Expert consensus recommendations on the use of randomized clinical trials for drug approval in psychiatry- comparing trial designs.

The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular.

Development and technical validation of a smartphone-based pediatric cough detection algorithm.

INTRODUCTION: Coughing is a common symptom in pediatric lung disease and cough frequency has been shown to be correlated to disease activity in several conditions. Automated cough detection could provide a noninvasive digital biomarker for pediatric clinical trials or care. The aim of this study was to develop a smartphone-based algorithm that objectively and automatically counts cough sounds of children. METHODS: The training set was composed of 3228 pediatric cough sounds and 480,780 noncough sounds from various publicly available sources and continuous sound recordings of 7 patients admitted due to respiratory disease. A Gradient Boost Classifier was fitted on the training data, which was subsequently validated on recordings from 14 additional patients aged 0-14 admitted to the pediatric ward due to respiratory disease. The robustness of the algorithm was investigated by repeatedly classifying a recording with the smartphone-based algorithm during various conditions. RESULTS: The final algorithm obtained an accuracy of 99.7%, sensitivity of 47.6%, specificity of 99.96%, positive predictive value of 82.2% and negative predictive value 99.8% in the validation dataset. The correlation coefficient between manual- and automated cough counts in the validation dataset was 0.97 (p < .001). The intra- and interdevice reliability of the algorithm was adequate, and the algorithm performed best at an unobstructed distance of 0.5-1 m from the audio source. CONCLUSION: This novel smartphone-based pediatric cough detection application can be used for longitudinal follow-up in clinical care or as digital endpoint in clinical trials.

Placebo-To be or not to be? Are there really alternatives to placebo-controlled trials?

Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials.