Placebo Effects and Neuromodulation: Ethical Considerations and Recommendations.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

How prevalent are financial conflicts of interest in dermatology randomized controlled trials? A cross-sectional study.

Since the last assessment of conflicts of interest (COIs) in dermatology randomized controlled trials (RCTs) in 2004, several countries have introduced transparency databases. We assessed the prevalence of financial COIs in dermatology RCTs and quantified payments from study sponsors to academic/clinical authors using transparency databases, which are available in the USA, France, Australia, Belgium and the Netherlands, while the UK has a noncompulsory transparency database. We included RCTs from the top 10 dermatology journals and the top 7 general medical journals published in 2019. The study assessed 83 RCTs, and COIs were identified in 69%. The highest prevalence was in exclusively industry-funded trials (46/47, 98%), which consisted of personal payments to an academic/clinical author (96% of trials) and having authors who were employees/stockholders (96%). Payments were identified for 31/56 (55%) academic/clinical first/final authors (median payment US$28 746, maximum US$597 299, interquartile range US$17 061-146 253), and 24/31 payments (77%) payments were each > US$10 000.

Transparency in surgical randomized clinical trials: cross-sectional observational study.

BACKGROUND: RCTs provide the scientific basis upon which treatment decisions are made. To facilitate critical review, it is important that methods and results are reported transparently. The aim of this study was to explore transparency in surgical RCTs with respect to trial registration, disclosure of funding sources, declarations of investigator conflicts and data-sharing. METHODS: This was a cross-sectional review of published surgical RCTs. Ten high-impact journals were searched systematically for RCTs published in years 2009, 2012, 2015 and 2018. Four domains of transparency were explored: trial registration, disclosure of funding, disclosure of investigator conflicts, and a statement relating to data-sharing. RESULTS: Of 611 RCTs, 475 were eligible for analysis. Some 397 RCTs (83.6 per cent) were registered on a trial database, of which 190 (47·9 per cent) had been registered prospectively. Prospective registration increased over time (26 per cent in 2009, 33·0 per cent in 2012, 54 per cent in 2015, and 72·7 per cent in 2018). Funding disclosure was present in 55·0, 65·0, 69·4 and 75·4 per cent of manuscripts respectively. Conflict of interest disclosure was present in 49·5, 89·1, 94·6 and 98·3 per cent of manuscripts across the same time periods. Data-sharing statements were present in only 15 RCTs (3·2 per cent), 11 of which were published in 2018. CONCLUSION: Trial registration, disclosure of funding and disclosure of investigator conflicts in surgical RCTs have improved markedly over the past 10 years. Disclosure of data-sharing plans is exceptionally low. This may contribute to research waste and represents a target for improvement.

ANTECEDENTES: Los ensayos clínicos aleatorizados y controlados (randomized controlled trials, RCT) proporcionan la base científica para la toma de decisiones terapéuticas. Es importante que los métodos y los resultados se presenten de forma transparente para facilitar la revisión crítica. El objetivo de este estudio fue investigar la transparencia en los RCTs del ámbito quirúrgico según su registro, declaraciones de las fuentes de financiación del estudio y conflicto de interés de los investigadores, así como información referente a compartir los datos. MÉTODOS: Revisión transversal de RCTs quirúrgicos publicados. Se realizó una búsqueda sistemática de los RCTs publicados en 10 revistas de alto impacto en los años 2009, 2012, 2015 y 2018. Se exploraron cuatro dominios de transparencia: el registro de los ensayos, la declaración de los fondos utilizados, la declaración de los conflictos de los investigadores y la información referente a la forma de compartir los datos. RESULTADOS: De 611 RCTs, se incluyeron en el análisis 475. Un total de 397 (83,6%) estudios se registraron en una base de datos de ensayos clínicos, de forma prospectiva en 190 (47,9%). El registro prospectivo aumentó a lo largo del tiempo (26,0% en 2009, 33,0% en 2012, 53,5% en 2015 y 72,7% en 2018). Se mencionaban las fuentes de financiación en el 55%, 65%, 69,4% y 75,4% de los manuscritos, respectivamente. La declaración de conflictos de interés estuvo presente en el 49,5%, 89,1%, 94,6% y 98,3% de los manuscritos en esos mismos períodos de tiempo. Las declaraciones relativas a compartir los datos de la investigación constaban en solo 15 (3,2%) RCTs, 11 de los cuales fueron publicados en el 2018. CONCLUSIÓN: En los últimos 10 años ha mejorado de forma notable el registro de los ensayos y las declaraciones de las fuentes de financiación y conflicto de interés en los RCTs quirúrgicos. La declaración referente a compartir los datos es excepcionalmente baja, lo que puede contribuir al desperdicio de la investigación y constituye un objetivo de mejora.

[The naked king in the pandemic: about the production and communication of scientific knowledge at the time of SARS-CoV-2.] / Il re nudo nella pandemia: sulla produzione e comunicazione del sapere scientifico ai tempi di SARS-CoV-2.

The SARS-CoV-2 pandemic has lifted the veil about how medical knowledge is produced and disseminated. Action Bias, together with economic, academic and media-related interests, has concurred to generate and spread low-value and even unreliable information about some hypothetical therapeutic interventions for CoViD-19. Not only this "infodemic" has weakened people's ability to make informed health choices, but it also has influenced the process of new evidence generation through the violation of the equipoise principle. The CoViD-19 infodemic has further highlighted the need for reliable health information and for people to enter the process of understanding and promoting valuable research. Through a randomized controlled trial, the Informed Health Choices project has shown that it is not impossible neither quixotic to better orient people about health choices since primary school. Similar competencies should be disseminated to everyone through sources that are selected and validated for their capability of reporting evidence based health information about the effects of treatments.

Authors of clinical trials seldom reported details when declaring their individual and institutional financial conflicts of interest: a cross-sectional survey.

BACKGROUND: The main objective of this study was to document details of both individual and institutional financial conflicts of interest (FCOIs) reported by the authors of clinical trials. An additional objective was to assess the predictors of having at least one author reporting any FCOI. METHODS: We used a sample of randomized controlled trials from a previous cross-sectional survey and included the trials, which reported at least one FCOI disclosure. We categorized the types of disclosed FCOI as grant, employment income, personal fees, nonmonetary support, drug or equipment supplies, patent, stocks, and other types. We collected data on the characteristics of the included RCTs, of the authors, and of the reported FCOI disclosures. We conducted descriptive analyses and a regression analysis to assess the predictors of having at least one author reporting any FCOI. RESULTS: All 108 included RCTs reported being funded, with 58% reporting funding by a private-for-profit source. Out of 1,687 authors, 814 (48%) reported at least one, and a median of 2, FCOI disclosures. Of the 814 reporting disclosures, far more reported individual FCOIs (99%) than institutional FCOIs (6%). The most commonly reported individual FCOI subtypes were grant (49%), personal fees (48%), and employment income (22%). Of the 99% of disclosures that included the source of FCOI, a private-for-profit entity provided the funds in 85%. Reporting about the relation of the FCOI source's to the product investigated in the trial, the timing of FCOI, and monetary value of FCOI was limited. Reporting of FCOIs proved most strongly associated with author affiliation being an academic institution (OR = 2.981; 95% CI: 2.415-3.680) and trial funding from entity other than a private-for-profit entity (OR = 2.809; 95% CI: 2.274-3.470). CONCLUSION: Approximately half of the trial authors report individual FCOIs, often three or more, but seldom provide details related to source's relation to the trial, or the timing and monetary value of the FCOI.

Pro-Con Perspectives on Ethics in Surgical Research: Update from the 39th Annual Surgical Infection Society Meeting.

Background: Surgical research is potentially invasive, high-risk, and costly. Research that advances medical dogma must justify both its ends and its means. Although ethical questions do not always have simple answers, it is critically important for the clinician, researcher, and patient to approach these dilemmas and surgical research in a thoughtful, conscientious manner. Methods: We present four ethical issues in surgical research and discuss the opposing viewpoints. These topics were presented and discussed at the 39th Annual Meeting of the Surgical Infection Society as pro-con debates. The presenters of each opinion developed a succinct summary of their respective reviews for this publication. Results: The key subjects for these pro-con debates were: (1) Should patients be enrolled for time-sensitive surgical infection research using an opt-out or an opt-in strategy? (2) Should patients who are being enrolled in a randomized controlled trial (RCT) comparing surgery with a non-operative intervention pay the costs of their treatment arm? (3) Should the scientific community embrace open access journals as the future of scientific publishing? (4) Should the majority of funding go to clinical or basic science research? Important points were illustrated in each of the pro-con presentations and illustrated the difficulties that are facing the performance and payment of infection research in the future. Conclusions: Surgical research is ethically complex, with conflicting demands between individual patients, society, and healthcare economics. At present, there are no clear answers to these and the many other ethical issues facing research in the future. Answers will only come from continued robust dialogue among all stakeholders in surgical research.

Reporting of drug trial funding sources and author financial conflicts of interest in Cochrane and non-Cochrane meta-analyses: a cross-sectional study.

OBJECTIVE: To (1) investigate the extent to which recently published meta-analyses report trial funding, author-industry financial ties and author-industry employment from included randomised controlled trials (RCTs), comparing Cochrane and non-Cochrane meta-analyses; (2) examine characteristics of meta-analyses independently associated with reporting funding sources of included RCTs; and (3) compare reporting among recently published Cochrane meta-analyses to Cochrane reviews published in 2010. DESIGN: Review of consecutive sample of recently published meta-analyses. DATA SOURCES: MEDLINE database via PubMed searched on 19 October 2018. ELIGIBILITY CRITERIA FOR SELECTING ARTICLES: We selected the 250 most recent meta-analyses listed in PubMed that included a documented search of at least one database, statistically combined results from ≥2 RCTs and evaluated the effects of a drug or class of drugs. RESULTS: 90 of 107 (84%) Cochrane meta-analyses reported funding sources for some or all included trials compared with 21 of 143 (15%) non-Cochrane meta-analyses, a difference of 69% (95% CI 59% to 77%). Percent reporting was also higher for Cochrane meta-analyses compared with non-Cochrane meta-analyses for trial author-industry financial ties (44% versus 1%; 95% CI for difference 33% to 52%) and employment (17% versus 1%; 95% CI for difference 9% to 24%). In multivariable analysis, compared with Cochrane meta-analyses, the odds ratio (OR) for reporting trial funding was ≤0.11 for all other journal category and impact factor combinations. Compared with Cochrane reviews from 2010, reporting of funding sources of included RCTs among recently published Cochrane meta-analyses improved by 54% (95% CI 42% to 63%), and reporting of trial author-industry financial ties and employment improved by 37% (95% CI 26% to 47%) and 10% (95% CI 2% to 19%). CONCLUSIONS: Reporting of trial funding sources, trial author-industry financial ties and trial author-industry employment in Cochrane meta-analyses has improved since 2010 and is higher than in non-Cochrane meta-analyses.

Ethical issues in the design and conduct of stepped-wedge cluster randomized trials in low-resource settings.

BACKGROUND: Stepped-wedge cluster randomized trials (SW-CRTs) are increasingly popular in health-related research in both high- and low-resource settings. There may be specific ethical issues that researchers face when designing and conducting SW-CRTs in low-resource settings. Knowledge of these issues can help to improve the ethical conduct of SW-CRTs in a global health context. METHODS: We performed an ethical analysis of two studies using SW-CRT designs in low-resource settings: the Que Vivan Las Madres study conducted from 2014 to 2017 in Guatemala and the Atmiyata study conducted from 2017 to 2018 in rural parts of India. For both case studies, we identified and evaluated the classification of the study as research or nonresearch and the ethical issues regarding the justification of the design, including the delayed rollout of an intervention that had a promising effect. RESULTS: In our case studies, some minor ethical issues surfaced about the registration and stakeholder pressure on the order of randomization, but both included good justification for the design and delayed rollout. Our analysis did, however, demonstrate that careful consideration of the role of randomization and registration of the trials is important. DISCUSSION: SW-CRTs can provide an opportunity for rigorous evaluation of interventions destined to be rolled out on the basis of limited evidence. Furthermore, in SW-CRTs, the underlying objective is often to provide a robust evaluation of the effectiveness for generalized dissemination, and this makes the SW-CRT no less a research study than any other form of cluster randomized trial. CONCLUSION: The design and conduct of stepped-wedge cluster randomized trials raises at least two ethical issues that need special consideration in both high- and low-resource settings: the justification for using the design, specifically the delayed rollout of the intervention to the control group, and the classification of the study as research or nonresearch. In our case studies, these issues did not seem to raise special ethical scrutiny in low-resource settings. Further ethical evaluation will hopefully result in specific ethical guidelines for the use of SW-CRTs in both high- and low-resource settings to contribute to responsible functioning of these trials and adequate protection of participants.

Community perspectives on randomisation and fairness in a cluster randomised controlled trial in Zambia.

BACKGROUND: One important ethical issue in randomised controlled trials (RCTs) is randomisation. Relatively little is known about how participating individuals and communities understand and perceive central aspects of randomisation such as equality, fairness, transparency and accountability in community-based trials. The aim of this study was to understand and explore study communities' perspectives of the randomisation process in a cluster RCT in rural Zambia studying the effectiveness of different support packages for adolescent girls on early childbearing. METHODS: In this explorative study, in-depth semi-structured interviews were carried out in 2018 with 14 individuals who took part in the randomisation process of the Research Initiative to Support the Empowerment of Girls (RISE) project in 2016 and two traditional leaders. Two of the districts where the trial is implemented were purposively selected. Interviews were audio recorded and fully transcribed. Data were analysed by coding and describing emergent themes. RESULTS: The understanding of the randomisation process varied. Some respondents understood that randomisation was conducted for research purposes, but most of them did not. They had trouble distinguishing research and aid. Generally, respondents perceived the randomisation process as transparent and fair. However, people thought that there should not have been a "lottery" because they wanted all schools to receive equal or balanced benefits of the interventions. CONCLUSIONS: Randomisation was misunderstood by most respondents. Perceived procedural fairness was easier to realize than substantive fairness. Researchers working on Cluster Randomised Controlled Trials (CRCTs) should consider carefully how to explain randomisation.

Issues, challenges, and the way forward in conducting clinical trials among neonates: investigators' perspective.

Clinical trials are essential to test the safety and efficacy of new treatments in any population. The paucity of drug trials especially in the neonatal population has led to the widespread use of unlicensed or off-label medications, exposing them to the risks of drug toxicity and ineffective treatment. Ethical and operational challenges are no longer considered valid excuses for not conducting drug trials in neonates. We recently participated in a combined phase-2 and phase-3 trial investigating a new indigenous goat lung surfactant extract (GLSE) for the treatment of respiratory distress syndrome (RDS) in preterm neonates. In this article, we share pertinent challenges faced by us during the trial to better inform and foster-positive discussion among drug developers, administrators, regulatory authorities, patient advocacy groups, and researchers. Also, we provide many tools developed for the GLSE trial that can be modified and used by prospective trialists.

Rights to social determinants of flourishing? A paradigm for disability and public health research and policy.

BACKGROUND: The term evidence based medicine was introduced in the early 1990s in clinical medicine to educate clinicians about how to assess the 'credibility' of research to ensure best treatments for their patients. The evidence based medicine paradigm has become more diffuse in times of austerity and randomised controlled designs are being used to address complex issues in public health and disability research. This research is not addressing inequalities in terms of disability nor how people can live well with disabilities. MAIN TEXT: We argue that there are four ways that public health research needs to change if it wants to address inequalities linked to disability: 1) rethinking theoretical connections between public health and disability; 2) building ethics and equity into interventions through a human rights approach; 3) ensuring ethical inclusion through intersectionality; and 4) evaluating policy and other social impacts to ensure they capture diversity. We argue that these are key issues to building a social determinants of flourishing. CONCLUSIONS: We need to understand how disability might have an accumulative impact across the life course, as well as how to ensure equity for people living with disabilities. This means conceptualising a social determinants of flourishing where we evaluate how exactly randomised controlled trials and public health interventions, not only lead to greater equality but also ensure rights to health and wellbeing.

Conflicts of interest and outcomes of clinical trials of antidepressants: An 18-year retrospective study.

Pharmaceutical sponsorship, funding sources, and investigators' conflicts of interest may be potential influencers in the conduct and results of clinical trials, as well as in the promotion of psychiatric drug therapies. We report the results of an audit of randomized controlled trials (RCTs) of antidepressants conducted from 2000 to 2017. We searched the Web of Science databases with a comprehensive search strategy to identify phase 2 and 3 RCTs. Out of the 1085 articles initially located, a total of 291 RCTs were identified and included in the final analyses. A higher percentage of RCTs conducted by employees of pharmaceutical companies reported favorable results than those with academic or governmental funding (76.90% vs. 60.60%); however, this association was not significant (Χ2 = 2.47, P = 0.18). The data were further analyzed using bivariate and cluster analytical approaches, and the nonsignificant association persisted in both cases. However, analyses of industry-funded placebo-controlled trials (a subgroup of the 291 RCTs) revealed a higher proportion of results that were reported as significant compared to their counterparts with other funding sources (67% vs. 33%). This association was statistically significant (Χ2 = 9.56, P = 0.002), indicating that there is evidence in support of conflicts of interest as a potential bias in the outcomes of RCTs conducted for antidepressants.

Association of author's financial conflict of interest with characteristics and outcome of rheumatoid arthritis randomized controlled trials.

OBJECTIVE: To examine the prevalence, types and temporal trends of reported financial conflicts of interest (FCOIs) among authors of drug therapy randomized controlled trials (RCTs) for RA and their association with study outcomes. METHODS: We identified original, non-phase 1, parallel-group, drug therapy RA RCTs published in the years 2002-03, 2006-07, and 2010-11. Two investigators independently obtained trial characteristics data. Authors' FCOIs were classified as honoraria/consultation fees receipt, employee status, research grant, and stock ownership. Multivariable logistic regression was performed to identify whether FCOIs were independently associated with study outcome. RESULTS: A total of 146 eligible RCTs were identified. Of these, 83 (58.4%) RCTs had at least one author with an FCOI [employee status: 63 (43.2%), honoraria/consultation fees receipt: 49 (33.6%), research grant: 30 (20.5%), and stock ownership: 28 (19.2%)]. A remarkable temporal increase in reporting of honoraria/consultation fees receipt, research grant, and stock ownership was seen. The reporting of any FCOI itself was not associated with positive outcome [50/73 (68.5%) with author FCOI vs 36/52 (69.2%) without author FCOI, P = 0.93]. However, honoraria/consulting fees receipt was independently associated with increased likelihood of a positive outcome [adjusted odds ratio (95% CI) of 3.24 (1.06-9.88)]. In general, trials with FCOIs were significantly more likely to be multicentre, have larger enrolment, use biologic or a small molecule as the experimental intervention, and have better reporting of some methodological quality measures. CONCLUSION: FCOI reporting in RA drug RCT authors is common and temporally increasing. Receipt of honoraria/consulting fees was independently associated with a positive study outcome.

Towards theoretically robust evidence on health equity: a systematic approach to contextualising equity-relevant randomised controlled trials.

Reducing inequalities in health and the determinants of health is a widely acknowledged health policy goal, and methods for measuring inequalities and inequities in health are well developed. Yet, the evidence base is weak for how to achieve these goals. There is a lack of high-quality randomised controlled trials (RCTs) reporting impact on the distribution of health and non-health benefits and lack of methodological rigour in how to design, power, measure, analyse and interpret distributional impact in RCTs. Our overarching aim in this paper is to contribute to the emerging effort to improve transparency and coherence in the theoretical and conceptual basis for RCTs on effective interventions to reduce health inequity. We endeavour to achieve this aim by pursuing two more specific objectives. First, we propose an overview of three broader health equity frameworks and clarify their implications for the measurement of health inequality in RCTs. Second, we seek to clarify the relationship between theory and translational challenges that researchers would need to attend to, in order to ensure that equity-relevant RCTs are coherently grounded in theory.