Biosimilar infliximab introduction into the gastro-enterology care pathway in a large acute Irish teaching hospital: a story behind the evidence

Background and aim: Biosimilar medicines are not considered exact replicas of originator biological medicines. As a result, prescribers can be hesitant to introduce such medicines into the clinical setting until evidence surfaces confirming their safety and effectiveness. In Ireland, a national biosimilar medicines policy is currently in development but the decision to prescribe biosimilar medicines remains at the discretion of the physician. The aim of this descriptive review is to tell the story of the evidence used by a large acute Irish teaching hospital to introduce biosimilar infliximab CT-P13 for the treatment of inflammatory bowel disease (IBD) in a safe and timely manner into routine care. Methods: To explore the evidence supporting the effective introduction of biosimilar infliximab in a large acute Irish teaching hospital, a literature review was conducted. Evidence consisted of published studies, reviews, reports, position statements, articles, clinical guidelines, and recommendations from national bodies, regulatory authorities and professional organizations. All evidence was published in English. Results and discussion: In September 2014, the accumulated evidence base provided physicians with reassurance to prescribe biosimilar infliximab CT-P13 for new patients suffering from IBD in this large acute Irish teaching hospital. In September 2016, as the evidence base grew, physicians began to safely and confidently switch patients from the originator infliximab product to the biosimilar product. Conclusion: There was a significant time lag between regulatory approval and clinical acceptance given that the European Medicines Agency had granted market authorization for biosimilar infliximab CT-P13 three years prior to the initiation of this hospital's switching process. Although conservative in their execution, the authors conclude that with the existential concern and uncertainty still surrounding biosimilar medicines, a distinct and individualized approach for biosimilar medicine implementation is required. It is with hope that the Irish biosimilar medicines policy will improve upon biosimilar medicine clinical acceptance once published

Occupationally related bilateral calcific tendonitis of Flexor carpi ulnaris: case report

We present a case of bilateral calcific tendonitis of the Flexor Carpi Ulnaris attributable to repetitive wrist action which was occupationally related. This was treated conservatively with avoidance of aggravating movement, resting splints and anti inflammatory medication when acute flare ups occurred. Since avoidance of repetitive strain on the wrists he has had no further flare ups in over 2 years. This is the only case of bilateral calcific tendonitis of Flexor Carpi Ulnaris that has been reported in the literature, further more it is the only one which has been attributed to occupation and settled following a change of career

Enhancing practitioners’ confidence in recruitment and consent in the EcLiPSE trial: A mixed-method evaluation of site training – a Paediatric Emergency Research in the United Kingdom and Ireland (PERUKI) study

Background: EcLiPSE (Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children) is a randomised controlled trial (RCT) in the United Kingdom. Challenges to success include the need to immediately administer an intervention without informed consent and changes in staffing during trial conduct, mainly due to physician rotations. Using literature on parents' perspectives and research without prior consent (RWPC) guidance, we developed an interactive training package (including videos, simulation and question and answer sessions) and evaluated its dissemination and impact upon on practitioners' confidence in recruitment and consent. Methods: Questionnaires were administered before and immediately after training followed by telephone interviews (mean 11 months later), focus groups (mean 14 months later) and an online questionnaire (8 months before trial closure).Results: One hundred and twenty-five practitioners from 26/30 (87%) participating hospitals completed a questionnaire before and after training. We conducted 10 interviews and six focus groups (comprising 36 practitioners); 199 practitioners working in all recruiting hospitals completed the online questionnaire. Before training, practitioners were concerned about recruitment and consent. Confidence increased after training for explaining (all scale 0-5, 95% CIs above 0 and p values < 0.05): the study (66% improved mean score before 3.28 and after 4.52), randomisation (47% improvement, 3.86 to 4.63), RWPC (72% improvement, 2.98 to 4.39), and addressing parents' objections to randomisation (51% improvement, 3.37 to 4.25). Practitioners rated highly the content and clarity of the training, which was successfully disseminated. Some concerns about staff availability for training and consent discussions remained.Conclusions: Training improved practitioners' confidence in recruitment and RWPC. Our findings highlight the value of using parents' perspectives to inform training and to engage practitioners in trials that are at high risk of being too challenging to conduct

Seven-step framework to enhance practitioner explanations and parental understandings of research without prior consent in paediatric emergency and critical care trials

Background: Alternatives to prospective informed consent enable the conduct of paediatric emergency and critical care trials. Research without prior consent (RWPC) involves practitioners approaching parents after an intervention has been given and seeking consent for their child to continue in the trial. As part of an embedded study in the 'Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children' (EcLiPSE) trial, we explored how practitioners described the trial and RWPC during recruitment discussions, and how well this information was understood by parents. We aimed to develop a framework to assist trial conversations in future paediatric emergency and critical care trials using RWPC. Methods: Qualitative methods embedded within the EcLiPSE trial processes, including audiorecorded practitioner-parent trial discussions and telephone interviews with parents. We analysed data using thematic analysis, drawing on the Realpe et al (2016) model for recruitment to trials. Results: We analysed 76 recorded trial discussions and conducted 30 parent telephone interviews. For 19 parents, we had recorded trial discussion and interview data, which were matched for analysis. Parental understanding of the EcLiPSE trial was enhanced when practitioners: provided a comprehensive description of trial aims; explained the reasons for RWPC; discussed uncertainty about which intervention was best; provided a balanced description of trial intervention; provided a clear explanation about randomisation and provided an opportunity for questions. We present a seven-step framework to assist recruitment practice in trials involving RWPC. Conclusion: This study provides a framework to enhance recruitment practice and parental understanding in paediatric emergency and critical care trials involving RWPC. Further testing of this framework is required

Medicines and Healthcare products Regulatory Agency’s “Consultation on proposals for legislative changes for clinical trials”: a response from the Trials Methodology Research Partnership Adaptive Designs Working Group, with a focus on data sharing

In the UK, the Medicines and Healthcare products Regulatory Agency consulted on proposals “to improve and strengthen the UK clinical trials legislation to help us make the UK the best place to research and develop safe and innovative medicines”. The purpose of the consultation was to help finalise the proposals and contribute to the drafting of secondary legislation. We discussed these proposals as members of the Trials Methodology Research Partnership Adaptive Designs Working Group, which is jointly funded by the Medical Research Council and the National Institute for Health and Care Research. Two topics arose frequently in the discussion: the emphasis on legislation, and the absence of questions on data sharing. It is our opinion that the proposals rely heavily on legislation to change practice. However, clinical trials are heterogeneous, and as a result some trials will struggle to comply with all of the proposed legislation. Furthermore, adaptive design clinical trials are even more heterogeneous than their non-adaptive counterparts, and face more challenges. Consequently, it is possible that increased legislation could have a greater negative impact on adaptive designs than non-adaptive designs. Overall, we are sceptical that the introduction of legislation will achieve the desired outcomes, with some exceptions. Meanwhile the topic of data sharing — making anonymised individual-level clinical trial data available to other investigators for further use — is entirely absent from the proposals and the consultation in general. However, as an aspect of the wider concept of open science and reproducible research, data sharing is an increasingly important aspect of clinical trials. The benefits of data sharing include faster innovation, improved surveillance of drug safety and effectiveness and decreasing participant exposure to unnecessary risk. There are already a number of UK-focused documents that discuss and encourage data sharing, for example, the Concordat on Open Research Data and the Medical Research Council’s Data Sharing Policy. We strongly suggest that data sharing should be the norm rather than the exception, and hope that the forthcoming proposals on clinical trials invite discussion on this important topic

Space-based research in fundamental physics and quantum technologies

Space-based experiments today can uniquely address important questions related to the fundamental laws of Nature. In particular, high-accuracy physics experiments in space can test relativistic gravity and probe the physics beyond the Standard Model; they can perform direct detection of gravitational waves and are naturally suited for precision investigations in cosmology and astroparticle physics. In addition, atomic physics has recently shown substantial progress in the development of optical clocks and atom interferometers. If placed in space, these instruments could turn into powerful high-resolution quantum sensors greatly benefiting fundamental physics. We discuss the current status of space-based research in fundamental physics, its discovery potential, and its importance for modern science. We offer a set of recommendations to be considered by the upcoming National Academy of Sciences' Decadal Survey in Astronomy and Astrophysics. In our opinion, the Decadal Survey should include space-based research in fundamental physics as one of its focus areas. We recommend establishing an Astronomy and Astrophysics Advisory Committee's interagency ``Fundamental Physics Task Force'' to assess the status of both ground- and space-based efforts in the field, to identify the most important objectives, and to suggest the best ways to organize the work of several federal agencies involved. We also recommend establishing a new NASA-led interagency program in fundamental physics that will consolidate new technologies, prepare key instruments for future space missions, and build a strong scientific and engineering community. Our goal is to expand NASA's science objectives in space by including ``laboratory research in fundamental physics'' as an element in agency's ongoing space research efforts.Comment: a white paper, revtex, 27 pages, updated bibliograph

Fifteen-minute consultation: An evidence-based approach to research without prior consent (deferred consent) in neonatal and paediatric critical care trials

What do we mean by research without prior consent (deferred consent)? Emergency research with critically unwell children is vital to make sure that the most ill and injured children benefit from evidence-based healthcare.1 Ethical guidance require that consent be sought from parents (or legal representatives) on behalf of their children2 before research is initiated, yet concerns about problems in seeking parents’ consent when their child is critically ill have been a significant barrier to conducting clinical trials.3 ,4 Taking time out to seek informed consent before starting treatment will often be difficult to justify as delaying any intervention in an emergency could diminish a child's chances of recovery. Parents will usually be highly distressed in a critical care situation, and many will struggle to make an informed decision about research in the limited time available. Many countries have legislated to permit variations to informed consent and allow progress in research to develop critical care treatments.5–7 While the details vary, a common feature is that informed consent is not requested before the patient receives the intervention being researched.8 In the USA, the Food and Drug Administration (FDA) Exception from Informed Consent (EFIC) essentially ‘waives’ informed consent, although practitioners must show that they have attempted to contact legal representatives and tried to provide the opportunity to ‘opt out’ of a trial.5 ,9 The FDA's detailed guidance aims to assist researchers in implementing EFIC,10 ,11 although the accompanying public consultation requirements have led to varied practice and costly delays in setting up trialsCATCH was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number 08/13/47). CONNECTwas funded by Wellcome Trust (WT095874MF) and supported by the MRC Network of Hubs for Trials Methodology Research (MR/L004933/1- R/N42)

Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature

Background: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. Methods: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a ‘‘cost’’ weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identifiedwas further validated in a new RNA sequencing dataset comprising 411 febrile children. Findings: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort andbenchmarked against existingdichotomousRNA signatures. Conclusions: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. Funding: European Union’s Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC

Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT.

BACKGROUND:Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence. OBJECTIVE:To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management. DESIGN:A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent. SETTING:Participants were recruited from 30 paediatric emergency departments in the UK. PARTICIPANTS:Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment. INTERVENTIONS:Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg). MAIN OUTCOME MEASURES:Primary outcome - time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes - further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions. RESULTS:Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20-not assessable) minutes in the levetiracetam group and 45 (interquartile range 24-not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions. LIMITATIONS:First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of 'cessation of all signs of continuous, rhythmic clonic activity' as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups. CONCLUSIONS:Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials. FUTURE WORK:Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus. TRIAL REGISTRATION:Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 58. See the NIHR Journals Library website for further project information