Novelties in Dermatology
Biosimilars in Dermatology: Current Situation (Part II)
Biosimilares en dermatología. Situación actual (parte ii)
L. Puiga,
, G. Carreterob, E. Daudénc, C. Ferrándizd, S.E. Marróne, A. Martorellf, B. Pérez-Suárezg, C. Rodriguez-Cerdeirah, R. Ruiz-Villaverdei, J.L. Sánchez-Carazoj, M. Velascok, on behalf of the Psoriasis Group of the Academia Española de Dermatología y Venereología
Autor para correspondencia
a Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
b Servicio de Dermatología, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
c Servicio de Dermatología, Hospital Universitario de La Princesa, Madrid, Spain
d Servicio de Dermatología, Hospital Universitario Germans Trias i Pujol (HUGiT), Badalona, Barcelona, Spain
e Unidad Clínica de Dermatología, Hospital de Alcañiz, Instituto Aragonés de Ciencias de la Salud (IACS), Alcañiz, Spain
f Servicio de Dermatología, Hospital de Manises, Valencia, Spain
g Servicio de Dermatología, Hospital Morales Meseguer, Murcia, Spain
h Servicio de Dermatología, Complejo Hospitalario de Vigo, EOXI, Vigo, Spain
i UGC Dermatología, Hospital Universitario Virgen de las Nieves, Granada, Spain
j Servicio de Dermatología, Hospital General Universitario de Valencia, Valencia, Spain
k Servicio de Dermatología, Hospital Arnau de Vilanova, Valencia, Spain
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"apellidos" => "Velasco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">k</span>" "identificador" => "aff0055" ] ] ] 11 => array:1 [ "colaborador" => "on behalf of the Psoriasis Group of the Academia Española de Dermatología y Venereología" ] ] "afiliaciones" => array:11 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitario de La Princesa, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitario Germans Trias i Pujol (HUGiT), Badalona, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad Clínica de Dermatología, Hospital de Alcañiz, Instituto Aragonés de Ciencias de la Salud (IACS), Alcañiz, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital de Manises, Valencia, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Morales Meseguer, Murcia, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Servicio de Dermatología, Complejo Hospitalario de Vigo, EOXI, Vigo, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "UGC Dermatología, Hospital Universitario Virgen de las Nieves, Granada, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital General Universitario de Valencia, Valencia, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Arnau de Vilanova, Valencia, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Biosimilares en dermatología. Situación actual (parte <span class="elsevierStyleSmallCaps">ii</span>)" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Extrapolation to Other Indications</span><p id="par0005" class="elsevierStylePara elsevierViewall">In September 2013, the European Medicines Agency (EMA) approved CT-P13, the first biosimilar of the monoclonal antibody infliximab. This biosimilar antibody was developed by Celltrion and launched in Spain on February 16, 2015 (after the patent for Remicade had expired) under the names of Remsima (Celltrion Healthcare Hungary Kft, distributed by Kern Pharma) and Inflectra (Hospira UK Ltd). This product is approved for all of Remicade's indications (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn disease, ulcerative colitis, and plaque psoriasis, and Crohn disease and ulcerative colitis in children), although the comparative clinical trials were only conducted in patients with rheumatoid arthritis and ankylosing spondilytis.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> The Canadian medicines agency (Health Canada), the EMA, and the Food and Drug Administration (FDA) are the main agencies to have taken a stance on the regulatory considerations for permitting extrapolation of indications in biosimilar medicines. The EMA considered the results of the trials for patients with rheumatoid arthritis to be sufficiently sensitive to permit extrapolation to all other indications. Health Canada, in contrast, has not approved extrapolation for indications in inflammatory bowel disease because of differences in the in vitro antibody-dependent cytotoxicity assays, potential differences in the mechanism of action of the agent in these indications, and the lack of clinical trials.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">When interpreting the comparative studies of this first biosimilar monoclonal antibody to be approved, certain considerations need to be addressed<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">3–5</span></a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1.</span><p id="par0015" class="elsevierStylePara elsevierViewall">In comparative clinical trials in patients with rheumatoid arthritis and ankylosing spondylitis, participants are allowed to use methotrexate. Methotrexate is a drug that is indicated in its own right for the treatment of rheumatoid arthritis. It also enhances the action of infliximab and other tumor necrosis factor inhibitors (anti-TNF) by reducing immunogenicity. In rheumatoid arthritis, combined use is common. However, in other indications such as psoriatic arthritis, Crohn disease, ulcerative colitis, and plaque psoriasis, anti-TNF agents are usually used in monotherapy or in combination with other immunosuppressive drugs. Rheumatoid arthritis may therefore not be the most sensitive disease for measuring significant differences between drugs.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2.</span><p id="par0020" class="elsevierStylePara elsevierViewall">With regard to the mechanism of action, antigen neutralization only requires binding to the Fab fraction of immunoglobulin, whereas antigen-dependent cell cytotoxicity and induction of apoptosis require the participation of the Fab and Fc fractions of the monoclonal antibody, acting on the appropriate receptors of the effector cell. The first of the above mechanisms of action appears to be key in rheumatoid arthritis, whereas the second is more important in inflammatory bowel disease.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3.</span><p id="par0025" class="elsevierStylePara elsevierViewall">With regard to immunogenicity, the FDA recommends using the most sensitive population to detect it, that is, the one at greatest risk of developing an immune response to the drug through formation of antidrug antibodies. This process is closely correlated with side effects, which are mainly acute and include events such as infusion-related reactions in the case of infliximab. In this case, the ankylosing spondylitis population is perhaps not the most sensitive because these patients have been shown to develop antidrug antibodies less frequently than patients with plaque psoriasis, Crohn disease, and ulcerative colitis.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4.</span><p id="par0030" class="elsevierStylePara elsevierViewall">In terms of safety, comparative clinical studies in patients with rheumatoid arthritis and ankylosing spondylitis did not include pediatric patients or patients who were receiving immunosuppressants other than methotrexate, and so extrapolation in these cases would require extreme caution.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5.</span><p id="par0035" class="elsevierStylePara elsevierViewall">From the pharmacokinetic point of view, there are also differences in the clearance rate according to the patients’ underlying disease, as clearance ie 45% higher in patients with Crohn disease than in those with rheumatoid arthritis. This clearance rate may also be affected by the use of concomitant medication and development of antidrug antibodies.</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">Some scientific societies have started to pronounce against extrapolation of indications, or in favor of doing so provided that effective and safe clinical use is guaranteed, supported by appropriate postmarketing pharmacovigilance systems for the product.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">5,6</span></a> When the target organ (musculoskeletal system, digestive tract, or skin) differs and there may be differences in terms of mechanism of action, it is recommended to conduct independent clinical trials to confirm the extrapolation, and evaluate each case on an individual basis.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">7</span></a> Although absolute certainty is impossible to achieve, the degree of uncertainty is less for biosimilars than for the innovative product. In fact, biosimilars have been on the European market for several years, and their performance has been as expected in all approved indications, including the extrapolated ones.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Traceability</span><p id="par0045" class="elsevierStylePara elsevierViewall">The EMA, in collaboration with the member states of the European Union (EU), is obliged to draw up, update, and publish in the public domain the list of drugs that are subject to additional follow-up, that is, medicinal products authorized in the EU that contain a new active substance which, on 1 January 2011, was not contained in any previously authorized medicinal product as well as any biological medicinal product authorized thenceforth (Articles 17 and 23 of EC Regulation 1235/2010). As regards pharmacovigilance and notification of adverse events, Directive 2010/84/EU amends Article 102 of Directive 2001/83/EU, requiring member states to enact appropriate measures for identifying any prescribed biologic drug that is dispensed or sold in their territory and to record the trade name and batch number in the event that an adverse event is reported.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In any case, traceability will be possible only through large pharmacovigilance databases and through specific studies and registries. The supply chain shall be identified and it shall be possible to trace the drug in the event of adverse reactions occurring during treatment.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Interchangeability and Substitution</span><p id="par0055" class="elsevierStylePara elsevierViewall">The requirements for interchangeability have not been completely defined.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">10</span></a> In the United States, the Biologics Price Competition and Innovation (BPCI) Act requires the following conditions for a product to be considered interchangeable<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a>: the biologic has to be biosimilar to the reference drug; the biosimilar can be expected to give the same clinical result as the reference product in a given patient; and, for a biosimilar administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between products should not be greater than the use of the reference drug without such alternation or switch.</p><p id="par0060" class="elsevierStylePara elsevierViewall">According to many experts, substitution (by the pharmacist, without approval of the prescriber) may be harmful for the patient, hinder pharmacovigilance, and reduce the traceability of the biosimilar.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">12</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The regulations vary according to each region. In the United States, the FDA has established that a biosimilar that complies with the requirements of the BPCI act can automatically be substituted. In Europe, the EMA delegates the responsibility for this decision to the member states. For the time being, few member states have clearly defined their position, and the regulatory requirement in Spain is confusing and pending development.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The scientific societies of the different specialties that use biologics are taking positions on the question of substitution, among other issues. In a recent position statement, the Spanish Society of Rheumatology concluded that “biologic agents are not generic versions of their reference product and so are not automatically interchangeable. The substitution of a biologic agent with a biosimilar is a medical act that should be performed exclusively by the prescribing physician with the consent of the patient.”<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">13</span></a> For its part, the Spanish Society for Digestive Diseases, along with the Spanish Society of Pharmacology, in an article describing their institutional stance, concludes that substituting a biosimilar for a biologic reference agent is an unacceptable practice.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">14</span></a> The organizations of patients with chronic diseases (whose members number more than 5 million) have also pronounced in this respect, and are against interchangeability and substitution of a biologic with a biosimilar.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Current Situation in Dermatology and Future Prospects</span><p id="par0075" class="elsevierStylePara elsevierViewall">The approval of an infliximab biosimilar by the EMA has paved the way for other biosimilars of original biologics whose patent is close to expiry.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">16</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Currently, clinical trials are ongoing with biosimilars of etanercept and adalimumab, both in psoriasis and rheumatoid arthritis. In the case of psoriasis, the trial of the etanercept biosimilar GP2015 (Sandoz/Hexal, trial identification NCT01891864), with 546 patients, is expected to finish in April of 2015. There are also 2 ongoing trials of biosimilars of adalimumab (whose patent expires in 2018): APB 501 by Amgen, with 350 patients (NCT01970488) with expected end date of June 2015, and GP2017 by Sandoz/Hexal, with 448 patients (NCT02016105), expected to finish in August 2015.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Of note, not all the drugs that have been marketed as biosimilars in some countries comply with the European legislation. For example, etanercept has 2 biosimilar products produced in China. One of these, despite similar affinity and bioactivity to the original, has a different molecular mass, amino acid composition, and glycosylation pattern, thus not meeting the EU requirements for recognition as a biosimilar.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">17</span></a> Strictly speaking, this agent can only be considered as an intended copy. Regulatory harmonization and development of pharmacovigilance systems are necessary in countries with regulations less stringent than those of the EMA.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Final Considerations</span><p id="par0090" class="elsevierStylePara elsevierViewall">The biologics market looms large but also risky. Only large companies appear able to enter the sector and navigate regulatory issues. Part of the initial investment requires acquisition of the original product for the clinical trials, and also implementation of the pharmacovigilance measures demanded by the regulatory authorities. There is also the risk of additional costs arising from extension of the original patent protection and intellectual property litigation, which not may only delay the launch of stockpiled product but also cause losses if the expiry date is exceeded. Nevertheless, the manufacturing process for biosimilars is less expensive than that of the original, since the technology used is more up to date. In addition, biosimilars require fewer clinical trials than the original for approval in different indications. Cost is also an important driver for the healthcare systems: biosimilars are expected to reduce procurement costs not only because the biosimilar itself is less expensive but because the price of the corresponding original may decrease, either through market pressures or as a result of regulatory impositions.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Progress will not be easy for biosimilars, as they require appropriate distribution and supply logistics, as well as a special pharmacovigilance plan, with particular focus on potentially serious adverse effects. They will also need to overcome the initial reticence of physicians to use a product that has not been tested in specific clinical trials for the indication, and without the years of experience that reference products offer. Automatic substitution of the original product with a biosimilar is not feasible in the Spanish system without a medical prescription. In addition, if the difference in recommended retail price, the only initial advantage of the biosimilars, is evened out, it will be hard to convince the physicians to turn to a biosimilar as a first option.</p><p id="par0100" class="elsevierStylePara elsevierViewall">In any case, time will tell whether biosimilars are the solution to ensure access for a broad sector of the population to certain treatments which would otherwise be too expensive for health systems or whether the reference products will continue to be used due to lower costs resulting from competition with biosimilars.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflicts of Interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">L. Puig has received consultant fees and/or speakers fees from Abbvie, Amgen, Boehringer-Ingelheim, Celgene, Janssen, Leo-Pharma, Lilly, MSD, Merck-Serono, Novartis, and Pfizer, and has participated in clinical trials sponsored by Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, and VBL. G. Carretero has participated in clinical trials and postmarketing studies sponsored or funded by Abbvie, Celgene, Janssen, Lilly, MSD, Novartis, and Pfizer. He has received speaker or consultant fees from Abbvie, Celgene, Janssen, MSD, Novartis, Pfizer, and Leo Pharma. E. Daudén has carried out the following activities: advisory board member, consultant, grant recipient, research support, participation in clinical trials, paid talks with the following pharmaceutical companies: Abbvie/Abbott, Amgen, Janssen-Cilag, Leo Pharma, MSD, Pfizer, Novartis, Celgene, and Lilly. S.E. Marrón has received consultant and speaker fees from Abbvie, Janssen, Merck-Serono, MSD, and Pfizer. He has participated in clinical trials sponsored by Amgen and VBL. A. Martorell has received consultant fees and/or speaker fees, and/or has participated in clinical trials sponsored by Novartis, Abbvie, Janssen, Galderma, and Pfizer. B. Pérez-Suárez has received consultant fees and/or speaker fees, and has participated in clinical trials sponsored by Almirall, Abbvie, Janssen, and Pfizer. C. Rodríguez-Cerdeira has received consultant and speaker fees from Abbvie, Janssen, Merck-Serono, MSD, and Almirall. R. Ruiz-Villaverde has received consultant and speaker fees from Abbvie, Janssen, Merck-Serono, MSD, Novartis, and Pfizer. J.L. Sánchez-Carazo has received consultant, speaker, and advisory board member fees from Abbvie, Amgen, Celgene, Janssen, Lilly, MSD, Merck-Serono, Novartis, and Pfizer, and has participated in clinical trials sponsored by Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, and VBL. M. Velasco has participated in clinical trials sponsored by Pfizer España and has received consultant and speaker fees from Abbvie, Merck, Janssen, and Pfizer. The remaining authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres543965" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec563097" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres543966" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec563096" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Extrapolation to Other Indications" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Traceability" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Interchangeability and Substitution" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Current Situation in Dermatology and Future Prospects" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Final Considerations" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-04-23" "fechaAceptado" => "2015-04-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec563097" "palabras" => array:10 [ 0 => "Psoriasis" 1 => "Biosimilar" 2 => "Biologic" 3 => "Clinical trials" 4 => "Interchangeability" 5 => "Substitution" 6 => "Legislation" 7 => "Infliximab" 8 => "Etanercept" 9 => "Adalimumab" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec563096" "palabras" => array:10 [ 0 => "Psoriasis" 1 => "Biosimilar" 2 => "Biológico" 3 => "Ensayos clínicos" 4 => "Intercambiabilidad" 5 => "Sustitución" 6 => "Legislación" 7 => "Infliximab" 8 => "Etanercept" 9 => "Adalimumab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The first biosimilar version of a biologic agent used to treat psoriasis (infliximab) entered the Spanish market on February 16 of this year, and more biosimilars can be expected to follow in the coming months and years. Logically, this new situation will have economic repercussions and alter prescribing patterns among dermatologists. In this second part of the review, we will look at several somewhat contentious issues, such as the extrapolation of indications, interchangeability, and automatic substitution. We will also review the biosimilars with indications for psoriasis currently in the clinical development pipeline and assess their potential to offer comparable efficacy and safety to the reference product while contributing to the sustainability of the public health care system.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El 16 de febrero de este año se han comercializado en España los primeros biosimilares de un tratamiento biológico para la psoriasis (infliximab), y en los próximos meses y años está prevista la incorporación de otros biosimilares, con un previsible impacto económico y en los hábitos de prescripción dermatológicos. En esta parte de la revisión se abordan aspectos objeto de cierta controversia, como la extrapolación de indicaciones, la intercambiabilidad y sustitución automática, los biosimilares en fase clínica de desarrollo con indicaciones que incluyen la psoriasis, y unas consideraciones finales sobre el potencial de estos fármacos para proporcionar unas alternativas terapéuticas de eficacia y seguridad comparables a las de sus productos de referencia, contribuyendo a la sostenibilidad del sistema sanitario público.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Puig L, Carretero G, Daudén E, Ferrándiz C, Marrón SE, Martorell A, et al. Biosimilares en dermatología. Situación actual (parte <span class="elsevierStyleSmallCaps">ii</span>). 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 5 | 7 | 12 |
| 2024 Octubre | 67 | 43 | 110 |
| 2024 Septiembre | 93 | 35 | 128 |
| 2024 Agosto | 94 | 94 | 188 |
| 2024 Julio | 72 | 29 | 101 |
| 2024 Junio | 78 | 27 | 105 |
| 2024 Mayo | 78 | 28 | 106 |
| 2024 Abril | 80 | 28 | 108 |
| 2024 Marzo | 63 | 29 | 92 |
| 2024 Febrero | 47 | 38 | 85 |
| 2024 Enero | 53 | 30 | 83 |
| 2023 Diciembre | 56 | 15 | 71 |
| 2023 Noviembre | 34 | 25 | 59 |
| 2023 Octubre | 41 | 28 | 69 |
| 2023 Septiembre | 42 | 24 | 66 |
| 2023 Agosto | 38 | 9 | 47 |
| 2023 Julio | 42 | 29 | 71 |
| 2023 Junio | 59 | 24 | 83 |
| 2023 Mayo | 57 | 26 | 83 |
| 2023 Abril | 41 | 24 | 65 |
| 2023 Marzo | 57 | 21 | 78 |
| 2023 Febrero | 69 | 20 | 89 |
| 2023 Enero | 36 | 26 | 62 |
| 2022 Diciembre | 46 | 59 | 105 |
| 2022 Noviembre | 45 | 32 | 77 |
| 2022 Octubre | 29 | 18 | 47 |
| 2022 Septiembre | 36 | 33 | 69 |
| 2022 Agosto | 43 | 42 | 85 |
| 2022 Julio | 34 | 35 | 69 |
| 2022 Junio | 23 | 34 | 57 |
| 2022 Mayo | 24 | 25 | 49 |
| 2022 Abril | 32 | 35 | 67 |
| 2022 Marzo | 38 | 49 | 87 |
| 2022 Febrero | 22 | 27 | 49 |
| 2022 Enero | 33 | 54 | 87 |
| 2021 Diciembre | 30 | 51 | 81 |
| 2021 Noviembre | 27 | 51 | 78 |
| 2021 Octubre | 34 | 45 | 79 |
| 2021 Septiembre | 28 | 31 | 59 |
| 2021 Agosto | 28 | 29 | 57 |
| 2021 Julio | 26 | 29 | 55 |
| 2021 Junio | 39 | 24 | 63 |
| 2021 Mayo | 42 | 34 | 76 |
| 2021 Abril | 95 | 52 | 147 |
| 2021 Marzo | 84 | 18 | 102 |
| 2021 Febrero | 59 | 28 | 87 |
| 2021 Enero | 47 | 18 | 65 |
| 2020 Diciembre | 44 | 20 | 64 |
| 2020 Noviembre | 23 | 15 | 38 |
| 2020 Octubre | 25 | 19 | 44 |
| 2020 Septiembre | 42 | 24 | 66 |
| 2020 Agosto | 27 | 44 | 71 |
| 2020 Julio | 31 | 22 | 53 |
| 2020 Junio | 39 | 36 | 75 |
| 2020 Mayo | 28 | 17 | 45 |
| 2020 Abril | 41 | 26 | 67 |
| 2020 Marzo | 34 | 29 | 63 |
| 2020 Febrero | 7 | 6 | 13 |
| 2020 Enero | 6 | 0 | 6 |
| 2019 Diciembre | 8 | 6 | 14 |
| 2019 Noviembre | 4 | 2 | 6 |
| 2019 Octubre | 0 | 4 | 4 |
| 2019 Septiembre | 4 | 5 | 9 |
| 2019 Agosto | 4 | 5 | 9 |
| 2019 Julio | 4 | 17 | 21 |
| 2019 Junio | 4 | 20 | 24 |
| 2019 Mayo | 7 | 98 | 105 |
| 2019 Abril | 2 | 58 | 60 |
| 2019 Marzo | 4 | 9 | 13 |
| 2019 Febrero | 0 | 5 | 5 |
| 2019 Enero | 3 | 10 | 13 |
| 2018 Diciembre | 2 | 0 | 2 |
| 2018 Noviembre | 3 | 0 | 3 |
| 2018 Octubre | 4 | 0 | 4 |
| 2018 Septiembre | 7 | 3 | 10 |
| 2018 Agosto | 0 | 10 | 10 |
| 2018 Julio | 0 | 7 | 7 |
| 2018 Junio | 0 | 7 | 7 |
| 2018 Mayo | 0 | 6 | 6 |
| 2018 Abril | 0 | 1 | 1 |
| 2018 Marzo | 1 | 0 | 1 |
| 2018 Febrero | 16 | 5 | 21 |
| 2018 Enero | 34 | 8 | 42 |
| 2017 Diciembre | 28 | 9 | 37 |
| 2017 Noviembre | 24 | 12 | 36 |
| 2017 Octubre | 27 | 8 | 35 |
| 2017 Septiembre | 20 | 7 | 27 |
| 2017 Agosto | 22 | 13 | 35 |
| 2017 Julio | 21 | 19 | 40 |
| 2017 Junio | 21 | 22 | 43 |
| 2017 Mayo | 26 | 20 | 46 |
| 2017 Abril | 21 | 14 | 35 |
| 2017 Marzo | 18 | 30 | 48 |
| 2017 Febrero | 27 | 14 | 41 |
| 2017 Enero | 13 | 16 | 29 |
| 2016 Diciembre | 37 | 17 | 54 |
| 2016 Noviembre | 31 | 24 | 55 |
| 2016 Octubre | 21 | 21 | 42 |
| 2016 Septiembre | 0 | 2 | 2 |
| 2016 Agosto | 1 | 4 | 5 |
| 2016 Julio | 4 | 4 | 8 |
| 2016 Junio | 3 | 3 | 6 |
| 2016 Mayo | 3 | 9 | 12 |
| 2016 Abril | 2 | 5 | 7 |
| 2016 Marzo | 3 | 11 | 14 |
| 2016 Enero | 0 | 8 | 8 |
| 2015 Diciembre | 0 | 8 | 8 |
| 2015 Noviembre | 0 | 17 | 17 |
| 2015 Octubre | 0 | 22 | 22 |
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