Opinion Article
Biosimilars and Reference Biologics: Decisions on Biosimilar Interchangeability Require the Involvement of Dermatologists
Biosimilares y biológicos de referencia: la intercambiabilidad de los biosimilares requiere la participación del dermatólogo
L. Puig
Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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Fernández-Guarino, P.L. Ortiz-Romero, R. Fernández-Misa, C. Montalbán" "autores" => array:4 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Fernández-Guarino" ] 1 => array:2 [ "nombre" => "P.L." "apellidos" => "Ortiz-Romero" ] 2 => array:2 [ "nombre" => "R." "apellidos" => "Fernández-Misa" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Montalbán" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731013000355" "doi" => "10.1016/j.ad.2012.10.021" "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/S0001731013000355?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014001073?idApp=UINPBA000044" "url" => "/15782190/0000010500000005/v1_201405281018/S1578219014001073/v1_201405281018/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Opinion Article</span>" "titulo" => "Biosimilars and Reference Biologics: Decisions on Biosimilar Interchangeability Require the Involvement of Dermatologists" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "435" "paginaFinal" => "437" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "L. Puig" "autores" => array:1 [ 0 => array:3 [ "nombre" => "L." "apellidos" => "Puig" "email" => array:2 [ 0 => "lpuig@santpau.cat" 1 => "drlpuig@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Biosimilares y biológicos de referencia: la intercambiabilidad de los biosimilares requiere la participación del dermatólogo" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">On September 13, 2013, the European Medicines Agency (EMA) approved the first biosimilar<a class="elsevierStyleCrossRef" href="#fn0005"><span class="elsevierStyleSup">a</span></a> and treatment of moderate to severe psoriasis will be one of the indications. Undoubtedly this important news for dermatologists will have a major impact on prescribing patterns and management of patients with moderate to severe psoriasis.</p><p id="par0010" class="elsevierStylePara elsevierViewall">On June 27, 2013, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion and recommended that the EMA approve Inflectra (the applicant was Hospira UK) and Remsima (the applicant was Celltrion Healthcare Hungary Kft).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>These biosimilars (CT-P13, Remsima) have already been approved in South Korea.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The 2 manufacturers (Celltrion and Hospira) have reached an agreement to market 8 biosimilars in the United States, Europe, Canada, Australia, and New Zealand. The active substance in both cases is infliximab, and both are biological medicinal products, similar to the reference product Remicade (infliximab), approved in the European Union since August 13, 1999. Published studies suggest that both products have a quality, safety, and efficacy profile similar to Remicade (infliximab). Thus the clinical trials PLANETRA<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and PLANETAS<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> were able to show comparable efficacy to the innovator reference product infliximab in the treatment of active rheumatoid arthritis (in combination with methotrexate) and ankylopoietic spondylitis, respectively, as well as similar pharmacokinetic, pharmacodynamic, safety, and immunogenicity parameters to those of the original infliximab (innovator infliximab according to the terminology of the CHMP). Of note is that the marketing authorization application for biosimilars includes all the approved indications for Remicade, thereby setting a precedent in terms of extrapolating the results between indications which, according to guidance, should be examined in separate trials. Although the reduction in price proposed by the sponsor, Celltrion, could be as large as 30% compared to the original product, it is unlikely that the 2 biosimilars will be available in most European countries before February 2015, when the patent extension awarded to Johnson & Johnson expires. Johnson & Johnson and its partner, Merck & Co, could take legal action if these products are marketed before then.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">What are the implications for everyday clinical practice of the approval of the first monoclonal biosimilar, with full extrapolation to all indications, in the European Union?</p><p id="par0020" class="elsevierStylePara elsevierViewall">The introduction of biologic therapies for treating psoriasis has significantly improved the outcomes achievable with systemic treatments,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and has in turn led to a change in therapeutic objectives.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> With some reference products approaching their patent expiry date, several manufacturers are developing follow-on versions or biosimilar products, which are expected to improve patient access to these drugs in health systems such as the Spanish one, reducing drug procurement costs and introducing competition to force down prices.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Biosimilars are biologic products very similar to the reference product in terms of quality, safety, and efficacy (EMA) or safety, purity, and potency (Food and Drug Administration [FDA]). Similarity is defined as no relevant difference in any of the parameters (quality/purity, safety, efficacy/potency). Demonstration of chemical similarity is not enough to demonstrate functional equivalence and comparative pharmacokinetic and pharmacodynamic trials should be conducted in healthy volunteers or patients, and there should be at least 1 clinical trial to demonstrate the equivalence of each formulation available.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The variability of biological products depends not only on their amino acid sequence and primary structure, but also on posttranscriptional modifications such as glycosylation, methylation, oxidation, and deamination that may have an impact on tertiary structure (subunit folding) and quaternary structure (spatial configuration of the entire molecule). This in turn may lead to differences in affinity, selectivity, and functional, biological, and immunogenic activity compared to the reference biologic agent. Given that the manufacturers of biosimilars do not have access to the information on the production process of the patented reference product, it is very difficult to exactly replicate these posttranscriptional modifications, in contrast to small molecules (which will have exactly the same molecular structure as the reference product). The biosimilar is compared with the reference product by using validated analytical methods that enable the physical and chemical properties, biological activity, and purity and possible impurities to be determined. The directives currently in force allow for possible changes in the manufacturing process compared to the original, but the impact of these changes must be systematically assessed. Although biosimilars and their reference products are not identical, the same can be said for different batches of a reference biologic, given that the manufacturing processes are updated with each lifecycle. Changes might include switching the supplier of culture media, new purification methods, and even changes in the manufacturing facilities.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Glycosylation patterns are extremely sensitive to minimal changes in the manufacturing process, and these probably lead to differences in the immunogenicity of the biological product. In the case of erythropoietins, the development of antibodies against the drug has given rise to cases of cross immunity with the physiological molecule, with potentially fatal outcomes.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Such a situation is unlikely in the case of anticytokine antibodies. However, the development of antibodies against any biologic product may lead to blockade of its effect (neutralizing antibodies) or an increased clearance, in both cases reducing the clinical efficacy.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The nature of the antibody also contributes to the development of antibodies (the risk decreases according to whether the antibody is chimeric, humanized, or human) and induction regimens have been designed in part to achieve high serum concentrations and in part to induce tolerance to the development of these antibodies (intravenous administration contributes to this aim). The development of antibodies against the biologic agent appears to be more frequent in patients with autoimmune diseases, when administration is intermittent, and when background immunosuppressive medication (such as methotrexate) is not used. A recent metaanalysis in rheumatoid patients found that the presence of antibodies against the biologic product increases the risk of abandoning treatment and presenting with hypersensitivity reactions, whereas concomitant treatment with antirheumatic disease-modifying drugs reduces the risk of such antibodies.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The clinical relevance of the loss of response, which determines adherence to a biologic and the need for switching to another agent, has contributed to the development of assays for detecting antidrug antibodies and for measuring serum concentrations of different biologics; these are currently available commercially and can be used in the clinical setting.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The importance of these analytical techniques will no doubt increase when biosimilars are introduced. The extent to which they will be able to differentiate between biosimilars and their reference products remains to be seen.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The requirements for demonstrating similar clinical efficacy between a biosimilar and the reference biologic differ between the European Union (EU) and the United States. However, in both cases, at least 1 equivalence trial must be conducted with sufficient statistical power to demonstrate comparability of the 2 products in terms of efficacy and safety, that is, these products should be both noninferior and nonsuperior to the reference product.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> According to the EMA, immunogenicity should be assessed during the safety trial, whereas the FDA in the United States requires a comparative trial prior to marketing and another postmarketing trial. In both cases, a pharmacovigilance plan is required (and so it is essential to be able to distinguish the biosimilar, even when the drugs are prescribed interchangeably).</p><p id="par0045" class="elsevierStylePara elsevierViewall">There has been plenty of discussion as to whether the findings of a clinical trial can be extrapolated to other indications, allowing the approval of a biosimilar for a therapeutic indication for which it has not been clinically assessed. Such an approach seems reasonable if the mechanisms of action are known and are common to both indications. When the mechanisms of action are different or not fully understood, or when the target organs or systems are different, separate clinical trials are probably required. In any case, any extrapolation should be made on a case-by-case basis and clearly highlighted as such in the Summary of Product Characteristics or Package Insert of the product.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A completely different situation is the interchangeability of biosimilar products and their originals and, therefore, the possible clinical or therapeutic equivalence. This is discussed in another article in the same issue of this journal. Any generic drug is interchangeable with the original, and the pharmacist can make the change without the prior authorization of the prescribing physician. The guidelines of the EMA make no reference to interchangeability of biosimilars, and the leave the corresponding decisions in hands of the health authorities of each member state of the European Union. In contrast, the legislation in the United States allows the FDA to determine which biosimilars can be interchanged without consulting the physician. The definitive guidance, however, has yet to be published. The interchangeability of biosimilars would hinder the tasks of pharmacovigilance; hospital pharmacists would have to follow the regulations in each country and bear in mind that the same international nonproprietary name (INN) in the case of biologics does not imply they can be automatically be used interchangeably.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The role of biosimilars in the treatment of psoriasis and other skin diseases would in part be determined by the assurances provided to the dermatologists by the regulatory requirements in the approval procedure, and to a large extent by the pressures of the national and regional health authorities and hospital management to save money. Although a saving of 15% to 30% seems small compared to generics, biologics account for a high proportion of hospital drug expenditure. The decreased procurement cost of biosimilars will likely bring down the price of the original biologic products, particularly in situations where bidding is required. In addition, the manufacturers of the reference biologics are enhancing their biosimilar portfolio in an effort to diversify their business, minimize the price decreases, and avoid the subsequent impact on their market value.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In conclusion, the imminent arrival of biosimilars as therapeutic alternatives in dermatology should be welcomed if it allows savings to be made and more widespread access to treatment. The regulation introduced by the EMA in principle guarantees similarity between the approved biosimilars and the innovator product from the biochemical, pharmacokinetic, pharmacodynamic, immunogenic, and safety point of view for the indications in which trials have been performed. We should remember that the innovator biologics often end up becoming biosimilars of themselves (through changes in the manufacturing process) and in fact the regulatory framework for similarity is these cases is not so well defined as in the case of biosimilars. Although the good judgment of the experts at the EMA can be accepted a priori when they assess the extrapolation of indications, there are many gaps in our knowledge of the mechanism of action of different biologics, which can vary according to target organ. The clinician would feel much more assured with clinical trials that demonstrate the capacity to extrapolate the indication of the biosimilar to those of the original biologic when the target system/organ changes (musculoskeletal, digestive, or skin). Moreover, interchangeability brings with it issues with pharmacovigilance (if it is impossible to distinguish between biosimilars and originals) and ethics (can or should a treatment to which a patient is responding well be changed without the intervention of the prescribing physician and the consent of the patient?) In any case, it is imperative that the prescribing physician retains a say when making therapeutic decisions concerning biologics.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">Dr. Lluis Puig has received honoraria as a consultant and speaker for Abbvie, Boehringer, Janssen, Merck-Serono, MSD, Novartis, and Pfizer. He has participated in clinical trials sponsored by Abbvie, Amgen, Janssen, Lilly, MSD, Novartis, Pfizer, and VBL.</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:2 [ 0 => array:2 [ "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Remsima R, from Egis, will be marketed under this trade name in several central and eastern European countries, and under the trade name Flammegis R in several members of the Commonwealth of Independent States.</p>" ] 1 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Puig L. Biosimilares y biológicos de referencia: la intercambiabilidad de los biosimilares requiere la participación del dermatólogo. Actas Dermosifiliogr. 2014;105:435–437.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "European Medicines Agency recommends approval of first two monoclonal antibody biosimilars. Recommendation marks extension of biosimilar concept to new product-class [accessed July 12, 2013]. Available from: <a id="intr0005" class="elsevierStyleInterRef" href="http://www.ema.europa.eu/ema/index.jsp%3Fcurl=pages/news_and_events/news/2013/06/news_detail_001837.jsp%26mid=WC0b01ac058004d5c1">http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001837.jsp∣=WC0b01ac058004d5c1</a>" ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biosimilars in dermatology: Starting with infliximab" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 15 | 7 | 22 |
| 2024 October | 90 | 53 | 143 |
| 2024 September | 122 | 37 | 159 |
| 2024 August | 143 | 65 | 208 |
| 2024 July | 84 | 28 | 112 |
| 2024 June | 87 | 33 | 120 |
| 2024 May | 92 | 38 | 130 |
| 2024 April | 90 | 29 | 119 |
| 2024 March | 84 | 31 | 115 |
| 2024 February | 78 | 21 | 99 |
| 2024 January | 66 | 33 | 99 |
| 2023 December | 56 | 16 | 72 |
| 2023 November | 71 | 31 | 102 |
| 2023 October | 76 | 26 | 102 |
| 2023 September | 71 | 30 | 101 |
| 2023 August | 49 | 17 | 66 |
| 2023 July | 50 | 33 | 83 |
| 2023 June | 54 | 23 | 77 |
| 2023 May | 55 | 24 | 79 |
| 2023 April | 38 | 15 | 53 |
| 2023 March | 52 | 23 | 75 |
| 2023 February | 72 | 42 | 114 |
| 2023 January | 49 | 27 | 76 |
| 2022 December | 43 | 35 | 78 |
| 2022 November | 28 | 23 | 51 |
| 2022 October | 27 | 16 | 43 |
| 2022 September | 23 | 38 | 61 |
| 2022 August | 28 | 26 | 54 |
| 2022 July | 25 | 41 | 66 |
| 2022 June | 23 | 33 | 56 |
| 2022 May | 35 | 37 | 72 |
| 2022 April | 39 | 30 | 69 |
| 2022 March | 48 | 40 | 88 |
| 2022 February | 24 | 25 | 49 |
| 2022 January | 33 | 43 | 76 |
| 2021 December | 16 | 38 | 54 |
| 2021 November | 34 | 54 | 88 |
| 2021 October | 33 | 52 | 85 |
| 2021 September | 24 | 35 | 59 |
| 2021 August | 24 | 25 | 49 |
| 2021 July | 14 | 25 | 39 |
| 2021 June | 22 | 30 | 52 |
| 2021 May | 25 | 24 | 49 |
| 2021 April | 57 | 47 | 104 |
| 2021 March | 49 | 31 | 80 |
| 2021 February | 34 | 24 | 58 |
| 2021 January | 35 | 11 | 46 |
| 2020 December | 24 | 13 | 37 |
| 2020 November | 16 | 23 | 39 |
| 2020 October | 21 | 7 | 28 |
| 2020 September | 40 | 7 | 47 |
| 2020 August | 35 | 22 | 57 |
| 2020 July | 34 | 17 | 51 |
| 2020 June | 34 | 21 | 55 |
| 2020 May | 22 | 18 | 40 |
| 2020 April | 30 | 10 | 40 |
| 2020 March | 37 | 19 | 56 |
| 2020 February | 1 | 0 | 1 |
| 2020 January | 3 | 2 | 5 |
| 2019 December | 8 | 6 | 14 |
| 2019 November | 4 | 6 | 10 |
| 2019 October | 0 | 3 | 3 |
| 2019 September | 4 | 0 | 4 |
| 2019 August | 4 | 1 | 5 |
| 2019 July | 4 | 4 | 8 |
| 2019 June | 4 | 3 | 7 |
| 2019 May | 7 | 17 | 24 |
| 2019 April | 2 | 3 | 5 |
| 2019 March | 2 | 8 | 10 |
| 2019 February | 5 | 2 | 7 |
| 2019 January | 6 | 2 | 8 |
| 2018 November | 3 | 0 | 3 |
| 2018 October | 4 | 0 | 4 |
| 2018 September | 4 | 0 | 4 |
| 2018 June | 0 | 6 | 6 |
| 2018 May | 0 | 13 | 13 |
| 2018 April | 0 | 4 | 4 |
| 2018 March | 1 | 2 | 3 |
| 2018 February | 32 | 5 | 37 |
| 2018 January | 31 | 7 | 38 |
| 2017 December | 34 | 12 | 46 |
| 2017 November | 49 | 5 | 54 |
| 2017 October | 27 | 7 | 34 |
| 2017 September | 21 | 28 | 49 |
| 2017 August | 26 | 17 | 43 |
| 2017 July | 33 | 10 | 43 |
| 2017 June | 48 | 16 | 64 |
| 2017 May | 38 | 15 | 53 |
| 2017 April | 35 | 13 | 48 |
| 2017 March | 25 | 28 | 53 |
| 2017 February | 26 | 12 | 38 |
| 2017 January | 30 | 7 | 37 |
| 2016 December | 40 | 16 | 56 |
| 2016 November | 34 | 17 | 51 |
| 2016 October | 57 | 16 | 73 |
| 2016 September | 49 | 17 | 66 |
| 2016 August | 59 | 12 | 71 |
| 2016 July | 48 | 9 | 57 |
| 2016 June | 10 | 11 | 21 |
| 2016 May | 9 | 7 | 16 |
| 2016 April | 12 | 3 | 15 |
| 2016 March | 17 | 3 | 20 |
| 2016 February | 8 | 10 | 18 |
| 2016 January | 15 | 17 | 32 |
| 2015 December | 8 | 10 | 18 |
| 2015 November | 6 | 1 | 7 |
| 2015 October | 8 | 3 | 11 |
| 2015 September | 4 | 4 | 8 |
| 2015 August | 9 | 1 | 10 |
| 2015 July | 36 | 4 | 40 |
| 2015 June | 39 | 7 | 46 |
| 2015 May | 56 | 7 | 63 |
| 2015 April | 27 | 7 | 34 |
| 2015 March | 51 | 21 | 72 |
| 2015 February | 43 | 15 | 58 |
| 2015 January | 39 | 9 | 48 |
| 2014 December | 44 | 16 | 60 |
| 2014 November | 30 | 10 | 40 |
| 2014 October | 41 | 8 | 49 |
| 2014 September | 38 | 8 | 46 |
| 2014 August | 28 | 8 | 36 |
| 2014 July | 16 | 7 | 23 |
| 2014 June | 18 | 9 | 27 |
| 2014 May | 4 | 1 | 5 |
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