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

Published in: Volume 7 / Year 2018 / Issue 3
Category: Original Research
Page: 111-20
Author(s): , , , , ,
Visits: 992 total, 34 today
Keywords: adverse drug reaction, bevacizumab, biosimilar, monoclonal antibody, pharmacovigilance, safety profile

Introduction and study objectives: Benefit-risk evaluations are essential throughout the life cycle of a drug to guarantee therapeutic efficacy for the authorized indications without an unacceptable incidence of adverse effects. To achieve this, a registry, assessment of adverse drug reactions (ADRs) and other pharmacovigilance (PhV) procedures are mandatory. Due to the inherent variability of bioproduction, this is particularly important for biological medicines, including biosimilars. Bevax®, a biosimilar of the reference product bevacizumab (Avastin®), first launched in Argentina in November 2016 after authorization was granted in June 2016. Since launch, an active PhV programme has registered and assessed the incidence of ADRs related to the post-marketing use of Bevax®. The aim of this descriptive study was to analyse and summarize the data contained in the treatment registry (TR) surveillance database established to monitor the post-marketing use of Bevax®.
Methods: Data (including indications and associated ADRs) related to patients treated with Bevax® recorded in the Argentinian TR database from November 2016 to 28 May 2018 was analysed.
Results: 818 registry forms were collected during the study interval, from which follow-up was available for 416. The product was used for approved indications in most patients (N = 805, 98.4%). A total of 44 individual case safety reports (ICSRs) were received involving 51 ADRs (26 serious). The most frequently reported ADR was related to underlying disease progression (15 events), followed by off-label use (11 events) and hypertension (5 events). Other ADRs with more than one report were neutropenia, sepsis and epistaxis (two events each), whilst the remaining ADRs were reported as single events.
Discussion: Data from the Argentinian TR supports the clinical use of Bevax® for the authorized indications, with any associated ADRs generally being consistent with those of the reference product. There was no evidence of specific patterns and reports were generally in accordance with the known safety profile of bevacizumab. Nevertheless, the relatively low number of ICSRs precludes the establishment of a reliable safety profile for the product in this context.
Conclusion: This may be the first published report summarizing the post-marketing pattern of use and ADRs associated with a biosimilar in Latin America. It emphasizes the need to further develop and implement additional effective PhV activities to increase knowledge of biosimilar safety and to promote the rational use of these products.

Submitted: 13 June 2018; Revised: 17 October 2018; Accepted: 17 October 2018; Published online first: 30 October 2018

Introduction and Study objectives

A place for biosimilars
During recent years, biological products have been established as an effective and essential therapeutic approach to treat a host of potentially life-threatening conditions, including cancer [1]. A biological medicine is a substance derived from a living organism used for the prevention or treatment of disease. These include monoclonal antibodies, cell therapies, cytokines and growth factors [2, 3]. At the molecular level, they are typically large recombinant proteins with complex post-translational modifications. Unlike small molecule drugs, which can be chemically synthesized, biological drugs are produced by genetic recombination techniques in living cells, requiring advanced and complex manufacturing and production processes [2–4]. In spite of their clear utility as therapeutic agents, these products have a high per-unit acquisition cost due to elevated development and production costs [2]. Lack of access to expensive medications is a significant threat to global health care, involving complex sociopolitical factors. The problem is even more significant in low- and middle-income countries, such as those in Latin America [5]. The World Health Assembly in 2014 adopted a resolution recognizing the importance of increasing access to biotherapeutic products, by improving their affordability while assuring their quality, safety and efficacy [6]. Therefore, strategies to reduce cost and increase availability of such products are desirable. One such strategy is biosimilar development. A biosimilar refers to a biological product (a medicine that contains one or more active substances made by or derived from a biological source) that is similar (but not identical) to a previously authorized biological medicine (referred to as the originator or reference product) whose patent protection has expired [2, 4, 7-10]. The main rationale for the introduction of biosimilars is economic [4]. As occurs with generic drugs, their introduction into the market is likely to reduce costs substantially, thereby improving the availability of treatment for patients [1, 2, 4, 10].

Unlike small molecule drug products, biological therapies based on structurally complex, high molecular weight molecules cannot be reproduced in an identical form [11]. Due to such structural complexity and the inherent variability of biological expression systems, biological drugs including biosimilars, are expected to exhibit a certain degree of variability (microheterogeneity), even between different batches of the same product [9]. This variability affects the precise nature of the end product, which can potentially alter both the clinical efficacy and safety profile of the product [3, 4, 12]. A biosimilar should not exhibit significant variability compared to the reference product and all critical quality attributes, i.e. those important for the function of the molecule, must be comparable [13, 14]. However, a thorough comparison of structural and functional characteristics, product and process-related impurities of the biosimilar and the reference product is necessary, with any identified differences explained and the potential impact on the clinical performance of the biosimilar discussed [9, 12, 15-17]. To permit the use of a biosimilar and reference product for the same indications there should be no clinically meaningful differences in terms of efficacy and safety [18].

Regulatory perspective for biosimilars: post-authorization surveillance issues
The European Medicines Agency (EMA) has pioneered the regulatory framework for biosimilars and approved a total of 37 biosimilars (23 different applications) for 12 active substances since 2005 [19]. Regulatory authorities including EMA, US Food and Drug Administration (FDA) and World Health Organization (WHO) have adopted unique but similar measures for biosimilars, recognizing that the approval process for generic medicines cannot be applied to biosimilars [16]. Guidance from these organizations has been adopted as a reference for countries worldwide [8]. The consensus of the regulatory agencies is that the approval of biosimilars should be based on determination of similarity with the reference product, using evidence from comprehensive comparability studies and robust pharmaceutical quality data. By demonstrating high similarity with the reference medicine, the biosimilar can largely rely on the efficacy and safety data obtained with the reference product [4, 20].

However, since data from pre-authorization clinical studies may be insufficient to identify all potential differences between biological products, post-authorization monitoring is an essential requirement for refining the efficacy and safety profile of biosimilars [4, 20, 21]. As for all therapeutic agents, this monitoring is carried out through pharmacovigilance (PhV) practice, defined by WHO as ‘the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems’ [22]. PhV therefore emerges as a crucial tool in the identification and prevention of adverse drug reactions (ADRs), thus promoting patient safety and the rational use of medicines [21]. Although there are currently no specific safety requirements for biosimilars, it is widely recognized that PhV activities are of paramount importance for biological medicines due to the variability inherent to bioproduction [23, 24]. As a result, pharmaceutical companies are encouraged to implement an active PhV programme once a biosimilar is marketed, in which the need to ensure continuous product and batch traceability in clinical use is a key requirement [4, 8, 20, 21, 23–26]. Proposed surveillance strategies are varied but comprise several activities that exceed passive vigilance in order to collect real-world data. These active surveillance strategies might include surveillance of electronic healthcare databases, observational studies, targeted clinical investigations and treatment registries (TRs) [11, 27]. In addition, biosimilars are encouraged to participate in already established pharmacoepidemiological studies for the reference product with the aim to collect safety information on the molecule and not to compare the safety profi le of the biosimilar and reference product per se as the biosimilarity exercise has shown that the biosimilar is similar to the reference product [13].

Focusing on a bevacizumab biosimilar (Bevax®)
Biosimilars, in particular monoclonal antibodies, have been established as an essential component of the oncology treatment arsenal [1]. Among them, bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is an important therapeutic option for a variety of cancer types, with a generally good safety profi le [28-31]. Bevacizumab exerts its antineoplastic effects by inhibiting the activity of VEGF, the key driver of vasculogenesis and angiogenesis, resulting in regression of the tumour vasculature [29, 32]. The original bevacizumab (Avastin®, marketed by 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 [32]. It has since been approved for the treatment of other cancers, in combination with other chemotherapy agents [28, 29, 31–33]. The most common side effects of Avastin ® are hypertension, tiredness or asthenia (physical weakness), diarrhoea and abdominal pain, although more serious side effects, including gastrointestinal perforation, haemorrhage (bleeding) and arterial thromboembolism, have been reported [30]. A comprehensive list of ADRs related to bevacizumab and to Avastin® is available elsewhere [28, 34].

Bevax®, developed and supplied by Spanish-based mAbxience, is a biosimilar of Avastin® (bevacizumab). In Argentina, Bevax® was authorized in June 2016 [35] and commercialized from November 2016 by Laboratorios Elea Phoenix. Similar to its reference product, Bevax® is authorized in Argentina for the treatment of forms of cancer in combination with chemotherapy, including metastatic colorectal cancer, epithelial ovarian cancer, recurrent metastatic or persistent cervical cancer, metastatic breast cancer, advanced non-small cell lung cancer, glioblastoma, and advanced or metastatic renal cell carcinoma [35]. Currently, Bevax® is also commercialized in Ecuador and Paraguay. The safety profile of Bevax® is expected to be the same as its reference product, Avastin® [34]. Despite being structurally very similar, there has been continuous debate regarding whether biosimilars have different benefi t-risk profiles to the reference product, as their approval is based only on a comparability exercise and not an assessment of their benefit-risk profile [9, 10, 12, 18]. Since its launch, Bevax® has been subject to an active PhV programme as part of the risk management plan (RMP), created to establish its safety profile by assessing the incidence of ADRs related to its use. In line with European guidelines [13, 26, 36], PhV events are recorded by brand name, active pharmaceutical ingredient (API) and batch information to guarantee traceability. As an initial stage in this programme, a Treatment Registry (TR) was established in order to collect data from patients treated with Bevax®. This is useful to understand the clinical use of Bevax®, determine its safety profile and to support further safety assessment steps, which may include protocolized post-authorization safety studies (PASS).

The aim of this study was to describe and summarize data retrieved from the TR surveillance database on the biosimilar Bevax® established as part of the PhV programme for the product. Data were collected in Argentina between November 2016 and May 2018.

Methods

The data presented here were collected from the TR database implemented for Bevax® since its commercialization in November 2016. The TR was conducted in accordance with the RMP approved by Argentinian National Administration of Drugs, Foods and Medical Devices; ANMAT) in accomplishment of good pharmacovigilance practices (GVPs). The analysed patient data-set was anonymized using an Identification Code not related with patient personal data, following the applicable normative for personal data protection. The data lock point (DLP; the cut-off date for data inclusion in the study) for this report was 28 May 2018.

To establish the data registry, healthcare professionals (HCPs) treating patients with Bevax® were asked to complete three forms for each patient. First, an initial ‘Notification form’ in which information related to the patient (e.g. patient’s name, initials, sex, age, weight), performance status, clinical indication and treatment details (e.g. dose, frequency, date of first infusion) was registered. Approximately five months after starting treatment, an ‘Outcome form’ was sent to HCPs requesting information regarding treatment evolution in patients treated with Bevax®, including any ADR or case of death. If any product associated ADR or death occurred, HCPs were asked to complete an ‘ICSR (Individual Case Safety Report) form’, with the intention of gathering detailed information on the suspected ADR, including suspected drug reactions and medical history, in a similar format to standardized registry forms available elsewhere [37].

All detected 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. Furthermore, ADRs were classified as either ‘serious’ or ‘non-serious’. In general, a serious ADR would refer to any untoward 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 [38].

All data received in the TR database concerning Bevax® were extracted and analysed using appropriate descriptive statistics for either categorical or continuous variables.

Results

A total of 818 notification forms were registered in the TR database for patients who began treatment with Bevax® during the study period. Among these forms, follow-up information was available for 416 patients. The distribution of treatment duration for these patients was highly symmetrical as illustrated in Figure 1, showing a median (interquartile range) of 220 days (175 to 275 days). A total of 44 ICSRs describing ADRs associated with the product were received during the study period, amounting to 9.3% (95%CI: 6.7-11.9) of the total notification forms registered in the TR.

However, it should be noted that all safety information during the period covered by this study came from the TR and no additional ICSRs were independently reported.

Figure 1 pending for upload

Demographic data for the whole study population, as detailed on the notification forms for Bevax® retrieved in the TR and data regarding clinical indications for which the product was used, are summarized in Table 1. Most patients were women (51.8%), with a mean age of 60.5 years (ranging from 6 to 87 years). Men accounted for 41% with a mean age of 64.9 years (ranging from 69 to 88 years). The sex for six of the patients (0.7%) remained unknown since it was not recorded on the notification form. The mean age of the whole study population was of 64.5 years, with a range of 6 to 88 years.

In general, most patients (98.4%) received Bevax® for treating the types of cancer included in the authorized indications. Metastatic colorectal cancer was by far the most commonly treated indication (59.0%), followed by epithelial ovarian cancer (17.7%). As expected, breast and gynaecologic (cervical and ovarian) cancers were treated exclusively in women. However, for the remainder of the indications, men appeared to be treated more frequently with Bevax®, see Table 1. Additionally, for a small number of patients (1.3%) the product was used for treating a variety of other cancer types for which it is not currently authorized (unlabelled indications), although no specific patterns were detected. The use of the product for unlabelled indications was considered an ADR (off-label use) due to the potential for undetermined risks. Among them, there were four cases in which Bevax® was used in patients under the age of 18. As stated in the summary of product characteristics (SmPC) for Avastin® [34], since safety and efficacy has not been established in children under 18 years old, bevacizumab is only indicated in the adult population. Therefore, use in this population is considered off-label. However, no ADRs were reported in the four underage patients.

Table 1 pending for upload

Table 2 pending for upload

As described above, a total of 44 ICSRs (23 serious) were received during the study period. These ICSRs were associated with a total of 51 ADRs, 26 of which were considered serious events, see Table 2. The most frequently reported ADRs were related to a deterioration of the underlying disease (disease progression) and to the use of the product for an unauthorized indication (off-label use) with 15 and 11 occurrences, respectively. Hypertension was the next most reported ADR, with five occurrences. The remaining ADRs appeared mostly as single occurrences without any specific reporting pattern. The most commonly identified SOCs were related to general disorders and administration site conditions (including the ADR of disease progression) as well as injury, poisoning and procedural complications (including the ADR for off-label use). SOCs for vascular disorders (including events of hypertension) and skin and subcutaneous tissue disorders, were also identified, although with much lower frequencies. Of interest, and as detailed in Table 3, ADRs associated with Bevax® are in line with those expected with bevacizumab and are generally in accordance with those associated with the reference product Avastin®.

Twenty-three of the 44 ICSRs were related to serious ADRs and were therefore classified as serious cases. Death was reported in 20 of these serious cases, the majority (15 of the 20; 75%) resulting from disease progression. As further detailed in Table 4, four of the patients died during treatment: two of them as a result of developing sepsis, one due to a subarachnoid haemorrhage after severe thrombocytopenia and the remaining patient, with a previous history of cardiovascular disease, suffered sudden death. A fifth patient died from a stroke 44 days after taking the last dose of Bevax®. Lack of detailed additional information for these cases precluded more precise analysis. Sepsis, thrombocytopenia and cerebrovascular accidents associated with arterial thromboembolism are all serious ADRs known to be associated with the use of bevacizumab and are listed with a frequency ranging from common to very common [34]. Additionally, it should also be noted that the majority of these patients (4 out of 5) were over 65 years of age, see Table 4, a population in which the use of bevacizumab is associated with a higher frequency of thrombocytopenia and an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions [34].

Table 3 pending for upload

Table 4 pending for upload

Discussion

Biosimilar medicines have emerged as a valuable and affordable therapeutic option for treating a variety of conditions, including cancer. However, the complex nature of these products and the variability inherent to any biological expression system has generated a need for a robust regulatory environment and the implementation of active post-marketing PhV programmes, intended to gather data around the use of the biosimilar in clinical practice [4, 8, 20, 24, 25]. All biological products, including biosimilars, are subjected to a rigorous PhV programme within a RMP to continuously monitor for and appropriately manage the risks associated with their use [8, 24]. RMPs for biological products should focus on strengthening the PhV measures and implementing effective post-marketing surveillance to identify any ADRs, but particularly to identify immunogenicity risks associated with the variability inherent to biological products [21, 39]. Considering the known limitations of randomized clinical trials as well as those inherent to the abbreviated dossier submitted as part of the marketing application for biosimilars, post-marketing safety data, as that contained in TRs, appears as a valuable and necessary complement. In this context, PhV emerges as an important tool to obtain additional data for evaluating the safety of biosimilars. There is consensus among the major regulatory agencies that similarity to the reference product in terms of robust and comparable pharmaceutical quality is a mandatory requirement for the approval of a biosimilar [13, 15, 16]. Despite such consensus, there are numerous differences in the manner that regulatory authorities regulate the entrance of biosimilars into their markets. In Latin America, the subject of this study, regulatory authorities have begun to establish well described and standardized pathways that permit a biosimilar to gain commercial licensure. Although robust biosimilar legislation has been implemented in many Latin American countries, there remains a need to improve PhV systems in some of these countries and to encourage recognition of the value of PhV and related procedures [40, 41].

As a bevacizumab biosimilar, the safety profile of Bevax® is expected to be the same as its reference product Avastin®. However, as a biological product and due t o the variability inherent to bioproduction, some minor potential differences may exist between Bevax® and Avastin® that could have clinical and safety implications. Therefore, post-authorization studies evaluating the safety profile of bevacizumab and derived biosimilar products are of paramount importance. In this context, the present study intended to summarize and analyse the data retrieved from a TR data surveillance database established as part of the pharmacovigilance programme for Bevax®. To this purpose, safety data from the post-marketing use of the product contained in the TR received in Argentina during the period from November 2016 (when Bevax® was first commercialized) up to 28 May 2018 were retrieved, summarized and is herein presented.

Literature on post-marketing surveillance studies with biosimilars is scarce and, this may be the first published study to summarize the pattern of use and ADRs associated with a biosimilar from post-marketing, clinical experience in Latin America. The study analysed a total of 818 notification forms. Despite limitations due to the low number of ICSRs, the data presented here suggests Bevax® possesses a post-marketing safety and tolerability profile comparable to its reference product, Avastin®. ADRs associated with Bevax® in the present study are generally in concordance with that of the reference product Avastin®, see Table 3, since practically all ADRs associated with Bevax® are also listed events in the SmPC of the originator product [34]. Hypertension (high blood pressure), asthenia (weakness), arthralgia (joint pain), pyrexia (fever), epistaxis (nasal haemorrhage), as well as neutropenia and thrombocytopenia (reduced platelet count) reported here mostly as single occurring events, are all common side effects of bevacizumab which are also listed for Avastin, see Table 2 for details.

Some of the ADRs registered by Bevax® (e.g. subarachnoid haemorrhage and related cerebrovascular accident) are similar to those expected for the reference bevacizumab such as haemorrhage (bleeding) and arterial thromboembolism (blood clots in the arteries). Interestingly, commonly occurring events related to the gastrointestinal system such as diarrhoea, nausea and abdominal pain or gastrointestinal perforation (usually classified as serious events to bevacizumab) were not recorded for Bevax®. Disregarding non-specific ADRs or those associated with the use of any drug (e.g. disease progression and off-label use) hypertension was the most frequently reported ADR. Although other ADRs were reported, these mostly occurred as single events without a specific reporting pattern. All hypertension events were reported as non-serious. Furthermore, hypertension is a recognized ADR of bevacizumab [28] and is described in the SmPC of both Bevax® [35] and the reference product Avastin® [34], with the advice to manage symptoms, where possible, with anti-hypertensives. Besides death due to disease progression, death occurred in five additional cases. However, this is in line with data previously published for the reference product [42, 43] and, although lack of additional information for most of these cases precluded further analysis, death could be explained by the listed ADRs of the product and is commonly associated with the use of bevacizumab, especially in aged patients [30].

Previous studies have evaluated the post-authorization safety profile of Avastin® in daily medical practice in Italian [43] and French populations [42], in which the frequency and severity of reported ADRs associated with bevacizumab were generally in agreement with that described in the SmPC of the reference product and therefore in accordance with data presented for Bevax® in the present study. The safety profile for Bevax® therefore appears to be not only consistent with that of the reference product Avastin®, but also with that from in vitro and in vivo preclinical studies and with the clinical efficacy and safety profile demonstrated in a comparative clinical trial (Data on file) [44]. This was an open-label, parallel-group randomized controlled trial (BEVZ92-A-01-13) to compare pharmacokinetics, efficacy, safety, and imm unogenicity of the bevacizumab biosimilar BEVZ92 versus reference bevacizumab (Avastin) in combination with FOLFOX or FOLFIRI as first-line treatment in patients with metastatic colorectal cancer (NCT02069704). Overall, data regarding ADRs and therefore the safety profile of Bevax® is consistent with published data for the reference product and previously published data [30, 34]. Additionally, data available from the 818 individual notification forms for patients initiating treatment with Bevax® confirmed that most physicians prescribed the product for approved indications (98.4%), but in a small proportion of cases (1.3%) also for unauthorized indications, see Table 1. This is also in accordance with previous studies concerning the reference product Avastin®, which show use of bevacizumab for a variety of off-label conditions [42] but mostly for specified indications.

Despite the valuable data presented here, it is important to address the limitations of the present study. Methodological limitations must always be considered when collecting data on adverse effects, as the methods used for recording adverse events may influence the type and the frequency of effects reported. For example, patients may specify more adverse events when checking off a standardized list of symptoms than when reporting them spontaneously [45]. In this study however, the spontaneous nature of adverse event communication, the type of the ADRs reported and the physiopathological causes involved in most cases, suggest that a putative ‘nocebo’ effect has not significantly influenced the data recorded for Bevax® and considered in the present study. Although a substantial number of registry forms were collected in the TR, follow-up data were only available for approximately half of the forms. This was mostly due to a lack of follow-up caused by delays in receiving the outcome form and/or the ICSR from HCPs, resulting in a significant number of forms being received outside of the data lock point established for the study. Similarly, and as mentioned above, the number of ICSRs containing completed and detailed information was relatively low, accounting for less than 10% of the total notification forms received during the study period. Besides preventing a reliable assessment of the safety profile, this precluded a robust statistical analysis of confounders, which may have influenced estimates of ADR occurrences. Furthermore, additional factors, such as concomitant drug therapies, comorbidities, disease stage and disease-related risk, were not comprehensively considered. Since bevacizumab is used in addition to standard chemotherapy (e.g. capecitabine, paclitaxel, oxaliplatin, carboplatin, irinotecan), the effect of concomitant agents on the occurrence of ADRs cannot be excluded. Therefore, the present descriptive data regarding the safety profile of Bevax® must be considered purely exploratory since the small sample size and limited availability of detailed data restricted our ability to detect valuable trends. In the future, further comprehensive studies to evaluate the safety profile of Bevax®, and other biosimilar products, will be forthcoming. In particular, a post-authorization safety study (PASS) with a PhV collection data protocol is planned in Argentina for the near future.

Conclusion

To our knowledge, this is the first published report summarizing the pattern of use and ADRs associated with a biosimilar from post-marketing experience in Latin America. The Bevax® (bevacizumab) TR implemented as part of the RMP for the product in Argentina has proven to be a useful tool to enable reporting in oncological treatments involving this biosimilar product as reports coming from spontaneous sources are very limited in Argentina. Although a reliable safety profile of the product cannot be established here due to the limited number of ICSRs received during the study period, the ADRs associated with Bevax® are mostly in concordance with that of the reference product and consistent with previously published data.

The results of the TR support the implementation of additional actions to obtain further knowledge related to biosimilars, which is important to promote patient safety and improve the rational use of biosimilars. Further comprehensive safety studies to support benefit-risk evaluations for biosimilar products are currently being considered.

Regulatory basis for the approval of biosimilars in Argentina

In Argentina, the regulatory body for approval of all medicines, including the scientific evaluation of biologicals and biosimilars is the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (National Administration of Drugs, Foods and Medical Devices; ANMAT; www.anmat.gov.ar), under the authority of the Ministry of Health.

With the effort to harmonize regulatory requirements for Biological products, ANMAT published the first three guidelines (for both new and biosimilar molecules) throughout 2011–2012, in which the scientific principles for the evaluation and regulatory issues for the approval of biological products in Argentina were established. The specific guideline for the development of biosimilar products is established specifically through Disposition 7729/11 [46] approved on 14 November 2011. The main requirements in the guideline are as follows:

1. Reference product must be approved by ANMAT or any other regulatory agency (high regulatory/pharmacovigilance status, Australia, EU, Japan, USA) and be marketed in the same territories. Reference product must be approved with full dossier information.
2. Biosimilar applicant must provide API Information (aminoacid sequence, glycosylation site(s), post-translational modifications, secondary structure, tertiary structure, high-order structures, identification, biological activity (in the case of mAbs Fab/Fc functions), purity).
3. Biosimilar candidate must have the same pharmaceutical dosage form, route of administration, therapeutic indications. The manufacturing process used for the manufacture of the API and DP must be similar to those used for the reference product (cell line, upstream, downstream).
4. Applicant must perform an analytical comparability exercise to confirm the high similarity of the biosimilar candidate to the reference product.
5. The analytical comparability exercise must provide information about physicochemical characteristics, biological activity, mechanism of action, purity, glycosylation, postranslational modifications.
6. The need to perform preclinical and clinical studies will depend on the evidence obtained in the first stage of the analytical comparability exercise, and the type and nature of molecule to be evaluated. If clinical studies are requested, non-inferiority and equivalence studies are accepted. Efficacy endpoint should not be the primary endpoint of the study since efficacy has been already established by the reference product. If a PD marker is available, ANMAT [46] encourage its use in clinical studies.
7. Once the biosimilar is approved, the applicant must elaborate and apply a product-specific risk management plan.

Acknowledgements

The authors would like to thank all those researchers and healthcare professionals who participated in collection, recording and registry of the data used in this study and who proactively shared their experience of using our biosimilar product, as well as all the patients whose data were used in this study.

Funding

This study was supported by Laboratorio Elea Phoenix, SA and mAbxience Research SL.

Competing interests/Disclaimer: FF, MD, PRA and ES are employees of Laboratorio Elea Phoenix, the company that markets Bevax® in Argentina. NE is employed at mAbxience Research, the company that developed Bevax®. No disclaimer would affect Alvaro Romera.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Francisco Fernández1, MD
Matías Deprati1, MD
Patricia Rodríguez Acedo1, MD
Eduardo Spitzer1, BSc
Alvaro Romera2, MD
Nadia Español3, BSc

1Laboratorio Elea Phoenix, Gral. Juan Gregorio Lemos 2809 (B1613 AUE), Los Polvorines, Buenos Aires, Argentina
2Clinical Oncologist, Principal Investigator of Rosario Oncologic Institute, Córdoba 2457, Rosario – Santa Fe, Argentina
3mAbxience Research SL, 4/F, 28 Manuel Pombo Angulo, ES-28050, Madrid, Spain

Disclosure of Conflict of Interest Statement is available upon request.

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