Opinion Article
Biosimilars in Dermatology: Starting With Infliximab
Biosimilares en dermatología: infliximab para empezar
L. Puig
Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain
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A, Low-power magnification. B, Detail of neoplastic cells with a granular cytoplasm. C, The same specimen studied immunohistochemically with calretinin. D, Detail of calretinin-positive neoplastic cells.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Fuertes, C. Santonja, H. Kutzner, L. Requena" "autores" => array:4 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Fuertes" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Santonja" ] 2 => array:2 [ "nombre" => "H." "apellidos" => "Kutzner" ] 3 => array:2 [ "nombre" => "L." "apellidos" => "Requena" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S000173101200347X" "doi" => "10.1016/j.ad.2012.02.018" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S000173101200347X?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219013000322?idApp=UINPBA000044" "url" => "/15782190/0000010400000003/v1_201304241622/S1578219013000322/v1_201304241622/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Opinion Article</span>" "titulo" => "Biosimilars in Dermatology: Starting With Infliximab" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "175" "paginaFinal" => "180" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "L. Puig" "autores" => array:1 [ 0 => array:3 [ "nombre" => "L." "apellidos" => "Puig" "email" => array:1 [ 0 => "lpuig@santpau.cat" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Biosimilares en dermatología: infliximab para empezar" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">A recent event of considerable significance for the pharmaceutical industry may have been overlooked by many dermatologists in spite of its great relevance to our specialty: I refer to the approval of Remsima by South Korea's Food and Drug Administration (FDA) on July 23, 2012. Remsima (previously, CT-P13) is the first biosimilar version of a monoclonal antibody (specifically infliximab, or Remicade).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Although Reditux, a rituximab (MabThera) biosimilar, was approved in India in 2007, the Indian standards differ considerably from international ones, whereas the Korean standards do not.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Celltrion, the laboratory that developed CT-P13 and has invested some USD $200 million in Remsima so far,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> brought the results of the PLANET trials to the EULAR congress in Berlin earlier in 2012. Those trials, in which 125 centers in 19 different countries participated, included a phase I trial in 250 patients with ankylosing spondylitis and a phase III trial in 580 patients with rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The Korean firm has also applied to the European Medicines Agency (EMA) for approval of the new drug and plans to market it with Hospira<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> starting in 2014, when patents for Remicade expire in the European Union. Applications have also been filed in Asia, Central America, and South America, where Remicade is not under patent protection. Whether Celltrion has included other uses for Remicade in the applications is still unknown, given that EU standards stipulate that once comparability has been demonstrated, indications can be extrapolated if “adequately justified”–although adequacy is judged on a case-by-case basis. The EMA has also announced that another application for an infliximab biosimilar has been filed,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> although the name of the laboratory has not been revealed.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Without doubt, the starting pistol has been fired in a race between many competing laboratories in 3 geographic areas- Europe, the Far East, and India-as companies vie for the largest share of this particular pharmaceutical industry pie. Savings from widespread use of generics and biosimilars worldwide are potentially enormous. This interest along with the profit motive explains the large number of contenders jockeying for position even though their individual shares must remain small in the short term. Public health systems partially fund the development of biosimilars in countries like Korea and Singapore, and the authorities in Indonesia and Thailand are considering joining them provided quality, safety, and price are acceptable and the drugs target local health priorities. Countries like Korea and Japan, with well-established industrial and pharmaceutical capabilities, have also redirected industrial efforts to biotechnology. Something similar is happening in China and in emerging economies like India, Brazil, and Mexico, where some pharmaceutical companies have become strong producers of generics. An example is Dr Reddy's Laboratories, an Indian company that launched Reditux, a biosimilar that sells at half the price of the originator molecule and has increased the Indian market for rituximab treatment 10-fold.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A June 2012 agreement between Dr. Reddy's and Merck Serono will allow the Indian company to sell its product in Europe,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and the Indian producer has made similar agreements with GlaxoSmithKline for other biosimilars.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">When biosimilars enter the market, the expected benefits include lower costs that will make treatments more accessible to more patients and sustainable for health care systems. The main limitations–apart from possible problems with technology, efficacy or safety, and regulatory issues-will stem from tough legal battles that the owners of patents still in force can be expected to wage. The biosimilars industry accounts for 20% of research and development spending in the United States. In 2010, monoclonal antibodies alone made up a market segment amounting to USD $46 billion, and annual growth of 12% is expected.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> This sector therefore has strategic importance for US export policies and generates significant employment.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The biosimilars that have passed the EU approval process to date (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) include erythropoietins, granulocyte colony-stimulating factors, and somatropin; all these products have molecular weights 10 times lower than those of monoclonal antibodies, which are considered more complex molecules to produce and copy. Although the manufacture of biosimilars is now simpler and less costly, it remains complex.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Proteins are produced by inserting a fragment of DNA into a cloning vector for transfer to a selected cell line (such as Chinese hamster ovary cells) that is expanded in fermentation tanks (bioreactors). In principle, a complex purification, validation, and quality control process ensures product stability. However, the amino acid sequence is not the only concern in more complex molecules, such as immunoglobulins (with molecular weights of around 160<span class="elsevierStyleHsp" style=""></span>kDa). Other relevant characteristics that affect the activity and immunogenicity of the biological product include the molecule's tridimensional conformation or quaternary structure, in which methylation or glycosylation of certain residues intervene, as well as aggregation and the presence of impurities.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Because the manufacturers of biosimilars lack access to information about the production process of the patented originator, it is very difficult for them to replicate the glycosylation pattern of the innovator molecule. According to a proposal drafted in the United States, however, the original producer can gain access to the documents a competitor files to support an application for approval of a biosimilar. In this situation, it is impossible to manufacture an identical molecule unless industrial secrecy is violated or the original laboratory decides to create a copy of its own drug, changing the delivery device for example; rather, what can be developed is a biologically and clinically comparable molecule. Such drugs have been termed biosimilars in the EU, follow-on biologics in the United States, and subsequent entry biologics in Canada.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In developed countries, the approval processes for biosimilar drugs and generics differ. Generics are small, well-defined, chemically synthesized molecules and only their pharmacokinetic comparability must be demonstrated; moreover, as a certain range of comparability is tolerated, a generic might only meet requirements at the lower end of that range. Biosimilars, on the other hand, require additional studies beyond the demonstration of chemical similarity. Comparative pharmacokinetic and pharmacodynamic trials in healthy volunteers or patients must be undertaken at different phases, and if the originator molecule has been derived from more than a single biologic source, comparing all of them entails higher clinical trial costs. At least 1 clinical trial is required to demonstrate the equivalence (or noninferiority, which requires fewer patients and lowers costs) of each available formulation (for subcutaneous or intravenous administration, for instance).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">An equivalence trial must include a definition of the minimal clinically relevant difference between 2 treatments with regard to a measure of efficacy; in comparing response rates, a maximum allowable difference (Δ) on which to base an assumption of equivalence between a biosimilar and the innovator molecule has been considered to be 15%. As Δ increases, the sample required to test a hypothesis decreases; for example, if Δ is reduced by half, the required sample size increases 4-fold. The sample size also decreases when the numerical value of an outcome measure is greater; so for a given Δ, it will be cheaper to demonstrate the clinical comparability of a biosimilar if the efficacy endpoint is a 50% improvement in the psoriasis area severity index rather than a 75% improvement. It is important to remember that clinical trials are the driver in drug development costs, while production costs are marginal even for biologics. Thus, simplifying the clinical development process can make biosimilar drugs more affordable.</p><p id="par0045" class="elsevierStylePara elsevierViewall">A biosimilar product's efficacy can be extrapolated to other indications previously approved for the innovator drug when the pathogenic mechanisms are similar, with no need for independent clinical trials. However, the final decision rests with the regulatory authorities, who will rule on a case-by-case basis. All trials must evaluate the product's immunogenicity and safety and a pharmacovigilance program must have been designed and be ready for implementation following the product's approval.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The latest version of EMA regulations (effective, December 1, 2012)<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> is silent on the matter of allowing biosimilar products to be switched, or interchanged, for the originator drugs: that decision is actually the responsibility of each EU member state. In contrast, a generic can be freely interchanged for an original drug. US legislation (US Biologics Price Competition and Innovation Act<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>), on the other hand, allows the FDA to designate biosimilars that can be switched at the pharmacist's discretion without consulting the prescriber. Although switching biologics to biosimilars has been criticized for the reasons discussed above, in fact originator products themselves change over time,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> particularly when manufacturing processes are modified. For this reason, it is recommended that some leeway be established when setting limits on acceptable comparability for biosimilars with respect to the originators<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>; strictly speaking, the original manufacturer is actually producing a biosimilar of its own drug with each new batch or change in the manufacturing process. Therefore, rather than demonstrating maximum similarity to the originator, biosimilar drug producers should demonstrate that theirs is as similar to the originator as are the products in the various batches produced throughout the drug's lifetime on the market.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In fact, changes in formulation can cause adverse events: when human serum albumin was replaced with polysorbate 80 and glycine (as required by regulatory authorities) as stabilizers for epoetin alpha at the end of the 1990s, numerous cases of pure red cell aplasia occurred due to cross reactivity between circulating erythropoietin and antibodies that formed in response to the biologic.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Although such events are highly improbable when a product consists of an antibody against a pathogenic target rather than when it replaces a molecule with a physiological function, this outbreak has been a cautionary tale that both regulatory agencies and specialist prescribers take very seriously.</p><p id="par0060" class="elsevierStylePara elsevierViewall">At present, the EMA has issued clear directives<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and an abbreviated approval procedure for biosimilars, and the frameworks constructed by regulatory authorities in Canada, Japan, and Australia, for example, are similar. The ongoing debate on this point has been heated in the United States, and although an abbreviated pathway–known as the 351(k) application process–has been laid out for biosimilars there too, definitive rules have yet to be set down. Eventual producers of biosimilars can also become targets in fierce legal battles over patents in that country, and in consequence, even biosimilar manufacturers will probably ignore the abbreviated procedures and instead follow the traditional pathway for biologics–section 351(a) of the Biologic License Application–in order to avoid having to publish manufacturing procedures and specifications and to reduce their vulnerability to litigation.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In India, China, and some countries in South and Central America, regulation is not at all similar to that of the aforementioned countries and can be described as less stringent. “Alternative” biologics have therefore been approved in these countries even though they have marked chemical, pharmacokinetic, pharmacodynamic or clinical differences with respect to the originator molecule. Until the specifications for these biosimilars can meet the quality, purity, bioequivalence, immunogenicity, and safety standards of the EMA, the USFDA, or similar regulators, they circulate only in unregulated or semiregulated markets.</p><p id="par0065" class="elsevierStylePara elsevierViewall">For many reasons, we can expect to see the development of biosimilars for the biologics used to treat psoriasis (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>),<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> at least outside the United States, where current legislation protects innovator biologics for 12 years after FDA approval regardless of when the patent was filed.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Rituximab is the monoclonal antibody that has been with us the longest and several companies already market biosimilars or have products in advanced stages of clinical development.</p><p id="par0075" class="elsevierStylePara elsevierViewall">As for the fusion protein etanercept, Yisaipu and Etanar, produced by Shanghai CP Goujian Pharmaceutical Co, are equivalent products, sold in China and Colombia, respectively; the etanercept biosimilar Qiangke, produced by competitor Shanghai Celgen in partnership with Simcere Pharmaceuticals, was recently approved in China.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The Korean laboratory Hanwha has registered its biosimilar (HD203) with South Korean regulators and is planning to cooperate with Merck on the eventual distribution of the drug outside the United States.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The Japanese laboratory Daiichi Sankyo has come to an agreement with Coherus BioSciences to manufacture and distribute etanercept and rituximab biosimilars developed by the latter company,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> which specializes in biosimilars and has its headquarters in the United States. Once the new biosimilars are approved they will be sold through Daiichi Sankyo in Japan, South Korea, and Taiwan.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The approval of the Remicade biosimilar Remsima was mentioned at the beginning of this article, and Boehringer Ingelheim's adalimumab biosimilar (BI695501) is in the clinical development phase.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> PharmaPraxis plans to develop a Humira biosimilar in Brazil,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and Fujifilm Kyowa Kirin Biologics (a joint venture of the giant holding company Fujifilm and a Japanese biotechnology company) has plans for biosimilars of adalimumab and other biologics.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The patents for Remicade, Enbrel, and Humira will expire in most EU countries in 2014 (August 13), 2015 (February 1), and 2018 (April 16), respectively.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The situation is different in the United States. The patent for Humira (whose worldwide sales amounted to USD $7.9 billion last year<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>) expires on December 31, 2016, in spite of recent extensions.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> However, Abbot Laboratories has filed a “citizen petition” with the FDA asking the agency to decline to review any application for a Humira biosimilar filed before March 23, 2010, when the Biologic Price Competition and Innovation Act entered into effect to regulate the evaluation procedures. The petitioners argue that approval of such applications would endanger industrial secrets protected under the Fifth Amendment to the US Constitution.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The patent for Remicade is set to expire on September 4, 2018–20 years after it took effect. The case of Enbrel is also interesting. The US patent for this drug expires on October 23, 2012, but US Patent 8,063,182 was issued to Roche for it at the beginning of this year. The license for this molecule was ceded to Amgen (which acquired the previous licensee, Immunex, in 2002) after a one-time payment in 2004. Thus, the history of the patent filed in 1990 has been tortuous (or perhaps overtly twisted), but acceptance of the new filing gives Amgen 16 more years of protection for Enbrel in the United States.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In direct contrast with the litigious environment in the US pharmaceuticals industry, in Korea a cluster of high-tech industries with innovative capabilities (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>)<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> has emerged through joint ventures with giant industrial conglomerates such as Samsung Electronics.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> These large enterprises are redefining the strategic importance of the pharmaceutical sector. Similar developments are occurring in Japan. As for China, a few years ago the production of biosimilars was based on roller bottles and 100-L bioreactors in many facilities, but manufacturing processes are now being brought up to standard and the presence of China at large conferences bears witness to the vitality of the sector in that country.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Regardless of the short-term market impact of companies’ maneuvering, the boom in biosimilars will probably have played itself out in about 10 years, partly because the market will be saturated but also because patents for new innovator drugs will not yet be approaching their patent expiry dates.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">By then, biologics and biosimilars, with their many advantages of efficacy and safety, will have become much more affordable for patients and health care systems, and a powerful, newly-minted industry with advanced research and development capabilities and innovative production methods will have become well established.</p><p id="par0100" class="elsevierStylePara elsevierViewall">We in Spain can also hope to catch the wave-even if we are not world-class surfers and do not find jet skis affordable. At the very least, we can hope to be carried along in its wake rather than remain at the farthest edges in the second quarter of this century.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of Interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">Dr Lluis Puig has received consultancy and/or speaking fees or has participated in clinical trials funded by Abbott, Amgen, Celgene, Janssen, Merck Serono, MSD, Novartis, and Pfizer. All information in this article derives from sources that are freely available online or are published in journals indexed in PubMed.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Puig L. Biosimilares en dermatología: infliximab para empezar. Actas Dermosifiliogr. 2013;104:175–80.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Brand Name \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Active Substance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Therapeutic Area \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Approval Date \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Manufacturer \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abseamed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alpha \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anemia, cancer, chronic renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">August 28, 2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Medice Arzneimittel Pütter GmbH & Co KG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Binocrit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alpha \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anemia, chronic renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">August 28, 2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sandoz GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biograstim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer, hematopoietic stem-cell transplant, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">September 15, 2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CT Arzneimittel GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alpha Hexal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin alpha \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anemia, cancer, chronic renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">August 28, 2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hexal AG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim hexal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer, hematopoietic stem-cell transplant, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">February 6, 2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hexal AG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim ratiopharm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer, hematopoietic stem-cell transplant, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">September 15, 2008; withdrawn April 20, 2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ratiopharm GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nivestim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer, hematopoietic stem-cell transplant, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">June 8, 2010 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hospira UK Ltd. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Omnitrope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Somatropin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pituitary dwarfism, Prader-Willi syndrome, Turner syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">April 12, 2006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sandoz GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ratiograstim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer, hematopoietic stem-cell transplant, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">September 15, 2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ratiopharm GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Retacrit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin zeta \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anemia, autologous blood transfusion, cancer, chronic renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">December 18, 2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hospira UK Ltd. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Silapo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epoetin zeta \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anemia, autologous blood transfusion, cancer, chronic renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">December 18, 2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stada R & D AG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tevagrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer, hematopoietic stem-cell transplant, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">September 15, 2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Teva Generics GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Valtropin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Somatropin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pituitary dwarfism, Turner syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">April 24, 2006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BioPartners GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zarzio \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Filgrastim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer, hematopoietic stem-cell transplant, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">February 6, 2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sandoz GmbH \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab183308.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara">Source: McCamish and Woollett<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Biosimilars Approved by the European Medicines Agency as of July 1, 2012.<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Drug<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Manufacturer (Country) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Situation in April 2012 \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Adalimumab biosimilar</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>BI695501 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Boehringer Ingelheim Pharmaceuticals (Germany) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I clinical trials, in New Zealand \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Etanercept biosimilars</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yisaipu \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Shanghai CP Goujian Pharmaceutical Co. (China) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Marketed in China \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Etanar \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Shanghai CP Goujian Pharmaceutical Co. (China) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Marketed in China \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>HD203 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hanwha Chemical (South Korea) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase III clinical trials, in South Korea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>TuNEX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mycenax Biotech (Taiwan) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase III clinical trials, in Japan and South Korea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>LBEC0101 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LG Life Sciences Ltd. (South Korea) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I clinical trials, in South Korea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Avent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Avesthagen (India) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinical studies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PRX-106 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protalix Biotherapeutics (Israel) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinical studies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Infliximab biosimilar</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CT-P13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Celltrion (South Korea) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase III clinical trials, in South Korea and the United Kingdom \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Rituximab biosimilars</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Reditux \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dr Reddy's Laboratories (India) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Marketed in Bolivia, Chile, India, and Peru \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Kikuzubam \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Probiomed (Mexico) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Marketed in Bolivia, Chile, Mexico, and Peru \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>GP2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sandoz Biopharmaceuticals (Switzerland) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II clinical trials, in Argentina, Austria, Brazil, France, Germany, India, Italy, Spain, and Turkey \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>TL011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Teva Pharmaceutical Industries (Israel) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II clinical trials, in the Chech Republic, Hungary, Italy, Spain, and the United Kingdom \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CT-P10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Celltrion (South Korea) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I clinical trials, in South Korea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PF-05280586 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pfizer (United States) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I clinical trials, in the United States \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab183310.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara">Source: McCamish and Woollett<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p>" ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara">BioXpress Therapeutics S.A. (Switzerland) is developing biosimilars for for abatacept, adalimumab, etanercept, golimumab, infliximab, and tocilizumab.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Biosimilars Presently on the Market or Under Development for Treating Rheumatic Diseases and Psoriasis.<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a></p>" ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Originator Biologic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Main Indication \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Original Producer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">South Korean Companies Developing Biosimilars \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Enbrel \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rheumatoid arthritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amgen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hanwha Chemical Corporation; LG Life Sciences \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Remicade \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Crohn disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Centocor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Celltrion; LG Life Sciences \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MabThera \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biogen Idec \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Samsung; Celltrion; Green Cross Corporation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Herceptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Breast cancer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genentech \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Celltrion; Green Cross Corporation; Hanwha Chemical Corporation \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab183309.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Capability in South Korea.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:33 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "[Cited 8 Oct 2012]. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 16 | 10 | 26 |
| 2024 Octubre | 89 | 43 | 132 |
| 2024 Septiembre | 83 | 27 | 110 |
| 2024 Agosto | 121 | 73 | 194 |
| 2024 Julio | 93 | 28 | 121 |
| 2024 Junio | 109 | 27 | 136 |
| 2024 Mayo | 104 | 36 | 140 |
| 2024 Abril | 87 | 31 | 118 |
| 2024 Marzo | 70 | 32 | 102 |
| 2024 Febrero | 66 | 34 | 100 |
| 2024 Enero | 64 | 36 | 100 |
| 2023 Diciembre | 60 | 18 | 78 |
| 2023 Noviembre | 61 | 23 | 84 |
| 2023 Octubre | 54 | 22 | 76 |
| 2023 Septiembre | 43 | 29 | 72 |
| 2023 Agosto | 43 | 18 | 61 |
| 2023 Julio | 53 | 32 | 85 |
| 2023 Junio | 59 | 28 | 87 |
| 2023 Mayo | 52 | 23 | 75 |
| 2023 Abril | 52 | 18 | 70 |
| 2023 Marzo | 60 | 28 | 88 |
| 2023 Febrero | 61 | 28 | 89 |
| 2023 Enero | 61 | 30 | 91 |
| 2022 Diciembre | 70 | 35 | 105 |
| 2022 Noviembre | 71 | 19 | 90 |
| 2022 Octubre | 40 | 26 | 66 |
| 2022 Septiembre | 62 | 38 | 100 |
| 2022 Agosto | 38 | 33 | 71 |
| 2022 Julio | 34 | 32 | 66 |
| 2022 Junio | 43 | 28 | 71 |
| 2022 Mayo | 35 | 37 | 72 |
| 2022 Abril | 64 | 33 | 97 |
| 2022 Marzo | 58 | 48 | 106 |
| 2022 Febrero | 44 | 38 | 82 |
| 2022 Enero | 52 | 32 | 84 |
| 2021 Diciembre | 43 | 41 | 84 |
| 2021 Noviembre | 65 | 46 | 111 |
| 2021 Octubre | 59 | 64 | 123 |
| 2021 Septiembre | 56 | 52 | 108 |
| 2021 Agosto | 57 | 32 | 89 |
| 2021 Julio | 43 | 44 | 87 |
| 2021 Junio | 47 | 34 | 81 |
| 2021 Mayo | 72 | 36 | 108 |
| 2021 Abril | 88 | 106 | 194 |
| 2021 Marzo | 49 | 32 | 81 |
| 2021 Febrero | 59 | 27 | 86 |
| 2021 Enero | 45 | 29 | 74 |
| 2020 Diciembre | 35 | 18 | 53 |
| 2020 Noviembre | 21 | 20 | 41 |
| 2020 Octubre | 21 | 16 | 37 |
| 2020 Septiembre | 44 | 13 | 57 |
| 2020 Agosto | 31 | 33 | 64 |
| 2020 Julio | 21 | 24 | 45 |
| 2020 Junio | 36 | 38 | 74 |
| 2020 Mayo | 27 | 17 | 44 |
| 2020 Abril | 30 | 21 | 51 |
| 2020 Marzo | 40 | 19 | 59 |
| 2020 Febrero | 2 | 0 | 2 |
| 2020 Enero | 0 | 5 | 5 |
| 2019 Diciembre | 0 | 7 | 7 |
| 2019 Septiembre | 0 | 2 | 2 |
| 2019 Julio | 0 | 5 | 5 |
| 2019 Junio | 0 | 8 | 8 |
| 2019 Mayo | 0 | 20 | 20 |
| 2019 Abril | 0 | 22 | 22 |
| 2019 Marzo | 2 | 4 | 6 |
| 2019 Febrero | 3 | 5 | 8 |
| 2019 Enero | 1 | 4 | 5 |
| 2018 Diciembre | 4 | 4 | 8 |
| 2018 Noviembre | 9 | 0 | 9 |
| 2018 Octubre | 7 | 0 | 7 |
| 2018 Septiembre | 4 | 5 | 9 |
| 2018 Agosto | 0 | 11 | 11 |
| 2018 Julio | 0 | 54 | 54 |
| 2018 Junio | 0 | 34 | 34 |
| 2018 Mayo | 0 | 9 | 9 |
| 2018 Marzo | 4 | 1 | 5 |
| 2018 Febrero | 69 | 15 | 84 |
| 2018 Enero | 61 | 37 | 98 |
| 2017 Diciembre | 52 | 14 | 66 |
| 2017 Noviembre | 58 | 23 | 81 |
| 2017 Octubre | 47 | 10 | 57 |
| 2017 Septiembre | 62 | 21 | 83 |
| 2017 Agosto | 75 | 18 | 93 |
| 2017 Julio | 61 | 19 | 80 |
| 2017 Junio | 94 | 55 | 149 |
| 2017 Mayo | 91 | 34 | 125 |
| 2017 Abril | 77 | 21 | 98 |
| 2017 Marzo | 61 | 22 | 83 |
| 2017 Febrero | 54 | 14 | 68 |
| 2017 Enero | 54 | 18 | 72 |
| 2016 Diciembre | 67 | 40 | 107 |
| 2016 Noviembre | 165 | 23 | 188 |
| 2016 Octubre | 91 | 25 | 116 |
| 2016 Septiembre | 146 | 78 | 224 |
| 2016 Agosto | 150 | 58 | 208 |
| 2016 Julio | 112 | 44 | 156 |
| 2016 Junio | 10 | 22 | 32 |
| 2016 Mayo | 4 | 36 | 40 |
| 2016 Abril | 2 | 24 | 26 |
| 2016 Marzo | 4 | 26 | 30 |
| 2016 Febrero | 10 | 1 | 11 |
| 2016 Enero | 8 | 3 | 11 |
| 2015 Diciembre | 9 | 2 | 11 |
| 2015 Noviembre | 5 | 16 | 21 |
| 2015 Octubre | 7 | 17 | 24 |
| 2015 Septiembre | 12 | 1 | 13 |
| 2015 Agosto | 11 | 7 | 18 |
| 2015 Julio | 92 | 133 | 225 |
| 2015 Junio | 97 | 21 | 118 |
| 2015 Mayo | 108 | 36 | 144 |
| 2015 Abril | 138 | 21 | 159 |
| 2015 Marzo | 91 | 5 | 96 |
| 2015 Febrero | 94 | 5 | 99 |
| 2015 Enero | 92 | 6 | 98 |
| 2014 Diciembre | 116 | 20 | 136 |
| 2014 Noviembre | 138 | 10 | 148 |
| 2014 Octubre | 99 | 8 | 107 |
| 2014 Septiembre | 77 | 7 | 84 |
| 2014 Agosto | 55 | 5 | 60 |
| 2014 Julio | 48 | 7 | 55 |
| 2014 Junio | 69 | 11 | 80 |
| 2014 Mayo | 68 | 13 | 81 |
| 2014 Abril | 59 | 8 | 67 |
| 2014 Marzo | 73 | 23 | 96 |
| 2014 Febrero | 71 | 17 | 88 |
| 2014 Enero | 57 | 14 | 71 |
| 2013 Diciembre | 39 | 13 | 52 |
| 2013 Noviembre | 48 | 12 | 60 |
| 2013 Octubre | 23 | 18 | 41 |
| 2013 Septiembre | 22 | 13 | 35 |
| 2013 Agosto | 38 | 27 | 65 |
| 2013 Julio | 11 | 11 | 22 |
| 2013 Junio | 7 | 16 | 23 |
| 2013 Mayo | 3 | 9 | 12 |
| 2013 Abril | 4 | 5 | 9 |
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