Development of a core outcome set for clinical trials in rosacea: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey

BackgroundRosacea is a chronic inflammatory disorder affecting millions of individuals worldwide. Diagnosis is based on signs and symptoms with management and treatment aimed to suppress inflammatory lesions, erythema, and telangiectasia. While many clinical trials of rosacea exist, the lack of consensus in outcome reporting across all trials poses a concern. Proper evaluation and comparison of treatment modalities is challenging. In order to address the inconsistencies present, this project aims to determine a core set of outcomes which should be evaluated in all clinical trials of rosacea.Methods/designThis project will utilize a methodology similar to previous core outcome set research. A long list of outcomes will be extracted over four phases: (1) systematic literature review, (2) patient interviews, (3) other published sources, and (4) stakeholder involvement. Potential outcomes will be examined by the Steering Committee to provide further insight. The Delphi process will then be performed to prioritize and condense the list of outcomes generated. Two homogenous groups of physicians and patients will participate in two consecutive rounds of Delphi surveys. A consensus meeting, composed of physicians, patients, and stakeholders, will be conducted after the Delphi exercise to further select outcomes, taking into account participant scores. By the end of the meeting, members will vote and decide on a final recommended set of core outcomes. For the duration of the study, we will be in collaboration with both the Core Outcome Measures in Effectiveness Trials (COMET) and Cochrane Skin Group - Core Outcome Set Initiative (CSG-COUSIN).DiscussionThis study aims to develop a core outcome set to guide assessment in clinical trials of rosacea. The end-goal is to improve the reliability and consistency of outcome reporting, thereby allowing sufficient evaluation of treatment effectiveness and patient satisfaction.

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Points to consider for ethics committees in human gene therapy trials

Recent political developments and disclosures of serious adverse events in human gene therapy (HGT) with the death of 18-year old Jesse Gelsinger in the USA have shown that the clinical application of HGT raises some severe ethical issues. These have either been neglected or not yet been discussed to a satisfactory extent. In this paper, we will address this deficiency and develop strategies for a safer application of HGT. Such a study must first look closely at the science of HGT itself. We will evaluate the latest preclinical research, especially data on the viruses that are used as vectors and on modes of administration of vectors. We will put forward new arguments concerning the toxicity assessment of so-called 'gene drugs', the tissue and cell type specificity of the vectors, and the duration and on-set of gene expression. Secondly, we will look at procedural aspects of applied research ethics on the way to clinical application of HGT. There, informed consent (IC) and the patient-researcher relationship are of utmost concern. Furthermore, we will explore the problem of expertise in risk assessment and will show how current regulations foster conflicts of interests that create dilemma situations even for those researchers who act in the best interest of the patients. We will conclude the article with a set of questions for ethicists who have to decide about the quality of HGT protocols. This may contribute to the safety of patients participating in HGT trials and to achieving the aim of efficient application of HGT.     

关于干细胞临床产业化的一些思考

干细胞的基础研究和临床应用是近几年国内外的热点之一。但是因为没有产业化的明确途径,这个领域的产业化发展缓慢,很有可能像基因治疗和肿瘤疫苗的产业化一样无疾而终。本文探讨了干细胞治疗能够产业化之前需要解决的几个问题。从技术层面,我们比较了胚胎干细胞和成体干细胞,自体干细胞和异体干细胞的优缺点和国内外公司采取的一些途径。从政策方面,我们探讨了把干细胞治疗作为一种医疗技术还是一类医药产品的优缺点,比较了美国FDA和国内监管部门的相关政策,也提出了进一步的问题。最后,我们以美国FDA刚刚批准的Provenge为例,对细胞治疗和干细胞治疗的产业化提出了一些希望和想法。     

Multiplicity of inferences in clinical trials: adjustment methods, clinical interpretation issues

Multiplicity of inferences is present in a large majority of clinical trials and conducts to false analyses or interpretation issues. The main risk consists in false positive conclusions. A large number of statistical methods is available for controlling the rate of false positive conclusions. But formal adjustment is not necessary in all cases and depends on the aims of the study.     

Detecting potential safety issues in clinical trials by Bayesian screening

Patients in large clinical trials report many different adverse events, most of which will not have been anticipated in the protocol. Conventional hypothesis testing of between group differences for each adverse event can be problematic: Lack of significance does not mean lack of risk, the tests usually are not adjusted for multiplicity, and the data determine which hypotheses are tested. This paper describes a Bayesian screening approach that does not test hypotheses, is self-adjusting for multiplicity, provides a direct assessment of the likelihood of no material drug-event association, and quantifies the strength of the observed association. The approach directly incorporates clinical judgment by having the criteria for treatment association determined by the investigator(s). Diagnostic properties can be evaluated analytically. Application of the method to findings from a vaccine trial yield results similar to those found by methods using a false discovery rate argument and using a hierarchical Bayes approach.     

Antisense therapeutics in oncology: points to consider in their clinical evaluation

Novel therapeutics in oncology stem from a rational design of drugs targeting selective pathways that stimulate and maintain tumor cell growth. Many of these agents are cytostatic in action and also have a limited toxicity profile. However, some can be cytotoxic if they successfully modulate molecular pathways of apoptosis, such as bcl-2. This article discusses points to consider in the design of one class of cytostatic agents, antisense therapy. Our purpose is to stimulate designs that answer the question specifically with regard to proof-of-concept, and the concepts proposed should be viewed as ideas in development rather than firm recommendations.     

Current issues in the design and interpretation of clinical trials.

Though there have been considerable improvements in the use of statistical methods for clinical trials in recent years, there remain major practical difficulties in the design and interpretation of many trials. This paper concentrates on problems relating to randomisation, the overemphasis on significance testing, and the inadequate size of many trials. Each topic is illustrated by examples from recent trials.     

Getting ready for malaria elimination: a check list of critical issues to consider

In recent years, a renewed interest in malaria elimination and eradication hasemerged and seems to be rooting in the minds of the scientific community, publichealth specialists, funding bodies, policy makers and politicians. Malariaeradication will certainly benefit from improved and innovative tools;notwithstanding novel knowledge in fields ranging from basic science to mathematicalmodelling and health systems research. However, the elimination of malaria alsoencompasses a broad range of essential aspects that countries and other actors needto consider when thinking of embarking on such an adventure, including theimplementation of innovative strategies, the ability to incorporate the mostup-to-date evidence into policy, the integration of malaria into the broader healthagenda, the strengthening of surveillance and health systems, capacity building,funding, advocacy and, very importantly, research. While in some cases thisenthusiasm is clearly justified, some countries are still a long way fromrealistically advancing towards elimination. This paper attempts to provide guidanceon all the necessary issues that should be considered when initiating a malariaelimination program.     

A core system for the implementation of task sets

When performing tasks, humans are thought to adopt task sets that configure moment-to-moment data processing. Recently developed mixed blocked/event-related designs allow task set-related signals to be extracted in fMRI experiments, including activity related to cues that signal the beginning of a task block, "set-maintenance" activity sustained for the duration of a task block, and event-related signals for different trial types. Data were conjointly analyzed from mixed design experiments using ten different tasks and 183 subjects. Dorsal anterior cingulate cortex/medial superior frontal cortex (dACC/msFC) and bilateral anterior insula/frontal operculum (aI/fO) showed reliable start-cue and sustained activations across all or nearly all tasks. These regions also carried the most reliable error-related signals in a subset of tasks, suggesting that the regions form a "core" task-set system. Prefrontal regions commonly related to task control carried task-set signals in a smaller subset of tasks and lacked convergence across signal types.