Posicionamento da sociedade portuguesa de oncologia sobre a utilização de biosimilares para o tratamento oncológico

Posicionamento da sociedade portuguesa de oncologia sobre a utilização de biosimilares para o tratamento oncológico
The portuguese society of oncology position paper on the use of biosimilars for the treatment of cancer

Gabriela Sousa | José Luís Passos Coelho | Noémia Afonso | António Moreira | Deolinda Pereira | Hélder Mansinho | Helena Gervásio | Joana Cavaco Silva | Paulo Cortes


Afiliação:
Gabriela Sousa 
Serviço de Oncologia 
IPO Coimbra 
Coimbra 

José Luís Passos Coelho
Serviço de Oncologia 
Hospital da Luz e Hospital Beatriz Ângelo
Lisboa

Noémia Afonso
Serviço de Oncologia 
Centro Hospitalar do Porto 
Porto 

António Moreira 
Serviço de Oncologia
IPO de Lisboa
Lisboa

Deolinda Pereira
Serviço de Oncologia
IPO Porto 
Porto

Hélder Mansinho 
Serviço de Oncologia 
Hospital Garcia de Horta
Lisboa

Helena Gervásio 
Serviço de Oncolgia 
IPO Coimbra 
Coimbra 

Joana Cavaco Silva 
Scientific Consultant and Senior Medical Writer
Lisboa 

Paulo Cortes 
Serviço de Oncologia 
Hospital Lusíadas
Lisboa
Conflitos de interesses:
Nada a apontar

Autor para correspondência:
Gabriela Sousa
Rua da Quinta D’Abada, 108
3140-305 Pereira MMV
+351963330975
gsousa3140@gmail.com




Resumo
A aproximação do fim dos direitos de exclusividade para os anticorpos monoclonais cria a oportunidade para outras companhias competirem pelo desenvolvimento de versões semelhantes destes fármacos, ou biossimilares. Mas a complexidade intrínseca a estas moléculas levanta várias preocupações, particularmente no contexto oncológico.
Enquanto sociedade médica, a Sociedade Portuguesa de Oncologia (SPO) acredita que os oncologistas devem estar informados e preparados para utilizar estes fármacos do modo mais apropriado. Enquanto sociedade científica, a SPO está ciente da necessidade de opções terapêuticas sustentáveis, e está disposta a trabalhar em parceria pela sustentabilidade do Serviço Nacional de Saúde. É, pois, importante que os biossimilares alcancem os seus potenciais benefícios, preservando a qualidade, segurança e eficácia que foi estabelecida para as moléculas originais. 
Neste artigo de posicionamento, são apresentadas as principais evidencias científicas sobre biossimilares de anticorpos monoclonais, após uma revisão dos dados existentes na literatura, e emitidas recomendações que garantam a segurança e confiança dos doentes e instituições. O seu objetivo é sustentar a mais correta introdução de biossimilares na prática clínica oncológica.

Palavras chave: Biosimilar; Trastuzumab; Artigo de posicionamento; Oncologia

Abstract
With the upcoming expiration of exclusivity rights for reference monoclonal antibodies (mAbs), the door is open for companies to compete for the development of similar versions of these drugs, or biosimilars. But their high complexity raises several concerns, particularly in the oncology setting. 
As a medical society, the Portuguese Society of Oncology (SPO) believes that oncologists should be fully informed and prepared to make the most proper use of these drugs. As a scientific society, SPO is aware of the need for affordable treatment options, and is willing to work in partnership for the sustainability of the Portuguese healthcare system. It is therefore important that biosimilars fulfill their potential benefits, by preserving the quality, safety and efficacy that has been established for their originators. 
In this position paper, the main scientific evidences regarding biosimilars of mAbs are presented following a literature review, and recommendations made that ensure the safety and confidence of patients and institutions. Its goal is to support biosimilars’ utmost correct introduction into the Oncology clinical practice.

Keywords: Biossimilar; Trastuzumab; Position paper; Oncology


Introduction

Biologic medicinal products, or biologics, are a group of recombinant, protein-based drugs derived from genetically engineered cells (e.g., plants, animals, yeast, and bacteria)1. This technology, based on recombinant DNA, enabled the production of monoclonal antibodies (mAbs), a completely new and complex type of molecules.
For patients, the outcomes of biologics have been remarkable. Treatment with rituximab (MabThera/Rituxan) has halved the number of deaths for patients with non-Hodgkin’s lymphoma2. Treatment with trastuzumab (Herceptin) represented a paradigm shift in oncology from non-specific chemotherapy to a molecularly targeted approach3. Addition of trastuzumab to conventional cytotoxic chemotherapy improved overall response rates (ORR), time to progression (TTP) and overall survival (OS) rates4. 
As many of these drugs reach the end of their exclusivity trading rights, the opportunity to develop copies unfolds, stimulating competition and originating savings for the healthcare systems. However, unlike generic version of original drugs, the development of biosimilars is not straightforward. Exact copies of biologics cannot be made, due to their structural complexity and complicated manufacturing process5,6. 
Developing, evaluating and monitoring a biosimilar mAb in oncology is a new challenge that will require the joint effort and cooperation of all healthcare providers, from regulators, to industry, to oncologists, pharmacists, hospital administrations and patients. 
The intrinsic complexity of antibody structure, the heterogeneity introduced by the manufacturing process, and the potential difficulties associated with the introduction of biosimilar mAbs into clinical practice of oncology must be thoroughly discussed in advance, in order to guarantee that all necessary measures are in place to ensure that the previously established safety and efficacy are preserved.

Definition of biosimilar

Biosimilar products can be broadly defined as copies of an original reference biologic medicine, to which they have demonstrated similarity in terms of quality (physicochemical and biological), biologic activity, safety and efficacy by comparative analytical, pre-clinical and clinical assessments5,7. 
Biosimilars have been commercialized in Europe since 2006, starting with the approval of biosimilars of the molecularweight biologics somatotropin (2006), erythropoietin (2007) and filgrastim (2008)8. In September 2013, the European Commission granted marketing authorization for two biosimilars of the anti-tumor necrosis factor alpha (TNF-α) antibody infliximab9,10, which became the first mAb biosimilar to be approved by a regulatory agency. Patent marketing restrictions for other essential and widely used anticancer mAbs are currently approaching expiration date, and within the next few years these drugs will lose market exclusivity both in Europe and the USA, raising the opportunity for other companies to develop and market biosimilar products. 
Currently, several biosimilar versions of trastuzumab are under development, which when approved, will become the first biosimilar mAb available for cancer treatment. However, the high complexity of biologic drugs such as mAbs underscore the need for extensive evaluations during the biosimilar development and production process, and its use raises a number of new concerns.


The challenges of manufacturing biosimilars

Substantial differences exist between generics and biosimilars, which significantly impact on their manufacturing processes and end products. 
Generics are replicated compounds of small chemical molecules, which exist as homogeneous structures (>98% homogeneity), while biologics can exist as a mixture of different isoforms. Furthermore, the active substance of small molecule drugs can be identically replicated through well-defined chemical synthetic procedures11, while biopharmaceuticals cannot be identically copied12. 
Biologics are produced and isolated from living organisms (like bacteria, yeast and mammalian cells). Their highly complex three-dimensional structures, large dimensions (100–1000 times larger than a small molecule), and the need to produce them in host-cell systems, require a multi-step manufacturing process, each with a profound impact on the structure of the biologic molecule and the potential to introduce a number of heterogeneities and sources of variability. Furthermore, mAbs undergo post-translational modifications such as glycosylation), which need to be fully characterized, since even the smallest differences during the manufacturing process may alter the structure and activity of the molecules and impact on the quality, safety or efficacy of the product13. 
Consequently, it is unlikely that the manufacturing environment can be identically replicated, and hence that a perfectly similar molecule can be recreated from a biologic reference product.


Therapeutic mAbs in oncology

Therapeutic mAbs have existed since 1986, when the first was approved as an antirejection drug. Rituximab was the first anticancer mAb to be introduced in the market, but due to the exponential growth of the use of mAbs in the therapeutic setting, several others followed. 
One of the most widely used oncology mAbs is trastuzumab, approved for the treatment of metastatic breast cancer in 1998 and currently used in the treatment of 15–20% of all breast cancers14. Trastuzumab is an HER2-targeted mAb developed by Genentech as treatment for breast and gastric cancer with overexpression of HER2, a membrane-bound receptor tyrosine kinase. Trastuzumab has become the standard of care for patients with HER2-positive breast cancer approved in adjuvant and neoadjuvant settings as well as treatment for HER2-positive metastatic breast, gastric and gastroesophageal junction cancers15. 
Cetuximab and rituximab lost their patent protection in Europe in June 2014 and November 2013, respectively, and for bevacizumab this will happen in 2022. 
For intravenous (IV) trastuzumab, the patent exclusivity rights expired in Europe in 2014, and will expire in the USA in 2019. Due to its clinical relevance, trastuzumab is one of the main targets for the production of biosimilars, with several molecules lining up to compete with it, including four candidates in Europe undergoing clinical trials in breast cancer (PF-05280014, CT-P6, ABP 980 and SB3)16. 
MAbs used in oncology have no surrogate markers of clinical efficacy (unlike hemoglobin levels for erythropoietin or absolute neutrophil counts for filgrastim), and must therefore rely on clinical endpoints [ORR, complete response (CR), pathological complete response (pCR)] to demonstrate biosimilarity.
Regulatory procedures for the development of biosimilar mAbs in Europe
The regulatory pathway for the approval and market authorization of a biosimilar is different from that of both generics and reference products. 
Since they are not identical to their reference drugs, biosimilars require more thorough testing than generics. However, because they represent copies of molecules that have already undergone a rigorous clinical trial program, their regulatory process is somehow less exhaustive than that of their originators. It can be regarded as an accelerated clinical trial program that typically comprises extensive analytical and biological characterization and Phase I–III clinical studies17. Here, the goal is not to demonstrate patient benefit, since that has already been established for the reference product, but to assess efficacy and safety similarity between the biosimilar mAb and its reference product. Both the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recommend a Phase III equivalence trial design to compare a biosimilar candidate with its reference product6,18. 
Testing mAbs in a clinical setting is crucial because it is not yet possible to predict immunogenicity in humans through animal testing. Immunogenicity may originate unwanted immune responses to the drug, which can be triggered by one or more patient/disease-related factors. After the clinical development and successful approval by authorities, sponsors must put in place a pharmacovigilance plan to help fulfill some of the data gaps that still exist in the approval process. 
The EMA regulates biosimilar approval and marketing authorization in Europe. EMA has issued several guidelines regulating the development of biosimilars, including guidelines for the development and testing of biosimilar mAbs6,19. According to EMA, clinical studies of biosimilar mAbs should use the most sensitive and homogenous patient populations, as well as sensitive clinical endpoints, so that differences in safety, efficacy and immunogenicity between the reference product and the biosimilar can be imputed to product characteristics rather than to patient- and disease-related factors. 
The early breast cancer (EBC) population, either in the neoadjuvant or adjuvant setting, can be considered homogenous and, hence, a sensitive population to extrapolate data on biosimilar approval to a more heterogeneous patient population in metastatic breast cancer (MBC). Populations of patients with metastatic disease are highly heterogeneous due to a high number of confounding factors, such as location of metastasis, time from diagnosis of metastasis, performance status and number and type of prior therapies20, while EBC populations are less likely to have some of these confounding factors. However, the majority of clinical trials involve patients from the metastatic setting, and since this may not be the most sensitive patient population, data obtained are not sufficiently robust to allow extrapolation to an early potentially curative setting21. 
Selection of endpoints in cancer indications is also a challenge in biosimilar trials. The EMA privileges the use of shorter-term efficacy endpoints, as ORR or CR rate, over longterm survival endpoints (progression free-, disease free- or overall survival), since the first are less likely to be influenced by disease-related parameters that accumulate over time, as performance status, tumor burden or previous lines of treatment6.


Post-approval commitments: additional monitoring and risk management plan

In contrast to generic drugs, where the benefit/risk profile is considered the same as for the innovator product, the postmarketing monitoring of the safety of a biosimilar is a formal regulatory requirement in the EU. 
In 2013, EMA released Module 10 of their Good Pharmacovigilance Practices22. This module refers to medicines recently approved, but which require additional monitoring or other requirements above and beyond the routine drug safety and pharmacovigilance practices. These products are designated in their labeling (SmPC, patient leaflets, etc.) with an inverted black triangle. New biologics and biosimilars fall within this scope. 
Next to the black triangle, a standard explanatory statement is also included: "This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.” The aim of this measure is to make healthcare providers and patients aware that the medication in question has particular safety issues that are being actively tracked and monitored. Its presence is a signal to prescribers and patients to report suspected adverse reactions (ADRs) which the EMA terms "enhanced reporting”.
Marketing holders are also required to submit a Risk Management Plan (RMP). This RMP is part of the pharmacovigilance plan that biologic manufacturers must submit as part of the marketing authorization application, which intends to identify any immunogenicity differences and product-associated safety risks not observed during clinical testing, and provide a framework to rapidly report and manage such incidences. It includes information on i) a medicine’s safety profile, ii) how its risks will be prevented or minimized in patients, iii) plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine, iv) risk factors for developing ADRs, and v) methods for measuring the effectiveness of risk-minimization measures. 
Long-term post-marketing data are equally required for the biosimilar and its originator while they are on the market. This is the grounding to identify any safety issues, including rare ADRs, and to avoid that adverse events (AEs) occurring at a very low frequency are only identified and tracked when very large numbers of patients have been exposed. 
Several aspects of the post-approval pharmacovigilance plan are not regulated by EMA, including the name of drugs, interchangeability, automatic substitution and switching between biosimilars and their originators, all crucial aspects for a good surveillance and traceability system. 
In order to make monitoring effective, the correct and unequivocal identification and traceability of the drug is mandatory. The prescription of biologics and biosimilars should be made by brand name and batch number, since the International Nonproprietary Name (INN) alone is not sufficient to trace and identify a biologic/biosimilar drug. In accordance, regulation regarding pharmacovigilance of medicinal products for human use23 addresses the need for clear identification of biologic drugs when reporting AEs.


Extrapolation of indications

Extrapolation of indications is central for biosimilars, and it should be granted on a case-by-case basis and after extensive scientific justification6. It is possible to grant extrapolation if: a) medicines are similar in terms of the totality of evidence obtained both from pre-clinical and clinical studies, and the clinical trial program for biosimilar approval is robust enough; b) the mechanism of action is similar, or in case it is different or unknown, convincing data are presented; and c) safety profile of the biosimilar is sufficiently characterized and unacceptable immunogenicity is excluded. However, these assumptions are difficult to fulfill, because mAbs generally have multiple mechanisms of action, and it is extremely difficult to determine to what extent each mechanism contributes to the activity of a particular medicine and the exact role that key parts of the molecule play in activating different signaling cascades and events. 
Despite controversies, extrapolation with biosimilar mAbs is a reality in clinical practice, where biosimilars of the antibody infliximab (Remicade and Inflectra) have been approved for all the drug’s six indications (psoriasis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis) after a Phase I trial in ankylosing spondylitis and a Phase III trial in rheumatoid arthritis9,10. However, not all jurisdictions have the same approach. For instance, Health Canada authority did not allow extrapolation to inflammatory bowel diseases24. 
The EMA allows extrapolation of indications in the biosimilar setting as long as the mechanism of action is the same across indications, and/or a robust body of scientific evidence is provided, based on strong clinical efficacy and safety data for the biosimilar, and on clinical experience with the original drug6. For biosimilar mAbs specifically, it is hypothesized that extrapolation of indications is legitimate as long as the clinical efficacy and immunogenicity testing are done in the most sensitive patient population25. For HER2-positive breast cancer, this means clinical testing of a biosimilar trastuzumab in the adjuvant or neoadjuvant setting, with extrapolation to metastatic breast cancer; the reverse, however, may not be acceptable, since the metastatic setting does not allow for an appropriate evaluation of immunogenicity signals due to many patients being immune compromised, and the possibility of an increased risk of unpredictable immune responses. Trastuzumab has several approved indications in breast and gastric cancer, but the drug’s mechanism of action in each indication is unclear, and raises issues about the legitimacy of extrapolation. This is further hampered by the different patient populations and disease stages in which trastuzumab is used, which, in the case of breast cancer, mostly include metastatic breast cancer populations that are highly heterogeneous and make it inappropriate to extrapolate safety and efficacy data to other indications.


Labeling

Central to the manufacturing of biologics is a pharmacovigilance plan that allows to accurately trace which medicines a patient is given, and easily identify and report product-associated AEs. In this process, the correct identification of the medicine is fundamental. 
Many medicines are prescribed by their INN, which provides information regarding the composition and type of drug. Biosimilars, like generics, are given the same INN as the originator26, and their summary of product characteristics, or labels, are also very similar to the originator, meaning that it may not be recognized as a biosimilar. This constitutes a problem when tracking and reporting AEs, where it is of utmost importance to differentiate between the biosimilar and its originator. 
Consequently, EMA recommends that drug prescription should be made by brand name and not by INN27,28. Also, the following statement has been included on the label of biologic products: ‘‘in order to improve the traceability of biologic medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file’’, as has already been done for MabThera (rituximab)29 and Avastin (bevacizumab)30.


Interchangeability

Due to their simplicity, generic medicines are often considered therapeutically equivalent to the originators, and therefore these drugs are deemed ‘interchangeable’. 
However, for some generics interchangeability is not straightforward, as the cyclosporin example showed31. 
For biosimilars, granting the designation of "interchangeable” is more challenging, due to the subtle differences between an originator and its biosimilar. In the subject of interchangeability, both the EMA and the FDA differ in their approach. 
According to the FDA, an interchangeable biosimilar is "expected to produce the same clinical result as the reference product in any given patient”, and safety and efficacy risks cannot be greater than using the reference medicine without switching. 
In the EU, this is left for the member states to decide, for EMA does not have the legal authority to make this assessment. Norway has sponsored a Phase IV clinical study, the NORSWITCH Study (ClinicalTrials.gov # NCT02148640), to gather data on the safety of switching between and originator and a biosimilar. Biosimilars, due to their slight differences and lack of clinical data in extrapolated indications, may not be regarded as therapeutically equivalent to the reference medicine, and hence interchangeable. Therapeutic equivalence in terms of safety and efficacy should be confirmed postapproval in real-life conditions. EMA does not pronounce on this issue, and each country in the EU is currently allowed to individually deliberate which medicines are interchangeable. This definition is very important, because if a medicine is considered interchangeable it can make switching easier or even automatic, provided that good registries and a traceability system are in place.


Automatic substitution

Automatic substitution consists of switching the prescription of a biologic for another or a biosimilar, without consulting the prescribing physician. This is a topic of hot debate, because it is questionable if such practice should be applied to biologics and biosimilars, or if it should be applied at all. Although different positions exist across countries regarding this issue, most of them do not allow automatic substitution of biologic and biosimilar medicines32. 
When products are considered interchangeable, pharmacists may be authorized to automatically substitute the same type of drugs for one another, and hence patients may receive either the biosimilar or the originator regardless of what the physician has prescribed and recorded. Due to this automatic switching, that can be done between originator and biosimilar but also between biosimilars, any ADRs developed by the patient can be attributed to an incorrect source by the physician, compromising the traceability of the biologic product. Furthermore, this allows patients to be switched between two similar biologic drugs, with increased risk of anti-drug antibodies, possibly leading to adverse immunologic reactions and decreased drug efficacy. 
Also of relevance is the fact that, whenever automatic substitution occurs, chances are that patients will not receive all the relevant information about the medicines being introduced after the switch. This can lead to medication errors, with patients taking extra doses of medicine or simply not complying with instructions previously given by the prescriber physician, due to confusion or the sudden appearance of AEs. 
In Portugal, automatic substitution may also occur at the level of the Informatic Prescription Systems operating in a variety of hospitals, with physicians prescribing a medicine by brand name, and the system itself automatically altering the prescription for another medicine based on the INN alone. This can be challenging in several situations, namely: 1) when therapeutic margins are narrow, 2) when a previous AE has occurred, and 3) in cases that require continuity of treatment33. In such cases, the physician is both unable to protect his medical judgment, or to prevent automatic substitution from occurring.


RECOMMENDATIONS OF THE PORTUGUESE SOCIETY OF ONCOLOGY ON THE USE OF BIOSIMILAR DRUGS IN THE TREATMENT OF CANCER

1) Drug selection based on clinical data 
Physician drug selection and prescription is the corollary of a technical and scientific process that takes into account several variables, including not only those related to the drug and the disease, but also to the patient. Cost must not be the only factor in drug selection. In every case, oncologists should base their decision on drug efficacy, drug safety and cost-effectiveness data, whenever available. It is important to keep in mind that clinicians and patients should be well informed about the medicines, and willing to comply with additional monitoring requirements.

2) Prescription by brand name and traceability
To enhance the pharmacovigilance of biosimilars following their marketing authorization, with their AE tracking and reporting, it is strongly recommended that physicians prescribe all biologics by brand name, particularly if biosimilars have the same INN as their originators. This will avoid confounding different commercial brands of biologics, and prevent automatic or accidental substitution or switching by pharmacies. Whenever possible, batch number should also be recorded to allow clear identification of the biologic medicine. Unlike generic drugs, since the reference product and the biosimilar are manufactured differently, it is essential to know exactly which product a patient is receiving at a given moment. 
The Portuguese Society of Oncology strongly recommends that each biosimilar is assigned a digital code print that enables its traceability from manufacturing to patient administration. Traceability is crucial, and, therefore, proper recording of the name of the medicine on the patient file is advised, following the recommendations already stated on the product information literature.

3) Extrapolation
The clinical evaluation of biosimilar cancer mAbs should be performed in homogeneous patient populations, to minimize the effect of clinical confounders, so that the true safety and efficacy of the biosimilar is evaluable. 
Oncologists should be involved in the clinical trial design to assure that the correct patient population is selected by the sponsor and that EMA requirements are met. The clinical evidence must be critically reviewed to evaluate whether it can be extrapolated to clinical indications other than those tested in the trials performed for drug approval. 
A monitoring pharmacovigilance program should be set up for each biosimilar, in which the physician should assume the responsibility to monitor patients accordingly.

4) Interchangeability
If a patient is treated with a biosimilar with clinical benefit and the expected drug toxicity, switching to another biosimilar should be discouraged. The decision to switch to another biologic should be made on a case-by-case basis and safeguard measures should be taken to ensure that patients with a good clinical response are not switched to another medicine for non-clinical reasons. If switching of the biologic is done, patients should be adequately informed and proper registries performed. 
For patients initiating treatment (naïve patients), the use of a biosimilar may be legitimate, provided the physician is consulted and the patient is properly informed. 
Physicians and patients should be aware of the need to monitor the effects of biologics and biosimilars, and should be willing to report any eventual AEs. Patients starting a new biologic or biosimilar, or undergoing drug switching, should be adequately informed and monitored for efficacy and safety.

5) Multiple treatment switches
Outcomes in oncology take a long time to occur and ineffective therapies can have fatal consequences. Therefore, it is strongly discouraged that patients are submitted to multiple drug switches throughout the course of therapy. Multiple switches can produce unexpected risks to patients (e.g., immunogenicity) and can hamper identification of the relationship of AEs to a specific biologic. When a patient is stable, with clinical drug benefit and without unexpected toxicities, treatment with that biologic should be maintained and not switched.

6) Automatic substitution
The decision to prescribe a specific biologic derives from an individualized analysis by the prescribing physician, and hence any treatment switches should not be done without the involvement of the treating physician. Automatic substitution of biologics and biosimilars is unacceptable and should not be authorized. Also, there is an urgent need to implement a prescription system (digital or paper) that registers the prescriber’s decision.

7) Transparency of labeling
Product literature, such as the Summary of Product Characteristics (SmPC), is a fundamental tool for oncologists, since all the information regarding a specific medicine is fully compiled and readily available. It should, therefore, be clearly stated that the medicine is a biosimilar. It should also be clear which information was obtained from clinical studies, which clinical studies were performed and which treatment indications were obtained through extrapolation, in order to help the patient´s physician to choose the most appropriate medicine for each circumstance. It should be clearly stated which information was obtained for the biosimilar and for the reference product. Transparent and clear literature contributes to a safe and effective use of medicines.

8) Pharmacovigilance requirements and additional monitoring
Given the limited number of patients studied during the registration process of a biosimilar, and the low incidence of some AEs, special emphasis should be given to risk-management/ pharmacovigilance, in order to detect potential safety signals. This can be achieved by collaborating with patient registries and clinical data monitoring systems established in several countries, and by recording safety information (including rare and serious AEs, and previously unreported safety signals that may have been observed) and immunogenicity data (since they may occur only in a small number of patients). For AEs caused by biologics/biosimilars, the brand name and batch number should be reported to unequivocally identify the suspected drug.

9) Registries and databases
A robust safety monitoring strategy must be implemented to protect patients and collect the long-term evidence required to provide oncologists and patients with the necessary assurances on safety and effectiveness. EMA recommends that all companies who hold the manufacturing authorization for biosimilars should participate in pharmacoepidemiological studies, including registries set up primarily to monitor the safety of the reference medicines. Ideally, a registry database should be implemented for all patients starting or switching to biosimilars, which should also include the AEs reported for the reference medicine.

10) Costs and tenders
While minimizing the cost of drugs is a societal imperative, patient care should be the undisputed primary concern of physicians. Therefore, although biosimilars have the potential to reduce drug costs in oncology, biosimilars must show evidence of similar patient benefit to the parental compound.

11) Multidisciplinary work and sharing of information
The introduction of new medicines, such as biosimilars, reinforces the need for a collaborative approach between caregivers, both at the hospital level and within the community. A good communication and sharing of information between clinical practice, pharmacy and hospitals is needed to ensure that all healthcare professionals are aware of the efficacy and toxicity of the different commercial brands of pharmaceutical products and that these data are rapidly forwarded to the prescribing clinician.

12) Increase knowledge and awareness on biologics and biosimilars
The healthcare system is complex, with many stakeholders making decisions that can ultimately impact on the clinical practice and safety of patients. All healthcare professionals would benefit from more information about biosimilars to optimize their use. The different stakeholders and health institutions, together with medical societies and patient organizations, should engage in a multidisciplinary approach, to promote meetings, exchange-forums and awareness-raising campaigns in order to increase knowledge about this issue and set up the conditions for the adequate use of biosimilars.


Acknowledgements
The authors would like to acknowledge the contributions of Dr. Nuno Miranda, from IPO Lisboa and coordinator of the National Program for Oncologic Diseases; Dr. Armando Alcobia, Head of Pharmacy Department of Hospital Garcia de Orta; Prof. Doctor João Gonçalves, from the Research Institute for Medicines of Faculty of Pharmacy, University of Lisbon (iMed.ULisboa); and Dr. José Aleixo, Medical Director at Pfizer, for this manuscript.

Funding
Sponsorship for this manuscript was received by Roche Farmacêutica Química, Lda.

Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Medical writing, editorial, and other assistance
Medical writing and editorial assistance in the preparation of this manuscript was provided by Doctor Joana Cavaco Silva (jo.cvsilva@gmail.com).

Disclosures
The authors declare the following competing interests: Gabriela Sousa received a speaker honorarium from AstraZeneca, Janssen, Sanofi and Roche, research grants from Pfizer, Roche, Astellas and Novartis, and participated in advisory boards from Pfizer, Roche, Janssen, Celgene, Pierre Fabre and Grünenthal. José Luís Passos Coelho received a speaker honorarium from Roche, Pfizer, Janssen, Celgene, Astellas, Novartis, Astra-Zeneca, Amgen and BMS, research grants from BMS, Amgen and Pfizer, and served in advisory boards from Roche, Pfizer, Janssen, Celgene, Astellas, Novartis, AstraZeneca, Amgen and BMS. Noémia Afonso received a speaker honorarium from Eisai, AstraZeneca and Celgene, research grants from Roche, Novartis, Pfizer and AstraZeneca, and served in advisory boards from Pfizer, Novartis, Celgene and PharmaMar; António Moreira received a speaker honorarium from Roche, research grants from Roche and Novartis, and served in advisory boards from Roche and Pierre Fabre. Deolinda Pereira received a speaker honorarium from Roche and Astellas, research grants from Roche, Janssen, Celgene, MSD, Amgen,and PharmaMar, and served in advisory boards from Roche, Pfizer, Janssen and AstraZeneca; Hélder Mansinho received a speaker honorarium from Janssen, OM Pharma, Leo Pharma, Celgene, Lilly, Merck and Amgen, research grants from Celgene, Roche, Astellas, Merck, Janssen and Pfizer, and served in advisory boards from Roche, Pfizer, Servier, Astellas, Janssen, OM Pharma, Leo Pharma, Celgene, Lilly, BMS and Merck; Helena Gervásio served in advisory boards from AstraZeneca; Paulo Cortes received a speaker honorarium from Roche, BMS, MSD and Pierre Fabre, research grants from Roche, Amgen and AstraZeneca, and served in advisory boards from Roche, Pfizer, MSD and AstraZeneca.

Compliance with ethics guidelines
This article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.


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