Biosimilarity is not a transitive property: implication for interchangeability, naming and pharmacovigilance

Abstract:
Current regulations do not require a given biosimilar to remain similar to its reference biological over time. However, two products that were initially deemed biosimilar or interchangeable could each undergo unique patterns of drift and evolution in their manufacturing processes (divergence), ultimately resulting in two products that would be no longer biosimilar. In cases where divergence in potency, safety and immunogenicity may be present, care should be taken with multiple switches between reference and biosimilar products: each time a switch occurs, the difference between products could be greater. Taking into account that post-marketing comparative biosimilarity validation is not required, drift, evolution and divergence may present greater challenges when assessing biosimilar. In a marketplace with multiple biosimilars of a given reference product and in the context of interchangeability with drift and divergence, pharmacovigilance systems should be strengthened.

Submitted: 25 October 2021; Revised: 9 December 2021; Accepted: 14 December 2021; Published online first: 27 December 2021

Background

Currently, regulatory agencies in most of the world have established the requirements to achieve biosimilarity between two biological products. However, there is no mandatory legal obligation to perform quality or clinical studies that directly compare the biosimilar versus originator products in the post-approval period. Loss of biosimilarity over time could have important implications for the way in which regulators and healthcare providers handle safety surveillance, product ­naming, interchangeability, and medical records. Thus, biosimilars introduce new challenges because two products that were initially deemed biosimilar (or interchangeable) could each undergo unique patterns of variation resulting in two products that are no longer biosimilar (nor interchangeable). In this context, it would be essential that regulatory agencies adopt measures to minimize the risk of possible adverse events or lack of efficacy of treatments with biologicals, such as to determine extended biosimilarity and interchangeability standards and to strengthen pharmacovigilance systems.

Changes in the production process: comparability concept

During manufacturing process, the cell culture and fermentation processes are particularly critical and sensitive in terms of defining the identity, purity and potency of the approved biological. Modifications of parameters in any of these steps may impact cell culture performance, leading to variability in the quality of the recombinant protein [1].

Throughout the product life cycle of an approved biological molecule, a manufacturer may implement process changes to incorporate technological advances or efficiencies. Regulatory agencies evaluate these changes carefully and use scientific comparability criteria to determine whether there is a potential impact on the safety or efficacy that underlies its approval. The evolution of the changes introduced by the manufacturer follows a comparability exercise between the pre- and post-change product; and depending on the nature and extent of the manufacturing change, routine control measures and analytical tests may not be sufficient to assess the impact of the change on a product’s quality, safety and efficacy; this may necessitate non-clinical and clinical evaluations [2].

Until the mid-1990s, manufacturers of innovative biological products faced significant regulatory hurdles in making changes to their own manufacturing processes. But, in 1996, the US Food and Drug Administration (FDA) changed the paradigm for conducting comparability assessments of biological products in order to facilitate this approach. The agency’s justification for an increase in regulatory flexibility was based on recognition of the advances in analytical methodology and, perhaps more important, on the reasoning that ‘knowledge of the process involved in the manufacture of the product is an integral component in determining the design of an appropriate comparability assessment program’ [3].

The evolution of the regulations in Europe was certainly different from those of FDA. In 2001, the European Medicines Agency (EMA) established a comparability approach with the adoption of the Committee for Proprietary Medicinal Products (CPMP) by the ‘Guideline on comparability of medicinal products containing biotechnology-derived protein as active substances’ [4]. This guidance focused on comparability in the context of a change in the manufacturing process of a given product, but also, at the same time, on ‘comparability exercise’ that would need to be conducted to support an application for a product claimed to be similar to an already marketed product, with the recommendation that, in this latter case, additional preclinical and clinical studies (potentially a full data package) would be required. However, no ‘essentially similar’ product was approved based on this guidance, until, in 2005, a new independent pathway for the approval of ‘biosimilars medicinal products’ was introduced [5].

Later, other regulatory bodies provided analogous guidelines, culminating in the International Conference on Harmonization Comparability Guidance ICH Q5E, which acknowledges that ‘the demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product’. Currently, the principles of the comparability exercise established on ICH Q5E are recognized by regulatory authorities throughout the world [6].

In addition to the changes that manufacturers usually implement in manufacturing processes of an approved biological for a variety of reasons (including the need to comply with regulatory commitments, improve product quality and yield, and improve manufacturing efficiency and reliability), the technology transfer between different manufacturers is considered another potential scenario where comparability exercise would be performed. In this scenario, the company that developed the innovator product transfers the know-how and the full history of the manufacturing process to another manufacturer, similar to when a company opens its own second manufacturing site. All the information regarding critical quality attributes (CQAs), raw material, excipient suppliers, purification, formulation studies, containers, stability data, analytical methods, and product packaging would be available for consideration by the other manufacturer. Access to the full range of innovator manufacturing information fundamentally distinguishes this comparability approach from the situation facing the biosimilar product manufacturer [7].

Comparability versus biosimilarity

A biosimilar is a biopharmaceutical that has demonstrated similar CQAs, biological function, clinical efficacy and safety to that of an already licensed biological reference product. Then, biosimilarity must first be proved in an extensive analytical comparability exercise, systematically evaluating the quality and similarity of the biosimilar product and the originator product across dozens of physicochemical, biological and pharmacological CQAs, before establishing equivalence in clinical efficacy and safety [8].

Therefore, the scientific principles to establish the impact of a change in manufacturing process of a biological product (comparability) and those necessary to the generation of a biosimilar taking an innovator biological as a reference product (biosimilarity) are not the same. The potential for differences between an innovator biological and a biosimilar is greater than that between a biological before and after a manufacturing change [9].

The comparability practice as described within ICH Q5E applies to a single product before and after process changes within a single manufacturer. ICH Q5E would not sufficiently cover differences in the manufacturing process of the biosimilar compared to that of the reference product including expression ­system, recombinant DNA plasmid, fermentation system, control strategy, and purification process, process-related and product-related, formulation, container-closures system, drug product manufacturing and storage [10, 11].

The regulatory agency that most appropriately establishes the differences between biosimilarity and comparability is FDA in the ‘Scientific considerations in demonstrating biosimilarity to a reference protein product; Guidance for industry’, which states that: ‘Demonstrating that a proposed product is biosimilar to a reference product typically will be more complex than assessing the comparability of a product before and after manufacturing changes made by the same manufacturer. Even though some of the scientific principles described in ICH Q5E may also apply in the demonstration of biosimilarity, in general, FDA anticipates that more data and information will be needed to establish biosimilarity than would be needed to establish that a manufacturer’s post-manufacturing change product is comparable to the pre-manufacturing change product’ [12].

By contrast, from 2003, EMA uses the term comparability when evaluating both inter- as well as intra-manufacturing changes and as the explicit basis for biosimilars development [4]. More recently, EMA has used the expression ‘biosimilar comparability’ to clarify the context but not to change the concept as a scientific matter. Furthermore, EMA considers that, with the extensive experience of regulators and sponsors in highly regulated markets, comparability is the universal standard for judging interchangeability of pre- and post-manufacturing changes of any biological. With the development of the biosimilar approval pathway, the scientific approach underlying interchangeability can be broadly applied to an originator product undergoing a manufacturing change or a biosimilar at initial approval or a biosimilar undergoing a manufacturing change [13].

On interchangeability, the US legislation is much stricter and more specific, and differs substantially from EMA’s position. In 2019, FDA issued the guideline ‘Considerations in demonstrating interchangeability with a reference product; Guidance for industry’, in which it established that a biosimilar is not interchangeable with the innovative biological until the sponsor provides scientific and clinical evidence that supports such property of the biosimilar. In this guideline, FDA states that the term interchangeable or interchangeability means that the biological product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. In this way, interchangeability is directly related to automatic substitution at the pharmacy level [14].

The interchangeability between innovator biological and biosimilar is not regulated in other countries of the world. However, it is an important scientific issue that is under constant debate.

Impact of drift, evolution and divergence on biosimilarity and interchangeability

Currently, one important question under debate is how to ­manage the oversight of a biosimilar if its reference product undergoes a change in its quality profile (or vice versa, if a biosimilar undergoes a change). In other words, is a biosimilar a ‘biosimilar forever’ or just a ‘biosimilar for licensing purposes’ that has a life cycle of its own after approval?

Biological product quality changes resulting from process variation may be unintended or intended. Unintended process variation may occur owing to the impact of uncontrolled variables and can result in gradual changes over time or in a sudden shift in a quality attribute, a process called manufacturing drift. The source of the change may not be well understood and may be an unintended result of changes outside of the manufacturer’s control [15].

As mentioned in the previous section, additional changes in product quality may be the result of intentional changes made by the manufacturers of biological medicines to the manufacturing process and can range from changes in manufacturing sites to changes in suppliers or cell culture media. Also, changes to a manufacturing process are sometimes made to introduce new technologies that can improve productivity. This type of change in the manufacturing process, called evolution, has been observed in most, if not all, approved biologicals on the market today since their initial approval [16].

Put together, normal variability, drift and evolution may present greater challenges when assessing biosimilars, and much more when they are evaluated as possible interchangeable products. Two products that were initially deemed biosimilar or interchangeable could each undergo unique patterns of drift and evolution, ultimately resulting in two products that are no ­longer biosimilar nor interchangeable. This process is defined as divergence [17].

Divergence is not just a hypothetical phenomenon. In some cases, divergence can occur for biologicals transferred between licensing partners, where the partners retain some right of reference to the originator’s development data, and also divergence can certainly occur and is arguably more likely with completely independent entities that have no right of reference to proprietary information collected during development, such as biosimilars manufacturers.

The case of epoetin alfa is an example of both types of divergence. Epoetin alfa is manufactured by separate entities for the US, Japan and Europe. Subcutaneous administration of Eprex® (epoetin alfa) in patients with chronic kidney disease (CKD) was banned in Europe between 2002 and 2006 after increasing reports of anti-erythropoietin (EPO) antibody-mediated pure red cell aplasia (PRCA) [18]. An investigation revealed that the transient increase of anti-EPO antibody mediated PRCA was associated with a change in the formulation/composition of the product. More precisely, the excipient of the formulation, human serum albumin, was replaced with polysorbate-80. This route of administration was subsequently restored after the sponsor addressed the manufacturing issue. Meanwhile, the corresponding US product did not implement the formulation change and retained the original route of administration on its label. The reason for the increase in PRCA observed with Eprex® has been associated with safety issues become apparent only in the post-marketing setting when larger numbers of patients are being treated [19].

Currently, a wider group of innovator, biosimilar and second-generation epoetin products are available across different markets [20]. Epoetins are heavily glycosylated proteins. Glycosylation profile is a CQA of epoetins, as it has a crucial influence upon in vivo biological and clinical activity [21]. Marketing authorization of biosimilar epoetin alfa products, e.g. Binocrit® and Silapo®, by EMA was based upon detailed biosimilarity exercises with the innovator product, Eprex®. In a recent study, the glycosylation profiles of Eprex® and the two approved biosimilars Binocrit® and Silapo® were characterized and compared. The products exhibit notable differences in N- and O-glycosylation, including attributes, such as sialic acid occupation, O-acetylation, N-acetyllactosamine extended antennae and sulphated/penta-sialylated N-glycans, which have the potential to cause divergency. The study highlights the need for continued monitoring of epoetin glycosylation, ideally allied to pharmacological data, in order to ensure consistency and therapeutic equivalence between products over time. In a marketplace where multiple epoetins are available, there exists the potential for divergence of glycosylation profiles, and therefore therapeutic potencies. It was evidenced that, post-authorization product surveillance and life-cycle management of epoetin alfa biosimilars, which may involve process manufacturing changes, can occur independently of Eprex® and to produce divergence in their clinical performance [22].

Regulatory controls are in place to ensure comparability of stand-alone biologicals before and after manufacturing changes. However, manufacturing changes to the biosimilar will not trigger repeated biosimilarity testing with the innovator; therefore, a standard of biosimilarity that is achieved at the time of approval of the biosimilar may not be maintained over time. Taking into account the possibility that divergence occurs, the similarity assessment should be an ongoing exercise that requires the biosimilar candidate to be assessed throughout the life cycle of the product. In addition to continuous biosimilarity, one important challenge for regulatory agencies is to demonstrate whether interchangeability is maintained in the longer term, particularly following changes to either the originator or (multiple) biosimilar product versions, see Figure 1 [6].

Figure 1

Biosimilarity is not a transitive property

The relationship between a given biosimilar product and its reference product is unique and not transitive to other biosimilars. This is a consequence of the fact that biosimilars are not structurally identical to their reference biological products or to each other. Although differences between a biosimilar and its reference product are evaluated for equivalent clinical effects during biosimilarity assessment, it is unlikely that potential differences between any two indirectly related biosimilars will be formally evaluated. Indeed, there is no regulatory requirement to ensure that all biosimilars of a particular reference biological differ in a similar qualitative manner or to the same extent. Furthermore, biosimilar pathways permit variations in pharmaceutical attributes, clinical development approaches, and regulatory outcomes, resulting in further diversity of attributes among approved biosimilars [23].

The more important implication of this diversity is that biosimilars should not be used in practice in the same manner as multiple-source generic drugs. By definition, a generic medicine is interchangeable. A prescriber need not select any particular version, i.e. they are prescribed by the International Nonproprietary Name (INN) or generic name, and substitution among generic equivalents is commonly practiced at the pharmacy level without prescriber involvement [24]. Because biosimilars may vary across the ranges of structural and functional acceptance criteria, they should not be treated like multisource drugs and then none of the generic drug practices are advisable for biosimilars. Rather, once approved, they should be considered as individual therapeutic alternatives, stand-alone products, with all of the associated regulatory requirements. In practice, and in the context of multiple biosimilar versions of a single biological reference product, this means that biosimilars should be prescribed and tracked in medical records by a unique name, and clinicians should be involved in decisions to switch patients from one biological to another, particularly when a given biosimilar has not been qualified as interchangeable with the prescribed biological.

As was described above, uncorrected manufacturing process drift and/or evolution of one or both products, originator and biosimilar, could result in product divergence, and this divergence can occur between an originator and a biosimilar and between multiple biosimilar products. Divergence should not lead to a change in the safety or efficacy of each single product, originator and biosimilar(s), but could potentially result in clinically meaningful differences, e.g. potency, safety, or immunogenicity profile, during a chronic treatment interchanging biological. In cases where divergence may be present, care should be taken with multiple switches: each time a switch occurs, the difference between products will be greater. The most relevant cases may be divergence in potency (although both approved products are still effective, switching between them could cause a disruption in dosing), and divergence in immunogenicity profile (a patient could be exposed to one less immunogenic product and then be switched to the more immunogenic product) [25].

Concluding remarks

Three dynamic actions could be taken by regulatory agencies in order to control, at least partially, the clinical impact of divergence between innovator biologicals and biosimilars:

(1) Strengthen pharmacovigilance systems

Pharmacovigilance is especially important for biologicals because of their susceptibility to changes in the manufacturing process and the possibility that drift, evolution, or divergence may have adverse consequences for patients. A robust, product-specific pharmacovigilance system for biologicals may require special policy measures such as mandatory use of distinguishable names for prescribing.

(2) Determine interchangeability standards

Currently, only FDA has established the scientific basis to determine if a biosimilar should be deemed interchangeable with an innovator biological [14]. However, no regulatory mechanisms are currently in place to ensure continued interchangeability in the event of product drift, evolution or divergence. Thus, products that were interchangeable at the time of approval might continue to be considered interchangeable by regulators even though the quality attributes of the originator and biosimilar products have diverged.

(3) Establish the differences between comparability and biosimilarity

The impact of a particular change and any product evolution can be readily evaluated by comparability exercise. To the contrary, in biosimilar development, almost every aspect of the manufacturing process may have changed, and the only point of reference is the reference drug product. As biological manufacturers do not have access to the originator manufacturing process as a point of reference, comparing the biosimilar product to the reference product (biosimilarity) is necessarily a more complex process.

Competing interests: None.

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

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Author: Pablo Matar, PhD, Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario (UNR), Santa Fe 3100, (2000) Rosario, Argentina; and National Scientific and Technical Research Council (CONICET), Rosario, Argentina

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New monoclonal antibody biosimilars approved in 2015 in Latin America: position statement of the Latin American Forum on Biosimilars on biosimilarity, interchangeability and extrapolation of indications

Author byline as per print journal: Valderílio Feijó Azevedo1,2, Alejandra Babini3,4, Fabio Vieira Teixeira5,6, Igor Age Kos1,2, Pablo Matar7

Introduction: The Latin American Forum on Biosimilars (FLAB) is an annual meeting that brings together various stakeholders, including key opinion leaders, the pharmaceutical industry, academics, patients, lawyers and other healthcare professionals, to present and discuss recent findings regarding biosimilars. In 2015, the meeting theme was interchangeability and automatic substitution. Regarding biosimilarity, interchangeability and extrapolation of indications, the discussion centred on two products in Brazil and Argentina: CT-P13, an infliximab biosimilar; and RTXM83, a rituximab biosimilar. Here, we conduct a critical analysis of the available scientific and medical information on these products to establish a FLAB position statement in the context of the current regulations in Brazil and Argentina.
Biosimilarity, interchangeability and extrapolation of indications: RTXM83 is still not approved in Brazil and is currently under a technology transfer agreement. In Argentina, the drug was approved for commercialization under the name Novex, with extrapolation of indications for rheumatoid arthritis, which according to the Argentinian Society of Rheumatology, lacks the necessary clinical data for such an approval. CT-P13 is already approved in Brazil, and is on the market. The approval was based on the data presented in the PLANETAS and PLANETRA studies. Interchangeability will not be considered for this product until further studies are presented.
Discussion: Based on the available evidence, CT-P13 is the only biological molecule marketed in Latin America that can be considered a true biosimilar. Extrapolation is only acceptable when the diseases for which the reference product is intended to treat are entirely similar. Extrapolation based on only preclinical studies is not acceptable. Conversely, although the proposed rituximab biosimilar (RTXM83) was approved by ANMAT (National Administration for Medicines, Food and Medical Technology) in Argentina, clinical data demonstrating its equivalence with the reference rituximab, is necessary before RTXM83 can be considered a true biosimilar.

Submitted: 15 March 2016; Revised: 30 May 2016; Accepted: 31 May 2016; Published online first: 13 June 2016

Introduction

The annual Latin American Forum on Biosimilars (FLAB) was first held in 2010 with the aim of bringing key stakeholders within the community together to discuss aspects of biosimilars. Attended by key opinion leaders, representatives from the pharmaceutical industry, academics, patients, lawyers and healthcare professionals, FLAB is sponsored or supported by different organizations, including the pharmaceutical industry such as AbbVie, Janssen, Pfizer, Sandoz, Sanofi; patient organizations and Latin American medical societies such as Brazilian Society of Rheumatology, Argentinian Society of Rheumatology, GEDIB (Brazilian Study Group of Inflammatory Bowel Diseases) among others; some regulatory agencies such as ANVISA (Agencia Nacional de Vigilancia Sanitaria), COFEPRIS (Comisión Federal para la Protección contra Riesgos Sanitarios), ANAMED (Agencia Nacional de Medicamentos), have sent representatives to the Forum in order to discuss regulatory aspects of biosimilars approved in their countries. The 2015 meeting was held in Brasília, Brazil, with the theme of ‘Interchangeability and Automatic Substitution’, and saw the approval of two potential biosimilars in different Latin American countries.

The World Health Organization (WHO) defines similar biotherapeutic products (SBPs) as products that are similar in terms of quality, safety and efficacy to an already-licensed reference biotherapeutic product (RBP) [1]. An SBP is tested for biosimilarity via a biosimilarity exercise in which it is compared with existing products using the same procedures. Within this biosimilarity exercise, there are three levels of evaluation: quality evaluation (i.e. physicochemical and biological characterization), non-clinical evaluation and clinical evaluation. Clinical evaluation seeks to demonstrate the comparable safety and efficacy of the SBP with the RBP. It is a stepwise procedure that begins with pharmacokinetic (PK) and pharmacodynamic (PD) studies, followed by efficacy and safety clinical trial(s). Given that biotherapeutic products are biologically active molecules capable of inducing immune responses, immunogenicity is an important consideration within the evaluation of safety. In our opinion, all biological products supported by a full biosimilarity exercise can be considered true biosimilars. Conversely, products that are not fully supported by scientific information, including comparative clinical data, cannot be considered biosimilars.

In Europe, a similar definition has been established that states: ‘biosimilars are copy biologicals with a clear and effective regulatory route for approval, which allows marketing of safe and efficacious biological products’ [2]. This conceptual idea has been well established by the European Medicines Agency’s (EMA) guidelines [3], which have led to the approval of several biosimilars in Europe, including the first biosimilar monoclonal antibody (mAb), the anti-tumour necrosis factor (anti-TNF) drug infliximab. In September 2013, the Committee for Medicinal Products for Human Use (CHMP) of EMA, approved the use of biosimilar of Remicade™ under the trade names of Remsima™ and Inflectra™ [4, 5].

Other biosimilar mAbs and fusion proteins that are currently being investigated include: rituximab, which is in the early stages of clinical trials; and adalimumab and etanercept, which are in phase III clinical trials.

The main objective of this paper is to provide a critical analysis of the results of the biosimilarity exercises carried out on two products that have been recently approved in Brazil and Argentina: CT-P13, an infliximab biosimilar; and RTXM83, a proposed rituximab biosimilar. As a result, we have established a FLAB position statement on the approval of these drugs in the context of the current regulations in Brazil and Argentina.

Biosimilarity, interchangeability and extrapolation of indications: the case of CT-P13 and RTXM83 in Brazil and Argentina

At present, a number of countries in Latin America have specific regulations concerning the approval of SBPs (Argentina, Brazil, Chile, Costa Rica, Cuba, Guatemala, Mexico, Panama, Peru and Venezuela). In general, regulations consider the international standards set out by EMA, in combination with local input and scientific principles based on WHO guidelines. Most legislation for biosimilar approval considers it essential to implement a system of pharmacovigilance after product commercialization, to ensure that the safety and efficacy of biosimilars can be evaluated [6].

In Argentina, resolutions outlining the requirements for biopharmaceuticals and biosimilar products (No. 7075 [7] and 7729 [8]) were published in 2011 by the ANMAT. Resolution No. 7729 specifically states the requirements for the approval of biosimilars. Of note, Article 6 states that the comparative exercise between the reference product and proposed biosimilar must be accompanied by non-clinical and clinical studies in order to be approved. In 2012, ANMAT enacted Resolution No. 3397, which established the requirements for the approval of biological medicines obtained using DNA recombinant technology, including mAbs [9].

In 2013, the Brazil-based pharmaceutical company, Libbs, and the Chemo Group’s biotechnology company, mAbxience, signed a licensing and technology transfer agreement for several biosimilar mAbs developed by mAbxience, including the rituximab biosimilar. A clinical trial sponsored by mAbxience entitled: ‘A Randomized, Double-blind, Phase III Study Comparing Biosimilar Rituximab (RTXM83) Plus CHOP Chemotherapy Versus a Reference Rituximab Plus CHOP (R-CHOP) in Patients With Diffuse Large B-cell Lymphoma (DLBCL) Given as First Line’ was registered under the ClinicalTrials.gov identifier NCT02268045 on 19 September 2014. Libbs and Elea, an Argentina-based company, are among the collaborators that worked towards establishing this protocol. This study is a non-inferiority trial and is currently recruiting participants. Despite this, in Argentina, ANMAT enacted Regulation No. 7060 (dated 2 October 2014), which authorized the commercialization of the biopharmaceutical product Novex (sponsored by Elea), that contains the rituximab biosimilar, RTXM83 [10]. As clinical trials are ongoing, it is evident that this was approved by ANMAT without any clinical data which is contrary to legislation [79].

Novex is now being distributed in hospitals and health centres in Argentina to be administered to patients diagnosed with rheumatoid arthritis (RA). As this product has been approved without clinical data, the Argentine Society of Rheumatology has issued a statement suggesting their associates do not administer Novex to patients.

In contrast, a very different situation exists in Brazil. The infliximab biosimilar, CT-P13 (Remsima™), sponsored by Celltrion, received market approval by ANVISA in 29 April 2016. This approval was based on full clinical development, including a phase I clinical trial, known as the PLANETAS trial [11], which compared treatment with CT-P13 to innovator infliximab in individuals with active ankylosing spondylitis. The outcomes, pharmacokinetics and clinical efficacy, including the Assessment in Ankylosing Spondylitis Response Criteria (ASAS) 20 and ASAS 40 responses, were similar in both treatment groups; and the product safety profiles were also comparable up to week 30. After this, a phase III clinical trial, known as the PLANETRA trial [12], was performed, which compared CT-P13 to innovator infliximab in patients with active RA who did not respond well to methotrexate treatment. Equivalence was demonstrated in the American College of Rheumatology 20% (ACR 20) response at week 30. Currently, several trials with proposed biosimilars are in progress and it seems highly likely that approval and marketing of new products will be requested in the near future [13].

Discussion

Evidence suggests that, although the infliximab biosimilar, CT-P13, was approved in Brazil following full development that demonstrated clinical biosimilarity, interchangeability with the infliximab innovator is not guaranteed. Biosimilars cannot be considered interchangeable or a substitute for their reference product based solely on biosimilarity evidence. It should be left to the clinician’s judgement to choose whether to switch from an originator to a biosimilar. Other paramedical individuals and healthcare payers should not be allowed to change prescriptions or impose the use of biosimilars instead of their originator. Biosimilars should be considered interchangeable if the manufacturer has demonstrated that the drug can produce similar effects to the reference product in any given patient. Moreover, Brazilian medical societies point out that when a biological product is administered to an individual more than once, the risk, in terms of safety or diminished efficacy, of alternating between using the biosimilars and the reference product, is not greater than the risk of using the reference product without such alteration or switch [12]. The best approach should be to conduct a rigorous clinical study to evaluate the possibility of the reference and biosimilar being interchangeable.

The NOR-SWITCH trial (NCT02148640) [14] is a prospective randomized study that aims to examine the ease with which CT-P13 can be interchanged with the infliximab innovator. The authors plan to recruit 500 patients with five different indications for infliximab: RA, plaque psoriasis, ankylosing spondylitis (AS), Crohn’s disease (CD) and ulcerative colitis (UC). All patients will be treated with the infliximab innovator for six months. After this time, half will switch to treatment with CT-P13 and the other half will remain on the infliximab innovator. After 52 weeks, clinical observations will be made by physicians and patients to determine the efficacy of the switch. It is hoped that this will provide robust evidence in support of switching from the reference product to the biosimilar. However, it is generally accepted that clinical trials to assess interchangeability should have crossover or Balaam’s design [15], neither of which are incorporated in this trial; therefore, it cannot be considered an appropriate interchangeability study. No biosimilar should be considered interchangeable until proven by clinical medical evidence [16].

An example of such an interchangeability trial was recently carried out in Italy. Data from the Prospective Observational Cohort Study on patients with inflammatory bowel disease receiving Therapy with BIOsimilars (PROSIT-BIO), obtained from patients with UC and CD, was presented at the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD), VII National Congress in Palermo [17]. With 397 patients (174 UC and 223 CD), this is the largest interchangeability study carried out to date. It demonstrated that comparable efficacy was observed in patients who were switched from the infliximab innovator to the infliximab biosimilar (93 patients), compared to patients receiving a biosimilar who had previously been naïve to anti-TNF (217 patients), and patients receiving a biosimilar who had previously been exposed to one or more biologicals (87 patients) (response rate 95% vs 92% vs 91%, respectively). Safety was also found to be comparable across the patient groups.

Extrapolation of indications is a regulatory decision. CT-P13 is an example of this because it was extrapolated in more than 50 countries including Brazil. This decision is controversial because the biosimilarity of CT-P13 was tested in only two disease models, RA and AS, and then extrapolated to inflammatory bowel disease. The Brazilian regulation of biosimilars, such as RDC 55/2010, has two pathways: individual and comparability. When a biosimilar is only submitted to the individual pathway, it is not possible to extrapolate indications. Submissions must also be made to the comparability pathway in order to enable the extrapolation of indications.

Conversely, Argentinian regulation of biosimilars does not permit extrapolation of indications. The case of the rituximab biosimilar RTXM83, which was approved in Argentina, is challenging. To the best of our knowledge, this product has been approved for all the indications of the rituximab innovator without any clinical data. Therefore, this product is not a true biosimilar because biosimilarity, with respect to the reference product, has not been fully demonstrated.

Statement

Based on the evidence, CT-P13 is the only monoclonal antibody marketed in Latin America that can be considered a true biosimilar. Extrapolation is only acceptable when the diseases for which the reference product is used to treat are entirely similar. Extrapolation based on only preclinical studies is unacceptable. Currently, there is no clinical evidence to support that CT-P13 and the reference product are interchangeable.

Conversely, although the proposed rituximab biosimilar (RTXM83) was approved by ANMAT in Argentina, clinical data demonstrating its equivalence with the reference rituximab is necessary before RTXM83 can be considered a true biosimilar.

The interest in biosimilars is growing in Latin America due to a number of factors, including the large proportion of healthcare resources that are used to import high cost branded biologicals. Biosimilars are expected to reduce drug expenditure, assuming that they achieve similar clinical results as the reference product. The need for well-defined pathways and regulations for the review, approval and pharmacovigilance of biosimilars, as well as greater transparency of the actions of governments, are required to facilitate appropriate biosimilar approval and usage. As both Brazil and Argentina have specific regulations concerning the approval of biosimilars, their governments are responsible for guaranteeing the approval of safe and effective biosimilar products.

Disclosure of financial support: The authors declare they have not received any financial incentive to write this paper. This work was not produced with any financial support.

Visit the link www.biossimilares2016.com.br for further information on FLAB.

Competing interests: Adjunct Professor Valderílio Feijó Azevedo is a speaker for AbbVie, AstraZeneca, BMS, Celltrion, Janssen, Novartis, Pfizer, Roche, Sanofi, UCB; and has produced graphic material to AbbVie, Janssen, BMS, Pfizer. He is also a member of the advisory board of AbbVie, AstraZeneca, BMS, Janssen, Merck Serono, Pfizer. Alejandra Babini declares that she is President of the Argentinian Rheumatology Society. She is a consultant, speaker and member of the advisory board of AbbVie and Pfizer. Fabio Vieira Teixeira declares that he is a consultant, speaker and a member of the advisory board of Janssen and Hospira/Pfizer. He is also a consultant and speaker of Ferring and Nestlé. Igor Age Kos and Pablo Matar declare no relevant conflict of interests to participate in this authorship.

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

Authors

Adjunct Professor Valderílio Feijó Azevedo1,2, MD, PhD, MBA
Alejandra Babini3,4
Professor Fabio Vieira Teixeira5,6, MSc, MD, PhD
Igor Age Kos1,2
Pablo Matar7

1Federal University of Paraná, Rua Alvaro Alvin, Casa 18 Seminário, Curitiba-Paraná PR 80740–080, Brazil
2Edumed-Health Research and Biotech, 2495 Avenue Bispo Dom José, Seminário
Curitiba-Paraná, Brazil CEP 80440080
3Hospital Italiano Córdoba – Argentina
4Argentinian Society of Rheumatology, Callao 384 Piso 2 Dto 6, CABA, Buenos Aires, Argentina (C1022AAQ)
5Medical Director of Gastrosaude Clinic-Marilia, 62 Sao Paulo Avenue, 17509-190 Marilia, Sao Paulo, Brazil
6Brazilian Study Group on Bowel Inflammatory Diseases
7CONICET – The Argentinian Scientific andTechnical Research Council, Centro Científico Tecnológico Rosario – CONICET
Consejo Nacional de Investigaciones Científicas y Técnicas, Ocampo y Esmeralda, Rosario 2000 – Santa Fe, Argentina

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Author for correspondence: Adjunct Professor Valderilio Feijó Azevedo, MD, PhD, MBA, Rua Alvaro Alvim 224 casa 18, Seminário, Curitiba-Paraná CEP 80440–080, Brazil

Disclosure of Conflict of Interest Statement is available upon request.

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