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1.
BMJ ; 368: l6802, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964641

RESUMO

OBJECTIVES: To study the impact of blinding on estimated treatment effects, and their variation between trials; differentiating between blinding of patients, healthcare providers, and observers; detection bias and performance bias; and types of outcome (the MetaBLIND study). DESIGN: Meta-epidemiological study. DATA SOURCE: Cochrane Database of Systematic Reviews (2013-14). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Meta-analyses with both blinded and non-blinded trials on any topic. REVIEW METHODS: Blinding status was retrieved from trial publications and authors, and results retrieved automatically from the Cochrane Database of Systematic Reviews. Bayesian hierarchical models estimated the average ratio of odds ratios (ROR), and estimated the increases in heterogeneity between trials, for non-blinded trials (or of unclear status) versus blinded trials. Secondary analyses adjusted for adequacy of concealment of allocation, attrition, and trial size, and explored the association between outcome subjectivity (high, moderate, low) and average bias. An ROR lower than 1 indicated exaggerated effect estimates in trials without blinding. RESULTS: The study included 142 meta-analyses (1153 trials). The ROR for lack of blinding of patients was 0.91 (95% credible interval 0.61 to 1.34) in 18 meta-analyses with patient reported outcomes, and 0.98 (0.69 to 1.39) in 14 meta-analyses with outcomes reported by blinded observers. The ROR for lack of blinding of healthcare providers was 1.01 (0.84 to 1.19) in 29 meta-analyses with healthcare provider decision outcomes (eg, readmissions), and 0.97 (0.64 to 1.45) in 13 meta-analyses with outcomes reported by blinded patients or observers. The ROR for lack of blinding of observers was 1.01 (0.86 to 1.18) in 46 meta-analyses with subjective observer reported outcomes, with no clear impact of degree of subjectivity. Information was insufficient to determine whether lack of blinding was associated with increased heterogeneity between trials. The ROR for trials not reported as double blind versus those that were double blind was 1.02 (0.90 to 1.13) in 74 meta-analyses. CONCLUSION: No evidence was found for an average difference in estimated treatment effect between trials with and without blinded patients, healthcare providers, or outcome assessors. These results could reflect that blinding is less important than often believed or meta-epidemiological study limitations, such as residual confounding or imprecision. At this stage, replication of this study is suggested and blinding should remain a methodological safeguard in trials.


Assuntos
Ensaios Clínicos como Assunto , Projetos de Pesquisa Epidemiológica , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/organização & administração , Ensaios Clínicos como Assunto/normas , Humanos , Variações Dependentes do Observador , /estatística & dados numéricos , Projetos de Pesquisa/normas
3.
Gut ; 69(1): 32-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30979718

RESUMO

INTRODUCTION: The optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a consensus that the current situation in which most medications used in children with IBD are prescribed as off-label without sufficient paediatric data is unacceptable. Shortening the time lag between adult and paediatric approval of drugs is of the upmost importance. In this position paper we aimed to provide guidance from the global clinical research network (Pediatric Inflammatory Bowel Disease Network, PIBDnet) for designing clinical trials in PIBD in order to facilitate drug approval for children. METHODS: A writing group has been established by PIBDnet and topics were assigned to different members. After an iterative process of revisions among the writing group and one face-to-face meeting, all statements have reached consensus of >80% as defined a priori. Next, all core members of PIBDnet voted on the statements, reaching consensus of >80% on all statements. Comments from the members were incorporated in the text. RESULTS: The commentary includes 18 statements for guiding data extrapolation from adults, eligibility criteria to PIBD trials, use of placebo, dosing, endpoints and recommendations for feasible trials. Controversial issues have been highlighted in the text. CONCLUSION: The viewpoints expressed in this paper could assist planning clinical trials in PIBD which are both of high quality and ethical, while remaining pragmatic.


Assuntos
Ensaios Clínicos como Assunto/métodos , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fatores Etários , Produtos Biológicos/administração & dosagem , Produtos Biológicos/uso terapêutico , Criança , Ensaios Clínicos como Assunto/normas , Relação Dose-Resposta a Droga , Aprovação de Drogas/métodos , Fármacos Gastrointestinais/administração & dosagem , Humanos , Seleção de Pacientes , Projetos de Pesquisa , Índice de Gravidade de Doença , Resultado do Tratamento
5.
Psychiatr Hung ; 34(4): 393-402, 2019.
Artigo em Húngaro | MEDLINE | ID: mdl-31767799

RESUMO

This is a discussion paper on research in clinical pharmacology in the field of psychiatry. In addition to other factors the decline in discovery and development of new drugs in the field of psychiatry and the developments and growing complexity in the field of clinical trial technology, including outsourcing and risk based monitoring, reduced the number of young clinical researchers interested in this important field. The challenges posed by the restructuring within the pharmacological industry - including digitalization - should induce changes in the structure and in the processes of clinical pharmacology research and in the training of clinical research staff members. The approval of esketamine nasal spray for treatment resistant depression by the FDA and the results of research with psychedelics call for more education and training in this specific field.


Assuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/organização & administração , Psiquiatria/educação , Pesquisadores/educação , Pesquisadores/provisão & distribução , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Humanos , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Sprays Nasais , Serviços Terceirizados
6.
Rev Med Suisse ; 15(670): 2058-2061, 2019 Nov 06.
Artigo em Francês | MEDLINE | ID: mdl-31696682

RESUMO

N-of-1 trials therapeutic tests allow an objective evaluation of treatment efficacy in a single patient. Thereby, they can support off-label prescriptions, or promote treatment safety and efficiency in chronic patients through the deprescription of useless drugs. They also encourage active participation of patients in their medical care. Practically a treatment is compared to a placebo in double blind during a series of randomly alternating periods. Statistical analysis comparing measurements performed in the patient throughout the test enable to evaluate objectively treatment efficacy. The performance of this type of test is now offered to patients and practitioners by the Service of Clinical Pharmacology in the University Hospital of Lausanne.


Assuntos
Ensaios Clínicos como Assunto/métodos , Prática Clínica Baseada em Evidências/métodos , Método Duplo-Cego , Humanos , Uso Off-Label , Suíça , Resultado do Tratamento
7.
Gynecol Oncol ; 155(3): 473-482, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31703812

RESUMO

OBJECTIVE: We analyzed comprehensive genomic sequencing results from paired ovarian cancer samples to identify changes in mutational events over time. METHODS: DNA from paired FFPE tumor samples from 50 ovarian cancer patients in the Clearity Foundation Data Repository was analyzed for genomic mutations (GM), copy number alterations (CNA), microsatellite status (MS), tumor mutation burden (TMB), and loss of heterozygosity (LOH) by hybrid-capture, next-generation sequencing of up to 315 genes. Genomic profiles were compared between samples from the same patient. Poor quality results excluded 6 pairs from all analyses and 9 from CNA or LOH. RESULTS: Forty-four patients with predominantly advanced stage disease (34, 77%) and serous histology (31, 70%) received a median of 3 intervening treatment regimens (range 1-13). Analysis of 22 primary and recurrent sample pairs and 22 recurrent tumor pairs detected a median of 2 GM (range 0-5) and 1 CNA (range 0-6)/sample. TMB, MS, and LOH results were mostly concordant across paired samples. GM were consistent across most pairs [32/44 (73%) concordant], while CNA concordance was less [18/35 (51%)]. No changes were detected in therapeutically relevant GM, but 23% of patients had GM or CNA in the second sample that affect clinical trial eligibility. CONCLUSIONS: Paired ovarian cancer samples demonstrate stable genomic alterations across time. However, discordance was observed for some genes used as eligibility criteria for molecularly targeted clinical trials. Repeat tumor testing may be useful in cases where eligibility for such trials is deemed important after consideration of testing costs and potential clinical benefit.


Assuntos
Ensaios Clínicos como Assunto/métodos , Neoplasias Ovarianas/genética , Seleção de Pacientes , Adulto , Idoso , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Dosagem de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Perda de Heterozigosidade , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia
8.
Expert Rev Clin Pharmacol ; 12(11): 1033-1036, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31633383

RESUMO

Introduction: In the era of 'precision' oncology, novel clinical trial designs have emerged, in order to better address the final goal of translating the above-mentioned preclinical discoveries into the clinic. Nonetheless, in aiming to achieve the greatest clinical benefit to patients, some limitations of these novel approaches from the statistical, methodological and practical point of view need to be overcome.Areas covered: In the present review, a short overview of basket trials, umbrella trials and platform trials are discussed, in particular advantages and disadvantages of such experimental approaches.Expert opinion: Master protocols represent the future of clinical oncology research. The possibility of investigating multiple biomarkers and therapeutic regimens under one study is a strong advantage over traditional trials, and it can lead to quick implementation of new, promising treatments or biomarkers into the clinic.


Assuntos
Ensaios Clínicos como Assunto/métodos , Neoplasias/terapia , Projetos de Pesquisa , Pesquisa Biomédica/métodos , Humanos , Medicina de Precisão/métodos , Pesquisa Médica Translacional/métodos
11.
Health Qual Life Outcomes ; 17(1): 156, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619266

RESUMO

BACKGROUND: Patient-reported outcomes (PROs) are commonly collected in clinical trials and should provide impactful evidence on the effect of interventions on patient symptoms and quality of life. However, it is unclear how PRO impact is currently realised in practice. In addition, the different types of impact associated with PRO trial results, their barriers and facilitators, and appropriate impact metrics are not well defined. Therefore, our objectives were: i) to determine the range of potential impacts from PRO clinical trial data, ii) identify potential PRO impact metrics and iii) identify barriers/facilitators to maximising PRO impact; and iv) to examine real-world evidence of PRO trial data impact based on Research Excellence Framework (REF) impact case studies. METHODS: Two independent investigators searched MEDLINE, EMBASE, CINAHL+, HMIC databases from inception until December 2018. Articles were eligible if they discussed research impact in the context of PRO clinical trial data. In addition, the REF 2014 database was systematically searched. REF impact case studies were included if they incorporated PRO data in a clinical trial. RESULTS: Thirty-nine publications of eleven thousand four hundred eighty screened met the inclusion criteria. Nine types of PRO trial impact were identified; the most frequent of which centred around PRO data informing clinical decision-making. The included publications identified several barriers and facilitators around PRO trial design, conduct, analysis and report that can hinder or promote the impact of PRO trial data. Sixty-nine out of two hundred nine screened REF 2014 case studies were included. 12 (17%) REF case studies led to demonstrable impact including changes to international guidelines; national guidelines; influencing cost-effectiveness analysis; and influencing drug approvals. CONCLUSIONS: PRO trial data may potentially lead to a range of benefits for patients and society, which can be measured through appropriate impact metrics. However, in practice there is relatively limited evidence demonstrating directly attributable and indirect real world PRO-related research impact. In part, this is due to the wider challenges of measuring the impact of research and PRO-specific issues around design, conduct, analysis and reporting. Adherence to guidelines and multi-stakeholder collaboration is essential to maximise the use of PRO trial data, facilitate impact and minimise research waste. TRIAL REGISTRATION: Systematic Review registration PROSPERO CRD42017067799.


Assuntos
Ensaios Clínicos como Assunto/métodos , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Ensaios Clínicos como Assunto/economia , Ensaios Clínicos como Assunto/psicologia , Análise Custo-Benefício , Humanos , Projetos de Pesquisa/normas
13.
Expert Rev Clin Pharmacol ; 12(11): 1037-1046, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607179

RESUMO

Introduction: Antimicrobial resistance poses a substantial threat to global public health since it decreases the probability of effectively treating an infection and increases the risk of morbidity and mortality.Areas covered: In this review, the authors discuss the advantages and disadvantages of classical and novel trial designs for evaluating novel antibiotics for infections due to multidrug-resistant organisms (MDRO). An inductive literature search was performed using different keywords pertinent to the reviewed topics.Expert opinion: The need for active, effective compounds has strengthened regulatory, academic, and industry cooperation, leading to the recent approval of some novel anti-MDRO agents, with other promising compounds being also in the late phase of clinical development. Nonetheless, some important issues regarding the design of clinical trials have gained importance that are peculiar for novel anti-MDRO agents and should be addressed for continuing to guarantee the availability of effective treatments in the future. Very importantly, concerted cooperation with regulatory agencies will always be needed for continuously discussing and refining the acceptable level of evidence to be pursued through non-conventional and/or innovative trial designs or development strategies. Failure to do so would seriously pose the risk of perpetuating the unmet need for effective anti-MDRO agents.


Assuntos
Antibacterianos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Projetos de Pesquisa , Adulto , Antibacterianos/farmacologia , Desenho de Drogas , Farmacorresistência Bacteriana Múltipla , Humanos
14.
Biomed Environ Sci ; 32(8): 614-623, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31488237

RESUMO

OBJECTIVE: To develop methods for determining a suitable sample size for bioequivalence assessment of generic topical ophthalmic drugs using crossover design with serial sampling schemes. METHODS: The power functions of the Fieller-type confidence interval and the asymptotic confidence interval in crossover designs with serial-sampling data are here derived. Simulation studies were conducted to evaluate the derived power functions. RESULTS: Simulation studies show that two power functions can provide precise power estimates when normality assumptions are satisfied and yield conservative estimates of power in cases when data are log-normally distributed. The intra-correlation showed a positive correlation with the power of the bioequivalence test. When the expected ratio of the AUCs was less than or equal to 1, the power of the Fieller-type confidence interval was larger than the asymptotic confidence interval. If the expected ratio of the AUCs was larger than 1, the asymptotic confidence interval had greater power. Sample size can be calculated through numerical iteration with the derived power functions. CONCLUSION: The Fieller-type power function and the asymptotic power function can be used to determine sample sizes of crossover trials for bioequivalence assessment of topical ophthalmic drugs.


Assuntos
Ensaios Clínicos como Assunto/métodos , Soluções Oftálmicas/farmacocinética , Administração Tópica , Estudos Cross-Over , Humanos , Modelos Teóricos , Tamanho da Amostra , Equivalência Terapêutica
16.
BMC Cancer ; 19(1): 863, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470823

RESUMO

BACKGROUND: Most clinical trials on colorectal cancer (CRC) exclude cases who have history of a prior malignancy. However, no prior research studied this history's actual impact on the survival of CRC. In the paper, we study the effects of having a malignancy preceding CRC diagnosis on its survival outcomes. METHODS: CRC patients diagnosed during 1973-2008 were reviewed using the SEER 18 database. We calculated overall survival and cancer-specific survival of subsequent CRC, and more specifically stage IV CRC, using Kaplan-Meier test and adjusted Cox models. RESULTS: A total 550,325 CRC patients were reviewed, of whom 31,663 had history of a prior malignancy. The most commonly reported sites of a prior malignancy were: prostate, breast, urinary bladder, lung, and endometrium. Patients with history of a prior non-leukemic malignancy or history of a prior leukemia were found to have worse overall survival (HR = 1.165 95%CI = 1.148-1.183, P < 0.001) and (HR = 1.825 95%CI = 1.691-1.970, P < 0.001), respectively. However, CRC patients with history of a prior non-leukemic malignancy showed an improved colorectal cancer-specific survival (HR = .930 95%CI = .909-.952, P < 0.001). Analysis of stage IV CRC patients showed that patients with history of any non-leukemic malignancy did not have a significant change in overall survival. Whereas, patients with a prior leukemia showed a worse overall survival (HR = 1.535, 95%CI = 1.303-1.809, P < 0.001). When analyzed separately, right CRC and left CRC showed similar survival patterns. CONCLUSION: A prior malignancy before CRC -in general- can be associated with worse clinical survival outcomes. These worse outcomes are not observed in stage IV CRC. Considering these results when including/excluding stage IV CRC patients with prior malignancies in clinical trials may play help improve their generalizability.


Assuntos
Ensaios Clínicos como Assunto/métodos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Leucemia/epidemiologia , Definição da Elegibilidade , Feminino , Humanos , Leucemia/complicações , Masculino , Estadiamento de Neoplasias , Seleção de Pacientes , Projetos de Pesquisa , Estudos Retrospectivos , Programa de SEER , Análise de Sobrevida
18.
BMC Med ; 17(1): 152, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31370839

RESUMO

BACKGROUND: Adaptive designs are a wide class of methods focused on improving the power, efficiency and participant benefit of clinical trials. They do this through allowing information gathered during the trial to be used to make changes in a statistically robust manner - the changes could include which treatment arms patients are enrolled to (e.g. dropping non-promising treatment arms), the allocation ratios, the target sample size or the enrolment criteria of the trial. Generally, we are enthusiastic about adaptive designs and advocate their use in many clinical situations. However, they are not always advantageous. In some situations, they provide little efficiency advantage or are even detrimental to the quality of information provided by the trial. In our experience, factors that reduce the efficiency of adaptive designs are routinely downplayed or ignored in methodological papers, which may lead researchers into believing they are more beneficial than they actually are. MAIN TEXT: In this paper, we discuss situations where adaptive designs may not be as useful, including situations when the outcomes take a long time to observe, when dropping arms early may cause issues and when increased practical complexity eliminates theoretical efficiency gains. CONCLUSION: Adaptive designs often provide notable efficiency benefits. However, it is important for investigators to be aware that they do not always provide an advantage. There should always be careful consideration of the potential benefits and disadvantages of an adaptive design.


Assuntos
Ensaios Clínicos como Assunto/métodos , Projetos de Pesquisa , Humanos
20.
Clin Drug Investig ; 39(11): 1031-1044, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31420854

RESUMO

BACKGROUND: The combination of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor having different biological targets has become an integral part of the treatment of pulmonary arterial hypertension; however, several clinical studies have reported conflicting results. OBJECTIVE: The objective of this meta-analysis was to evaluate the effect of an endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination in pulmonary arterial hypertension. METHODS: After performing a comprehensive literature search in MEDLINE, Cochrane and the International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from seven relevant articles (publications till December 2018). PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed in the selection, analysis and reporting of findings. The odds ratio and mean difference were calculated to estimate the difference in clinical worsening, 6-minute walking distance, pulmonary vascular resistance and N-terminal pro-brain natriuretic peptide between the groups. Quality assessment was performed using the risk of bias assessment tool and a meta-regression for probable variables affecting effect size. RESULTS: The random-effect model analysis revealed an odds ratio of 0.56 [95% confidence interval (CI) 0.41-0.76; p = 0.0002] for clinical worsening, mean difference of 15.64 (95% CI 2.67-28.61; p = 0.02) for 6-minute walking distance, - 1.66 (95% CI - 3.82 to 0.50; p = 0.13) for pulmonary vascular resistance and - 21.04 (95% CI - 26.87 to - 15.22; p < 0.00001) for N-terminal pro-brain natriuretic peptide. The meta-regression showed no statistically significant association between the dose and duration of treatment and outcomes (odds ratio of clinical worsening and mean difference of 6-minute walking distance). CONCLUSIONS: In pulmonary arterial hypertension, endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination therapy significantly improved 6-minute walking distance, clinical worsening and N-terminal pro-brain natriuretic peptide compared with the monotherapy but did not offer any advantage in improving pulmonary vascular resistance. PROSPERO REGISTRATION NO: CRD42018091133.


Assuntos
Antagonistas dos Receptores de Endotelina/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/administração & dosagem , /tratamento farmacológico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Ensaios Clínicos como Assunto/métodos , Quimioterapia Combinada , Antagonistas dos Receptores de Endotelina/metabolismo , Humanos , Pulmão/metabolismo , Inibidores da Fosfodiesterase 5/metabolismo , /metabolismo , Resultado do Tratamento
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