected adverse drug reactions within the European Economic Area (EEA) [12].

We retrieved all reports related to biosimilars of three antitumor biological products reported as suspected drugs bevacizumab, rituximab, and trastuzumab, and we compared their safety profile to the corresponding reference products (Avastin®, MabThera®, and Herceptin®, respectively). We considered the EU-licenced biosimilars which have been authorized before the year 2021: three different biosimilar bevacizumabs (Aybintio®, Mvasi®, Zirabev®), five biosimilar rituximabs (Blitzima®, Rixathon®, Riximyo®, Ruxience®, Truxima®), and six biosimilar trastuzumabs (Herzuma®, Kanjinti®, Ogivri®, Ontruzant®, Trazimera®, Zercepac®). Table 2 lists these medicine products with their respective dates of approval and the patent expiry dates for the corresponding reference products.

Table 2.

Bevacizumab, rituximab, and trastuzumab: reference products and biosimilar agents approved in the European Union considered in our study.

Reference Product Authorization Date Patent Expiry Date Biosimilar Agent Approval Date
Bevacizumab Avastin ® 2005 2022 Aybintio ® 19 August 2020
Mvasi ® 15 January 2018
Zirabev ® 14 February 2019
Rituximab MabThera ® 1998 2013 Blitzima ® 13 July 2017
Rixathon ® 15 June 2017
Riximyo ® 15 June 2017
Ruxience ® 1 April 2020
Truxima ® 17 February 2017
Trastuzumab Herceptin ® 2000 2014 Herzuma ® 8 February 2018
Kanjinti ® 16 May 2018
Ogivri ® 12 December 2018
Ontruzant ® 15 November 2017
Trazimera ® 26 July 2018
Zercepac ® 27 July 2020

We performed our retrospective analysis on biosimilars, which have more time on the market, and take into account that two of them received a marketing authorization valid throughout the European Union in 2020 (Ruxience® on 1 April 2020 and Aybintio® on 19 August 2020); we considered the 2-year period between 1 January 2021 and 31 December 2022 in order to analyze and compare as many biosimilars as possible over an equal period of time.

2.1. Descriptive Analysis

The extracted reports were identified by a unique EU Local Number, reporting information on the report type (spontaneous or from clinical studies), primary source qualification (healthcare professional or non-healthcare professional), EV gateway receipt date, patient sex and age group, MedDRA preferred terms (PT), seriousness criteria, and suspect and concomitant drugs. All ADRs are categorized using the Medical Dictionary for Regulatory Activities (MedDRA), a specific standardized medical terminology to facilitate sharing of regulatory information internationally for medical products used by humans. MedDRA terms are arranged in a five-tiered multi-axial hierarchy, which provides increasing specificity as one descends it [13]. At the top-level of hierarchy there are 27 System Organ Classes (SOC), which incorporate at the lower levels High Level Group Terms (HLGTs) and High Level Terms (HLTs). Each member of the next level, Preferred Terms (PTs), is a distinct descriptor (single medical concept) for a symptom, sign, disease diagnosis, therapeutic indication, investigation, surgical or medical procedure, and medical social or family history characteristic. Finally, one or more Lower Level Terms (LLTs) correspond to each PT; the LLTs are effectively entry terms that include synonyms and lexical variants [14,15,16]. One or more symptoms can be reported for each EV report. We analyzed all the reports related to the reference drugs and their biosimilars included in this study performing a descriptive analysis. For each drug, the notoriety of the adverse reactions was ascertained by checking if the most frequently reported ADRs were listed in the corresponding Summary of the Product Characteristics (SPCs) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33].

2.2. Statistical Analysis

We performed comparative analysis using the Reporting Odds Ratio (ROR) with 95% confidence interval as statistical parameter to evaluate medicine-reaction pairs distribution. ROR allows for a quantitative approach using 2 × 2 contingency tables, comparing the frequency of a drug-reaction pair with all the others in the database. An increased frequency for the drug-reaction pair can be assumed if ROR is >1. The biosimilars and their respective original products were analyzed separately. A disproportionality analysis was carried out between the ADRs associated to biosimilars and each respective reference product. The EMA provides guidance on signal detection and management in pharmacovigilance to define a signal of disproportionate reporting in the EV system, and these criteria were used in this present study. The following criteria were applied: the lower bound of the 95% confidence interval greater than one; the number of individual cases greater than or equal to three for active substances contained in medicinal products included in the additional monitoring list in accordance with REG Art 23 (see GVP Module X), unless the sole reason for inclusion on the list is the request of a post-authorization safety study (PASS); five for the other active substances; and the event belongs to the Important Medical Event list [34]. (https://www.ema.europa.eu/en/documents/other/screening-adverse-reactions-eudravigilance_en.pdf. Accessed on 31 March 2023)

3. Results

3.1. Descriptive Analysis

Figure 1 describes the number of reports for bevacizumab, trastuzumab, and rituximab biologics and their respective biosimilars. Table 3, Table 4 and Table 5 summarize the characteristics of each report by patients’ sex (female, male, and unknown), age range (0–17 years, 18–64 years, 65–85 years, over 85 years, and unknown), and type of reporter (healthcare professional, and non-healthcare professional) for all medicine products in study. A total of 13,306 reports were collected for these products: 9806 reports (74%) referred to the original products and 3500 (26%) to biosimilars.

Figure 1.

Figure 1

Number of reports for bevacizumab, rituximab, and trastuzumab biologics in 2021 and 2022 divided between the originators and the respective biosimilars, expressed in percentages. Yellow for Avastin®, green for MabThera®, and blue for Herceptin®.

Table 3.

Demographic characteristics and reporter type for reports of rituximabs.

Characteristics Rituximab
Originator Biologic
MabThera®
(n = 1657)
Biosimilar
Blitzima ®
(n = 7)
Rixathon®
(n = 422)
Riximyo®
(n = 39)
Ruxience ®
(n = 1024)
Truxima ®
(n = 830)
Sex Female 872 (52.6) 1 (14.2) 237 (56.2) 28 (71.8) 683 (66.7) 189 (22.8)
Male 753 (45.4) 3 (42.8) 169 (40) 11 (28.2) 336 (32.8) 134 (16.1)
Unknown 32 (2) 3 (42.8) 16 (3.8) 0 (0) 5 (0.5) 507 (61.1)
Age (years) 0–17 47 (2.8) 0 (0) 17 (4) 0 (0) 3 (0.3) 20 (2.4)
18–64 768 (46.4) 3 (42.8) 203 (48.1) 19 (48.7) 542 (52.9) 222 (26.8)
65–85 568 (34.3) 1 (14.2) 144 (34.1) 9 (23.1) 444 (43.3) 107 (12.9)
>85 22 (1.3) 0 (0) 11 (2.6) 1 (2.6) 21 (2.1) 6 (0.7)
Unknown 252 (15.2) 3 (42.8) 47 (11.1) 10 (25.6) 14 (1.4) 475 (57.2)
Reporter type Healthcare Professional 1511 (91.2) 7 (100) 407 (96.4) 38 (97.4) 980 (95.7) 783 (94.3)
Non Healthcare Professional 146 (8.8) 0 (0) 15 (3.6) 1 (2.6) 44 (4.3) 47 (5.7)

Table 4.

Demographic characteristics and reporter type for reports of bevacizumabs.

Characteristics Bevacizumab
Originator Biologic
Avastin ® (n = 5100)
Biosimilar
Aybintio®
(n = 15)
Mvasi ®
(n = 403)
Zirabev®
(n = 138)
Sex Female 2088 (40.9) 9 (60) 223 (55.3) 66 (47.8)
Male 2609 (51.2) 6 (40) 167 (41.4) 69 (50)
Unknown 403 (7.9) 0 (0) 13 (3.2) 3 (2.2)
Age (years) 0–17 27 (0.5) 0 (0) 0 (0) 1 (0.7)
18–64 1451 (28.5) 7 (46.7) 180 (44.7) 85 (61.6)
65–85 2343 (45.9) 8 (53.3) 162 (40.2) 42 (30.4)
>85 264 (5.2) 0 (0) 4 (1) 3 (2.2)
Unknown 1015 (19.9) 0(0) 57 (14.1) 7 (5.1)
Reporter type Healthcare Professional 4573 (89.7) 15 (100) 386 (95.8) 125 (90.6)
Non Healthcare Professional 527 (10.3) 0 (0) 17 (4.2) 13 (9.4)

Table 5.

Demographic characteristics and reporter type for reports of trastuzumabs.

Characteristics Trastuzumab
Originator Biologic
Herceptin®
(n = 3049)
Biosimilar
Herzuma ®
(n = 198)
Kanjinti ®
(n = 93)
Ogivri ®
(n = 38)
Ontruzant ®
(n = 232)
Trazimera ®
(n = 59)
Zercepac ®
(n = 2)
Sex Female 2778 (91.1) 171 (86.4) 92 (99) 36 (94.7) 227 (97.8) 53 (89.8) 2 (100)
Male 184 (6) 3 (1.5) 0 (0) 2 (5.3) 5 (2.2) 5 (8.5) 0 (0)
Unknown 87 (2.9) 24 (12.1) 1 (1) 0 (0) 0 (0) 1 (1.7) 0 (0)
Age (years) 0–17 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
18–64 1815 (59.5) 127 (64.1) 45 (48.4) 15 (39.5) 148 (63.8) 32 (54.2) 2 (100)
65–85 542 (17.8) 35 (17.7) 18 (19.4) 11 (28.9) 77 (33.2) 23 (39) 0 (0)
>85 30 (1) 4 (2) 2 (2.2) 0 (0) 0 (0) 0 (0) 0 (0)
Unknown 661 (21.7) 32 (16.2) 28 (30) 12 (31.6) 7 (3) 4 (6.8) 0 (0)
Reporter type Healthcare Professional 2655 (87.1) 195 (98.5) 84 (90.3) 36 (94.7) 229 (98.7) 52 (88.1) 2 (100)
Non Healthcare Professional 394 (12.9) 3 (1.5) 9 (9.7) 2 (5.3) 3 (1.3) 7 (11.9) 0 (0)

We analyzed a total of 36,200 reported PTs; 23,592 (65%) PTs were identified from reports for original products and 12,608 (35%) PTs for biosimilars. The proportions of reports from females were higher than from males for both categories: 58.5% vs. 36.2% for original products, and 57.6% vs. 26% for biosimilars. However, in 16.4% reports for the biosimilars, the information on sex was missing. Most of the reports referred to patients aged 18–64 years and a slightly lower percentage to those of the age group 65–85 years. Roughly 20% of the reports concerning originator biologics and biosimilars were missing information about patients’ age. Approximately 90% of reports were submitted by healthcare professionals.

3.2. Statistical Analysis

For the disproportionality analysis, all 13,306 safety reports had been examined, corresponding to 36,200 drug-reaction pairs. Reported ADRs referring to incorrect product storage, routine laboratory tests or incorrect administration, were not considered because they were not pertinent to our investigation. Overall, almost all of the most frequently reported and statistically significant ADRs for biosimilars were non-serious and listed in the corresponding SPCs. Bevacizumab biosimilars vs. Avastin®: asthenia n = 32 reactions, ROR 2.63 [CI 95% 1.81–3.82], neuropathy peripheral n = 29, ROR 2.44 [CI 95% 1.65–3.61], abdominal pain n = 28 ROR 3.92 [CI 95% 2.58–5.94]. Rituximab biosimilars vs. MabThera®: COVID-19 n = 169 reactions, ROR 1.73 [CI 95% 1.42–2.09], pruritus n = 163, ROR 1.96 [CI 95% 1.6–2.41], throat irritation n = 135 ROR 4.9 [CI 95% 3.55–6.74]. Trastuzumab biosimilars vs. Herceptin®: diarrhea n = 78 reactions, ROR 1.55 [CI 95% 1.23–1.95], chills n = 68, ROR 2.07 [CI 95% 1.61–2.66], nausea n = 57 ROR 1.6 [CI 95% 1.22–2.1]. Table 6, Table 7 and Table 8 show the most frequently reported and statistically significant ADRs for biosimilars compared to their original products by number of ADRs. Among these drug-reaction pairs we identified (on the basis of the Important Medical Event terms list [34]), serious reactions are listed below. Bevacizumab biosimilars vs. Avastin ®: neuropathy peripheral n = 29 reactions, ROR 2.44 [CI 95% 1.65–3.61], neutropenia n = 24 reactions, ROR 1.75 [CI 95% 1.14–2.67], thrombocytopenia n = 18 ROR 2 [CI 95% 1.22–3.3], seizure n = 13 ROR 4.42 [CI 95% 2.3–8.5]. Rituximab biosimilars vs. MabThera ®: rheumatoid arthritis n = 69 reactions, ROR 4.62 [CI 95% 2.76–7.74], immune thrombocytopenia n = 59 reactions, ROR 9.22 [CI 95% 3.71–22.88], mantle cell lymphoma n = 34 ROR 15.9 [CI 95% 1.6–158.05], systemic lupus erythematosus n = 34 ROR 7.95 [CI 95% 2.13–29.65]. Trastuzumab biosimilars vs. Herceptin ®: neutropenia n = 32 reactions, ROR 3.29 [CI 95% 2.23–4.87], thrombocytopenia n = 16 ROR 2.59 [CI 95% 1.48–4.53], hypokalaemia n = 7 reactions, ROR 2.52 [CI 95% 1.03–6.16]. Furthermore, we analyzed the drug-reaction pairs with a higher and statistically significant ROR, which are listed as follows. Bevacizumab biosimilars vs. Avastin®: weight increased n = 14 reactions, ROR 8.58 [CI 95% 4.17–17.65], general physical deterioration n = 12 reactions, ROR 8.16 [CI 95% 3.72–17.9], chills n = 12 ROR 5.65 [CI 95% 2.76–11.58]. Rituximab biosimilars vs. MabThera®: blood pressure fluctuation n = 116 reactions, ROR 27.36 [CI 95% 8.55–87.51], heart rate irregular n = 48 reactions, ROR 22.48 [CI 95% 2.38–211.89], ear pruritus n = 39 ROR 18.24 [CI 95% 1.88–177.4]. Trastuzumab biosimilars vs. Herceptin®: hypertransaminasaemia n = 8 reactions, ROR 18.77 [CI 95% 3.52–100.17], bronchospasm n = 4 ROR 9.36 [CI 95% 1.32–66.58], paraesthesia n = 34, ROR 7.35 [CI 95% 4.8–11.26].

Table 6.

The most frequent and statistically significant ADRs related to Rituximab biosimilars compared to MabThera® reported in EudraVigilance.

Rituximab.
ADR N N* ROR CI 95%_Lower CI 95%_Upper
COVID-19 169 46 1.73 1.42 2.09
Pruritus 163 39 1.96 1.6 2.41
Throat irritation 135 13 4.9 3.55 6.74
Blood pressure fluctuation 116 2 27.36 8.55 87.51
Malaise 112 8 6.59 4.28 10.14
Nausea 112 38 1.38 1.09 1.75
Condition aggravated 108 5 10.17 5.69 18.19
Fatigue 106 21 2.37 1.78 3.15
Headache 105 19 2.59 1.93 3.48
Hypertension 102 32 1.49 1.15 1.93
Blood pressure increased 93 32 1.36 1.04 1.77
Pain 93 7 6.24 3.85 10.13
Erythema 88 21 1.96 1.45 2.66
Cough 78 17 2.15 1.53 3.01
Arthralgia 77 8 4.51 2.82 7.22
Rheumatoid arthritis 69 7 4.62 2.76 7.74
Urticaria 63 14 2.1 1.43 3.1
Immune thrombocytopenia 59 3 9.22 3.71 22.88
Weight increased 50 6 3.9 2.13 7.14
Heart rate irregular 48 1 22.48 2.38 211.89
Throat tightness 46 6 3.59 1.94 6.64
Pain in extremity 40 6 3.12 1.65 5.89
Ear pruritus 39 1 18.24 1.88 177.4
Illness 38 3 5.92 2.24 15.65
Weight decreased 36 5 3.36 1.64 6.91
Heart rate decreased 35 2 8.18 2.2 30.38
Mantle cell lymphoma 34 1 15.9 1.6 158.05
Systemic lupus erythematosus 34 2 7.95 2.13 29.65
Chest pain 33 1 15.43 1.54 154.16
Anxiety 32 3 4.98 1.83 13.55
Joint swelling 31 3 4.83 1.77 13.2
Blood pressure systolic increased 29 1 13.55 1.33 138.53
Musculoskeletal stiffness 28 3 4.36 1.56 12.14
Therapeutic product effect incomplete 27 1 12.61 1.22 130.67
Blood pressure decreased 26 5 2.43 1.12 5.28
Fall 26 4 3.03 1.26 7.28
Paraesthesia 26 2 6.07 1.55 23.77
C-reactive protein increased 25 5 2.33 1.06 5.11
Peripheral swelling 24 4 2.8 1.15 6.82
Somnolence 24 3 3.73 1.3 10.72
Feeling hot 21 3 3.27 1.11 9.64
Abdominal discomfort 19 2 4.43 1.06 18.53

ADR adverse drug reaction, N number of suspected ADRs to biosimilars, N* number of suspected ADRs to MabThera® ROR reporting odds ratio, CI 95%_lower lower limit of the 95% confidence interval, CI 95%_upper upper limit of the 95% confidence interval.

Table 7.

The most frequent and statistically significant ADRs related to Bevacizumab biosimilars compared to Avastin® reported in EudraVigilance.

Bevacizumab
ADR N N* ROR CI 95%_Lower CI 95%_Upper
Asthenia 32 75 2.63 1.81 3.82
Neuropathy peripheral 29 73 2.44 1.65 3.61
Abdominal pain 28 44 3.92 2.58 5.94
Blood pressure increased 28 65 2.65 1.77 3.96
Fatigue 25 92 1.66 1.1 2.52
Neutropenia 24 84 1.75 1.14 2.67
Vomiting 24 86 1.71 1.12 2.61
Constipation 19 41 2.84 1.72 4.68
Drug ineffective 19 66 1.76 1.09 2.85
Headache 19 54 2.15 1.32 3.51
Dizziness 18 27 4.09 2.39 6.99
Thrombocytopenia 18 55 2 1.22 3.3
Dyspnoea 14 40 2.14 1.21 3.8
Weight decreased 14 39 2.19 1.23 3.9
Weight increased 14 10 8.58 4.17 17.65
Epistaxis 13 42 1.89 1.05 3.42
Seizure 13 18 4.42 2.3 8.5
Chills 12 13 5.65 2.76 11.58
Cough 12 24 3.06 1.6 5.85
General physical health deterioration 12 9 8.16 3.72 17.9

ADR adverse drug reaction, N number of suspected ADRs to biosimilars, N* number of suspected ADRs to Avastin® ROR reporting odds ratio, CI 95%_lower lower limit of the 95% confidence interval, CI 95%_upper upper limit of the 95% confidence interval.

Table 8.

The most frequent and statistically significant ADRs related to Trastuzumab biosimilars compared to Herceptin® reported in EudraVigilance.

Trastuzumab
ADR N N* ROR CI 95%_Lower CI 95%_Upper
Diarrhea 78 239 1.55 1.23 1.95
Chills 68 157 2.07 1.61 2.66
Nausea 57 169 1.6 1.22 2.1
Asthenia 38 96 1.87 1.33 2.63
Infusion related reaction 38 54 3.34 2.34 4.77
Paraesthesia 34 22 7.35 4.8 11.26
Dyspnoea 32 66 2.29 1.57 3.34
Neutropenia 32 46 3.29 2.23 4.87
Anaemia 30 58 2.44 1.65 3.62
Tremor 28 26 5.1 3.26 7.98
Arthralgia 21 31 3.19 1.95 5.22
Hypersensitivity 19 36 2.48 1.5 4.12
Pruritus 19 48 1.86 1.14 3.04
Erythema 18 21 4.04 2.31 7.04
Hypertension 18 36 2.35 1.4 3.95
Myalgia 18 19 4.46 2.53 7.87
Back pain 17 28 2.86 1.65 4.93
Thrombocytopenia 16 29 2.59 1.48 4.53
Abdominal pain 12 27 2.08 1.1 3.95
Epistaxis 12 20 2.82 1.45 5.48
Oxygen saturation decreased 12 14 4.03 1.99 8.17
Tachycardia 11 15 3.44 1.67 7.09
Hypotension 9 9 4.69 1.96 11.23
Rhinorrhoea 9 7 6.03 2.37 15.37
Hypertransaminasaemia 8 2 18.77 3.52 100.17
Drug hypersensitivity 7 6 5.47 1.88 15.93
Feeling cold 7 8 4.1 1.53 11.01
Hypokalaemia 7 13 2.52 1.03 6.16
Syncope 7 6 5.47 1.88 15.93
Blood creatinine increased 6 7 4.02 1.36 11.84
Bronchospasm 4 2 9.36 1.32 66.58
Gamma-glutamyltransferase increased 4 4 4.68 1.07 20.39

ADR adverse drug reaction, N number of suspected ADRs to biosimilars, N* number of suspected ADRs to Herceptin® ROR reporting odds ratio, CI 95%_lower lower limit of the 95% confidence interval, CI 95%_upper upper limit of the 95% confidence interval.

4. Discussion

Biosimilars require the submission of a Risk Management Plan, including further safety study, for their approval to be granted. Their safety profile is also monitored through pharmacovigilance activities once they are on the market, in the same way as the other medicines [1,3]. The spontaneous reporting system remains a cornerstone of pharmacovigilance since it allows the early detection of possible safety signals and the continuous monitoring and evaluation of potential safety issues in relation to reported ADRs [35]. In particular, it is crucial to identify rare or long-term ADRs that may not have been captured during the limited duration and controlled settings of premarketing clinical trials [36,37,38]. Spontaneous reporting system represents an important tool for identifying previously unknown ADRs and emerging safety issues since the data are collected from a wide range of healthcare providers, including physicians, pharmacists, and also patients. Moreover, post marketing data encompass a broader patient population compared to those involved in strictly controlled clinical trials settings, including, for instance, those with co-morbidities, concomitant medications, and vulnerable groups. This allows the system to reflect data on general population, real-world clinical practice, and patient experiences. However, pharmacovigilance studies such as this present one, based on spontaneous reporting system, have some limitations. First, the lack of denominator data, such as the number of patients exposed to a particular drug, does not allow for the accurate calculation of incidence rates, or determining the true risk associated with the use of a specific medication. Secondly, the information contained in the reports may be incomplete and inaccurate, may lack essential details, have inconsistencies, or be subjected to data entry errors. The quality and completeness of the reported data can affect the reliability and validity of the data. In addition, the lack of comprehensive information on the patient’s medical history, the usage of concomitant medications, and other relevant factors make it difficult to assess a causal relationship between the medication and reported ADR. Finally, and above all, the system is affected by the drawback of underreporting, owing to various factors such as lack of awareness, uncertainty about causality, lack of time or perception that reporting is burdensome [39,40,41,42]. This last limitation can affect the validity and accuracy of ROR estimates since its calculations are based on the assumption that the reporting rate is constant across all medications and ADRs. Furthermore, Reporting Odds Ratio does not intend to establish a causality relation between a drug and a given adverse reaction but simply to detect a safety signal. To overcome these limitations, it is crucial to integrate ROR with other pharmacovigilance methods, such as signal detection algorithms, disproportionality analyses, and additional observational or experimental studies. These complementary approaches can provide a more comprehensive understanding of the safety profile of a drug and minimize the impact of limitations.

This study provided post-marketing pharmacovigilance evidence in ADR reporting of originator biologics and corresponding biosimilars marketed in the EU, focusing on reported ADRs and the detection of disproportionality. Overall, during the study period the number of reports in EV for reference products has slightly increased in 2022 compared to the previous year, meanwhile, the number of reports for biosimilars has noticeably raised. This trend is evident for biosimilars of rituximab, most of reports referred to Ruxience® and Truxima®, even though the number of reports for the reference product MabThera® was a bit lower in 2022. The increasing number of reports for biosimilars in EV may reflect the significant increase in biosimilar usage in the EU in response to incentive programs instituted by individual member states, health authorities, and payers over the last few years [43,44]. In this contest, it is important to mention that the EU is leading the way with regard to the approvals, utilization, and realization of cost savings of biosimilars [45,46].

Almost all of the most frequently reported ADRs for analyzed biologics were non-serious, listed in the corresponding SPCs and in line with the studies by Giezen et al. [47,48,49]; thus, the adverse reactions to biologics that are included in their safety profiles are mostly related to their pharmacologic actions and immunologic reactions, e.g., immunogenicity and injection site reactions. Among serious, not listed in SPCs, and statistically significant ADRs, we focused on three adverse reactions of rituximab biosimilars: rheumatoid arthritis, mantle cell lymphoma, and systemic lupus erythematosus. Specifically, the signal of disproportionate reporting for rheumatoid arthritis referred to Ruxience® and Truxima®, while mantle cell lymphoma and systemic lupus erythematosus only to Truxima®. We observed that in almost all reports that had those three ADRs, Ruxience®, and Truxima® were used for rheumatoid arthritis, while Truxima® for mantle cell lymphoma and systemic lupus erythematosus. In particular, Truxima® was used off-label for the last two indications. These three reported ADRs lead to different interpretations. It can be argued that it is simply a writing mistake of the reporters, with rheumatoid arthritis, mantle cell lymphoma, and systemic lupus erythematosus being the target disease for the molecules in study rather than an adverse reaction. From another side, it cannot be excluded that the mention of the target disease in the field of adverse reactions may be understood as a statement of the disease progression due to therapeutic ineffectiveness. The high number of these PTs and their statistically significant ROR in our data makes this second interpretation preferable. These may be investigated by future pharmacoepidemiology studies. However, it is essential to acknowledge that ADR reporting can be influenced by several factors, such as drug usage patterns, and the underreporting is an important limit of spontaneous reporting databases like EV.

The results of this study show an overall comparability in safety profiles between the biosimilars and original biologics. Our findings are also in line with those of Kurki et al. [50], who investigated data on post-marketing safety of biosimilar mAbs up to 7 years post-approval, and observed no significant differences between the safety profiles of biosimilars and their reference products, no new or unexpected adverse reactions and no differences in the ADRs’ severity. The evidence acquired over 10 years of clinical experience shows that biosimilars approved through EMA can be used as safely and effectively in all their approved indications as other biological medicines [1]. Biosimilars have the potential to create a more sustainable healthcare system since the number of biosimilars in development in oncology is rising, especially biosimilars of bevacizumab, rituximab, and trastuzumab [51]. Copies of original biologics and biosimilars have lowered the costs and increased access to biologicals throughout the EU. Savings from the impact of biosimilar competition continues to grow: as of 2022, the cumulative savings at list prices from the impact of biosimilar competition in Europe reached over EUR 30 billion [52]. Therefore, biosimilars are key in significant economic savings of healthcare systems, allowing more patients to access modern therapies while offering comparable safety and efficacy profiles.

5. Conclusions

Biological therapies are a cost-effective alternative that have revolutionized the treatment of oncologic diseases. Based on the analysis of ADR reports from EudraVigilance, there were no significant differences in the safety profiles between bevacizumab, trastuzumab, and rituximab biosimilars and their respective originators in Europe. These findings provide reassurance regarding the safety equivalence of biosimilars and support their use as viable alternatives to originator biologics. As with any medication, constant pharmacovigilance monitoring is essential to ensure the ongoing safety of these products.

Abbreviations

ADR Adverse Drug Reaction
EEA European Economic Area
EMA European Medicines Agency
EU European Union
EV EudraVigilance
FDA United States Food and Drug Administration agency
mAb monoclonal antibody
MedDRA Medical Dictionary for Regulatory Activities
PT Preferred term
RP reference product
ROR Reporting Odds Ratio
SPC Summary of the Product Characteristic

Author Contributions

Substantial contributions to conception or design of the work (D.M., V.N., G.S.L. and N.M.), or the acquisition (V.N.), analysis (V.N. and D.M.) or interpretation of data for the work (V.N., G.S.L., D.M. and N.M.). Drafting of the work (V.N. and D.M.) or revising it critically for important intellectual content (N.M. and G.S.L.). All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors report no conflict of interest.

Funding Statement

This research received no external funding.

Footnotes

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References

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.


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