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2.
Trials ; 20(1): 416, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291974

RESUMO

'Assumptions are made and most assumptions are wrong' (Albert Einstein) Clinical trial conduct must be consistent with trial design, yet conducting the trial according to plan remains a major challenge.We discuss the importance of optimal co-applicant team formation in trial leadership, appropriate delegation of tasks and staff supervision arrangements. Finally, we discuss five standard documents which we believe require particular attention. With appropriate engagement by or with co-applicants during the preparation of these five standard documents, we believe many of the pitfalls trials commonly experience can be avoided. The risks inherent in failing to identify and address mistaken assumptions during the preparation of these documents are discussed and recommendations for best practice suggested.


Assuntos
Ensaios Clínicos como Assunto/normas , Delegação Vertical de Responsabilidades Profissionais/normas , Liderança , Projetos de Pesquisa/normas , Pesquisadores/normas , Protocolos de Ensaio Clínico como Assunto , Comitês de Monitoramento de Dados de Ensaios Clínicos/normas , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Comportamento Cooperativo , Interpretação Estatística de Dados , Controle de Formulários e Registros/normas , Formulários como Assunto , Humanos , Comunicação Interdisciplinar , Participação dos Interessados
3.
Kennedy Inst Ethics J ; 29(1): 33-49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080176

RESUMO

This article describes oversight mechanisms for clinical research that have developed substantially over the last few decades, including institutional review boards and data safety and monitoring boards. LeRoy Walters and others in the 1970s in the US thoughtfully described the importance of fundamental ethical principles and the application of bioethics to clinical research. Dr. Walters's important essay and work with the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research helped identify and explain ethical principles that guide research. These principles, subsequently enunciated by the Commission in the Belmont Report, remain central to our understanding of the ethics of clinical research and are the foundation of our regulations. In this article, I review some history, successes, and challenges of IRBs and DSMBs to exemplify the significance of understanding and applying ethical principles to the design and conduct of clinical research, and to honor Dr. Walters's contributions.


Assuntos
Bioética , Pesquisa Biomédica/ética , Comitês de Monitoramento de Dados de Ensaios Clínicos/história , Comitês de Monitoramento de Dados de Ensaios Clínicos/normas , Comitês de Ética em Pesquisa/história , Comitês de Ética em Pesquisa/normas , Ética em Pesquisa , Pesquisa Biomédica/legislação & jurisprudência , Comitês de Monitoramento de Dados de Ensaios Clínicos/legislação & jurisprudência , Barreiras de Comunicação , Conflito de Interesses , Comitês de Ética em Pesquisa/legislação & jurisprudência , Regulamentação Governamental/história , Política de Saúde/legislação & jurisprudência , História do Século XX , Experimentação Humana/ética , Experimentação Humana/história , Experimentação Humana/legislação & jurisprudência , Humanos , Consentimento Livre e Esclarecido/ética , Legislação como Assunto , Experimentação Humana não Terapêutica/ética , Guias de Prática Clínica como Assunto , Política Pública/legislação & jurisprudência , Medição de Risco , Estados Unidos
4.
Trials ; 20(1): 227, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995932

RESUMO

BACKGROUND: Triggered monitoring in clinical trials is a risk-based monitoring approach where triggers (centrally monitored, predefined key risk and performance indicators) drive the extent, timing, and frequency of monitoring visits. The TEMPER study used a prospective, matched-pair design to evaluate the use of a triggered monitoring strategy, comparing findings from triggered monitoring visits with those from matched control sites. To facilitate this study, we developed a bespoke risk-based monitoring system: the TEMPER Management System. METHODS: The TEMPER Management System comprises a web application (the front end), an SQL server database (the back end) to store the data generated for TEMPER, and a reporting function to aid users in study processes such as the selection of triggered sites. Triggers based on current practice were specified for three clinical trials and were implemented in the system. Trigger data were generated in the system using data extracted from the trial databases to inform the selection of triggered sites to visit. Matching of the chosen triggered sites with untriggered control sites was also performed in the system, while data entry screens facilitated the collection and management of the data from findings gathered at monitoring visits. RESULTS: There were 38 triggers specified for the participating trials. Using these, 42 triggered sites were chosen and matched with control sites. Monitoring visits were carried out to all sites, and visit findings were entered into the TEMPER Management System. Finally, data extracted from the system were used for analysis. CONCLUSIONS: The TEMPER Management System made possible the completion of the TEMPER study. It implemented an approach of standardising the automation of current-practice triggers, and the generation of trigger data to inform the selection of triggered sites to visit. It also implemented a matching algorithm informing the selection of matched control sites. We hope that by publishing this paper it encourages other trialists to share their approaches to, and experiences of, triggered monitoring and other risk-based monitoring systems.


Assuntos
Coleta de Dados/normas , Estudos Multicêntricos como Assunto/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Algoritmos , Comitês de Monitoramento de Dados de Ensaios Clínicos/normas , Confiabilidade dos Dados , Humanos , Medição de Risco , Fatores de Risco , Fatores de Tempo
6.
Trials ; 20(1): 27, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621764

RESUMO

BACKGROUND: Paracetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. NAC has reduced efficacy for preventing liver injury in those patients who present later after overdose. We designed a randomised study investigating the safety and tolerability of a superoxide dismutase (SOD) mimetic, calmangafodipir (PP100-01), co-treatment with a 12-h NAC regimen compared with NAC treatment alone in patients with POD. METHODS/DESIGN: We have designed an open-label, randomised, exploratory, rising dose design, NAC-controlled, phase 1 safety and tolerability study in patients treated with NAC for POD. A total of 24 patients will be assigned into one of three dosing cohorts of eight patients (n = 6 for PP100-01 and NAC; n = 2 for NAC alone). The doses of PP100-01 are 2, 5, and 10 µmol/kg. The primary outcome is the safety and tolerability of PP100-01 when co-administered with a 12-h NAC regimen compared with NAC treatment alone. Furthermore, the study will explore if PP100-01 has potential efficacy for the treatment of paracetamol-induced liver injury by measurement of conventional clinical and exploratory biomarkers. DISCUSSION: The aim of the study is to test the safety and tolerability of a SOD mimetic, PP100-01, in combination with a 12-h NAC regimen in patients presenting within 24 h of POD. This study will provide valuable data regarding the incidence of adverse events caused by the 12-h NAC plus PP100-01 regimen and may provide evidence of PP100-01 efficacy in the treatment of paracetamol-induced liver injury. TRIAL REGISTRATION: EudraCT, 2017-000246-21; ClinicalTrials.gov, NCT03177395 . Registered on 6 June 2017.


Assuntos
Acetaminofen/envenenamento , Acetilcisteína/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ácido Edético/análogos & derivados , Fosfato de Piridoxal/análogos & derivados , Acetilcisteína/administração & dosagem , Comitês de Monitoramento de Dados de Ensaios Clínicos , Ensaios Clínicos Fase I como Assunto , Interpretação Estatística de Dados , Overdose de Drogas , Quimioterapia Combinada , Ácido Edético/administração & dosagem , Ácido Edético/efeitos adversos , Feminino , Humanos , Masculino , Fosfato de Piridoxal/administração & dosagem , Fosfato de Piridoxal/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
7.
Ther Innov Regul Sci ; 53(3): 301-306, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29911403

RESUMO

With the growth in co-development deals between pharmaceutical companies and the increased use of contract research organizations (CROs) in drug development, more and more employees are encountering projects that require working across different companies. Navigating the mix of corporate cultures as well as variations in standards and procedures can lead to unanticipated challenges and delays. The development of ertugliflozin, a recently approved medicine for type 2 diabetes mellitus, involved both co-development and CRO engagement across 4 companies. Challenges to combining processes and systems across the 4 companies were encountered and resolved. Early decisions for adoption of standards and processes as well as the organization of committees and communication pathways were key to the success of this ambitious program. Here we share our experiences and lessons learned with respect to the analysis and reporting of clinical trial results.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ensaios Clínicos Fase III como Assunto/normas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Comitês de Monitoramento de Dados de Ensaios Clínicos , Indústria Farmacêutica , Humanos , Serviços Terceirizados
8.
Ther Innov Regul Sci ; 53(3): 293-300, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29991276

RESUMO

The Biopharmaceutical Section of the American Statistical Association (ASA) formed a Safety Monitoring Working Group to strengthen collaborations between biostatisticians and safety scientists. The task began by surveying current needs and practices regarding available statistical safety tools and methods, regulatory guidance, and processes needed to support their implementation. The goal is for biostatisticians to become fully engaged safety team members by having the necessary safety skill set including appropriate methodology, regulatory guidance and access to appropriate tools. In this publication, we will discuss our survey results that reveal current practices at 22 pharmaceutical companies and demonstrate how the survey instrument can be used to map an action plan for meeting the demand for improved quantitative safety monitoring.


Assuntos
Comitês de Monitoramento de Dados de Ensaios Clínicos/organização & administração , Ensaios Clínicos como Assunto/normas , Bioestatística , Humanos , Segurança do Paciente , Sociedades Científicas , Inquéritos e Questionários , Estados Unidos
9.
Trials ; 19(1): 607, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400977

RESUMO

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a serious threat to human health. Although early blood pressure (BP) elevation is closely associated with a poor prognosis, the optimal antihypertensive regimen for acute-phase ICH remains controversial. In ICH, pain, sleep deprivation, and stress are usually the main causes of dramatic BP increases. While traditional antihypertensive treatment resolves the increased BP, it does not address the root cause of the disease. Remifentanil relieves pain and, when combined with dexmedetomidine's antisympathetic action, can restore elevated BP to normal levels. Here, we seek to validate the efficacy and safety of applying sufficient analgesia in combination with a minimal sedation program versus antihypertensive drug therapy for the early and rapid stabilization of BP in ICH patients. METHODS/DESIGN: We are conducting a multicenter, prospective, randomized controlled, single-blinded, superiority clinical trial across 15 hospitals. We will enroll 354 subjects in mainland China, and all subjects will be randomized into experimental and control groups in which they will be given remifentanil combined with dexmedetomidine or antihypertensive drugs (urapidil, nicardipine, and labetalol). The primary endpoint will be the systolic BP control rate within 1 h of treatment initiation, and the efficacy and safety of the antihypertensive regimens will be compared between the two groups. Secondary endpoints include the incidence rate of early hemorrhage growth, neurological function, duration of intensive care unit (ICU) stay, and staff satisfaction with the treatment process. DISCUSSION: We hypothesize that applying sufficient analgesia in combination with minimal sedation will act as an effective and safe antihypertensive strategy in ICH and that this treatment strategy could, therefore, be widely used as an ICH acute-phase therapy. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03207100 . Registered on 22 July 2017.


Assuntos
Analgesia , Anti-Hipertensivos/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Sedação Consciente , Hipertensão/tratamento farmacológico , Comitês de Monitoramento de Dados de Ensaios Clínicos , Interpretação Estatística de Dados , Dexmedetomidina/uso terapêutico , Humanos , Farmacovigilância , Estudos Prospectivos , Remifentanil/uso terapêutico , Tamanho da Amostra , Método Simples-Cego
10.
Trials ; 19(1): 621, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419939

RESUMO

BACKGROUND: Sharing interim result measures by the Data Safety Monitoring Board (DSMB) with non-DSMB members is an important issue that can affect trial integrity. Currently, it is unclear if there are demographic factors associated with sharing such information. This study's objective is to primarily explore the demographic factors associated with the DSMB sharing certain interim result measures and secondarily, explore demographic factors associated with the perceived usefulness in sharing certain interim result measures, with non-DSMB members. METHODS: We conducted an online survey of members of the Society of Clinical Trials (SCT) and International Society of Clinical Biostatistics (ISCB) in 2015 asking their professional views on the DSMB sharing interim trial results, specifically the interim control event rate (IControlER), interim combined even rate (ICombinedER), adaptive conditional power (ACP) and unconditional conditional power (UCP) with non-DSMB members. Binary logistic and multiple linear regressions were used to explore if demographic factors were associated with sharing a certain interim result measure and the perceived usefulness of sharing that interim result measure, respectively. Multiple imputation (MI) was used to evaluate the impact of missing data as a sensitivity analysis. RESULTS: Approximately 3136 (936 from SCT + ~ 2200 from ISCB) members were invited (response rate of 12%; [371/3136]. Two main findings: (1) involvement in more than 15 private industry-sponsored trials was associated with not endorsing the sharing of the IControlER (odds ratio [OR] = 2.92; 95% confidence interval [CI]: 1.31, 6.52]; p = 0.012), and (2) involvement in more than 15 private industry-sponsored trials was associated positively with an increase in the perceived usefulness in sharing the ACP by 2.35 points (beta coefficient estimate = 2.35 [95% CI: 0.45, 4.05], p = 0.017. The findings were similar after sensitivity analyses. CONCLUSIONS: An individual involved with more than 15 trials that had some form of private industry sponsorship is a demographic factor associated with NOT sharing the IControlER by the DSMB and an increased perceived usefulness in sharing the ACP at interim. Further studies are needed to evaluate for these demographic factors given the limitations of this study related to missing data. Due to some key limitations, regarding high non-response and missing data, we caution interpreting the results as definitive, but rather look at them as a first exploratory step to find potential associations for further evaluation.


Assuntos
Comitês de Monitoramento de Dados de Ensaios Clínicos , Ensaios Clínicos como Assunto , Disseminação de Informação , Humanos , Modelos Logísticos
11.
Trials ; 19(1): 622, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419940

RESUMO

BACKGROUND: Premature ejaculation (PE) is the most common sexual dysfunction among men. According to patients, the general practitioner (GP) is the appropriate professional with whom to discuss this issue. However, few patients receive the medical help needed because GPs find it difficult to talk to their patients about sex. A previous qualitative study provided six strategies described by GPs who had tackled the topic during consultation. A pilot study showed that using one of these strategies after a training course led to an increase in the rate of consultations where the topic was raised: an increase from 6.6 to 30.8%. The aim of this study is to compare whether training in communication skills with these six strategies is more effective than usual care on the incidence of patients bringing up the topic of PE with their GP. METHODS: A cluster randomised controlled trial, stratified over four areas comparing an intervention group, which will receive the six strategies training session, and a control group, which ensures routine medical care. The primary outcome is to investigate the efficacy of a training in communication skills directed towards this pathology, compared with usual care procedures, on the incidence of patients bringing up the topic of PE with their GP. The secondary objective relates to the variation in the quality of life of patients after having recently addressed the topic of PE. Quality of life will be evaluated using the SF-12 health scale, with scoring filled in by the patient immediately after the consultation and 4 weeks later. The patients suffering from PE will be identified if their score is higher than 9 on the Premature Ejaculation Diagnostic Tool filled in 4 weeks after the consultation. The number of patients necessary to highlight a significant difference between the two groups from 5 to 20% is 101. Therefore, a total of 600 patients is expected, 300 in each arm (40 GPs, 15 patients per GP; risk α = 5%; power = 90%; intra-cluster correlation coefficient ρ = 0.2; Hawthorne effect = 15%; lost-to-follow-up rates for GPs = 10% and for patients = 20%). DISCUSSION: The implication for practice is the improvement in the quality of patient-centred care within a topic area which encompasses almost 30% of male sex-related complaints. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02378779 . Registered on 3 February 2015.


Assuntos
Comunicação , Ejaculação Precoce/terapia , Atenção Primária à Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Encaminhamento e Consulta , Comitês de Monitoramento de Dados de Ensaios Clínicos , Coleta de Dados , Humanos , Masculino , Ejaculação Precoce/psicologia , Tamanho da Amostra , Comportamento Sexual
12.
Trials ; 19(1): 593, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30376893

RESUMO

BACKGROUND: Trauma is the leading cause of morbidity and mortality in children in the United States. The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage, however, the drug has not been evaluated in a clinical trial in severely injured children. We designed the Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC) trial to evaluate the feasibility of conducting a confirmatory clinical trial that evaluates the effects of TXA in children with severe trauma and hemorrhagic injuries. METHODS: Children with severe trauma and evidence of hemorrhagic torso or brain injuries will be randomized to one of three arms: (1) TXA dose A (15 mg/kg bolus dose over 20 min, followed by 2 mg/kg/hr infusion over 8 h), (2) TXA dose B (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), or (3) placebo. We will use permuted-block randomization by injury type: hemorrhagic brain injury, hemorrhagic torso injury, and combined hemorrhagic brain and torso injury. The trial will be conducted at four pediatric Level I trauma centers. We will collect the following outcome measures: global functioning as measured by the Pediatric Quality of Life (PedsQL) and Pediatric Glasgow Outcome Scale Extended (GOS-E Peds), working memory (digit span test), total amount of blood products transfused in the initial 48 h, intracranial hemorrhage progression at 24 h, coagulation biomarkers, and adverse events (specifically thromboembolic events and seizures). DISCUSSION: This multicenter trial will provide important preliminary data and assess the feasibility of conducting a confirmatory clinical trial that evaluates the benefits of TXA in children with severe trauma and hemorrhagic injuries to the torso and/or brain. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02840097 . Registered on 14 July 2016.


Assuntos
Antifibrinolíticos/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Hemorragia/tratamento farmacológico , Tronco/lesões , Ácido Tranexâmico/uso terapêutico , Adolescente , Criança , Pré-Escolar , Comitês de Monitoramento de Dados de Ensaios Clínicos , Método Duplo-Cego , Humanos , Lactente , Estudos Multicêntricos como Assunto , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
J Glob Oncol ; 4: 1-11, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30241268

RESUMO

PURPOSE: As cancer burden has risen worldwide, physicians, patients, and their advocates have become aware that the clinical cancer trial research paradigm is not ubiquitous. Furthermore, the number and characteristics of trials that are registered in low- and middle-income countries (LMICs) compared with that in high-income countries (HICs) are unknown. METHODS: We collected retrospective data on trials for breast, lung, and cervical cancer registered in ClinicalTrials.gov or with the WHO International Clinical Trial Registry Platform between 2010 and 2017. The data were then classified as trials within LMICs or HICs using definitions from the World Bank. RESULTS: Included in these analyses were 6,710 trials, of which 3,164 (47%) were breast cancer trials, 3,283 (49%) were lung cancer trials, and 263 (4%) were cervical cancer trials. There were 1,951 (29%) trials from LMICs and 4,759 (71%) trials from HICs ( P < .001). Although the proportion of phase III trials in HICs versus LMICs was similar (18% v 17%; P = .66), the number of phase I trials in LMICs was significantly lower than that of HICs (20% v 2%; P < .001). For several LMICs with the highest mortality-to-incidence ratios for breast, lung, or cervical cancer, there were no cancer trials registered in the registration data bases searched for this work. CONCLUSION: There are differences in access to cancer clinical trials in LMICs compared with HICs. Several factors, such as excessive cost and a lack of infrastructure and expertise, may explain these differences.


Assuntos
Neoplasias da Mama/epidemiologia , Ensaios Clínicos como Assunto , Neoplasias Pulmonares/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias da Mama/economia , Neoplasias da Mama/terapia , Comitês de Monitoramento de Dados de Ensaios Clínicos , Países em Desenvolvimento , Feminino , Pesquisa sobre Serviços de Saúde , Humanos , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/terapia , Estudos Retrospectivos , Neoplasias do Colo do Útero/economia , Neoplasias do Colo do Útero/terapia
15.
Clin Trials ; 15(6): 600-609, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30132361

RESUMO

BACKGROUND/AIMS: In multi-site clinical trials, where trial data and conduct are scrutinised centrally with pre-specified triggers for visits to sites, targeted monitoring may be an efficient way to prioritise on-site monitoring. This approach is widely used in academic trials, but has never been formally evaluated. METHODS: TEMPER assessed the ability of targeted monitoring, as used in three ongoing phase III randomised multi-site oncology trials, to distinguish sites at which higher and lower rates of protocol and/or Good Clinical Practice violations would be found during site visits. Using a prospective, matched-pair design, sites that had been prioritised for visits after having activated 'triggers' were matched with a control ('untriggered') site, which would not usually have been visited at that time. The paired sites were visited within 4 weeks of each other, and visit findings are recorded and categorised according to the seriousness of the deviation. The primary outcome measure was the proportion of sites with ≥1 'Major' or 'Critical' finding not previously identified centrally. The study was powered to detect an absolute difference of ≥30% between triggered and untriggered visits. A sensitivity analysis, recommended by the study's blinded endpoint review committee, excluded findings related to re-consent. Additional analyses assessed the prognostic value of individual triggers and data from pre-visit questionnaires completed by site and trials unit staff. RESULTS: In total, 42 matched pairs of visits took place between 2013 and 2016. In the primary analysis, 88.1% of triggered visits had ≥1 new Major/Critical finding, compared to 81.0% of untriggered visits, an absolute difference of 7.1% (95% confidence interval -8.3%, +22.5%; p = 0.365). When re-consent findings were excluded, these figures reduced to 85.7% versus 59.5%, (difference = 26.2%, 95% confidence interval 8.0%, 44.4%; p = 0.007). Individual triggers had modest prognostic value but knowledge of the trial-related activities carried out by site staff may be useful. CONCLUSION: Triggered monitoring approaches, as used in these trials, were not sufficiently discriminatory. The rate of Major and Critical findings was higher than anticipated, but the majority related to consent and re-consent with no indication of systemic problems that would impact trial-wide safety issues or integrity of the results in any of the three trials. Sensitivity analyses suggest triggered monitoring may be of potential use, but needs improvement and investigation of further central monitoring triggers is warranted. TEMPER highlights the need to question and evaluate methods in trial conduct, and should inform further developments in this area.


Assuntos
Comitês de Monitoramento de Dados de Ensaios Clínicos/normas , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Estudos Prospectivos , Projetos de Pesquisa/normas
16.
PLoS One ; 13(7): e0201037, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30048484

RESUMO

BACKGROUND: Data Monitoring Committees (DMCs) are essential to the good conduct of many trials. Typically they comprise a small expert group which monitors safety, efficacy, progress and early outcome data as trials recruit. DMCs can recommend protocol revisions and early stopping of a trial. As DMC meetings usually consider unblinded interim data confidentially, their deliberations are seldom exposed to research scrutiny. Although there have been some case studies from trials from mixed specialties which offer insights into some of the common issues faced by DMCs, we have, however, little empirical information about the challenges faced within specific clinical settings. METHODS: In-depth interviews with participants in the BRACELET Study on death and bereavement in neonatal intensive care trials produced qualitative accounts of experiences and views of a subgroup of 18 DMC members. These interviews explored views of DMC members in relation to the clinical context of neonatal intensive care and the conduct of neonatal intensive care trials. RESULTS: Interviewees felt that an understanding of both the neonatal intensive care setting and population was crucial in a DMC. They considered the neonatal intensive care research population especially vulnerable, and that outcomes that included both death and severe disability raised particular challenges rarely faced in other settings. In exploring these key outcomes they were mindful of the need to meet high scientific standards and the needs of babies in the trials and their families. DMC members discussed particular difficulties around the composite outcome of death and severe disability, especially when mortality data were available long before data on longer term disability. While statistical stopping guidance is helpful, DMC members described decisions about stopping, revising or continuing a trial being informed by a wider set of considerations and discussions than a pre-set p value. These included potentially competing needs of current trial participants and future patients, and reflections on the nature of benefit and harm. Given their cognisance of the potential impact and consequences of the decisions made by DMCs in this setting of life, death, and disability, interviewees commonly used the imagery of bravery, and described DMCs either holding or losing their nerve. CONCLUSIONS: DMCs for trials in other fields may also face difficult ethical trade-offs in monitoring composite outcomes. The experience from this sample of DMC members suggest that for neonatal intensive care trials there are some very specific challenges seldom faced elsewhere. The vulnerability of the population, and the different timescales for essential data becoming available to inform decisions, presented particular challenges. We suggest that it is important to consider the challenges raised in other settings to better understand the complex work of these committees and to prepare future generations of DMC members.


Assuntos
Comitês de Monitoramento de Dados de Ensaios Clínicos , Ensaios Clínicos como Assunto , Terapia Intensiva Neonatal , Luto , Morte , Tomada de Decisões , Humanos , Recém-Nascido
18.
Clin Trials ; 15(4): 352-358, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30021496

RESUMO

Before a novel treatment can be deemed a clinical success, an assessment of its risk-benefit profile must be made. One of the inherent challenges for this assessment comes from the multiplicity that arises from comparing treatment groups across multiple outcomes. Composite outcomes that summarize a patient's clinical status, or severity, across a prioritized list of safety and efficacy outcomes have become increasing popular. In this article, we review these approaches and illustrate through examples some of the challenges and complexities of a composite derived from prioritized outcomes, such as the win ratio. These challenges include the difficult tension between the analytical validity that comes from choosing a pre-specified outcome and an evaluation that is responsive to unexpected safety events that arise during the course of a trial. Other challenges include a sensitivity of the resulting test statistic to the underlying censoring distribution and other nuisance parameters. Approaches that resolve some of the difficulties of the analytical challenges associated with prioritized outcomes are then discussed. Ultimately, a composite outcome of net clinical benefit is another decision tool, but one to be used alongside more traditional analyses of efficacy and safety, and with the broader perspective that investigators, the data safety monitoring board, and regulators bring to an evaluation of risk-benefit.


Assuntos
Ensaios Clínicos como Assunto/normas , Interpretação Estatística de Dados , Comitês de Monitoramento de Dados de Ensaios Clínicos , Humanos , Medição de Risco
20.
Trials ; 19(1): 378, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30005659

RESUMO

BACKGROUND: Conducting research can be time consuming, difficult and challenging. Guidance and pragmatic advice focussing on randomised controlled trial conduct are available but do not necessarily constitute comprehensive guidance. A successful trial is one that recruits to time and target and collects high-quality data within the originally agreed budget. Standardised trial management tools have outlined key project management elements for a successful trial as a method of ensuring good practice in research trials: initiation, planning, execution, monitoring and closure. Lessons are also frequently learnt during the development and conduct of trials but rarely shared for the benefit of others. For the wider research team, the key focus will always be on the execution and delivery of a study. The aim of this study was to evaluate the acceptability of clinical trials management methods, focussing on study execution and monitoring, as implemented in the National Institute for Health Research Health Technology Assessment Programme-funded Obsessive Compulsive Treatment Efficacy Trial (OCTET). METHODS: Workshops, questionnaires and semi-structured interviews were used to explore acceptability of trial management methods with members of the OCTET Trial research team. Nine members participated in the focus group, 10 completed a questionnaire and 20 were interviewed as part of qualitative work for the main OCTET study. Data was collected and analysed using thematic analysis. RESULTS: Six key themes were identified: support; communication; processes; resources; training and ethos. Clear and open communication, enthusiasm and accessibility of the trial managers and chief investigator were consistently noted as an important facet of the successful running of the trial. Clear resources and training materials were also found to be crucial in helping staff to work within the trial setting. Constructive suggestions were also made for improvement of these resources; for example, including both checklists and flowcharts within trial processes. CONCLUSION: Organisation, openness and positivity are crucial for executing a trial successfully, whilst clear and focussed processes and resources are essential in monitoring and controlling the trial progress. Although derived from a single study, these findings are likely to be applicable to the successful conduct of all trials. Trial managers should consider developing these elements when setting up a study. TRIAL REGISTRATION: Clinical Trial Registry, ID: ISRCTN73535163 . Registered prospectively on 5 April 2011.


Assuntos
Ensaios Clínicos como Assunto/organização & administração , Eficiência Organizacional , Estudos Multicêntricos como Assunto , Transtorno Obsessivo-Compulsivo/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Pesquisadores/organização & administração , Comitês de Monitoramento de Dados de Ensaios Clínicos/organização & administração , Ensaios Clínicos como Assunto/economia , Ensaios Clínicos como Assunto/métodos , Comportamento Cooperativo , Confiabilidade dos Dados , Inglaterra , Humanos , Comunicação Interdisciplinar , Estudos Multicêntricos como Assunto/economia , Estudos Multicêntricos como Assunto/métodos , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Seleção de Pacientes , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto/economia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Pesquisadores/economia , Pesquisadores/psicologia , Fatores de Tempo , Resultado do Tratamento , Fluxo de Trabalho
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