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GCP has become the gold-standard for clinical research; initiated as a guideline pertaining to new drug development, it became a law in many countries, extending its scope to include all research. GCP is an excellent document that outlines the responsibilities of stakeholders involved in clinical research. Widely acclaimed, and deservedly so, it is considered as the “go-to” document whenever questions arise during the conduct of a clinical trial. This article presents another narrative, one that has not been articulated so far. Irrespective of whether we consider GCP as a law or a guideline, it is viewed as an “official” document, without the overt realisation that this was actually an initiative of the pharmaceutical industry, the “masters of mankind”. While the stress on documentation and monitoring in GCP was justified, its over-interpretation led to increased costs of clinical trials, with the result that smaller companies find it difficult to conduct the already expensive trials. GCP as an idea is now so entrenched within the scientific community that the real aims which led to its birth and that can be mined from the ICH website, like the need for market expansion, have remained largely unnoticed and undocumented, and are being expressed here.

Background Although discontinuation is common in clinical trials, no study has been conducted to analyse the current situation and reasons for the suspension or discontinuation of drug clinical trials in China. This study aims to analyse the general characteristics and reasons for the discontinuation of registered clinical trials in mainland China and to identify the associated factors. Methods We conducted a cross-sectional observational study of discontinued trials registered in the Drug Trial Registration and Information Publication Platform before March 31, 2020. All trials with a status of terminated or stopped recorded in the platform were classified as discontinued trials and included in the analysis. The basic characteristics of the discontinued trials were recorded, reasons for trial discontinuation were recorded and divided into 4 categories as drug development strategy, trial planning, trial conduct and studied drug. Pearson’s chi-square test and fisher’s exact test were used to compare the differences in reasons for discontinuation between neoplasm trials and non-neoplasm trials, and to examine the associations of trial characteristics with different reasons related to trials discontinuation. Results Three hundred twelve discontinued trials were included in this study. The studied drugs were mainly chemical drugs [229 (73.4%)], and indications of the studied drugs were mainly neoplasms [77 (24.7%)]. Geographical location of the discontinued trials were mostly in northern [114 (36.5%)] and eastern [96 (30.8%)] China. Study type of the included trials was mainly bioequivalence studies [97 (31.1%)]. The most common reason for trial discontinuation was commercial or strategic decision [84 (26.9%)], followed by futility/lack of efficacy [70 (22.4%)]. The number of trial centers, sample size and whether participants had been enrolled were significantly associated with trial discontinuation (P P 500 showed a higher rate of trial discontinuation due to studied drug related reasons (P P < 0.05). Besides, neoplasm trials showed a higher rate of trial discontinuation due to poor recruitment and safety comparing with non-neoplasm trials (P < 0.05). Conclusions Trial discontinuation in China mainly occurred because of commercial or strategic decision and futility/lack of efficacy of the studied drug. Clinical trials with multiple centers and a large sample size may more likely be discontinued due to trial conduct related reasons such as good clinical practice. Discontinuation due to drug safety and lack of efficacy in multiple center trials with a large sample size deserves more attention to avoid resources wastes. Full communication with regulatory authorities such as Center for Drug Evaluation and research institutes to develop a feasible protocol is important for sponsors to avoid trial discontinuation due to protocol issues.

Key Points Question What is the evidence for nonpharmacological interventions to treat persistent postconcussion symptoms? Findings Following a systematic review and meta-analysis of 19 randomized clinical trials comprising 2007 participants, using the Grading of Recommendations, Assessment, Development, and Evaluations method, weak recommendations for the following were assigned: systematic provision of early information and advice, use of graded physical exercise, vestibular rehabilitation, manual treatment of neck and back, psychological treatment, and interdisciplinary rehabilitation. No studies were identified regarding oculomotor vision treatment, resulting in a consensus-based statement. Meaning Based on very low to low certainty of evidence or on consensus, individually tailored nonpharmacological treatment of persistent symptoms was recommended, both through specific disciplines and interdisciplinary rehabilitation., This systematic review and meta-analysis assesses the outcomes related to 7 nonpharmacological interventions for persistent postconcussion symptoms in adults and provides recommendations for clinical practice., Importance Persistent (>4 weeks) postconcussion symptoms (PPCS) are challenging for both patients and clinicians. There is uncertainty about the effect of commonly applied nonpharmacological treatments for the management of PPCS. Objective To systematically assess and summarize evidence for outcomes related to 7 nonpharmacological interventions for PPCS in adults (aged >18 years) and provide recommendations for clinical practice. Data Sources Systematic literature searches were performed via Embase, MEDLINE, PsycINFO, CINAHL, PEDro, OTseeker, and Cochrane Reviews (via MEDLINE and Embase) from earliest possible publication year to March 3, 2020. The literature was searched for prior systematic reviews and primary studies. To be included, studies had to be intervention studies with a control group and focus on PPCS. Study Selection A multidisciplinary guideline panel selected interventions based on frequency of use and need for decision support among clinicians, including early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of neck and back, oculomotor vision treatment, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. To be included, studies had to be intervention studies within the areas of the predefined clinical questions, include a control group, and focus on symptoms after concussion or mild traumatic brain injury. Data Extraction and Synthesis Extraction was performed independently by multiple observers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data abstraction and data quality assessment. Included studies were assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the Cochrane Risk of Bias (randomized clinical trials) tool. Meta-analysis was performed for all interventions where possible. Random-effects models were used to calculate pooled estimates of effects. The level and certainty of evidence was rated and recommendations formulated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Main Outcomes and Measures All outcomes were planned before data collection began according to a specified protocol. The primary outcomes were the collective burden of PPCS and another outcome reflecting the focus of a particular intervention (eg, physical functioning after graded exercise intervention). Results Eleven systematic reviews were identified but did not contribute any primary studies; 19 randomized clinical trials comprising 2007 participants (1064 women [53.0%]) were separately identified and included. Evidence for the 7 interventions ranged from no evidence meeting the inclusion criteria to very low and low levels of evidence. Recommendations were weak for early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of the neck and back, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. No relevant evidence was identified for oculomotor vision treatment, so the panel provided a good clinical practice recommendation based on consensus. Conclusions and Relevance Based on very low to low certainty of evidence or based on consensus, the guideline panel found weak scientific support for commonly applied nonpharmacological interventions to treat PPCS. Results align with recommendations in international guidelines. Intensified research into all types of intervention for PPCS is needed.

Introduction Today, it is widespread practice to postpone frozen embryo transfer (FET) in a modified natural cycle (mNC) for at least one menstrual cycle after oocyte retrieval and failed fresh embryo transfer or freeze-all. The rationale behind this practice is the concern that suboptimal ovarian, endometrial or endocrinological conditions following ovarian stimulation may have a negative impact on endometrial receptivity and implantation. However, two recent systematic reviews and meta-analyses based on retrospective data did not support this practice. As unnecessary delay in time to transfer and pregnancy should be avoided, the aim of this study is to investigate if immediate single blastocyst transfer in mNC-FET is non-inferior to standard postponed single blastocyst transfer in mNC-FET in terms of live birth rate. Methods and analysis Multicentre randomised controlled non-blinded trial including 464 normo-ovulatory women aged 18–40 years undergoing single blastocyst mNC-FET after a failed fresh or freeze-all cycle. Participants are randomised 1:1 to either FET in the first menstrual cycle following the stimulated cycle (immediate FET) or FET in the second or subsequent cycle following the stimulated cycle (postponed FET). The study is designed as a non-inferiority trial and primary analyses will be performed as intention to treat and per protocol. Ethics and dissemination Ethical approval has been granted by the Scientific Ethical Committee of the Capital Region of Denmark (J-nr.: H-19086300). Data will be handled according to Danish law on personal data protection in accordance with the general data protection regulation. Participants will complete written consent forms regarding participation in the study and storage of blood samples in a biobank for future research. The study will be monitored by a Good Clinical Practice (GCP)-trained study nurse not otherwise involved in the study. The results of this study will be disseminated by publication in international peer-reviewed scientific journals. Trial registration number NCT04748874; Pre-results.

Introduction: To assess clinical practices in root canal treatments (RCTs) performed by general dental practitioners under 2 different reward schemes applied in public dental services. Methods: This study used a retrospective design with tooth as the observation unit. The data included all teeth (n = 547) with nonsurgical primary RCT completed in 2016. Electronic documents included treatment details and radiographs. RCT assessment covered 4 key items: taking pre- and postoperative radiographs, using a rubber dam, measuring working length. Assessed dichotomies indicated whether practices were adequate. Dentists' reward schemes were "salaried" and "fee-for-service." Chi squared tests analyzed frequency differences. Results: RCTs formed 2 groups by the reward scheme: 305 RCTs were performed by salaried dentists and 242 by fee-for-service dentists. Preoperative radiographs were diagnosable for 76.1% and postoperative radiographs, for 95.1% of all RCTs. Rubber dam use was documented for 28.9% of the RCTs, more frequently when performed by salaried than by fee-for-service dentists (43.9% vs 9.9%, P < .001). Working length measurement was documented for 72.9% of the RCTs, more frequently for RCTs performed by salaried than by fee-for-service dentists (85.2% vs 57.4%, P < .001). All 4 key items were assessed as adequate in 19.0% of all RCTs, more frequently when performed by salaried than by fee-for-service dentists (29.5% vs 5.8%, P < .001). Conclusions: Deficiencies in RCTs, particularly underuse of rubber dams call for further research to understand the reasons for noncompliance with good clinical practice guidelines.

Aim The novel coronavirus disease‐2019 (COVID‐19) is a major health problem and has affected innumerable people around the world. The current online‐based study was conducted to assess the knowledge, attitude and practice (KAP) of dental students and professionals during the early days of lockdown in India from 2 April to 1 May 2020. Methodology An online‐based cross‐sectional study was undertaken through WhatsApp messenger and e‐mail groups among dental students and professionals. The KAP on COVID‐19 was ascertained using an investigator designed and validated questionnaire. The results were stratified based on student vs professionals. The data were expressed as frequency and percentage analysed using the chi‐square/Fishers exact test using IBM version 17. A probability value of

Background The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is undertaking a major revision of ICH E6 Good Clinical Practice (GCP) decided to involve external stakeholders in ICH-GCP renovation. Activities such as surveys and public conferences have taken place in the United States, European Union, and Japan. For stakeholder engagement in Japan, a designated research group conducted a survey of academic stakeholders. Methods A total of 105 academic stakeholders from 18 institutions responded to the survey. The research group developed recommendations reflecting the survey results and the opinions from patients and the public. Results The survey showed the top four principles needing renovation were (i) informed consent (Chapter 2.9, 12.4% of respondents believed it needed renovation), (ii) systems for quality assurance (Chapter 2.13, 9.5%), (iii) information on an investigational product (Chapter 2.4, 5.7%), and (iv) procedures on clinical trial information (Chapter 2.10, 5.7%). The top three sections identified as needing renovation were: (i) informed consent (Chapter 4.8, 27.6%), (ii) monitoring (Chapter 5.18, 22.9%), and (iii) composition, functions, and operations of the ethics committee (Chapter 3.2, 14.3%). Recommendations included clarification of ICH-GCP’s scope, proportionality in various aspects of clinical trials, diversity and liquidity of ethics committee members, modernization of informed consent procedures, variations in monitoring, and regulatory grade when using real-world data. Conclusion The recommendations from Japanese investigators and patients have been submitted to the ICH E6 Expert Working Group, which will strengthen the robustness of the GCP renovation.

Introduction Argon plasma coagulation (APC) alone is effective and safe at treating weight regain following Roux-en-Y gastric bypass (RYGB). However, technical details of the treatment vary widely among studies. Therefore, we aimed to create good clinical practice guidelines through a modified Delphi consensus, including experts from the collaborative Bariatric Endoscopy Brazilian group. Methods Forty-one locally renowned experts were invited to the consensus by email. Experiences of > 150 APC-treated cases or authorship of relevant articles were the eligibility criteria. An initial questionnaire with short-answer questions was distributed to the experts. The organizing committee converted the responses into statements for an online 2-day voting webinar. Consensus was defined as more than 67% of positive answers. Three consecutive voting rounds were planned with discussion and statement refinements between rounds. Results Thirty-seven experts fulfilled eligibility criteria and attended the live webinar voting. The total number of patients treated by the panel was 12,349. By the third round, all 79 statements reached consensus. The recommendations include the definition of dilated gastrojejunal anastomosis as ≥ 15 mm, minimum regain of 20% of the lost weight to indicate the APC therapy, 6 to 8 weeks as the ideal interval between ablation sessions, and stopping treatment when the stoma reaches

Introducción: El presente artículo resume la guía de práctica clínica (GPC) para el tamizaje, diagnóstico, y tratamiento inicial del cáncer de próstata localizado y localmente avanzado en el Seguro Social del Perú (EsSalud). Objetivo: Proveer recomendaciones clínicas basadas en evidencia para el tamizaje, diagnóstico, y tratamiento inicial de adultos con cáncer de próstata localizado y localmente avanzado en EsSalud. Material y Métodos: Se conformó un grupo elaborador de la guía (GEG) que incluyó médicos especialistas y metodólogos, el cual formuló preguntas clínicas. Se realizaron búsquedas sistemáticas de revisiones sistemáticas y –cuando fue considerado pertinente– estudios primarios en PubMed durante el 2020 y 2021. Se seleccionó la evidencia para responder cada una de las preguntas clínicas planteadas. Se evaluó la certeza de evidencia usando la metodología Grading of Recommendations Assessment, Development, and Evaluation (GRADE). En reuniones de trabajo periódicas, el GEG usó la metodología GRADE para revisar la evidencia y formular las recomendaciones. La GPC fue revisada por expertos externos antes de su aprobación. Resultados: La GPC abordó 06 preguntas clínicas, divididas en 03 temas: tamizaje, diagnóstico, y tratamiento inicial. En base a dichas preguntas se formularon 08 recomendaciones (04 fuertes y 04 condicionales), 10 puntos de buena práctica clínica, y 04 flujogramas. Conclusión: Se emitieron recomendaciones basadas en evidencia para el manejo de pacientes con esta patología. Background: This article summarizes the clinical practice guide (CPG) for the screening, diagnosis, and initial treatment of localized and locally advanced prostate cancer in the Social Security of Peru (EsSalud). Objective: To provide evidencebased clinical recommendations for the screening, diagnosis, and initial treatment of adults with localized and locally advanced prostate cancer in EsSalud. Methods: A guideline development group (GDG) was formed, which included specialist physicians and methodologists, who formulated clinical questions. Systematic searches of systematic reviews were conducted and - when deemed relevant - primary studies in PubMed during 2020 and 2021. Evidence was selected to answer each of the proposed clinical questions. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. In periodic working meetings, the GEG used the GRADE methodology to review the evidence and formulate recommendations. The CPG was reviewed by external experts before its approval. Results: The CPG addressed 06 clinical questions, divided into 03 topics: screening, diagnosis, and initial treatment. Based on these questions, 08 recommendations were formulated (04 strong and 04 conditional), 10 points of good clinical practice, and 04 flow charts. Conclusion: Evidence-based recommendations were issued for the management of patients with this pathology.

Over-the-counter antiaging formulations aim to prevent or minimize the signs of aging skin, and to maintain the benefits obtained from different cosmetic procedures. Even though a huge selection of such products is available on the market, evidence and good clinical practice of the data supporting their use are oftentimes lacking. In this systematic review, the authors reviewed scientific data available in the published literature on the most common ingredients used in antiaging cosmetics, with a particular focus on in vivo studies.

Opioid-related mortality in adolescents is spreading in the US, with prescription opioids playing a crucial role in the development of addiction. We traced back to the process leading to the so called “opioid overflow”, trying to identify any modifiable attitude.Since the late 1990s, pain was labelled as the “fifth vital sign” and its proper management was prompted, encouraging the use of opioids for any pain scored at a Numerical Rating Scale (NRS) of 7 or higher. This assumption has some remarkable limitations. NRS is a proxy of pain severity in children, and pain measurement should be strengthened by a more comprehensive pain evaluation. Moreover, while remaining a fundamental therapeutic right of patients suffering postoperative or chronic severe pain, opioids show no evidence of superiority respect to non-opioid regimens in the management of pain from several acute conditions.Italy, as other European countries, is often reluctant to the use of opioids, even when highly recommendable, missing the opportunity of properly treating those selected patients with severe pain. Both attitudes can be viewed as the result of an extreme simplification of the complex process of pain evaluation and treatment, by means of a ‘one-size-fits-all’ approach.This highlights the need for a systematic and patient-tailored attitude to children in pain, avoiding applying guidelines without question. Good clinical practice must rely on guidelines, which, however, as often based on partial and insufficient data, can be questioned by emerging new evidence, and should not substitute our rational thinking, and capability to understand each patient, avoiding excessive conformism.

The National Task Force for Covid-19 of the Indian Council of Medical Research (ICMR) in a bulletin dated March 21, 2020 recommended the use of hydroxychloroquine for prophylaxis in asymptomatic health care workers caring for suspected or confirmed patients and household contacts of confirmed patients. This is cause for concern with regard to bioethics and good clinical practice. The evidence for the efficacy of chloroquine and hydroxychloroquine is currently derived from open label trials and cell culture studies with no conclusive evidence available from randomised clinical trials. Hydroxychloroquine also carries contraindications in the case of conditions such as maculopathy, retinopathy and QTc prolongation and should be used with caution in vulnerable populations such as children, pregnancy, lactation and the elderly. Despite this, there has been a rush to procure and self-medicate with hydroxychloroquine, which has been addressed by the National Task Force. The WHO and the FDA have not found adequate evidence to recommend any specific medication for the treatment of Covid-19. While further evidence is awaited, including from trials registered with the FDA and the ICMR, it is recommended that the administration of hydroxychloroquine for chemo-prophylaxis be considered on a case by case basis with monitoring by a registered medical practitioner including electrocardiography (ECG). The potential for retinal and cardiac toxicity must also be borne in mind. It is further recommended that a public advisory regarding the need for caution in chemo-prophylaxis be made available in the public domain. Keywords: Coronavirus, Covid-19, SARS-CoV-2, hydroxychloroquine, chloroquine, chemoprophylaxis, bioethics, evidence- based medicine.

Background: Good Clinical Practice is an international standard for the design and conduct of clinical trials to ensure ethical and scientific integrity. Recent National Institutes of Health policy mandates Good Clinical Practice training for all investigators and staff involved in National Institutes of Health–funded clinical trials, yet approaches to Good Clinical Practice training vary widely. There are limited data on Good Clinical Practice knowledge among the clinical trial workforce and no evidence regarding effective methods to learn Good Clinical Practice. Methods: We used an exploratory sequential mixed-methods design. We conducted 18 exploratory qualitative interviews with clinical research coordinators to help inform the development of the quantitative survey. We then administered a validated 32-item, multiple-choice test of Good Clinical Practice knowledge with a survey of work and training experiences to 625 clinical research coordinators at three academic medical centers in the United States. Variables that were significantly associated with Good Clinical Practice knowledge were entered into a multiple regression analysis to identify unique predictors of Good Clinical Practice knowledge. We controlled for verbal–numerical reasoning and learning orientation. Results: During qualitative interviews, clinical research coordinators reported that formal Good Clinical Practice training had value but they simultaneously emphasized the importance of experience, day-to-day practice, and observing colleagues and mentors as essential to supplement formal training. In our quantitative survey, five variables predicted a total of 22% of variance in Good Clinical Practice knowledge scores: years of experience as a clinical research coordinator, working on diverse types of trials, supporting industry-funded trials, being certified in clinical research coordination, and aggregated hours of online and face-to-face training (in that order). Conclusion: The duration and richness of experience as a clinical research coordinator were the strongest predictors of Good Clinical Practice knowledge, a finding consistent with our exploratory qualitative interview results. Our findings suggest that formal online and face-to-face training has a minimal influence on Good Clinical Practice knowledge. The type of training—whether online or face to face—does not make a significant difference in Good Clinical Practice knowledge scores. Much of the variance in Good Clinical Practice knowledge remains unexplained, calling for further research in this area.

Background: Clinical trials are an integral part of translating new basic science research into therapeutics. It is crucial for those who run clinical trials to realize the gravity of their responsibilities as principal investigators. Methods: This review focuses on the relevant investigator responsibilities under the Code of Federal Regulations Title 21, the contents of Form 1572, FDA inspections, and methods to improve compliance. Results: While responsibility for day-to-day study activities can be delegated to outside entities and to study staff, a clinical principal investigator who has signed US Food and Drug Administration (FDA) Form 1572 is held responsible for noncompliance and misconduct by anyone working on the study. Depending on the infraction, consequences can range from a publicly posted warning letter by the FDA to criminal prosecution and fines or imprisonment. Conclusion: Investigators are not only responsible for producing high-quality, meaningful, scientific research, but they are also responsible for maintaining public trust. If the principal investigator acts with integrity and provides training and oversight of employees, FDA inquiries should go smoothly. Following good clinical practice standards for clinical research will result in quality data collection and facilitate the analysis and publication process.

Background: Several meta-analyses have tried to defi ne the role of minimally invasive approaches. However, further evidence to get a wider spread of these methods is necessary. Current studies describe minimally invasive surgery as a possible alternative to open surgery but deserving further clarifi cation. However, despite the increasing interest, the difficulty of planning prospective studies of adequate size accounts for the low level of evidence, which is mostly based on retrospective experiences. A multi-institutional prospective study allows the collection of an impressive amount of data to investigate various aspects of minimally invasive procedures with the opportunity of developing several subgroup analyses. A prospective data collection with high methodological quality on minimally invasive and open gastrectomies can clarify the role of diff erent procedures with the aim to develop specifi c guidelines. Methods and analysis: a multi-institutional prospective database will be established including information on surgical, clinical and oncological features of patients treated for gastric cancer with robotic, laparoscopic or open approaches and subsequent follow-up. The study has been shared by the members of the International study group on Minimally Invasive surgery for GASTRIc Cancer (IMIGASTRIC) The database is designed to be an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centers. Ethics: This study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevant laws/regulations. Trial registration number: NCT02751086

Background Infants born extremely preterm are at high risk of dying or suffering from severe brain injuries. Treatment guided by monitoring of cerebral oxygenation may reduce the risk of death and neurologic complications. The SafeBoosC III trial evaluates the effects of treatment guided by cerebral oxygenation monitoring versus treatment as usual. This article describes the detailed statistical analysis plan for the main publication, with the aim to prevent outcome reporting bias and data-driven analyses. Methods/design The SafeBoosC III trial is an investigator-initiated, randomised, multinational, pragmatic phase III trial with a parallel group structure, designed to investigate the benefits and harms of treatment based on cerebral near-infrared spectroscopy monitoring compared with treatment as usual. Randomisation will be 1:1 stratified for neonatal intensive care unit and gestational age (lower gestational age ( Discussion In line with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, we have developed and published this statistical analysis plan for the SafeBoosC III trial, prior to any data analysis. Trial registration ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

Introduction Three Italian scientific associations of different specialties (AMD, Associazione Medici Diabetologi—for diabetologists; ANMCO,Associazione Nazionale Medici Cardiologi Ospedalieri—for cardiologists; SIMG, Società Italiana di Medicina Generale—for General Practitioners) designed this study to assess whether an integrated care organization comprising three different specialists can improve adherence and can achieve the guidelines targets in a population of individuals with type 2 diabetes, without established cardiovascular disease but at high risk (≥ 20% at 10 years according to the CUORE.ISS risk cards) compared with the current standards of care provided by the Italian National Health Service. Methods Thirty primary care centers (general practitioners, GPs), 30 cardiology centers and 30 diabetes centers have been selected by the scientific associations, disseminated in the national territory, on the basis of proven previous cooperation in other studies. Each primary care center will enroll 100 type 2 diabetic subjects, > 45 years old, with no established cardiovascular disease, but with a high risk due to the presence of at least one other risk factor besides diabetes over the cutoff [hypertension > 135/80 mmHg, LDL cholesterol > 70 mg/dl, tobacco smoke, first-degree familiarity for CHD (coronary heart disease), central obesity according the WHO criteria]. Fifteen of 30 selected primary care centers, chosen randomly, will continue the treatment of the 100 identified patients according to their “usual care,” driven by Good Clinical Practice and by current guidelines (control group or “UC”—usual care), collecting all available clinical and instrumental data and transferring them to the electronic CRF. The remaining 15, after informed consent, will submit their 100 patients each in a specific integrated pathway, which entails the mandatory operational integration and exchange of information with the diabetes specialists and cardiologists pertaining to the same previously identified area. The integrated care path for the patients in the proband group (IC, integrated care) is based on application of the recommendations of the Italian Guidelines aimed at achieving the proposed targets for the main risk factors [LDL

Data obtained from controlled clinical trials remains the gold standard for the evaluation of treatment efficacy and safety. This information is used in systematic reviews and meta-analysis providing data for evidence-based medicine (EBM) statements and conclusions which are preferred by regulatory and academic groups when decisions and recommendations need to be given. The quantity and diversity of real-world data (RWD) have been increasing exponentially as technology and integrated electronic medical records have made this information increasingly accessible and useful for outcomes research and regulatory purposes. There are increasing interest and potential for converting RWD into real-world evidence that, through careful analysis and interpretation, can be used to inform healthcare decision-making. In this article, we present a concise summary of the literature about the role of EBM and RWD in allergen immunotherapy. We are aiming to evaluate their influence on current and future decisions for good clinical practice parameter recommendations.

Introduction:The National Institute of Health has mandated good clinical practice (GCP) training for all clinical research investigators and professionals. We developed a GCP game using the Kaizen-Education platform. The GCP Kaizen game was designed to help clinical research professionals immerse themselves into applying International Conference on Harmonization GCP (R2) guidelines in the clinical research setting through case-based questions.Methods:Students were invited to participate in the GCP Kaizen game as part of their 100% online academic Masters during the Spring 2019 semester. The structure of the game consisted of 75 original multiple choice and 25 repeated questions stemming from fictitious vignettes that were distributed across 10 weeks. Each question presented a teachable rationale after the answers were submitted. At the end of the game, a satisfaction survey was issued to collect player satisfaction data on the game platform, content, experience as well as perceptions of GCP learning and future GCP concept application.Results:There were 71 total players who participated and answered at least one question. Of those, 53 (75%) answered all 100 questions. The game had a high Cronbach’s alpha, and item analyses provided information on question quality, thus assisting us in future quality edits before re-testing and wider dissemination.Conclusions:The GCP Kaizen game provides an alternative method for mandated GCP training using principles of gamification. It proved to be a reliable and an effective educational method with high player satisfaction.

A review of studies published between January 1, 1984 and January 31, 2019 was performed with the aim of analysing the efficacy and adverse effects of commonly used adjuvants to in vitro fertilisation. The authors preferentially selected recent systematic reviews and randomised control trials (where available) from an electronic literature search. The review showed that low molecular weight heparin, corticosteroids and embryo glue may be of use in selected patient groups. Other adjuncts (such as growth hormone, assisted hatching, endometrial disruption and dehydroepiandrosterone) cannot currently be recommended as collated results showed no overall benefit to clinical pregnancy rates or live birth rates. There is a significant lack of robust evidence in this field, and areas in particular need of further research have been highlighted. In conclusion, caution should be exercised in prescribing adjuvants in in vitro fertilisation, either individually or in combination as further research is needed to ascertain their efficacy. Many adjuvants carry the risk of adverse effects which should also be considered. Patients should be clearly informed of the evidence, and where it is lacking, for these treatments. There is a need for further good quality trials to address the questions regarding best practice.

In preparation for the International Society for Clinical Densitometry Position Development Conference (PDC) 2019 in Kuala Lumpur, Malaysia, a cross-calibration and precision task force was assembled and tasked to review the literature, summarize the findings, and generate positions to answer 4 related questions provided by the PDC Steering Committee, which expand upon the current ISCD official positions on these subjects. (1) How should a provider with multiple dual-energy X-ray absorptiometry (DXA) scanners of the same make and model calculate least significant change (LSC)? (2) How should a provider with multiple DXA systems with the same manufacturer but different models calculate LSC? (3) How should a provider with multiple DXA systems from different manufacturers and models calculate LSC? (4) Are there specific phantom procedures that one can use to provide trustworthy in vitro cross calibration for same models, different models, and different makes? Based on task force deliberations and the resulting systematic literature reviews, 3 new positions were developed to address these more complex scenarios not addressed by current official positions on single scanner cross calibration and LSC. These new positions provide appropriate guidance to large multiple DXA scanner providers wishing to offer patients flexibility and convenience, and clearly define good clinical practice requirements to that end.

While many of the principles of assessing risk to self and others in adults are applicable to risk assessments of children and adolescents, developmental and legal factors regarding youths give rise to some significant differences. This article highlights major differences in assessing and managing risk in working with suicidal and homicidal youths and gives suggestions for reducing clinicians’ liability in these challenging cases.

Background Investigator-initiated clinical studies (IITs) are crucial to generate reliable evidence that answers questions of day-to-day clinical practice. Many challenges make IITs a complex endeavour, for example, IITs often need to be multinational in order to recruit a sufficient number of patients. Recent studies highlighted that well-trained study personnel are a major factor to conduct such complex IITs successfully. As of today, however, no overview of the European training activities, requirements and career options for clinical study personnel exists. Methods To fill this knowledge gap, a survey was performed in all 11 member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardised questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the landscape of academic training opportunities, to facilitate the exchange of expertise and experience among countries and to identify new fields of action. Results The survey found that training for Good Clinical Practice (GCP) and investigator training is offered in all but one country. A specific training for study nurses or study coordinators is also either provided or planned in ten out of eleven countries. A majority of countries train in monitoring and clinical pharmacovigilance and offer specific training for principal investigators but only few countries also train operators of clinical research organisations (CRO) or provide training for methodology and quality management systems (QMS). Minimal requirements for study-specific functions cover GCP in ten countries. Only three countries issued no requirements or recommendations regarding the continuous training of study personnel. Yet, only four countries developed a national strategy for training in clinical research and the career options for clinical researchers are still limited in the majority of countries. Conclusions There is a substantial and impressive investment in training and education of clinical research in the individual ECRIN countries. But so far, a systematic approach for (top-down) strategic and overarching considerations and cross-network exchange is missing. Exchange of available curricula and sets of core competencies between countries could be a starting point for improving the situation. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Background/objectives Paediatric skin, considered sensitive, and infant skin, more susceptible to percutaneous toxicity, require specially formulated cosmetic products. As recently shown, early use of emollients in infants “at risk” of developing atopic dermatitis has shown controversial results in reducing the incidence of atopic dermatitis. Development of dermo‐cosmetic products for this specific population should especially ensure tolerance and safety. In absence of good clinical practice guideline, we propose here a stepwise approach for the development of paediatric cosmetic skincare products. Methods Our stepwise methodology for cosmetics aimed at paediatrics, starts with in vitro assessment of product's ingredients safety, followed by preclinical and clinical evaluations of the final product, including sequentially: (1) Repeated Open Application Test (ROAT), (2) Human Repeated Insult Patch Test (HRIPT), (3) In‐use dermatological and ophthalmological tolerance studies (sequentially in 3a: healthy adults, 3b: healthy paediatric subjects and finally 3c: paediatric patients). We also describe the integrated cosmetovigilance–toxicological surveillance during the clinical development phase and postmarketing. Results As illustrated with one dermo‐cosmetic product intended to be used as a preventative/maintenance treatment for atopic dermatitis in paediatric population, we show that using this stepwise methodology to test a product reduces potential risks of irritation and contact dermatitis in this sensitive population. Conclusion Standardized ethical stepwise development approach is needed to ensure the commercialization of safe and well‐tolerated dermo‐cosmetics for paediatrics. The approach described here could potentially serve as guidance for evaluation of new paediatric cosmetic products.

ObjectivesOn 19 June 2019, assisted dying became lawful in Victoria, the second most populous state in Australia. Section 8 of theVoluntary Assisted Dying Actis a legislative safeguard that is designed to ensure a patient’s request for assistance to die is voluntary. This section prohibits health practitioners from initiating a conversation about assisted dying with the patient. This article explores the potential implications of this prohibition for effective communication between doctors and their patients, and the ability of doctors to provide high quality end-of-life (EOL) care in some cases.MethodThe authors reviewed and analysed literature on the importance of communication at the EOL including the need to understand and appropriately respond to Desire to Die or Desire to Hasten Death statements. A legal critique of section 8 of the VictorianVoluntary Assisted Dying Actwas also undertaken to determine the scope of this new duty and how it aligns with existing legal obligations that would otherwise require doctors to provide information about EOL options requested by a patient.ResultsContemporary literature suggests that open and honest communication between doctor and patient including the provision of information about all EOL options when sought by the patient represents good clinical practice and will lead to optimal EOL care. The provision of such information also reflects professional, ethical and legal norms.ConclusionDespite (arguably) promoting an appropriate policy objective, the legislative prohibition on health professionals initiating conversations about voluntary assisted dying may, in cases where patients seek information about all EOL options, lead to less optimal patient outcomes.

Traumatic spinal cord injury is a relatively rare injury in Denmark but may result in serious neurological consequences. For decades, prehospital spinal stabilisation with a rigid cervical collar and a hard backboard has been considered to be the most appropriate procedure to prevent secondary spinal cord injuries during patient transportation. However, the procedure has been questioned in recent years, due to the lack of high-quality studies supporting its efficacy. A national interdisciplinary task force was therefore established to provide updated clinical guidelines on prehospital procedures for spinal stabilisation of adult trauma patients in Denmark. The guidelines are based on a systematic review of the literature and grading of the evidence, in addition to a standardised consensus process. This process yielded five main recommendations: A strong recommendation against spinal stabilisation of patients with isolated penetrating trauma; a weak recommendation against the prehospital use of a rigid cervical collar and a hard backboard for ABCDE-stable patients; and a weak recommendation for the use of a vacuum mattress for patient transportation. Finally, our group recommends the use of our clinical algorithm to ensure good clinical practice. Electronic supplementary material The online version of this article (10.1186/s13049-019-0655-x) contains supplementary material, which is available to authorized users.

The vitamin E-bonded polysulfone membrane hemodialyzer (ViE™-21) was evaluated in a clinical study for regulatory submission. Seventeen patients on hemodialysis were treated with conventional high-flux hemodialyzers for 2 weeks (Pre-ViE phase) and switched to the ViE-21 for 36 sessions (ViE phase) followed by an additional 2 weeks on conventional hemodialyzers (Post-ViE phase). Reduction ratios of urea, creatinine, beta-2-microglobulin, albumin, and ultrafiltration coefficients (KUF) were measured once during the Pre-ViE phase and twice during the ViE phase. Moreover, biocompatibility markers [leucocyte count, platelet count, and activated complement factor (C3a) levels] were evaluated pre-dialysis, 15 min after initiation, and post-dialysis. During the study, type and number of adverse events (AEs), and device malfunctions were recorded. ViE-21 reduction ratios and KUF were not noticeably different than those of conventional hemodialyzers. Fluctuations of leucocyte counts and C3a concentrations were similar using ViE-21 and conventional hemodialyzers; however, the platelet count fluctuation was lower in ViE-21 sessions. The frequency of episodes of hypotension occurring during the ViE phase was lower than that occurring during the Pre- and Post-ViE phases. In conclusion, this study provided performance and safety data of the ViE-21 for regulatory application. The data suggest that vitamin E-bonded hemodialyzers are beneficial in lowering platelet activation and frequency of intradialytic hypotension. Larger randomized controlled trials are needed to confirm these findings.

Introduction:There is a clear need to educate and train the clinical research workforce to conduct scientifically sound clinical research. Meeting this need requires the creation of tools to assess both an individual’s preparedness to function efficiently in the clinical research enterprise and tools to evaluate the quality and effectiveness of programs that are designed to educate and train clinical research professionals. Here we report the development and validation of a competency self-assessment entitled the Competency Index for Clinical Research Professionals, version II (CICRP-II).Methods:CICRP-II was developed using data collected from clinical research coordinators (CRCs) participating in the “Development, Implementation and Assessment of Novel Training In Domain-Based Competencies” (DIAMOND) project at four clinical and translational science award (CTSA) hubs and partnering institutions.Results:An exploratory factor analysis (EFA) identified a two-factor structure: the first factor measures self-reported competence to perform Routine clinical research functions (e.g., good clinical practice regulations (GCPs)), while the second factor measures competence to perform Advanced clinical functions (e.g., global regulatory affairs). We demonstrate the between groups validity by comparing CRCs working in different research settings.Discussion:The excellent psychometric properties of CICRP-II and its ability to distinguish between experienced CRCs at research-intensive CTSA hubs and CRCs working in less-intensive community-based sites coupled with the simplicity of alternative methods for scoring respondents make it a valuable tool for gauging an individual’s perceived preparedness to function in the role of CRC as well as an equally valuable tool to evaluate the value and effectiveness of clinical research education and training programs.

Mobile laboratories provide diagnostic capabilities for routine surveillance and patient identification during an outbreak. In either situation, they face many challenges including identification of the appropriate assay(s) to employ, logistical arrangements, and providing for the health and safety of the laboratory staff. Great strides have been made over the last decade in the development of mobile laboratories with assays that require minimal infrastructure and technical experience. This knowledge and expertise have been developed in partnership with many researchers and public health officials who live in regions prone to infectious disease outbreaks. Mobile laboratories should now also be used in the evaluation of novel vaccines and therapeutics in remote locations. Clinical mobile laboratories will include similar diagnostic capabilities as outbreak response mobile labs, but will also include additional point-of-care instruments operated under Good Clinical Practice guidelines. They will also operate rigorous data management plans so that the data collected will satisfy regulatory agencies during the licensure process. Failure to deploy an adequate clinical mobile laboratory when administering a novel biological product in a remote location is a significant limitation to any collected scientific data that could ultimately undermine clinical development and availability of life-saving interventions.

China has the largest number of diabetic patients in the world. In the past 2 decades, the prevalence of diabetes in China has increased dramatically, and the current status of diabetes control in the diabetic population is not satisfactory. Although insulin is currently recognized in diabetes treatment guidelines as the therapeutic option for patients not adequately controlled by diet/exercise and oral agents, the proportion of patients with type 2 diabetes using insulin is still very low, and the time when insulin therapy is initiated is relatively late. In using insulin injections, concerns about the complexity of the treatment regimen, a fear of needles, and other psychological barriers can affect insulin treatment, impacting on patient compliance and potentially resulting in a poor treatment response. Another type of insulin injection device that has become available recently, the needle-free injector, is now being used in clinical practice because of its unique features and patients’ injection experiences. The aims of this study are to investigate the efficacy and safety of the needle-free injector-based insulin treatment in blood glucose control in patients with type 2 diabetes, as compared with a conventional needle-based insulin treatment, and to evaluate patient satisfaction with the different insulin delivery methods. A prospective, multicenter, randomized, open-label, parallel-group clinical trial was designed and implemented in China. A total of 420 patients with type 2 diabetes from ten research centers will be enrolled in the study. The primary efficacy endpoint is the change in the glycosylated hemoglobin (HbA1c) level from baseline to after 16 weeks of treatment after randomization. Secondary efficacy endpoints include measurements of blood glucose concentrations, the rate of achieving the target HbA1c level of less than 7%, patients’ quality-of-life (as determined by the SF-36 questionnaire), the insulin dose administered, compliance with insulin therapy, and patients’ satisfaction with their injection device. The study was approved by the Independent Ethics Committee (IEC) of Peking University Peoples Hospital and was conducted in accordance with the moral, ethical, and scientific principles of the declaration of Helsinki and the provisions of good clinical practice (GCP) in China. Written informed consent will be obtained from all participants before any study-related procedures are implemented. It is hoped that the study will provide evidence for the clinical application of the needle-free injector by providing data on its efficacy and safety, as compared with a conventional insulin pen, in the Chinese type 2 diabetes population. When available, the results will be published in an international peer-reviewed journal. ClinicalTrials.gov Identifier, NCT03243903. Registration date, August 9, 2017. Beijing QS Medical Technology Co., Ltd.

INTRODUCTION: Lumbar and cervical spine pains are one of the biggest health problems in modern society. Among the physical resources aimed at reducing the perception of pain in the spine, the therapeutic massage stands out. Following the principles of good clinical practice, it is expected that the techniques performed can be reproducible. Objectives: To investigate, through an initial exploration of the question, how appropriate is the description of the physiotherapy technique in randomized controlled trials of spinal massage. METHODS: An electronic search strategy was carried out on Medline through Pubmed. The search was restricted to the literature in English and Portuguese. We included Randomized Clinical Trials whose therapeutic massage was the main intervention performed in the spine. The parameters evaluated were: 1) pressure of manipulation, 2) direction of movements, 3) velocity of movements, 4) rhythm of movements, 5) frequency of movements and 6) duration of sessions. Twelve studies were included in this critical review of the evidence. Most of the studies did not report or report in a dubious manner, the pressure of manipulation, velocity of movements and rhythm of movements. Only 66% (n = 8) of the studies adequately reported the direction of movement. CONCLUSION: Physiotherapy techniques for spinal massage are not usually adequately described in randomized controlled trials. We suggest the improvement of reports of randomized clinical trials in the field of manual therapy.

Background Pancreatic cancer is a refractory malignancy, and the development of a new effective treatment strategy is needed. We generated a dendritic cell vaccine by culturing monocytes obtained by apheresis of blood from each patient, inducing their differentiation into dendritic cells, and pulsing with tumor antigen peptides. However, the clinical efficacy of the vaccine has not been established. We therefore decided to conduct an exploratory clinical trial of dendritic cell vaccine loaded with Wilms’ tumor gene 1 peptides (TLP0-001) as a potential new treatment for patients with advanced pancreatic cancer refractory to standard chemotherapy. Methods This is an investigator-initiated, double-blind, comparative trial. The patients were allocated to two groups in a 1:1 ratio through a central registration by dynamic allocation. A total of 185 patients with inoperable or metastatic pancreatic cancer who were refractory or intolerant to standard primary chemotherapy with gemcitabine plus nab-paclitaxel will be allocated to secondary treatment either with placebo in combination with S-1 (the control group) or TLP0-001 in combination with S-1 (the investigational product group). The primary objective of this trial is to evaluate the safety and efficacy (as measured by overall survival) of the investigational product by comparing the two groups. This clinical trial will be performed in accordance with Japanese Good Clinical Practice guidelines. Discussion Clinical trials of the standard regimen, including gemcitabine, for advanced pancreatic cancer are ongoing worldwide. However, a strategy for after the primary treatment has not been established. We therefore decided to conduct this study to evaluate the safety and efficacy of TLP0-001 as a secondary treatment for pancreatic cancer in anticipation of the approval of this new drug in Japan. This trial is conducted with full consideration of safety, as it is the first-in-human clinical trial of TLP0-001; thus, the trial will be conducted only at the Second Department of Surgery at Wakayama Medical University until the safety is confirmed by interim analysis. We plan to conduct a multicenter trial at 18 institutions in Japan after confirmation of the safety. Trial registration University Hospital Medical Information Network Clinical Trials Registry, UMIN000027179. Registered on 9 April 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3332-5) contains supplementary material, which is available to authorized users.

Positron Emission Tomography (PET) is a functional nuclear medicine imaging technique which clinical value in oncology has been demonstrated. PET indications are constantly evolving, thanks to the contribution of research. The use of PET in oncology has been the subject of recommendations according to the Standard-Options-Recommendations methodology from the Federation Nationale des Centres de Lutte Contre le Cancer in 2002, updated in 2003. However, many scientific works have been published since 2003 and new tracers have also obtained a marketing authorization in France. The objective of this work was therefore to update the recommendations established in 2003. In this context, in collaboration with the Societe francaise de medecine nucleaire, a working group was set up for the development of good clinical practice recommendations under the HAS-INCA methodological label. The present document is issued from a comprehensive review of the literature and rigorous appraisal by a panel of national experts, organ specialists, clinical oncologists, surgeons, and imaging specialists. It is intended to be used as a guide to decision-making for those oncology teams that are able to manage patients in various situations in which the AMM label is not sufficiently precise.

In the majority of cancers, pathogenic variants are only found at the level of the tumor; however, an unusual number of cancers and/or diagnoses at an early age in a single family may suggest a genetic predisposition. Predisposition plays a major role in about 5 to 10% of adult cancers and in certain childhood tumors. As access to genomic testing for cancer patients continues to expand, the identification of Potential Germline Pathogenic Variants (PGPV) through tumor-DNA sequencing is also increasing. Statistical methods have been developed to infer the presence of a PGPV without the need of a matched normal sample. These methods are mainly used for exploratory research, for example in real-world Clinico-Genomic Databases/platforms (CGDB). These databases are being developed to support many applications such as targeted drug development, clinical trial optimization and post marketing studies. To ensure the integrity of data used for research, a quality management system should be established, and quality oversight activities should be conducted to assess and mitigate clinical quality risks (for patient safety and data integrity). As opposed to well-defined "good practice" quality guidelines (GxP) areas such as good clinical practice, there are no comprehensive instructions on how to assess the clinical quality of statistically derived variables from sequencing data such as PGPV. In this report, we aim to share our strategy and propose a possible set of tactics to assess the PGPV quality and to ensure data integrity in exploratory research.

Operation notes are essential documents in the surgical journey of a patient. Despite being essential, it is left to be written by surgical residents. The Royal College of Surgeons guidance, Good Clinical Practice, with its most recent version in 2014, dictates that surgeons must ensure that all medical records are accurate, comprehensive, legible, and contemporaneous. Improving the quality of operation notes automatically improves communication among healthcare workers and helps prevent errors and litigations.

Clinical research conducted to Good Clinical Practice (GCP) standards is increasingly being undertaken in resource-constrained low-income and middle-income countries (LMICs) settings. This presents unique challenges that differ from those faced in high-income country (HIC) contexts, due to a dearth of infrastructure and unique socio-cultural contexts. Field experiences by research teams working in these LMIC contexts are thus critical to advancing knowledge on successful research conduct in these settings. The Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine has operated in The Gambia, a resource-constrained LMIC for over 70 years and has developed numerous research support platforms and systems. The unit was the lead clinical collaborator in a recently completed Expanded Program on Immunization Consortium (EPIC) study, involving a multicountry collaboration across five countries including the USA, Canada, Belgium, Papua New Guinea and The Gambia. The EPIC study recruited and completed follow-up of 720 newborn infants over 2 years. In this paper, we provide in-depth field experience covering challenges faced by the Gambian EPIC team in the conduct of this study. We also detail some reflections on these challenges. Our findings are relevant to the international research community as they highlight practical day-to-day challenges in conducting GCP standard clinical research in resource-constrained LMIC contexts. They also provide insights on how study processes can be adapted early during research planning to mitigate challenges.

Background Data monitoring of clinical trials is a tool aimed at reducing the risks of random errors (e.g. clerical errors) and systematic errors, which include misinterpretation, misunderstandings, and fabrication. Traditional ‘good clinical practice data monitoring’ with on-site monitors increases trial costs and is time consuming for the local investigators. This paper aims to outline our approach of time-effective central data monitoring for the SafeBoosC-III multicentre randomised clinical trial and present the results from the first three central data monitoring meetings. Methods The present approach to central data monitoring was implemented for the SafeBoosC-III trial, a large, pragmatic, multicentre, randomised clinical trial evaluating the benefits and harms of treatment based on cerebral oxygenation monitoring in preterm infants during the first days of life versus monitoring and treatment as usual. We aimed to optimise completeness and quality and to minimise deviations, thereby limiting random and systematic errors. We designed an automated report which was blinded to group allocation, to ease the work of data monitoring. The central data monitoring group first reviewed the data using summary plots only, and thereafter included the results of the multivariate Mahalanobis distance of each centre from the common mean. The decisions of the group were manually added to the reports for dissemination, information, correcting errors, preventing furture errors and documentation. Results The first three central monitoring meetings identified 156 entries of interest, decided upon contacting the local investigators for 146 of these, which resulted in correction of 53 entries. Multiple systematic errors and protocol violations were identified, one of these included 103/818 randomised participants. Accordingly, the electronic participant record form (ePRF) was improved to reduce ambiguity. Discussion We present a methodology for central data monitoring to optimise quality control and quality development. The initial results included identification of random errors in data entries leading to correction of the ePRF, systematic protocol violations, and potential protocol adherence issues. Central data monitoring may optimise concurrent data completeness and may help timely detection of data deviations due to misunderstandings or fabricated data.

Introduction Many studies have explored patients’ experiences of dialysis and other treatments for kidney failure. This is the first qualitative multi-site international study of how staff perceive the process of a patient’s transition from peritoneal dialysis to in-centre haemodialysis. Current literature suggests that transitions are poorly coordinated and may result in increased patient morbidity and mortality. This study aimed to understand staff perspectives of transition and to identify areas where clinical practice could be improved. Methods Sixty-one participants (24 UK and 37 Australia), representing a cross-section of kidney care staff, took part in seven focus groups and sixteen interviews. Data were analysed inductively and findings were synthesised across the two countries. Results For staff, good clinical practice included: effective communication with patients, well planned care pathways and continuity of care. However, staff felt that how they communicated with patients about the treatment journey could be improved. Staff worried they inadvertently made patients fear haemodialysis when trying to explain to them why going onto peritoneal dialysis first is a good option. Despite staff efforts to make transitions smooth, good continuity of care between modalities was only reported in some of the Australian hospitals where, unlike the UK, patients kept the same consultant. Timely access to an appropriate service, such as a psychologist or social worker, was not always available when staff felt it would be beneficial for the patient. Staff were aware of a disparity in access to kidney care and other healthcare professional services between some patient groups, especially those living in remote areas. This was often put down to the lack of funding and capacity within each hospital. Conclusions This research found that continuity of care between modalities was valued by staff but did not always happen. It also highlighted a number of areas for consideration when developing ways to improve care and provide appropriate support to patients as they transition from peritoneal dialysis to in-centre haemodialysis.

Background Use of 11C-Choline PET/CT is gaining ground in detecting hyperfunctioning parathyroid glands in primary hyperparathyroidism. The purpose of this study was to evaluate the robustness of 11C-Choline PET/CT by assessing intra- and inter-observer agreement to determine whether the method was reader sensitive and therefore should only be performed at highly specialised sites with a high number of cases. PET/CT images of 40 patients diagnosed with primary hyperparathyroidism were anonymised and evaluated three times by three readers: an expert reader and two non-experts (non-experts were experienced in PET/CT imaging, but not in 11C-Choline PET/CT in the setting of primary hyperparathyroidism). Number of hyperfunctioning parathyroid glands, location relative to the thyroid gland and confidence of each assessment (low, moderate or high) were noted, and intra- and inter-observer agreement calculated using Fleiss’ kappa method. Sensitivities and specificities of the non-experts were calculated using the expert reader as gold standard. Results Intra-observer agreement was ‘good’ to ‘near perfect’ for all readers. Inter-observer agreement was good between non-experts and the expert, with kappa values ≥ 0.74. Sensitivities between non-experts and the expert were high, > 81%, when assessing which side and 75% when assessing thyroid quadrant. All specificities were > 94%. Reader certainties were ‘high’ in > 80% of cases for the expert and > 70% and > 65%, respectively for the two non-experts. Conclusion 11C-Choline PET/CT is not reader sensitive for the localisation of hyperfunctioning parathyroid glands and may therefore be safely implemented at sites that have a moderate number of cases. Access to a cyclotron laboratory is, however, a necessity for the production of 11C-Choline. The study was conducted in accordance with the Helsinki 2 declaration and The International Council for Harmonisation Guideline for Good Clinical Practice (ICH_GCP) clinical trial, approved by the Research Ethics Committee of the Capital Region of Denmark (Journal-nr.:H-18012490, date of approval: 18 June 2018) and the Danish Medicines Agency (EudraCT no. 2018-000726-63, date of approval: 6 June 2018). The GCP unit in Eastern Denmark has carried out regular monitoring of the trial according to GCP (ID: 2018-1050).

The COVID-19 pandemic affected millions of people globally with lasting effects on society, patients, investigators and health institutions. Clinical trials, our best tool to improve cancer treatment for patients through testing the clinical value of a new treatment, have been affected by the pandemic. The pandemic footprint represents both a risk of compromising development of new therapies and an opportunity to elicit discussion over a portfolio of broader reforms, applicable irrespective of pandemics, in order to improve the design and implementation of clinical trials in oncology. The administrative load should be reduced, without affecting the quality of research and principles of good clinical practice. Cancer centres are encouraged to adapt their research/operational structures to the requirements of molecular oncology and embrace novel trial designs. Technological and methodological leaps in telemedicine can convert physical to virtual visits while routine examinations may be performed in local institutions (co-research centres), maintaining adherence to good clinical and research practices. The adoption of broader inclusion criteria and clinically significant endpoints (survival, quality of life) should be promoted, co-existing with pathways for fast-track “conditional” drug approvals in areas of unmet need, based on surrogate endpoints that are linked to strict post-approval validation requirements. The utility of Real World Data as part of these validation requirements should be actively investigated. Lessons learnt from the SARS Cov2 pandemic can be developed in order to expand equitable access to clinical trials of a real world population, in a simplified and methodologically robust modus operandi, for the benefit of all our patients.

PurposeTo compare the efficacy and safety of intravitreal aflibercept (IVA) monotherapy versus aflibercept combined with reduced-fluence photodynamic therapy (RF-PDT) (IVA+RF-PDT) for the treatment of polypoidal choroidal vasculopathy (PCV).Methods and analysisMulticentred, double-masked, randomised controlled trial to compare the two treatment modalities. The primary outcome of the study is to compare the 52-week visual outcome of IVA versus IVA+RF PDT. One hundred and sixty treatment-naïve patients with macular PCV confirmed on indocyanine green angiography will be recruited from three centres in Singapore. Eligible patients will be randomised (1:1 ratio) into one of the following groups: IVA monotherapy group—aflibercept monotherapy with sham photodynamic therapy (n=80); combination group—aflibercept with RF-PDT (n=80). Following baseline visit, all patients will be monitored at 4 weekly intervals during which disease activity will be assessed based on best-corrected visual acuity (BCVA), ophthalmic examination findings, optical coherence tomography (OCT) and angiography where indicated. Eyes that meet protocol-specified retreatment criteria will receive IVA and sham/RF-PDT according to their randomisation group. Primary endpoint will be assessed as change in BCVA at week 52 from baseline. Secondary endpoints will include anatomical changes based on OCT and dye angiography as well as safety assessment. Additionally, we will be collecting optical coherence tomography angiography data prospectively for exploratory analysis.Ethics and disseminationThis study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the ICH E6 guidelines of Good Clinical Practice and the applicable regulatory requirements. Approval from the SingHealth Centralised Institutional Review Board has been sought prior to commencement of the study.Trial registration numberNCT03941587.

Background Psychotherapy for borderline personality disorder is often extensive and resource-intensive. Mentalisation-based therapy is a psychodynamically oriented treatment option for borderline personality disorder, which includes a case formulation, psychoeducation, and group and individual therapy. The evidence on short-term compared with long-term mentalisation-based therapy is currently unknown. Methods/design The Short-Term MBT Project (MBT-RCT) is a single-centre, parallel-group, investigator-initiated, randomised clinical superiority trial in which short-term (20 weeks) will be compared with long-term (14 months) mentalisation-based therapy for outpatients with subthreshold or diagnosed borderline personality disorder. Outcome assessors, data managers, the data safety and monitoring committee, statisticians, and decision-makers will be blinded to treatment allocation. Participants will be assessed before randomisation and at 8, 16, and 24 months after randomisation. The primary outcome will be the severity of borderline symptomatology assessed with the Zanarini Rating Scale for Borderline Personality Disorder. Secondary outcomes will be functional impairment (Work and Social Adjustment Scale), quality of life (Short-Form Health Survey 36—mental component), global functioning (Global Assessment of Functioning), and proportion of participants with severe self-harm. In this paper, we present a detailed statistical analysis plan including a comprehensive explanation of the planned statistical analyses, methods to handle missing data, and assessments of the underlying statistical assumptions. Final statistical analyses will be conducted independently by two statisticians following the present plan. Discussion We have developed this statistical analysis plan before unblinding of the trial results in line with the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice Guidelines, which should increase the validity of the MBT-RCT trial by mitigation of analysis bias. Trial registration ClinicalTrials.gov NCT03677037. Registered on 19 September 2018