RESUMO
BACKGROUND: Showing how engagement adds value for all stakeholders can be an effective motivator for broader implementation of patient engagement. However, it is unclear what methods can best be used to evaluate patient engagement. This paper is focused on ways to evaluate patient engagement at three decision-making points in the medicines research and development process: research priority setting, clinical trial design and early dialogues with regulators and health technology assessment bodies. OBJECTIVE: Our aim was to review the literature on monitoring and evaluation of patient engagement, with a focus on indicators and methods. SEARCH STRATEGY AND INCLUSION CRITERIA: We undertook a scoping literature review using a systematic search, including academic and grey literature with a focus on evaluation approaches or outcomes associated with patient engagement. No date limits were applied other than a cut-off of publications after July 2018. DATA EXTRACTION AND SYNTHESIS: Data were extracted from 91 publications, coded and thematically analysed. MAIN RESULTS: A total of 18 benefits and 5 costs of patient engagement were identified, mapped with 28 possible indicators for their evaluation. Several quantitative and qualitative methods were found for the evaluation of benefits and costs of patient engagement. DISCUSSION AND CONCLUSIONS: Currently available indicators and methods are of some use in measuring impact but are not sufficient to understand the pathway to impact, nor whether interaction between researchers and patients leads to change. We suggest that the impacts of patient engagement can best be determined not by applying single indicators, but a coherent set of measures.
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Tomada de Decisões , Participação do Paciente , Pesquisa , Família , HumanosRESUMO
Drug development is a complex, resource intensive and long process in any disease area, and developing medicines to treat rare diseases presents even more challenges due to the small patient populations, often limited disease knowledge, heterogeneous clinical manifestations, and disease progression. However, common to all drug development programs is the need to gather as much information as possible on both the disease and the patients' needs ahead of the development path definition. Here, we propose a checklist named START, a tool that provides an overview of the key pillars to be considered when starting an orphan drug development: STakeholder mapping, Available information on the disease, Resources, and Target patient value profile. This tool helps to build solid foundations of a successful patient-centered medicines development program and guides different types of developers through a set of questions to ask for guidance through the starting phase of a rare disease therapeutic pathway.
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Produção de Droga sem Interesse Comercial , Doenças Raras , Humanos , Doenças Raras/tratamento farmacológico , Desenvolvimento de MedicamentosRESUMO
BACKGROUND: Academic-sponsored trials for rare diseases face many challenges; the present paper identifies hurdles in the set-up of six multinational clinical trials for drug repurposing, as use cases. METHODS: Six academic-sponsored multinational trials aiming to generate knowledge on rare diseases drug repurposing were used as examples to identify problems in their set-up. Coordinating investigators leading these trials provided feedback on hurdles linked to study, country, and site set up, on the basis of pre-identified categories established through the analysis of previous peer-reviewed publications. RESULTS: Administrative burden and lack of harmonization for trial-site agreements were deemed as a major hurdle. Other main identified obstacles included the following: (1) complexity and restriction on the use of public funding, especially in a multinational set up, (2) drug supply, including procurement tendering rules and country-specific requirements for drug stability, and (3) lack of harmonization on regulatory requirements to get trial approvals. CONCLUSION: A better knowledge of the non-commercial clinical research landscape and its challenges and requirements is needed to make drugs-especially those with less commercial gain-accessible to rare diseases patients. Better information about existing resources like research infrastructures, clinical research programs, and counseling mechanisms is needed to support and guide clinicians through the many challenges associated to the set-up of academic-sponsored multinational trials.
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Reposicionamento de Medicamentos , Doenças Raras , Ensaios Clínicos como Assunto , Humanos , Organizações , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológicoRESUMO
BACKGROUND: Treatments are often unavailable for rare disease patients, especially in low-and-middle-income countries. Reasons for this include lack of financial support for therapies and onerous regulatory requirements for approval of drugs. Other barriers include lack of reimbursement, administrative infrastructure, and knowledge about diagnosis and drug treatment options. The International Rare Diseases Research Consortium set up the Rare Disease Treatment Access Working Group with the first objective to develop an essential list of medicinal products for rare diseases. RESULTS: The Working Group extracted 204 drugs for rare diseases in the FDA, EMA databases and/or China's NMPA databases with approval and/or marketing authorization. The drugs were organized in seven disease categories: metabolic, neurologic, hematologic, anti-inflammatory, endocrine, pulmonary, and immunologic, plus a miscellaneous category. CONCLUSIONS: The proposed list of essential medicinal products for rare diseases is intended to initiate discussion and collaboration among patient advocacy groups, health care providers, industry and government agencies to enhance access to appropriate medicines for all rare disease patients throughout the world.
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Aprovação de Drogas , Doenças Raras , Humanos , Doenças Raras/tratamento farmacológicoRESUMO
The number of available therapies for rare diseases remains low, as fewer than 6% of rare diseases have an approved treatment option. The International Rare Diseases Research Consortium (IRDiRC) set up the multi-stakeholder Data Mining and Repurposing (DMR) Task Force to examine the potential of applying biomedical data mining strategies to identify new opportunities to use existing pharmaceutical compounds in new ways and to accelerate the pace of drug development for rare disease patients. In reviewing past successes of data mining for drug repurposing, and planning for future biomedical research capacity, the DMR Task Force identified four strategic infrastructure investment areas to focus on in order to accelerate rare disease research productivity and drug development: (1) improving the capture and sharing of self-reported patient data, (2) better integration of existing research data, (3) increasing experimental testing capacity, and (4) sharing of rare disease research and development expertise. Additionally, the DMR Task Force also recommended a number of strategies to increase data mining and repurposing opportunities for rare diseases research as well as the development of individualized and precision medicine strategies.
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Pesquisa Biomédica , Mineração de Dados , Reposicionamento de Medicamentos , Doenças Raras/tratamento farmacológico , Big Data , Bases de Dados Factuais , HumanosRESUMO
BACKGROUND: Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers. METHODS: We performed systematic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential. CONCLUSIONS: The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.
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Estudos Multicêntricos como Assunto/métodos , Ensaios Clínicos Pragmáticos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , Atitude do Pessoal de Saúde , Confidencialidade , Comportamento Cooperativo , Equipamentos e Provisões , Europa (Continente) , Medicina Baseada em Evidências , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Estudos Multicêntricos como Assunto/economia , Estudos Multicêntricos como Assunto/legislação & jurisprudência , Terapia Nutricional , Ensaios Clínicos Pragmáticos como Assunto/economia , Ensaios Clínicos Pragmáticos como Assunto/legislação & jurisprudência , Ensaios Clínicos Controlados Aleatórios como Assunto/economia , Ensaios Clínicos Controlados Aleatórios como Assunto/legislação & jurisprudência , Doenças Raras/terapia , Projetos de Pesquisa/legislação & jurisprudência , Pesquisadores , Apoio à Pesquisa como AssuntoRESUMO
BACKGROUND: Evidence-based clinical practice is challenging in all fields, but poses special barriers in the field of rare diseases. The present paper summarises the main barriers faced by clinical research in rare diseases, and highlights opportunities for improvement. METHODS: Systematic literature searches without meta-analyses and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: Barriers specific to rare diseases comprise the difficulty to recruit participants because of rarity, scattering of patients, limited knowledge on natural history of diseases, difficulties to achieve accurate diagnosis and identify patients in health information systems, and difficulties choosing clinically relevant outcomes. CONCLUSIONS: Evidence-based clinical practice for rare diseases should start by collecting clinical data in databases and registries; defining measurable patient-centred outcomes; and selecting appropriate study designs adapted to small study populations. Rare diseases constitute one of the most paradigmatic fields in which multi-stakeholder engagement, especially from patients, is needed for success. Clinical research infrastructures and expertise networks offer opportunities for establishing evidence-based clinical practice within rare diseases.
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Medicina Baseada em Evidências/métodos , Doenças Raras , Projetos de Pesquisa , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Humanos , Cooperação Internacional , Estudos Multicêntricos como Assunto , Seleção de Pacientes , Doenças Raras/diagnóstico , Doenças Raras/epidemiologia , Doenças Raras/terapia , Sistema de Registros , Participação dos InteressadosRESUMO
Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.
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Medicina Baseada em Evidências , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Literatura de Revisão como Assunto , Prática Clínica Baseada em Evidências , HumanosAssuntos
Desenvolvimento de Medicamentos/métodos , Legislação de Medicamentos , Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Doenças Raras , União Europeia , Regulamentação Governamental , Humanos , Produção de Droga sem Interesse Comercial/métodos , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológicoAssuntos
Comitês Consultivos/organização & administração , Cooperação Internacional/história , Colaboração Intersetorial , Doenças Raras/terapia , Pesquisa Translacional Biomédica/organização & administração , Comitês Consultivos/história , Comitês Consultivos/normas , Ensaios Clínicos como Assunto , Guias como Assunto , História do Século XXI , Humanos , Prevalência , Doenças Raras/diagnóstico , Doenças Raras/epidemiologia , Doenças Raras/etiologia , Pesquisa Translacional Biomédica/economia , Pesquisa Translacional Biomédica/história , Pesquisa Translacional Biomédica/normasAssuntos
Cooperação Internacional , Colaboração Intersetorial , Participação do Paciente/tendências , Doenças Raras/diagnóstico , Pesquisa Translacional Biomédica/tendências , Acesso à Informação , Objetivos , Acessibilidade aos Serviços de Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/tendências , História do Século XXI , Humanos , Disseminação de Informação , Prevalência , Doenças Raras/epidemiologia , Doenças Raras/etiologia , Doenças Raras/terapia , Sistema de Registros , Pesquisa Translacional Biomédica/economia , Pesquisa Translacional Biomédica/história , Pesquisa Translacional Biomédica/organização & administraçãoRESUMO
Human enhancer of filamentation 1 (HEF1) is a multi-domain docking protein of the p130 Cas family. HEF1 is present at focal adhesions and is involved in integrin signalling mediating cytoskeleton reorganization associated with cell migration, adhesion or apoptosis. HEF1 functions are regulated in part by phosphorylation on tyrosine residues. HEF1 is also phosphorylated on serines/threonines leading to two isoforms refered to as p105 and p115. In most cases, the serine/threonine kinase(s) responsible for HEF1 phosphorylation have not been identified. In the present study, we have investigated HEF1 ser/thr phosphorylation. In the HCT-116 cell line transiently overexpressing Flag-HEF1 we showed that Hesperadin, a synthetic indolinone displaying antiproliferative effect and described as an inhibitor of various kinases including Aurora-B, prevented HEF1 phosphorylation induced by the ser/thr phosphatase PP2A inhibitor: okadaic acid (OA). In addition we showed that conversion of endogenous HEF1 p105 to p115 in HaCaT cells was prevented upon treatment with Hesperadin, resulting in accumulation of p105HEF1. We also identified serine 369 as the target site of phosphorylation by this Hesperadin-inhibited kinase in HCT-116. Finally, we provide evidence that phosphorylation on serine 369 but not phosphorylation on serine 296, triggers HEF1 degradation by the proteasomal machinery. These data suggest that conversion of p105 to p115 results from a ser-369-dependent phosphorylation mediated by an Hesperadin-sensitive kinase and regulates the half-life of HEF1.