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1.
Regul Toxicol Pharmacol ; 130: 105130, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35131340

RESUMO

Regulatory agency interaction occurs from before a candidate drug enters clinical development and all the way to marketing approval and beyond. This paper presents ways to enable successful interaction by avoiding issues, with an emphasis on nonclinical testing aspects. Strategic thinking as to whether an early regulatory agency meeting should occur is discussed and if yes, how to make it a success by generating relevant questions with proper preparation including a robust Briefing Document. Examples of unfavourable regulatory agency feedback during meetings is given which may have been avoided. Similarly, ways for successful regulatory submission in the form of a Clinical Trials Application (CTA) in Europe or an Investigational New Drug (IND) application in the US are considered with examples of comments that can be received from regulatory agencies. At marketing application stage with submission of a Marketing Authorisation Application (MAA) in Europe and a New Drug Application (NDA) or a Biologic License Application (BLA) in the US, a key document is the Nonclinical Overview and suggested content and potential deficiencies are presented to allow avoidance of adverse regulatory agency responses and time delay. Successful regulatory agency interaction involves robust scientific thinking, proper planning and well-written documentation.


Assuntos
Aprovação de Drogas/organização & administração , Órgãos Governamentais/organização & administração , Relações Interprofissionais , Europa (Continente) , Humanos , Aplicação de Novas Drogas em Teste/organização & administração , Marketing/organização & administração
2.
Stem Cells Transl Med ; 10 Suppl 2: S18-S30, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34724720

RESUMO

Mesenchymal stem/stromal cells (MSCs) have broad application prospects for regenerative medicine due to their self-renewal, high plasticity, ability for differentiation, and immune response and modulation. Interest in turning MSCs into clinical applications has never been higher than at present. Many biotech companies have invested great effort from development of clinical grade MSC product to investigational new drug (IND) enabling studies. Therefore, the growing demand for publication of MSC regulation in China necessitates various discussions in accessible professional journals. The National Medical Products Administration has implemented regulations on the clinical application of MSCs therapy. The regulations for MSCs products as drug have been updated in recent years in China. This review will look over the whole procedure in allogeneic MSC development, including regulations, guidance, processes, quality management, pre-IND meeting, and IND application for obtaining an approval to start clinical trials in China. The review focused on process and regulatory challenges in the development of MSCs products, with the goal of providing strategies to meet regulatory demands. This article describes a path for scientists, biotech companies, and clinical trial investigators toward the successful development of MSC-based therapeutic product.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Diferenciação Celular , China , Aplicação de Novas Drogas em Teste , Medicina Regenerativa
3.
AAPS J ; 23(6): 115, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34741215

RESUMO

The objective of this manuscript is to provide the reader with a hypothetical case study to present an immunogenicity risk assessment for a multi-specific therapeutic as part of Investigational New Drug (IND) application. In order to provide context for the bioanalytical strategies used to support the multi-specific therapeutic presented herein, the introduction focuses on known immunogenicity risk factors. The subsequent hypothetical case study applies these principles to a specific example HC-12, based loosely on anti-TNFα and anti-IL-17A bispecific molecules previously in development, structured as an example immunogenicity risk assessment for submission to health authorities. The risk of higher incidence and safety impact of anti-drug antibodies (ADA) due to large protein complexes is explored in the context of multi-specificity and multi-valency of the therapeutic in combination with the oligomeric forms of the targets.


Assuntos
Anticorpos Biespecíficos/imunologia , Anticorpos/imunologia , Medição de Risco/métodos , Humanos , Incidência , Interleucina-17/imunologia , Aplicação de Novas Drogas em Teste , Fatores de Risco , Fator de Necrose Tumoral alfa/imunologia
4.
J Pharmacol Toxicol Methods ; 111: 107098, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229067

RESUMO

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used. Here, we evaluated 226 secondary pharmacology profiles obtained from close to 90 unique sponsors. The results indicated that the most tested target in our set was the GABA benzodiazepine receptor (tested 168 times), the most hit target was adenosine 3 (hit 24 times), and the target with the highest hit percentage was the quinone reductase 2 (NQO2) receptor (hit 29% of the time). The overall results were largely consistent with those observed in previous publications. However, this study also identified the need for improvement in the submission process of secondary pharmacology studies by industry, which could enhance their utility for regulatory purpose. FDA-industry collaborative working groups will utilize this data to determine the best methods for regulatory submission of these studies and evaluate the need for a standard target panel.


Assuntos
Drogas em Investigação , Preparações Farmacêuticas , Indústria Farmacêutica , Drogas em Investigação/efeitos adversos , Aplicação de Novas Drogas em Teste , Estados Unidos , United States Food and Drug Administration
5.
BMC Cancer ; 21(1): 270, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711962

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) is a target for cancer therapy as it is overexpressed in a wide variety of cancers. Therapeutic antibodies that bind EGFR are being evaluated in clinical trials as imaging agents for positron emission tomography and image-guided surgery. However, some of these antibodies have safety concerns such as infusion reactions, limiting their use in imaging applications. Nimotuzumab is a therapeutic monoclonal antibody that is specific for EGFR and has been used as a therapy in a number of countries. METHODS: Formulation of IRDye800CW-nimotuzumab for a clinical trial application was prepared. The physical, chemical, and pharmaceutical properties were tested to develop the specifications to determine stability of the product. The acute and delayed toxicities were tested and IRDye800CW-nimotuzumab was determined to be non-toxic. Non-compartmental pharmacokinetics analysis was used to determine the half-life of IRDye800CW-nimotuzumab. RESULTS: IRDye800CW-nimotuzumab was determined to be non-toxic from the acute and delayed toxicity study. The half-life of IRDye800CW-nimotuzumab was determined to be 38 ± 1.5 h. A bi-exponential analysis was also used which gave a t1/2 alpha of 1.5 h and t1/2 beta of 40.8 h. CONCLUSIONS: Here, we show preclinical studies demonstrating that nimotuzumab conjugated to IRDye800CW is safe and does not exhibit toxicities commonly associated with EGFR targeting antibodies.


Assuntos
Drogas em Investigação/administração & dosagem , Imunoconjugados/administração & dosagem , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/toxicidade , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacocinética , Benzenossulfonatos/toxicidade , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Estabilidade de Medicamentos , Drogas em Investigação/farmacologia , Drogas em Investigação/toxicidade , Receptores ErbB/antagonistas & inibidores , Feminino , Meia-Vida , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/toxicidade , Indóis/administração & dosagem , Indóis/farmacocinética , Indóis/toxicidade , Aplicação de Novas Drogas em Teste , Masculino , Camundongos , Neoplasias/patologia , Neoplasias/cirurgia , Cirurgia Assistida por Computador/métodos , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Stem Cells Transl Med ; 10(2): 198-208, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32946199

RESUMO

Induced pluripotent stem cells (iPSC)-based therapies have been hailed as the future of regenerative medicine because of their potential to provide treatment options for most degenerative diseases. A key promise of iPSC-based therapies is the possibility of an autologous transplant that may engraft better in the longer-term due to its compatibility with the patient's immune system. Despite over a decade of research, clinical translation of autologous iPSC-based therapies has been slow-partly due to a lacking pre-defined regulatory path. Here, we outline regulatory considerations for developing an autologous iPSC-based product and challenges associated with the clinical manufacturing of autologous iPSCs and their derivatives. These challenges include donor tissue source, reprogramming methods, heterogeneity of differentiated cells, controls for the manufacturing process, and preclinical considerations. A robust manufacturing process with appropriate quality controls and well-informed, prospectively designed preclinical studies provide a path toward successful approval of autologous iPSC-based therapies.


Assuntos
Células-Tronco Pluripotentes Induzidas , Aplicação de Novas Drogas em Teste , Medicina Regenerativa/legislação & jurisprudência , Transplante Autólogo/legislação & jurisprudência , Diferenciação Celular , Humanos
9.
Biologicals ; 68: 3-8, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33097376

RESUMO

Tremendous progress has been made in recent years to produce functional cells for cell therapy products. Hundreds of clinical trials of stem cell products (SCPs) have shown promising therapeutic potential worldwide, including the products derived from human pluripotent stem cells (hPSCs), adult stem cells and mesenchymal stem cells (MSC). Before starting a clinical trial, comprehensive chemistry, manufacturing and control (CMC) study is required to assure the safety and quality consistency of SCPs. The heterogeneity of stem cell products arises from the variability in the donor tissues, isolation of cells and differentiation processes, and appropriate testing approaches are needed to characterize and release SCPs. Here we summarize the regulatory considerations of CMC study in Investigational New Drug (IND) application of SCPs in China based on the current knowledge, and they will be updated in the future with the advance of stem cell biology and regulatory science.


Assuntos
Diferenciação Celular , Terapia Baseada em Transplante de Células e Tecidos/métodos , Aplicação de Novas Drogas em Teste/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Pluripotentes/citologia , Terapia Baseada em Transplante de Células e Tecidos/normas , Química Farmacêutica/métodos , China , Aprovação de Drogas/métodos , Humanos , Aplicação de Novas Drogas em Teste/legislação & jurisprudência , Células-Tronco Mesenquimais/química , Células-Tronco Pluripotentes/química , Controle de Qualidade
10.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde | ID: lis-47722

RESUMO

Site do instituto Butantan dedicado a informações sobre a vacina contra o COVID-19. acesse o site para entender sobre os critérios de participação, como se inscrever, quais são os Centros de Pesquisa que participarão do estudo PROFISCOV, e muito mais


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Vacinas Virais/imunologia , Pessoal de Saúde/normas , Aplicação de Novas Drogas em Teste/métodos
16.
Multimedia | Recursos Multimídia | ID: multimedia-5592

RESUMO

O Governador João Doria confirmou nesta segunda-feira (6) que, pela segunda semana consecutiva, houve queda no número de mortes em decorrência do coronavírus em todo o estado de São Paulo. A nova redução reforça a tendência de achatamento progressivo da curva de óbitos da pandemia, que vem sendo apontada nas últimas semanas pelas autoridades de saúde. “São boas notícias, mas elas não devem ser celebradas com emoção. Mas, sim, com moderação para mantermos o foco em medidas de controle da pandemia, aumento da capacidade de atendimento do sistema de saúde, obrigatoriedade do uso de máscara e obediência à legislação e ao distanciamento social”, declarou o Governador. “Todos precisam ter paciência, resiliência e compreensão de que ainda estamos na pandemia”, reforçou Doria. De acordo com informações da Secretaria de Estado da Saúde e do Centro de Contingência do coronavírus, na semana entre 14 a 20 de junho, houve 1.913 mortes de pacientes contaminados no território paulista. Nos sete dias subsequentes, de 21 a 27 de junho, o número de vítimas fatais em decorrência da pandemia caiu para 1.769 óbitos. E no período entre 28 de junho a 4 de julho, foram 1.733 mortes. O número atual é 9,5% menor que o registrado há 16 dias. O Governador também apontou que São Paulo atingiu o menor índice da taxa de letalidade por coronavírus desde março, quando o estado registrou a primeira morte desde que a pandemia foi confirmada pela OMS (Organização Mundial de Saúde). Atualmente, a mortalidade é de 5% entre os casos confirmados de contaminação por coronavírus em todo o estado. “É o índice mais baixo de toda a série histórica”, destacou. “O objetivo principal é reduzir a curva de óbitos com a colaboração da maioria expressiva de prefeitas e prefeitos do interior, litoral e Grande São Paulo que têm nos ajudado neste sentido. Ao lado também do Ministério Público, Tribunal de Justiça e todos aqueles que respeitam a saúde, a medicina e fazem o correto enfrentamento da pandemia”, acrescentou Doria. Para o Secretário de Desenvolvimento Regional, Marco Vinholi, o aumento expressivo na testagem de coronavírus e o aumento robusto no número de leitos de UTI para pacientes com sintomas graves em hospitais públicos do estado são fatores fundamentais para a redução da mortalidade. “São Paulo não deixará ninguém sem atendimento. Já são mais de 2,5 mil respiradores distribuídos por todo o estado.” Saiba mais em: www.saopaulo.sp.gov.br/coronavirus/planosp


Assuntos
Betacoronavirus/efeitos dos fármacos , Pandemias/estatística & dados numéricos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Vacinas Virais/farmacologia , Institutos Governamentais de Pesquisa , Aplicação de Novas Drogas em Teste/métodos , Ensaio Clínico Fase II , Pneumonia Viral/epidemiologia , Infecções por Coronavirus/epidemiologia , Hospitais/provisão & distribuição , Número de Leitos em Hospital/estatística & dados numéricos , Unidades de Terapia Intensiva/provisão & distribuição , Monitoramento Epidemiológico , Máscaras/normas , Quarentena/organização & administração , Voluntários Saudáveis , Sistemas Locais de Saúde/organização & administração , Pessoal de Saúde , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Agência Nacional de Vigilância Sanitária , Potência de Vacina , Comércio/normas
18.
Am J Pathol ; 190(8): 1680-1690, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32473109

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for >100 years. Patients (n = 25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28, 2020, to April 14, 2020. Patients were transfused with convalescent plasma, obtained from donors with confirmed severe acute respiratory syndrome coronavirus 2 infection who had recovered. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 after transfusion. Clinical improvement was assessed on the basis of a modified World Health Organization six-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. At day 7 after transfusion with convalescent plasma, nine patients had at least a one-point improvement in clinical scale, and seven of those were discharged. By day 14 after transfusion, 19 (76%) patients had at least a one-point improvement in clinical status, and 11 were discharged. No adverse events as a result of plasma transfusion were observed. Whole genome sequencing data did not identify a strain genotype-disease severity correlation. The data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease.


Assuntos
Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Adulto , Idoso , Betacoronavirus/genética , COVID-19 , Feminino , Humanos , Imunização Passiva , Aplicação de Novas Drogas em Teste , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Texas , Sequenciamento Completo do Genoma , Adulto Jovem
19.
J Clin Invest ; 130(6): 2757-2765, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32254064

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e., "convalescent") plasma refers to plasma that is collected from individuals following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy for conferring immediate immunity to susceptible individuals. There are numerous examples in which convalescent plasma has been used successfully as postexposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East respiratory syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads, and improved survival. Globally, blood centers have robust infrastructure for undertaking collections and constructing inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections, and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs. treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, including evidence of benefit, regulatory considerations, logistical work flow, and proposed clinical trials, as scale-up is brought underway to mobilize this critical resource.


Assuntos
Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/uso terapêutico , Betacoronavirus/imunologia , Doadores de Sangue , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Humanos , Imunização Passiva/efeitos adversos , Aplicação de Novas Drogas em Teste , Pneumonia Viral/epidemiologia , Medição de Risco , SARS-CoV-2 , Estados Unidos , United States Food and Drug Administration
20.
Arthritis Res Ther ; 22(1): 65, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228698

RESUMO

OBJECTIVES: Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). METHODS: We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. RESULTS: The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0-10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. CONCLUSIONS: Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.


Assuntos
Cromonas/uso terapêutico , Aplicação de Novas Drogas em Teste/métodos , Nefrite Lúpica/tratamento farmacológico , Terapia de Salvação/métodos , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Estudos de Coortes , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/uso terapêutico , Quimioterapia de Indução/métodos , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
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