The Impact of Drug Trials With Financial Conflict of Interests on the Meta-Analyses: A Meta-Epidemiological Study

Background: Drug trials with potential financial conflict of interests (FCOIs) may influence trial design, drug dosage, comparators, and promising results are more likely to be reported. The objective of this study was to assess the impact of trials with FCOIs on evidence synthesis in meta-analyses (MAs). Methods: A total of 96 MAs from the Cochrane Library about drug trials were investigated. The primary outcomes examined the proportion of conclusions that would change with the exclusion of trials with potential FCOIs. If the proportion of changed conclusions was below the non-inferiority margin of 10%, we considered that it was not inferior to include the trials with potential FCOIs in the MAs. Results: Only 54.17% of MAs reported the funding sources of each included trial, and in 21.88% of MAs, the author-industry-related financial ties of each included trial were reported. When trials with FCOIs were excluded, the changed conclusions of effectiveness and major adverse events were 13.16% and 11.11%, respectively, and the I 2 decreased by 13.56% and 10.09%, respectively. For serious adverse events, the exclusion of FCOIs trials did not lead to any change in conclusions; however, the I 2 decreased by 24.24%. The impact of trials without reported FCOIs was also examined on evidence synthesis, and the results showed that the changed conclusions of effectiveness and major adverse events were 5.26% and 6.25%, respectively, indicating non-inferiority. However, the I 2 increased by 13.60% and 12.37%, respectively. Conclusion: In this meta-epidemiological study, we demonstrated that trials with FCOIs may not only influence the final outcome of MAs but may also increase the heterogeneity of results. It is suggested that all MAs fully report the FCOIs involved in evidence-based research and explore the impact of its FCOIs to better provide a more valuable reference for patients, clinicians, and policymakers.

Reading, Conducting, and Developing Systematic Review and Individual Patient Data Meta-Analyses in Psychiatry for Treatment Issues

Introduction: Individual participant data meta-analyses (IPD-MAs) include the raw data from relevant randomised clinical trials (RCTs) and involve secondary analyses of the data. Performed since the late 1990s, ~50 such meta-analyses have been carried out in psychiatry, mostly in the field of treatment. IPD-MAs are particularly relevant for three objectives: (1) evaluation of the average effect of an intervention by combining effects from all included trials, (2) evaluation of the heterogeneity of an intervention effect and sub-group analyses to approach personalised psychiatry, (3) mediation analysis or surrogacy evaluation to replace a clinical (final) endpoint for the evaluation of new treatments with intermediate or surrogate endpoints. The objective is to describe the interest and the steps of an IPD-MA method applied to the field of psychiatric therapeutic research.Method: The method is described in three steps. First, the identification of the relevant trials with an explicit description of the inclusion/exclusion criteria for the RCT to be incorporated in the IPD-MA and a definition of the intervention, the population, the context and the relevant points (outcomes or moderators). Second, the data management with the standardisation of collected variables and the evaluation and the assessment of the risk-of-bias for each included trial and of the global risk. Third, the statistical analyses and their interpretations, depending on the objective of the meta-analysis. All steps are illustrated with examples in psychiatry for treatment issues, excluding study protocols.Conclusion: The meta-analysis of individual patient data is challenging. Only strong collaborations between all stakeholders can make such a process efficient. An “ecosystem” that includes all stakeholders (questions of interest prioritised by the community, funders, trialists, journal editors, institutions, …) is required. International medical societies can play a central role in favouring the emergence of such communities.

Ethical Considerations of the Trial to Establish a Causal Linkage Between Mycotoxin Exposure and Child Stunting

Objectives Aflatoxins are fungal metabolites that commonly contaminate staple crops in tropical regions. Aflatoxin is a carcinogen and consumption at high-levels can lead to acute liver failure and aflatoxicosis. Multiple epidemiologic studies have shown an association between aflatoxin exposure in infants and young children and growth failure, but strong experimental evidence is lacking. The Trial to Establish a Causal Linkage Between Mycotoxin Exposure and Child Stunting being conducted in Tanzania is a cluster-randomized trial to assess the effect of reduced aflatoxin exposure on linear growth. Methods Prior to its design and launch, the multi-disciplinary research team conducted a critical review to determine the most salient ethical questions and dilemmas in the potential conduct of such a study and debated if and how this study could be designed to meet human subject ethical criteria. This critical review included trial protocols, methodologies and historical controversies in the areas of bio-medical, public health and environmental health research. Results This critical review identified three major questions: 1) Given what is already known about aflatoxin, should a question about the effect of this toxin on child growth be studied further in human subjects? 2) If the relationship between aflatoxin and stunting can be studied in humans, what is the most ethical study design to employ? 3)What is the most ethical intervention to randomly allocate? Conclusions Based on the critical review and in alignment with human subject principles and guidelines, we concluded that it was possible to conduct such a study. The trial and intervention were designed to advance scientific knowledge, maintain a favorable risk/benefit ratio, and respect participants, among other ethical principles. Funding Sources The Bill and Melinda Gates Foundation.

Chemoprophylaxis trial designs in epidemics: insights from a systematic review of COVID-19 study registrations

Background Chemoprophylactics against emerging epidemic and pandemic infectious diseases offer potential for prevention but require efficacy and safety analysis before widespread use can be recommended. Chemoprophylaxis with repurposed drugs enables deployment ahead of development of novel vaccines. It may have particular utility as a stopgap ahead of vaccine deployment or when vaccines become less effective on virus variants, in countries where there may be structural inaccessibility to vaccines or in specific risk-groups. Rapid implementation of robust trial designs is a persistent challenge in epidemics. We systematically reviewed SARS-CoV-2 and COVID-19 chemoprophylaxis trial registrations from the first 21 weeks of the pandemic to critically appraise significant design features and alignment of study populations to clinical and public health uses, and describe candidate chemoprophylactic agents. Methods We searched online international trial databases from 31 Dec 2019 to 26 May 2020 using keywords “proph*” or “prevention”. Trial protocols assessing efficacy of chemoprophylactic agents for COVID-19 were included. Trial components were screened for eligibility and relevant studies extracted. Key trial design features were assessed. Results We found 76 chemoprophylaxis study registrations, proposing enrolment of 208,367 people with median size of 490 (IQR 262–1710). A randomised design was specified for 63 trials, 61 included a control group and total proposed enrolment size was 197,010, median 600 (IQR 236–1834). Four protocols provided information on effect size sought. We estimate that for a control group attack rate of 10%, 66% of trials would be underpowered to detect a 50% effect size, and 97% of trials would be underpowered to detect a 30% effect size (at the 80% level). We found evidence of adaptive design in one trial registration only. Laboratory-confirmed infection with or without symptoms was the most common primary outcome. Polymerase chain reaction testing alone was used in 46% of trials, serological testing in 6.6% and 14.5% used both testing methods. Healthcare workers were the target population in 52/79 (65.8%) trials: 49 pre-exposure prophylaxis (PrEP) and 3 post-exposure prophylaxis (PEP). Sixteen trials (20.3%) planned PEP in close contacts. Five studies (6.3%) considered chemoprophylaxis in clinical-risk patients. Older adults were the focus of recruitment in only 3 (3.8%) studies (all long-term care facilities). Two (2.5%) studies of PrEP in the general population included older adults. Hydroxychloroquine was the most common candidate agent in 55/79 trials (69.6%), followed by chloroquine (4/79, 5.0%) and lopinavir/ritonavir (3/79, 3.8%). Conclusion Many registered COVID-19 chemoprophylaxis efficacy trials were underpowered to detect clinically meaningful protection at epidemiologically informed attack rates. This, compounded with the time that has taken to organise these trials as compared to the rapid development of COVID-19 vaccines, has rendered these trials of marginal importance. International coordination mechanisms and collaboration is required. Supporting the design of feasible chemoprophylaxis trials, large enough to generate strong evidence, early on in an epidemic using adaptive platform trial designs will allow structured entry and exit of candidate agents and rapid stand-up of trial infrastructure. Review protocol registration Our protocol is registered at https://www.osf.io/vp56f on May 20, 2020.

ROCSAN trial (GINECO-EN203b/ENGOT-EN8): A multicentric randomized phase II/III evaluating dostarlimab in combination with niraparib versus niraparib alone compared to chemotherapy in the treatment of endometrial/ovarian carcinosarcoma after at least one line of platinum based chemotherapy.

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) < 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.

Harvesting Energy from Buried Infrastructure: current UKCRIC research

&lt;p&gt;The UK Government has a commitment to reach net-zero emissions by 2050. Because 70% of heating comes from direct burning of natural gas, this target cannot be achieved without decarbonising the gas network. One of the best routes to decarbonise heating is through use of ground thermal energy storage coupled with ground source heat pump systems. However, heat pump systems retain high investments costs, mainly due to the expense of drilling dedicated ground heat exchangers (GHE) such as deep boreholes. One route to reducing these costs is to use buried infrastructure for simultaneous structural function and ground heat exchange. In the past deep foundations, embedded retaining walls and trial tunnels have all been used as GHE. &amp;#160;However, there is increasing interest in extending this approach to other shallow buried infrastructure, such as waste and drinking water distribution networks, and green infrastructure such as sustainable urban drainage and swales.&amp;#160;&lt;/p&gt;&lt;p&gt;The UK Collabatorium for Research in Infrastructure and Cities (UKCRIC) is a consortium founded by thirteen universities to provide an integrated research capability with a mission to underpin the renewal, sustainment and improvement of infrastructure and cities in the UK and elsewhere. Under the auspices of UKCRIC, a pump priming project called PLEXUS has been carried out. One of the research challenges of PLEXUS has been to consider how much heating and cooling capacity can be obtained from using civil engineering infrastructure as GHE, and whether there are any risks to original structural function from the GHE operation. &amp;#160;The project has included trial experiments for (i) soil element thermo-mechanical and thermo-hydraulic behaviour, (ii) the operation of sustainable urban drainage under heat injection, (iii) heat transfer characteristics of a near full scale water pipe segment, (iv) effects of temperature change on the formation of fats, oils and greases in waste water treatment systems. This paper will present a summary of key findings from the project and identify challenges for implementation of this valuable thermal resource.&amp;#160;&lt;/p&gt;

The association between registration status and reported outcomes in physiotherapy randomised controlled trials

Background/Aims Clinical trial registration has been proposed as a method of mitigating selective reporting in scientific research. It remains unknown whether trial registration is associated with reported outcomes in physiotherapy trials. This study aimed to analyse the association between registration status and outcome (the rejection or acceptance of a primary null hypothesis) for physiotherapy randomised controlled trials. Methods All randomised controlled trials reporting a physiotherapy intervention in publications listed in PubMed between 1 January 2017 and 30 June 2017 were included. Trial registration was determined based on the reporting of a registration number in the primary article or by identifying trials through trial registries. Results Of the 291 trials analysed, 176 (60.5%) were registered; 115 (39.5%) were not. There was no significant association between trial registration and outcome on multivariate analyses (Odds Ratio 1.65; 95% Confidence Interval (0.92–2.96); P=0.09). Only 22% of trials were prospectively registered. Conclusions Registration status and trial outcome are not associated in randomised controlled trials of physiotherapy interventions. The rate of physiotherapy trial registration remains low.

INNOVATIVE DECISIONS TO IMPROVE FOOD QUALITY AND SAFETY

The scope of the project consisted in research-based development of new complex food additives from lactic acid and its derivatives for enhancing microbiological safety and shelf life extension of healthy food products. The object of research included: trial samples of complex food additives from lactic acids and its derivatives. The samples were obtained chemically using the following basic components: food grade lactic acid with 79.6% base substance mass fraction; acetic acid with 99.8% base substance mass fraction; propionic acid with 99.6% base substance mass fraction; neutralizing agents for synthesis of salts of the acids used, and propylene glycol with 99.8% base substance mass fraction. The optimal balance of the ingredients in the formula of the additive delivers the optimal level of true acidity combined with antimicrobial and antioxidant effect, and enhances organoleptical performance and process parameters of food products. This complex food additive containing lactate and acetate features high counter-regulatory effect on testing cultures of pathogenic organisms of rope spoilage of wheat bread and can be used for production of non-perishable products. The use of complex food additive in the production of dressed fish preserves activates biochemical processes related to fish maturation and delivers improved product quality and extended shelf life.

Placebo design in WHO-registered trials of Chinese herbal medicine need improvements

Background Physical identical and pharmacological inert are the basic requirements for placebo design, which are essential in clinical trials to evaluate the efficacy of an intervention. However, it is difficult to makeup a placebo of Chinese herbal medicine (CHM) because of special color, taste and smell, etc. Currently, there is no specific requirements and standards for the creation of a CHM-placebo. The purpose of this study is to review the characteristics of the CHM-placebo design and application in registered clinical trials with CHM interventions and identify the common problems, if any. Methods The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) was systematically searched for CHM interventional trials with placebo-controlled design up to 31 December 2017. Registered information of each included trial was collected from specific registries involved in ICTRP through hyperlinks. Descriptive statistics were used to analyze the characteristics of placebo design in CHM trial registrations. Results A total of 889 CHM interventional trials were registered from 1999 to 2017, and 40.8% (363) of them included CHM-placebo control design. The common ways of their design were: placebo as sole control (191, 52.6%); placebo as add-on control with baseline treatment (84, 23.1%); and placebo as double-dummy control (57, 15.7%). Among 363 included trials, 46 (12.7%) reported the compositions of placebos, including CHM ingredients (17 trials), excipients and other agents (29 trials). 2 (0.6%) reported pharmacological inert testing, and 52 (14.3%) descripted their placebos to be physically identical with the CHMs. 14 (3.9%) reported quality control of placebos, and 2 (0.6%) provided blinding assessment of placebos. Conclusions The placebos included in most CHM trial registrations is not optimal in terms of placebo design, application, evaluation and reporting. Specific guidelines or standards of CHM-placebo design, including usage requirements, preparation specifications, quality assessments and reporting guidelines should be developed thus to improve their quality.

Challenges and threats of investigator-initiated multicenter randomized controlled trials: the BACE trial experience

<p class="abstract"><strong>Background:</strong> Investigator-initiated clinical research has become a complex environment. Increasing administrative tasks and costs, imposed by stringent regulatory demands, risk to reduce this creative, independent and indispensable research field. The objective of the present study was to illustrate the burden of non-scientific challenges associated with an investigator-initiated multicentre randomized controlled trial, based on the Belgian trial with azithromycin for Chronic obstructive pulmonary disease (COPD) Exacerbations requiring hospitalization (BACE) trial experience.</p><p class="abstract"><strong>Methods:</strong> The trial enrolled 301 patients with COPD, hospitalized for an acute exacerbation between 2014-2017, and assessed the potential of azithromycin, an off-patent antibiotic. Key experienced challenges were complemented with registry data from the Clinical Trial Centre of the University Hospital Leuven to outline the local clinical respiratory research field, quotations for the trial protocol obtained from 3 pharmaceutical companies to provide insight into the budget restraints and a participation survey to capture the consortium’s perspective.</p><p class="abstract"><strong>Results:</strong> 60% of the required sample size was enrolled. Key challenges included trial implementation, study drug and database management. Industry-initiated trials dominated the local research field (61%), whereas investigator-initiated prospective interventional and multicenter trials accounted for 19% and 13%, respectively. The triple quotation revealed the BACE trial to require 1.6 to 2.1-fold the amount when executed by the pharmaceutical industry. The survey identified the lack of a local study team as an important obstacle for participation, along with inadequate financial compensation and excessive administrative workload.</p><p class="abstract"><strong>Conclusions: </strong>Without an adaptation of current regulatory and funding policies to overcome non-scientific challenges, investigator-initiated clinical research is risking to further decline.</p>