The scientific impact of commercial and non-commercial clinical trials in Portuguese lnstitutions

Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019Background: The pharmaceutical industry is the lead promoter of clinical studies across the world and its focus is on the company’s molecules which are patented. Although there are fewer non-commercial clinical trials, the information provided in these studies is vastly important for the wellbeing of the society, not aiming at the protection of commercial interests. Concerning the impact of both types of clinical trials, commercial studies are frequently published in high-impact scientific journals, given the complexity and dimension of the study, which is mandatory to achieve a meaningful result. On the other hand, non-commercial trials, that are initiated by the investigators, capacitate them, contributing to a general capacity for the research, clinical study and impact. Objectives: This study aims to identify the scientific impact of the commercial and non-commercial clinical trials with Portuguese institutions as sponsors or/and participating country. Design and Methods: A systematic search of trial registrations from 01/10/2004 to 30/09/2018 – using four clinical trials registries (CTRs) – was carried out to identify the interventional clinical trials with Portugal as sponsor or participating country. Information about the sponsor, funders, intervention type, and therapeutic area was obtained from each CTR. Every completed study was screened for publications and data collected from databases were complemented with data contained in publications. The impact factor of each journal and quartile in the respective publication year was also registered. Outcome: For the first time, the scientific impact and characteristics of both commercial and non-commercial clinical trials implemented in Portugal were assessed considering four different clinical trials registries and the information gathered from publications of completed studies. It was a great achievement conducting this analysis on a high number of clinical trials, implicating an exhaustive methodological approach. Results: The number of commercial clinical trials (n= 1402) registered was higher than the non-commercial clinical trials (n= 339). A total of 970 commercial clinical trials were completed and only 280 (28.87%) were published, from those, only 24 (8.57%) had Portuguese authorship. On the other hand, 170 non-commercial clinical trials were completed studies, 54 (31.76%) were published and 38 (70.37%) of them had Portuguese authorship. Oncology is the therapeutic area with more commercial studies published (20.71%) and chemical drugs the most applied interventions (65.71%). Considering the publications of the non-commercial clinical trials, Cardiology/Vascular Diseases is the main area of concern (16.67%) and behavioral interventions the most studied (31.48%). Eighty-three percent of the clinical trials published were sponsored by the pharmaceutical industry. Nevertheless, the publications with Portuguese authorship (43.55%) had universities as lead sponsors. Commercial clinical trials took 1.82 ± 0.10 years to publish their results while non-commercial trials took 2.13 ± 0.21 years. These results were not statistically different (p > 0.05). Commercial clinical trials were published in journals with a higher mean impact factor than non-commercial clinical trials (21.65 ± 1.33 and 15.63 ± 3.27, respectively; p < 0.05). Also, commercial clinical trials with Portuguese authors have a mean impact factor higher than non-commercial trials (17.09 ± 4.80 and 6.42 ± 1.93, respectively; p < 0.05). Conclusions: In this study, we conclude that commercial and non-commercial trials are published in similar percentages (around 30%). Portuguese authorship in non-commercial clinical trials has a higher percentage of publications when compared to those from commercial clinical trials (70.37% vs 8.57%). Oncology is the therapeutic area of higher number of registered trials, but it is not the most target one in the publications of non-commercial clinical trials. The mean time from the end of a clinical trial to the publication of its results is around 2 years both for commercial and non-commercial clinical trials. On average, commercial trials are published in journals with higher Impact Factors, when compared to those from non-commercial trials. A higher difference is observed in publications with Portuguese authors (17.09 vs 6.42). The scientific output of this work so far: - Preliminary conclusions from part of this research project were previously presented as an oral communication (selected by abstract) at the Portuguese Society of Pharmacology annual meeting (February 2019) in Porto entitled: The scientific impact of investigator-initiated clinical trials in Portuguese institutions: a systematic search in clinical trials databases. - By invitation, the same work was presented in a class of the "Clinical Trials Monitor Career Initiation Course", which was held at the Faculty of Pharmacy of the University of Porto (February 2019).Introdução: A investigação clínica ou estudos clínicos, que faz parte do ramo das ciências da saúde, é qualquer tipo de investigação médica que envolva participantes humanos. Estes estudos têm como objetivo primário responder a questões científicas específicas e produzir conhecimento valioso para a compreensão de doenças humanas, prevenção ou tratamento de doenças e promoção da saúde. Os ensaios clínicos são muito importantes uma vez que providenciam as ferramentas essenciais para traduzir descobertas científicas em terapias inovadoras, permitem a comercialização de novos fármacos e têm um papel crucial na resposta a questões médicas e científicas. Estes estudos podem ser divididos em ensaios comerciais (promovidos por organizações comerciais como as indústrias farmacêuticas) e ensaios não comerciais (geralmente promovidos por uma organização sem fins lucrativos). Nos ensaios comerciais, os investigadores limitam-se a executar um protocolo definido pela indústria, capacitando o investigador para a execução e prestação de serviços. Por outro lado, nos ensaios não comerciais, os investigadores ou a instituição são os responsáveis pelo desenho e execução do protocolo do ensaio clínico, contribuindo para uma capacitação geral de investigação, de estudo clínico e de impacto científico. De facto, hoje em dia a indústria farmacêutica é a principal promotora de ensaios clínicos em todo mundo apesar do seu foco primário se prender com a comercialização das suas terapias. A proporção de ensaios clínicos não comerciais (ou seja, ensaios clínicos da iniciativa do investigador) é consideravelmente inferior. Ainda assim, a informação proveniente destes estudos é extremamente importante para o bem-estar geral da sociedade, uma vez que é imparcial e não existe nenhum interesse comercial associado. Considerando o impacto científico que ambos os tipos de ensaios clínicos promovem, existem ainda algumas divergências. Os estudos comerciais são frequentemente publicados em jornais com fatores de impacto elevados devido à grande complexidade e dimensão dos estudos que é essencial para atingir resultados relevantes e significativos. Por outro lado, os ensaios não comerciais são normalmente ensaios de menores dimensões, com restrições financeiras e cujos resultados são publicados em artigos científicos ou são apresentados em conferências, sendo associados a fatores de impacto inferiores. Objetivos: Este estudo tem como objetivo principal identificar o impacto científico dos ensaios comerciais e não comerciais que tenham instituições Portuguesas como promotores e /ou Portugal como país participante. Os objetivos secundários prendem-se com comparação nos ensaios comerciais e não comerciais relativamente à: identificação de autores portugueses nas publicações, verificação das áreas terapêuticas de maior interesse onde existe um maior número de publicações e também no tempo médio que decorre desde o término de um ensaio até a publicação dos seus resultados. Metodologia: Uma pesquisa sistemática desde 01/10/2004 a 30/09/2018 foi realizada utilizando quatro plataformas de registo online de ensaios clínicos – Clinicaltrials.gov, EU-CTR, ISRCTN, ANZCTR - para identificar os ensaios clínicos a incluir neste trabalho de investigação. Os três critérios de inclusão utilizados foram: ter como país participante Portugal, ser um estudo de intervenção e ter data de início entre 01/10/2004 a 30/09/2018. A informação relativa ao número de identificação do ensaio, promotor, financiador, tipo de intervenção, área terapêutica, data de início e título do estudo foi obtida através das plataformas de registo referidas acima. A classificação relativa à natureza dos ensaios clínicos (comerciais ou não comerciais) foi feita manualmente, através do nome do promotor do ensaio, uma vez que os registos de ensaios clínicos não possuem essa informação (à exceção da EU-CTR). Para selecionar as publicações, apenas foram considerados os ensaios completos. Para além disso, só a primeira publicação de resultados após o término dos ensaios é que foi considerada. Tendo em conta apenas os ensaios completos, as possíveis publicações foram procuradas através do número de identificação dos ensaios numa pesquisa na base de dados MEDLINE (PubMed). A informação recolhida foi utilizada para complementar a informação obtida nos registos online. Em cada publicação, o ano de publicação, o jornal onde o artigo foi publicado, o fator de impacto e o percentil do respetivo ano de publicação foram registados. Para analisar toda a informação obtida, foi efetuada uma análise descritiva dos resultados. Quando adequado, foi realizada uma análise estatística. As amostras utilizadas não seguiam uma distribuição normal pelo que foi utilizado um teste não paramétrico (teste de Mann-Withney para amostras independentes) com uma confiança de 95%. Relevância: Pela primeira vez, foi conduzido um estudo relativo ao impacto científico com informação detalhada das características dos ensaios comerciais e não comerciais em Portugal utilizando quatro plataformas de registos clínicos e cruzando essa informação com as publicações dos ensaios completos. Foi uma grande conquista conduzir essa análise num número tão elevado de ensaios clínicos, implicando uma abordagem metodológica exaustiva. A relevância de aceder ao impacto científico de ensaios clínicos comerciais e não comerciais de maneira comparativa é muito significativa. Não há dúvida de que as informações fornecidas pelos ensaios da iniciativa do investigador são extremamente importantes, uma vez que os dados clínicos gerados poderão ter um grande impacto nas políticas de saúde na Europa e inovar áreas clínicas que são desconsideradas pela indústria devido à sua lucratividade muito baixa ou inexistente. Além disso, ainda existem poucos ensaios não comerciais publicados em jornais científicos com fator de impacto mais alto quando comparados com os comerciais havendo uma necessidade urgente de entender e superar esse revés. Resultados: Foram identificados um maior número de ensaios clínicos comerciais registados (n= 1402) em comparação com o número de ensaios não comerciais (n= 339). Dentro dos ensaios comerciais, 970 estão completos e apenas 280 (28.87%) publicados, dos quais, 24 (8.57) têm autoria portuguesa. Por outro lado, 170 ensaios não comerciais estão completos, dos quais 54 (31.76%) estão publicados e 38 (70.37%) têm autoria portuguesa. A área oncológica é a área terapêutica mais estudada nos ensaios comerciais publicados (20.71%) e os fármacos químicos as intervenções mais estudadas (65.71%). Em relação aos ensaios não comerciais publicados, a cardiologia é a área de terapêutica de maior interesse (16.67%) e as intervenções comportamentais as mais aplicadas (31.48%). Relativamente à média dos fatores de impacto dos jornais onde os resultados dos ensaios são publicados, esta é significativamente superior (p 0.05). Conclusões: Quando comparados com os ensaios comerciais, os ensaios não comerciais têm uma maior percentagem de publicações e de publicações com autores portugueses. No entanto, é claro que os promotores comerciais publicam mais frequentemente em jornais com fatores de impacto e quartis mais elevados sobre áreas da medicina que são consideradas as mais prevalentes e incidentes no mundo. Os ensaios não comerciais dedicam-se sobretudo a estudos de cardiologia. Relativamente ao tempo médio para a publicação dos resultados, este é semelhante tanto para os ensaios comerciais como não comerciais (aproximadamente 2 anos). Ao comparar as médias dos fatores de impacto dos ensaios comerciais e não comerciais, existem algumas divergências significativas: embora os ensaios clínicos comercias sejam publicados em jornais com fatores de impacto superiores, a maioria destas publicações não tem autores portugueses, ao contrário do que se passa com a publicação de estudos não comercias. Será relevante, no futuro, desenvolver estratégias nacionais que passem pela inclusão de investigadores portugueses em estudos comercias desde uma fase inicial de preparação do estudo, bem como estimular a realização de estudos não comerciais com financiamento substancial para aumentar o impacto científico dos mesmos. Produção científica deste trabalho até à data: - As conclusões preliminares de parte deste projeto foram apresentadas anteriormente, numa comunicação oral (selecionada pelo Resumo) na reunião anual da Sociedade Portuguesa de Farmacologia (fevereiro 2019) no Porto, intitulada: O impacto científico dos ensaios clínicos iniciados por investigadores em instituições portuguesas: uma pesquisa sistemática em plataformas online de ensaios clínicos. - Por convite, o mesmo trabalho foi apresentado numa aula do "Curso de Iniciação à Carreira de Monitor de Ensaios Clínicos", que se realizou na Faculdade de Farmácia da Universidade do Porto (fevereiro 2019)

Methodological quality of network meta-analysis in dentistry : a meta-research

This meta-research aimed to provide an overview of the methodological quality and risk of bias of network meta-analyses (NMA) in dentistry. Searches for NMA of randomized clinical trials with clinical outcomes in dentistry were performed in databases up to January 2022. Two reviewers independently screened titles/ abstracts, selected full texts, and extracted the data. The adherence to PRISMA-NMA reporting guideline, the AMSTAR-2 methodological quality tool, and the ROBIS risk of bias tool were assessed in the studies. Correlation between the PRISMA-NMA adherence and the AMSTAR-2 and ROBIS results was also investigated. Sixty-two NMA studies were included and presented varied methodological quality. According to AMSTAR-2, half of the NMA presented moderate quality (n = 32; 51.6%). The adherence to PRISMA-NMA also varied. Only 36 studies (58.1%) prospectively registered the protocol. Other issues lacking of reporting were data related were data related to the NMA geometry and the assessment of results consistency, and the evaluation of risk of bias across the studies. ROBIS assessment showed a high risk of bias mainly for domains 1 (study eligibility criteria) and 2 (identification and selection of studies). Correlation coefficients between the PRISMA-NMA adherence and the AMSTAR-2 and ROBIS results showed moderate correlation (rho < 0.6). Overall, NMA studies in dentistry were of moderate quality and at high risk of bias in several domains, especially study selection. Future reviews should be better planned and conducted and have higher compliance with reporting and quality assessment tools

Stopping long-acting beta2-agonists (LABA) for children with asthma well controlled on LABA and inhaled corticosteroids.

BACKGROUND: Asthma is the most common chronic medical condition among children and is one of the most common causes of hospitalisation and medical visits. Poorly controlled asthma often leads to preventable exacerbations that require additional medications, hospital stays, or treatment in the emergency department.Long-acting beta2-agonists (LABA) are the preferred add-on treatment for children with asthma whose symptoms are not well controlled on inhaled corticosteroids (ICS). The US Food and Drug Administration has issued a 'black box' warning for LABA in asthma, and now recommends that they be used "for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved". OBJECTIVES: To compare the effect on asthma control and adverse effects of stepping down to inhaled corticosteroids (ICS)-only therapy versus continuing ICS plus LABA in children whose asthma is well controlled on combined ICS and LABA therapy. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, and also searched www.ClinicalTrials.gov, www.who.int/ictrp/en/, reference lists of primary studies and existing reviews, and manufacturers' trial registries (GlaxoSmithKline and AstraZeneca). We searched all databases from their inception to the present, and imposed no restriction on language of publication. The most recent search was done in April 2015. SELECTION CRITERIA: We looked for parallel randomised controlled trials of at least eight weeks' duration, available as published full text, abstract only, or unpublished data. We excluded studies including participants with other chronic respiratory comorbidities (for example bronchiectasis).We looked for studies in which children (18 years or younger) whose asthma was well controlled on any dose of ICS and LABA combination therapy were randomised to: a) step-down therapy to ICS alone or b) continued use of ICS and LABA.We included any dose of LABA (formoterol, salmeterol, vilanterol) and any dose of ICS (beclomethasone, budesonide, ciclesonide, mometasone, flunisolide, fluticasone propionate, fluticasone furoate, triamcinolone) delivered in a combination inhaler or in separate inhalers. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all records identified in the searches. We used a data extraction tool in Microsoft Excel to manage searches and document reasons for inclusion and exclusion, and to extract descriptive and numerical data from trials meeting the inclusion criteria.The prespecified primary outcomes were exacerbations requiring oral steroids, asthma control, and all-cause serious adverse events. MAIN RESULTS: Despite conducting extensive searches of electronic databases, trial registries and manufacturers' websites we identified no trials matching the inclusion criteria.After removing duplicates, we screened 1031 abstracts, and assessed 43 full-text articles for inclusion. We identified several adult studies, which will be summarised in a separate review (Ahmad 2014). The most common reasons for exclusion after viewing full texts were 'wrong comparison' (n = 22) and 'adult population' (n = 18).Some adult studies recruited adolescents from age 15, but none reported data separately for those under 18. AUTHORS' CONCLUSIONS: There is currently no evidence from randomised trials to inform the discontinuation of LABAs in children once asthma control is achieved with ICS plus LABA. It is disappointing that such an important issue has not been studied, and a randomised double-blind trial recruiting children who are controlled on ICS plus LABA is warranted. The study should be large enough to assess children of different ages, and to measure the important safety and efficacy outcomes suggested in this review over at least six months.The only randomised evidence for stopping LABA has been conducted in adults; it will be summarised in a separate review

Improving quality of care and outcome at very preterm birth: the Preterm Birth research programme, including the Cord pilot RCT

BACKGROUND:Being born very premature (i.e. before 32 weeks’ gestation) has an impact on survival and quality of life. Improving care at birth may improve outcomes and parents’ experiences. OBJECTIVES:To improve the quality of care and outcomes following very preterm birth. DESIGN:We used mixed methods, including a James Lind Alliance prioritisation, a systematic review, a framework synthesis, a comparative review, qualitative studies, development of a questionnaire tool and a medical device (a neonatal resuscitation trolley), a survey of practice, a randomised trial and a protocol for a prospective meta-analysis using individual participant data. SETTING:For the prioritisation, this included people affected by preterm birth and health-care practitioners in the UK relevant to preterm birth. The qualitative work on preterm birth and the development of the questionnaire involved parents of infants born at three maternity hospitals in southern England. The medical device was developed at Liverpool Women’s Hospital. The survey of practice involved UK neonatal units. The randomised trial was conducted at eight UK tertiary maternity hospitals. PARTICIPANTS:For prioritisation, 26 organisations and 386 individuals; for the interviews and questionnaire tool, 32 mothers and seven fathers who had a baby born before 32 weeks’ gestation for interviews evaluating the trolley, 30 people who had experienced it being used at the birth of their baby (19 mothers, 10 partners and 1 grandmother) and 20 clinicians who were present when it was being used; for the trial, 261 women expected to have a live birth before 32 weeks’ gestation, and their 276 babies. INTERVENTIONS:Providing neonatal care at very preterm birth beside the mother, and with the umbilical cord intact; timing of cord clamping at very preterm birth. MAIN OUTCOME MEASURES:Research priorities for preterm birth; feasibility and acceptability of the trolley; feasibility of a randomised trial, death and intraventricular haemorrhage. REVIEW METHODS:Systematic review of Cochrane reviews (umbrella review); framework synthesis of ethics aspects of consent, with conceptual framework to inform selection criteria for empirical and analytical studies. The comparative review included studies using a questionnaire to assess satisfaction with care during childbirth, and provided psychometric information. RESULTS:Our prioritisation identified 104 research topics for preterm birth, with the top 30 ranked. An ethnographic analysis of decision-making during this process suggested ways that it might be improved. Qualitative interviews with parents about their experiences of very preterm birth identified two differences with term births: the importance of the staff appearing calm and of staff taking control. Following a comparative review, this led to the development of a questionnaire to assess parents’ views of care during very preterm birth. A systematic overview summarised evidence for delivery room neonatal care and revealed significant evidence gaps. The framework synthesis explored ethics issues in consent for trials involving sick or preterm infants, concluding that no existing process is ideal and identifying three important gaps. This led to the development of a two-stage consent pathway (oral assent followed by written consent), subsequently evaluated in our randomised trial. Our survey of practice for care at the time of birth showed variation in approaches to cord clamping, and that no hospitals were providing neonatal care with the cord intact. We showed that neonatal care could be provided beside the mother using either the mobile neonatal resuscitation trolley we developed or existing equipment. Qualitative interviews suggested that neonatal care beside the mother is valued by parents and acceptable to clinicians. Our pilot randomised trial compared cord clamping after 2 minutes and initial neonatal care, if needed, with the cord intact, with clamping within 20 seconds and initial neonatal care after clamping. This study demonstrated feasibility of a large UK randomised trial. Of 135 infants allocated to cord clamping ≥ 2 minutes, 7 (5.2%) died and, of 135 allocated to cord clamping ≤ 20 seconds, 15 (11.1%) died (risk difference –5.9%, 95% confidence interval –12.4% to 0.6%). Of live births, 43 out of 134 (32%) allocated to cord clamping ≥ 2 minutes had intraventricular haemorrhage compared with 47 out of 132 (36%) allocated to cord clamping ≤ 20 seconds (risk difference –3.5%, 95% CI –14.9% to 7.8%). LIMITATIONS:Small sample for the qualitative interviews about preterm birth, single-centre evaluation of neonatal care beside the mother, and a pilot trial. CONCLUSIONS:Our programme of research has improved understanding of parent experiences of very preterm birth, and informed clinical guidelines and the research agenda. Our two-stage consent pathway is recommended for intrapartum clinical research trials. Our pilot trial will contribute to the individual participant data meta-analysis, results of which will guide design of future trials. FUTURE WORK:Research in preterm birth should take account of the top priorities. Further evaluation of neonatal care beside the mother is merited, and future trial of alternative policies for management of cord clamping should take account of the meta-analysis. STUDY REGISTRATION:This study is registered as PROSPERO CRD42012003038 and CRD42013004405. In addition, Current Controlled Trials ISRCTN21456601. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 8. See the NIHR Journals Library website for further project information

Investigating and dealing with publication bias and other reporting biases in meta-analyses:a review

A P value, or the magnitude or direction of results can influence decisions about whether, when, and how research findings are disseminated. Regardless of whether an entire study or a particular study result is unavailable because investigators considered the results to be unfavourable, bias in a meta-analysis may occur when available results differ systematically from missing results. In this paper, we summarize the empirical evidence for various reporting biases that lead to study results being unavailable for inclusion in systematic reviews, with a focus on health research. These biases include publication bias and selective nonreporting bias. We describe processes that systematic reviewers can use to minimize the risk of bias due to missing results in meta-analyses of health research, such as comprehensive searches and prospective approaches to meta-analysis. We also outline methods that have been designed for assessing risk of bias due to missing results in meta-analyses of health research, including using tools to assess selective nonreporting of results, ascertaining qualitative signals that suggest not all studies were identified, and generating funnel plots to identify small-study effects, one cause of which is reporting bias. This article is protected by copyright. All rights reserved

Proceedings of the Paris Open Science European Conference

For more than twenty years, the international research community has affirmed its support for open and collaborative practices that improve the quality, transparency, reproducibility and inclusiveness of science. In France, this orientation has been reflected in the adoption of two National Plans for Open Science, in 2018 and 2021. In this context and on the occasion of the French Presidency of the Council of the European Union, France organised the Open Science European Conference (OSEC) on 4 and 5 February 2022. This conference on the transformation of the research and innovation ecosystem in Europe was an opportunity to address in particular transparency in health research, the future of scientific publishing and the opening of codes and software produced in a scientific context, but also the necessary transformations of research assessment, summarised in the Paris Call presented during the event and calling for the creation of a coalition of actors committed to reforming the current system. This international event was organised was organised by the French Académie des sciences, the Ministry of Higher Education and Research, the French National Center for Scientific Research (CNRS), the National Institute of Health and Medical Research (Inserm), the High Council for Evaluation of Research and Higher Education (Hcéres), the National Research Agency (ANR), the University of Lorraine and the University of Nantes

The future for diagnostic tests of acute kidney injury in critical care: evidence synthesis, care pathway analysis and research prioritisation

Background: Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leading to significant mortality and morbidity, reduced quality of life and high short- and long-term health-care costs for the NHS. New diagnostic tests may offer an earlier diagnosis or improved care, but evidence of benefit to patients and of value to the NHS is required before national adoption. Objectives: To evaluate the potential for AKI in vitro diagnostic tests to enhance the NHS care of patients admitted to the intensive care unit (ICU) and identify an efficient supporting research strategy. Data sources: We searched ClinicalTrials.gov, The Cochrane Library databases, Embase, Health Management Information Consortium, International Clinical Trials Registry Platform, MEDLINE, metaRegister of Current Controlled Trials, PubMed and Web of Science databases from their inception dates until September 2014 (review 1), November 2015 (review 2) and July 2015 (economic model). Details of databases used for each review and coverage dates are listed in the main report. Review methods: The AKI-Diagnostics project included horizon scanning, systematic reviewing, meta-analysis of sensitivity and specificity, appraisal of analytical validity, care pathway analysis, model-based lifetime economic evaluation from a UK NHS perspective and value of information (VOI) analysis. Results: The horizon-scanning search identified 152 potential tests and biomarkers. Three tests, Nephrocheck® (Astute Medical, Inc., San Diego, CA, USA), NGAL and cystatin C, were subjected to detailed review. The meta-analysis was limited by variable reporting standards, study quality and heterogeneity, but sensitivity was between 0.54 and 0.92 and specificity was between 0.49 and 0.95 depending on the test. A bespoke critical appraisal framework demonstrated that analytical validity was also poorly reported in many instances. In the economic model the incremental cost-effectiveness ratios ranged from £11,476 to £19,324 per quality-adjusted life-year (QALY), with a probability of cost-effectiveness between 48% and 54% when tests were compared with current standard care. Limitations: The major limitation in the evidence on tests was the heterogeneity between studies in the definitions of AKI and the timing of testing. Conclusions: Diagnostic tests for AKI in the ICU offer the potential to improve patient care and add value to the NHS, but cost-effectiveness remains highly uncertain. Further research should focus on the mechanisms by which a new test might change current care processes in the ICU and the subsequent cost and QALY implications. The VOI analysis suggested that further observational research to better define the prevalence of AKI developing in the ICU would be worthwhile. A formal randomised controlled trial of biomarker use linked to a standardised AKI care pathway is necessary to provide definitive evidence on whether or not adoption of tests by the NHS would be of value. Study registration: The systematic review within this study is registered as PROSPERO CRD42014013919. Funding: The National Institute for Health Research Health Technology Assessment programme

Surgical treatments for women with stress urinary incontinence : the ESTER systematic review and economic evaluation

Funded by The National Institute for Health Research Health Technology Assessment programme.Peer reviewedPublisher PD

Identifying and understanding factors that affect the translation of therapies from the laboratory to patients: a study protocol

Background: The process of translating preclinical findings into a clinical setting takes decades. Previous studies have suggested that only 5-10% of the most promising preclinical studies are successfully translated into viable clinical applications. The underlying determinants of this low success rate (e.g. poor experimental design, suboptimal animal models, poor reporting) have not been examined in an empirical manner. Our study aims to determine the contemporary success rate of preclinical-to-clinical translation, and subsequently determine if an association between preclinical study design and translational success/failure exists. Methods: Established systematic review methodology will be used with regards to the literature search, article screening and study selection process. Preclinical, basic science studies published in high impact basic science journals between 1995 and 2015 will be included. Included studies will focus on publicly available interventions with potential clinical promise. The primary outcome will be successful clinical translation of promising therapies - defined as the conduct of at least one Phase II trial (or greater) with a positive finding. A case-control study will then be performed to evaluate the association between elements of preclinical study design and reporting and the likelihood of successful translation. Discussion: This study will provide a comprehensive analysis of the therapeutic translation from the laboratory bench to the bedside. Importantly, any association between factors of study design and the success of translation will be identified. These findings may inform future research teams attempting preclinical-to-clinical translation. Results will be disseminated to identified knowledge users that fund/support preclinical research