RESUMO
Extracellular vesicles (EVs) serve as an intrinsic system for delivering functional molecules within our body, playing significant roles in diverse physiological phenomena and diseases. Both native and engineered EVs are currently the subject of extensive research as promising therapeutics and drug delivery systems, primarily due to their remarkable attributes, such as targeting capabilities, biocompatibility, and low immunogenicity and mutagenicity. Nevertheless, their clinical application is still a long way off owing to multiple limitations. In this context, the Science Board of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan has conducted a comprehensive assessment to identify the current issues related to the quality and safety of EV-based therapeutic products. Furthermore, we have presented several examples of the state-of-the-art methodologies employed in EV manufacturing, along with guidelines for critical processes, such as production, purification, characterization, quality evaluation and control, safety assessment, and clinical development and evaluation of EV-based therapeutics. These endeavors aim to facilitate the clinical application of EVs and pave the way for their transformative impact in healthcare.
RESUMO
Polyethyleneimine (PEI) possesses various molecular weights (MWs), structures, and virus capture capacities. However, whether PEI can capture porcine circovirus (PCV) and animal cell-derived prion protein (PrPC) that may contaminate source materials is unclear. Therefore, we conducted a feasibility study to assess the effectiveness of PEI in removing PCV and PrPC as a model of pathogenic prions. The removal performance of PCV was evaluated by quantitative PCR using PEIs with various MWs, structures, and ion exchange capacities in Tris (pH 7.5) and acetate (pH 5.5) buffers under neutral (pH 7.5) to acidic (pH 5.5) conditions. Removal performances of PrPC were also evaluated by western blotting using PEIs with various MWs and structures. Tris buffer did not affect the ability of PEI-modified resins to remove PCV, whereas acetate buffer affected removal performances, except those of PEI-10K-Br and PEI-70K-Br, which showed high ion-exchange capacities. PrPC was captured by PEIs with high MWs, especially PEI-70K-Br, which was the most effective. The results of this feasibility study suggested that PEI-modified resin could remove PCV and PrPC. PEI-70K-Br with an ion-exchange capacity of at least 0.3 meq/mL appears suitable as a PEI molecule for pathogen capture or removal of PCV or PrPC from biological materials.
Assuntos
Circovirus , Polietilenoimina , Animais , Proteínas Priônicas , SuínosRESUMO
The World Health Organization (WHO) issued guidelines for the regulatory evaluation of biosimilars in 2009 and has provided considerable effort toward helping member states implement the evaluation principles in the guidelines into their regulatory practices. Despite this effort, a recent WHO survey (conducted in 2019-2020) has revealed four main remaining challenges: unavailable/insufficient reference products in the country; lack of resources; problems with the quality of some biosimilars (and even more with noninnovator products); and difficulties with the practice of interchangeability and naming of biosimilars. The following have been identified as opportunities/solutions for regulatory authorities to deal with the existing challenges: (1) exchange of information on products with other regulatory authorities and accepting foreign licensed and sourced reference products, hence avoiding conducting unnecessary (duplicate) bridging studies; (2) use of a "reliance" concept and/or joint review for the assessment and approval of biosimilars; (3) review and reassessment of the products already approved before the establishment of a regulatory framework for biosimilar approval; and (4) setting appropriate regulatory oversight for good pharmacovigilance, which is essential for the identification of problems with products and establishing the safety and efficacy of interchangeability of biosimilars.
Assuntos
Medicamentos Biossimilares/normas , Aprovação de Drogas , Farmacovigilância , Guias como Assunto , Troca de Informação em Saúde , Humanos , Inquéritos e Questionários , Organização Mundial da SaúdeRESUMO
The development of genome-editing technology could lead to breakthrough gene therapy. Genome editing has made it possible to easily knock out or modify a target gene, while current gene therapy using a virus vector or plasmid hampering modification with respect to gene replacement therapies. Clinical development using these genome-editing tools is progressing rapidly. However, it is also becoming clear that there is a possibility of unintended gene sequence modification or deletion, or the insertion of undesired genes, or the selection of cells with abnormalities in the cancer suppressor gene p53; these unwanted actions are not possible with current gene therapy. The Science Board of the Pharmaceuticals and Medical Devices Agency of Japan has compiled a report on the expected aspects of such genome-editing technology and the risks associated with it. This article summarizes the history of that discussion and compares the key concepts with information provided by other regulatory authorities.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , JapãoRESUMO
Recombinant viral vaccines expressing antigens of pathogenic microbes (e.g., HIV, Ebola virus, and malaria) have been designed to overcome the insufficient immune responses induced by the conventional vaccines. Our knowledge of and clinical experience with the new recombinant viral vaccines are insufficient, and a clear regulatory pathway is needed for the further development and evaluation of recombinant viral vaccines. In 2018, the research group supported by the Ministry of Health, Labour and Welfare, Japan (MHLW) published a concept paper to address the development of recombinant viral vaccines against infectious diseases. Herein we summarize the concept paper-which explains the Japanese regulatory concerns about recombinant viral vaccines-and provide a focus of discussion about the development of recombinant viral vaccines.
Assuntos
Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Vacinas Sintéticas/normas , Vacinas Virais/normas , Animais , Anticoncepcionais Masculinos/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hospedeiro Imunocomprometido , Japão , Microrganismos Geneticamente Modificados , Controle de Qualidade , Distribuição Tecidual , Vacinas Sintéticas/farmacologia , Vacinas Virais/farmacocinética , Replicação Viral/fisiologia , Eliminação de Partículas ViraisRESUMO
Recombinant adeno-associated virus (rAAV) vectors have recently been widely utilized for in in vivo gene therapy. The clinical dose definition of AAV vector requires the exact quantification as starting doses and for dose-escalation studies. Vector genome (vg) copies measured by quantitative PCR (qPCR) are commonly used for rAAV vector titration, and rAAV vector plasmids DNA is often used for qPCR standards, although the rAAV reference standard materials (RSMs) for serotypes 2 and 8 (rAAV2RSM and rAAV8RSM) are available from American Type Culture Collection. However, qPCR-based determination of the AAV vg is affected by the selection of the qPCR standard and the amplification target sites. In this study, we have developed a new PCR method, two-dimensional droplet digital PCR (2D ddPCR), for the absolute quantitation of target DNA and for evaluating the stability of the rAAV vector. The number of vg copies of rAAV2RSM determined by qPCR dramatically changed when standard plasmid DNAs with different conformations were treated with restriction enzymes, suggesting that qPCR amplification is significantly affected by the secondary structure of the standard. In contrast, the number of vg copies determined by ddPCR was unaffected by using primer probes for different positions of target sites or by the secondary structure conformation of the vg. Furthermore, the integrity of the AAV vg can be monitored using 2D ddPCR with fluorescein- and hexachloro-6-carboxy-fluorescine-labeled probes targeting different positions in the same rAAV genome. The titer of intact rAAV was highly correlated with rAAV activity in an accelerated (37°C) stability study. 2D ddPCR is a useful tool for rAAV vector quantitation and quality evaluation.
Assuntos
Dependovirus/genética , Vetores Genéticos , Reação em Cadeia da Polimerase/métodosRESUMO
Cell therapy using endothelial progenitor cells (EPCs) is a promising strategy for the treatment of ischemic diseases. Two types of EPCs have been identified: early EPCs and late EPCs. Late EPCs are able to form tube structure by themselves, and have a high proliferative ability. The functional marker(s) of late EPCs, which relate to their therapeutic potential, have not been fully elucidated. Here we compared the gene expression profiles of several human cord blood derived late EPC lines which exhibit different tube formation activity, and we observed that the expression of occludin (OCLN) in these lines correlated with the tube formation ability, suggesting that OCLN is a candidate functional marker of late EPCs. When OCLN was knocked down by transfecting siRNA, the tube formation on Matrigel, the S phase + G2 /M phase in the cell cycle, and the spheroid-based sprouting of late EPCs were markedly reduced, suggesting the critical role of OCLN in tube formation, sprouting, and proliferation. These results indicated that OCLN plays a novel role in neovascularization and angiogenesis.
Assuntos
Células Progenitoras Endoteliais/metabolismo , Neovascularização Fisiológica , Ocludina/metabolismo , Linhagem Celular , Proliferação de Células , Sangue Fetal/citologia , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Neovascularização Fisiológica/genética , Ocludina/genética , Interferência de RNA , Pontos de Checagem da Fase S do Ciclo Celular , Transdução de Sinais , Transcriptoma , TransfecçãoRESUMO
Oncolytic viruses, which include both naturally occurring wild-type viruses/attenuated viruses and genetically modified viruses, have recently been developed for use in innovative cancer therapies. Genetically modified oncolytic viruses possess the unique ability to replicate conditionally as a unique gene therapy product. Since oncolytic viruses exhibit prolonged persistence in patients, viral shedding and transmission to third parties should be major concerns for clinical trials along with the clinical safety and efficacy. Accordingly, studies are now underway to establish the safety and efficacy of oncolytic viruses.
Assuntos
Biotecnologia/legislação & jurisprudência , Ensaios Clínicos como Assunto/legislação & jurisprudência , Ensaios Clínicos como Assunto/normas , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Controle de Qualidade , Biotecnologia/normas , Qualidade de Produtos para o Consumidor , Humanos , Neoplasias/genéticaRESUMO
Endothelial progenitor cell (EPC) nomenclature remains ambiguous and there is a general lack of concordance in the stem cell field with many distinct cell subtypes continually grouped under the term "EPC." It would be highly advantageous to agree on standards to confirm an endothelial progenitor phenotype and this should include detailed immunophenotyping, potency assays, and clear separation from hematopoietic angiogenic cells which are not endothelial progenitors. In this review, we seek to discourage the indiscriminate use of "EPCs," and instead propose precise terminology based on defining cellular phenotype and function. Endothelial colony forming cells and myeloid angiogenic cells are examples of two distinct and well-defined cell types that have been considered EPCs because they both promote vascular repair, albeit by completely different mechanisms of action. It is acknowledged that scientific nomenclature should be a dynamic process driven by technological and conceptual advances; ergo the ongoing "EPC" nomenclature ought not to be permanent and should become more precise in the light of strong scientific evidence. This is especially important as these cells become recognized for their role in vascular repair in health and disease and, in some cases, progress toward use in cell therapy. Stem Cells Translational Medicine 2017;6:1316-1320.
Assuntos
Células Progenitoras Endoteliais/citologia , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Humanos , Neovascularização Fisiológica/fisiologia , Terminologia como AssuntoRESUMO
To develop cell therapies for ischemic diseases, endothelial progenitor cells (EPCs) have been expected to play a pivotal role in vascular regeneration. It is desirable to use a molecular marker that is related to the function of the cells. Here, a quantitative polymerase chain reaction array revealed that early EPCs derived from CD133(+) cells exhibited significant expression of MMP-9. Some populations of early EPCs expressed MMP-9 on the cell surface and others did not. We also attempted to separate the proangiogenic fraction from early EPCs derived from CD133(+) cells using a functional cell surface marker, and we then analyzed the MMP-9(+) and MMP-9(-) cell fractions. The MMP-9(+) cells not only revealed higher invasion ability but also produced a high amount of IL-8. Moreover, the stimulative effect of MMP-9(+) cells on angiogenesis in vitro and in vivo was prohibited by anti-IL-8 antibody. These data indicate that MMP-9 is one of the useful cell surface markers for the separation of angiogenic cells. Our treatment of early EPCs with hyaluronidase caused not only a downregulation of cell-surface MMP-9 but also a decrease in invasion ability, indicating that membrane-bound MMP-9, which is one of the useful markers for early EPCs, plays an important role in angiogenesis. Stem Cells 2016;34:1251-1262.
Assuntos
Antígeno AC133/metabolismo , Membrana Celular/enzimologia , Separação Celular , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica , Animais , Biomarcadores/metabolismo , Fracionamento Celular , Células Progenitoras Endoteliais/efeitos dos fármacos , Citometria de Fluxo , Perfilação da Expressão Gênica , Membro Posterior/irrigação sanguínea , Membro Posterior/patologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hialuronoglucosaminidase/farmacologia , Interleucina-8/metabolismo , Isquemia/patologia , Metaloproteinase 2 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Neovascularização Fisiológica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The regulations for the human use of advanced therapy medical products such as gene and cell therapy products have evolved in accordance with advance of clinical experience, scientific knowledge, and social acceptance to these technologies. In Japan, two laws, the Pharmaceuticals and Medical Devices (PMD) Act and the Act on the Safety of Regenerative Medicine (ASRM), were enacted in November 2014. The PMD Act defines regenerative medical products for the first time and introduces a system for the conditional and time-limited marketing authorization of regenerative medical products. Under ASRM, the responsibilities of medical institutions to ensure the safety and provide transparency of such medical technologies are described. Amendments to accompanying guidelines for these two Acts are currently in preparation. It is expected that the new legislative frameworks will promote the timely development of new products and technologies, to bring safe and effective regenerative medicines to Japanese patients.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/ética , Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Terapia Genética/legislação & jurisprudência , Marketing/legislação & jurisprudência , Medicina Regenerativa/legislação & jurisprudência , Pesquisa Translacional Biomédica/legislação & jurisprudência , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Ensaios Clínicos como Assunto , Terapia Genética/ética , Humanos , Japão , Segurança do Paciente/legislação & jurisprudência , Guias de Prática Clínica como Assunto , Controle de Qualidade , Medicina Regenerativa/ética , Projetos de Pesquisa , Pesquisa Translacional Biomédica/éticaRESUMO
Since the introduction of angiogenic cell therapy using early endothelial progenitor cells (EPCs), myeloid angiogenic cells (MACs) have been expected to be useful in treating ischemic diseases. In order to elucidate the angiogenic properties of MACs/EPCs, we clarified the characteristics of MACs as compared to M2 macrophages (MÏs). Comparison of the gene expression profiles of MACs and late EPCs revealed that MACs expressed greater amounts of metalloproteinase (MMP)-9. It should be noted that the profile of MMP-2/9 expression on the cell surface of MACs was similar to that of M2 MÏs, and that cell surface MMP-2/9 might be an active form based on molecular size. In addition, the invasion of MACs was prohibited not only by MMP-2/9 inhibitor, but also by the hyaluronidase treatment that caused the down-regulation of MMP-9 on the cell surface of MACs and inhibited their invasion activity. These results indicate that cell surface MMP-2/9 plays an important role in the high invasion ability of MACs. The conditioned medium of both MACs and M2 MÏs stimulated tube formation of endothelial cells in vitro. MACs caused an increase in vessel formation in in vivo models through the production of IL-8. We propose that the role of MACs with cell surfaces expressing MMP-2/9 is rapidly invading ischemic tissue.
Assuntos
Células Progenitoras Endoteliais/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Células Mieloides/metabolismo , Neovascularização Fisiológica , Meios de Cultivo Condicionados , Células Progenitoras Endoteliais/citologia , Humanos , Interleucina-8/biossíntese , Macrófagos/citologia , Macrófagos/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Células Mieloides/citologia , Isquemia Miocárdica/patologia , Isquemia Miocárdica/terapia , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Monoclonal antibody products and monoclonal antibody-based biopharmaceuticals have shown considerable effectiveness in the treatment for variety of diseases; cancer, auto-immune/auto-inflammation diseases and so on. Significant advance in monoclonal antibody products for cancer treatments was made with antibody-drug conjugates (ADC), and antibodies for blockade of immune checkpoints. Already 3 ADCs and 2 anti-immune-checkpoint antibodies products have been approved, and these monoclonal antibody-related product pipelines reach over 30. On the other hand, EU approved first monoclonal-antibody biosimilar, RemsimaTM (infliximab), suggesting that other monoclonal-antibody biosmilars will follow to the market. In this paper, several new issues about monoclonal antibody products will be discussed.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Descoberta de Drogas/tendências , Neoplasias/tratamento farmacológico , Medicamentos Biossimilares , Aprovação de Drogas , Guias como Assunto , Humanos , Imunoconjugados , Infliximab , Neoplasias/imunologiaRESUMO
Heparin is a sulfated glycosaminoglycan (GAG), which contains N-acetylated or N-sulfated glucosamine (GlcN). Heparin, which is generally obtained from the healthy porcine intestines, is widely used as an anticoagulant during dialysis and treatments of thrombosis such as disseminated intravascular coagulation. Dermatan sulfate (DS) and chondroitin sulfate (CS), which are galactosamine (GalN)-containing GAGs, are major process-related impurities of heparin products. The varying DS and CS contents between heparin products can be responsible for the different anticoagulant activities of heparin. Therefore, a test to determine the concentrations of GalN-containing GAG is essential to ensure the quality and safety of heparin products. In this study, we developed a method for determination of relative content of GalN from GalN-containing GAG in heparin active pharmaceutical ingredients (APIs). The method validation and collaborative study with heparin manufacturers and suppliers showed that our method has enough specificity, sensitivity, linearity, repeatability, reproducibility, and recovery as the limiting test for GalN from GalN-containing GAGs. We believe that our method will be useful for ensuring quality, efficacy, and safety of pharmaceutical heparins. On July 30, 2010, the GalN limiting test based on our method was adopted in the heparin sodium monograph in the Japanese Pharmacopoeia.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Medicamentos/prevenção & controle , Galactosamina/análise , Heparina/análise , Sulfatos de Condroitina/análise , Sulfatos de Condroitina/química , Dermatan Sulfato/análise , Dermatan Sulfato/química , Corantes Fluorescentes/química , Heparina/química , Hidrólise , Modelos Químicos , Reprodutibilidade dos Testes , para-Aminobenzoatos/químicaRESUMO
Cell therapies for severe ischemic diseases such as limb ischemia, acute myocardial infarction, and cerebral ischemia have been developed through in vitro and in vivo animal and clinical studies. Active cells for angiogenic cell therapy are believed endothelial progenitor cells (EPCs). EPCs have been extensively investigated to clarify their origin and biology. Many sources of EPCs have been proposed, including mononuclear cells (MNCs) fraction containing CD34(+) or CD133(+) (AC133(+)), isolated CD34(+) and AC133(+) cells, and induction and differentiation of EPCs from hematopoietic stem cells (HSCs). However, in vivo mechanisms by which EPCs contribute to neovascularization should be clarified. Many in vitro, in vivo, and clinical studies have been performed using these cells; angiogenic cell therapy will become an important regimen for severe ischemic diseases.
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Células Endoteliais/transplante , Isquemia/terapia , Transplante de Células-Tronco , Animais , Células Endoteliais/citologia , Humanos , Neovascularização FisiológicaRESUMO
HL60RG, a subline of human promyelocytic leukemia HL60 cells, has a increased growth rate than their parental cells. To gain information of the mechanisms involved in the increased growth rate of HL60RG, we performed a multiplex fluorescence in situ hybridization (M-FISH), standard cytogenetics analysis (G-banding) and genome scan using 10K SNP mapping array on both cell types. Characteristic genomic alterations in HL60RG cells were identified including uniparental disomy (UPD) of chromosome 1, and hemizygous deletion in 10p and 11p. However, no such defects were observed in HL60 cells. Changes in gene expression in HL60RG cells were determined using expression arrays (Affymetrix GeneChip, HU133A). Candidate genes associated with the rapid growth of HL60RG cells were identified. Two tumor necrosis factor receptors, TNFRSF1B (type II tumor necrosis factor-α receptor) and TNFRSF8 (also known as a tumor marker CD30), which are adjacently located on chromosome 1 showed opposing changes in gene expression in HL60RG cells-over-expression of TNFRSF8 and repression of TNFRSF1B. Differences in the DNA methylation status in the transcriptional regulatory regions of both genes between HL60 and HL60RG was detected by a methylation-specific PCR assay. In conclusion, alterations in chromosome and gene expression in HL60RG may be associated with increased growth rate.
Assuntos
Proliferação de Células , Células HL-60 , Análise em Microsséries , Mutação , Aberrações Cromossômicas , Metilação de DNA , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
New technologies are needed to deliver medicines safely and effectively. Polymeric nanoparticulate carriers are one such technology under investigation. We examined the intracellular trafficking of doxorubicin-bound block copolymers quantitatively and by imaging doxorubicin-derived fluorescence using confocal microscopy. The polymers were internalized by endocytosis and distributed in endosomal/lysosomal compartments and the endoplasmic reticulum; unlike free doxorubicin, the polymers were not found in the nucleus. Moreover, the ATP-binding cassette protein B1 (ABCB1) transporter may be involved in the efflux of the polymer from cells. This drug delivery system is attractive because the endogenous transport system is used for the uptake and delivery of the artificial drug carrier to the target as well as for its efflux from cells to medium. Our results show that a drug delivery system strategy targeting this endogenous transport pathway may be useful for affecting specific molecular targets.
Assuntos
Antibióticos Antineoplásicos/metabolismo , Doxorrubicina/metabolismo , Portadores de Fármacos , Polietilenoglicóis/metabolismo , Neoplasias do Colo do Útero/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/química , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Doxorrubicina/química , Composição de Medicamentos , Endocitose , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Feminino , Células HeLa , Humanos , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Lisossomos/metabolismo , Micelas , Microscopia Confocal , Polietilenoglicóis/química , Polietilenoglicóis/toxicidade , Interferência de RNA , Tecnologia Farmacêutica/métodos , Fatores de Tempo , Transfecção , Neoplasias do Colo do Útero/genéticaRESUMO
Recently, WHO, EU, Japan and Canada have published guidelines on biosimilar/follow-on biologics. While there seems to be no significant difference in the general concept in these guidelines, the data to be submitted for product approval are partially different. Differences have been noted in the requirements for comparability studies on stability, prerequisites for reference product, or for the need of comparability exercise for determination of process-related impurities. In Japan, there have been many discussions about the amount and extent of data for approval of follow-on biologics. We try to clarify the scientific background and rational for regulatory pathway of biosimilar/follow-on biologics in Japan in comparison with the guidelines available from WHO, EU and Canada. In this article, we address and discuss the scientific background underlying these differences to facilitate the harmonization of follow-on biologic principles in the guidelines in future.
Assuntos
Aprovação de Drogas/legislação & jurisprudência , Indústria Farmacêutica/legislação & jurisprudência , Indústria Farmacêutica/normas , Preparações Farmacêuticas/normas , Guias como Assunto , Humanos , Japão , Vigilância de Produtos Comercializados/normas , Vigilância de Produtos Comercializados/tendências , Controle de QualidadeRESUMO
To share the experience of reviewing clinical data required for the licensing of follow-on biologic products (biosimilar products and similar biotherapeutical products as EU and WHO terminology, respectively) in Japan, the data packages of two follow-on biologics, "Somatropin BS s.c. [Sandoz] (Omnitrope®)" and "Epoetin alfa BS [JCR]", which have been recently approved in Japan according to the "Guidelines for the Quality, Safety and Efficacy Assurance of Follow-on Biologics" published on March 4th 2009, are described. The clinical data package and indication of Somatropin BS/Omnitrope(®) were different in each country. In case of Epoetin alfa BS [JCR], non-clinical and clinical data-package was different from those of erythropoietin biosimilar products approved in EU. Submission of post-marketing surveillance plans for both products was required. Even though there seem to be differences in data requirements by each national regulatory authority, the accumulation of experience will provide the rationale and consensus on how to design the clinical trials for follow-on biologics.