scholarly journals Innovative approaches to investigator-initiated, multicentre paediatric clinical trials in Canada

BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e029024 ◽  
Author(s):  
Lauren E Kelly ◽  
Lawrence Richer ◽  
Samina Ali ◽  
Amy C Plint ◽  
Naveen Poonai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Emergency Room ◽  
Patient Engagement ◽  
Data Monitoring ◽  
Ethical Review ◽  
Lessons Learnt ◽  
The Uk ◽  
Effective Use

Data from clinical trials are needed to guide the safe and effective use of medicines in children. Clinical trials are challenging to design and implement in all populations, and children present additional considerations. Several regions including the UK, USA and Europe have established clinical trial infrastructure to capitalise on expertise and promote clinical trials enrolling children. Our objective is to describe the partnerships and operational considerations for the development of paediatric clinical trials infrastructure in Canada. We describe the design and conduct of four emergency room paediatric trials, with four separate sponsors, across four provinces in parallel. Operations discussed include multisite contract development, centralised risk-based data monitoring, ethical review and patient engagement. We conclude with lessons learnt, additional challenges and potential solutions to facilitate drug development for children in Canada.

Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient

2021 ◽  
Vol 16 ◽  
Author(s):  
Erica Winter ◽  
Scott Schliebner
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Rare Disease ◽  
Rare Diseases ◽  
Statistical Analyses ◽  
Clinical Trial Designs ◽  
Novel Approaches

: Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.

scholarly journals Reasons for Failed trials of Disease-modifying Treatments for Alzheimer Disease and their Contribution in Recent Research

2019 ◽  
Author(s):  
Konstantina G. Yiannopoulou ◽  
Aikaterini I. Anastasiou ◽  
Venetia Zachariou ◽  
SH Pelidou
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Alzheimer Disease ◽  
Drug Development ◽  
Inappropriate Drug ◽  
Trial Methodology ◽  
Prodromal Ad ◽  
Csf Biomarker ◽  
Disease Modifying ◽  
Drug Development Research

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Current drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

scholarly journals Clinical Trials and the Drive to Material Standardisation

2017 ◽  
pp. 30-44 ◽  
Author(s):  
Catherine M. Montgomery
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
External Validity ◽  
Three Dimensions ◽  
Material Objects ◽  
Pragmatic Trials ◽  
Positive Effects ◽  
Ethnographic Data ◽  
The Uk

There have long been calls to reduce the bureaucratization of clinical trials and make them more ‘sensible’, with the focus on approvals and guidelines. Here, I focus on the mundane environments of a multi-centre clinical trial to ask how ‘sensible’ it is to standardize trials at the level of material objects. Drawing on ethnographic data collected in the UK, South Africa and Vietnam, I present three vignettes of material standardisation. While acknowledging some positive effects, I argue that standardising in this way may be antithetical to sustainable and relevant clinical research.  Three dimensions of this are discussed: 1) the external validity of evidence from pragmatic trials 2) the gap between experimentation and implementation and 3) long-term site capacity to conduct research.  Drawing on the literature on ‘situated standardisation’, the paper concludes by suggesting a greater acknowledgement of the need for trials not only to be ‘sensible’ but also ‘situated’.

scholarly journals It is unprecedented: trial management during the COVID-19 pandemic and beyond

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Eleanor J. Mitchell ◽  
Khaled Ahmed ◽  
Suzanne Breeman ◽  
Seonaidh Cotton ◽  
Lynda Constable ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Collection ◽  
Trial Management ◽  
National Network ◽  
Intervention Delivery ◽  
New Ways Of Working ◽  
The Future ◽  
Working Together ◽  
The Uk

Abstract The COVID-19 pandemic has presented unique challenges for the clinical trial community, both in the rapid establishment of COVID-19 clinical trials and many existing non-COVID-19 studies either being temporarily paused (whether that is a complete pause or pause in some activities) and/or adapting their processes. Trial managers have played a key role in decision-making, undertaking risk assessments and adapting trial processes, working closely with other members of the research team. This article presents some of the ways in which trial management processes have been altered and the key role that trial managers have played. It has been born out of discussions between trial managers in the UK who are members of the UK Trial Managers’ Network (UKTMN), a national network of trial management professionals managing non-commercial trials. In these unprecedented times, clinical trials have faced many uncertainties and broad-ranging challenges encompassing a range of activities including prioritising patient safety amidst the pandemic, consenting and recruiting new participants into trials, data collection and management and intervention delivery. In many cases, recruitment has been paused whilst mitigations have been put in place to continue data collection. Innovative solutions have been implemented to ensure we continue, where possible, to deliver high-quality clinical trials. Technology has provided many solutions to these challenges, and trial managers have adapted to new ways of working whilst continuing to deliver their clinical trials. Trial management groups are now faced with new uncertainties around re-starting clinical trials, and it is unclear currently how this will go, though working together with sponsors, funders and site teams is clearly a priority. Clinical trial teams have worked together to ensure their trials have adapted quickly whilst ensuring participant safety is given utmost importance. There are clear examples where the trial community have come together to share experiences and expertise, and this should continue in the future to ensure the innovative practices developed become embedded in the design and conduct of clinical trials in the future.

scholarly journals Challenges for funders in monitoring compliance with policies on clinical trials registration and reporting: analysis of funding and registry data in the UK

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e035283 ◽  
Author(s):  
Rachel L Knowles ◽  
Kam Pou Ha ◽  
Julia Mueller ◽  
Frances Rawle ◽  
Rosa Parker
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Medical Research ◽  
Research Funding ◽  
Controlled Trial ◽  
Monitoring Systems ◽  
Clinical Trial Registry ◽  
Funding Body ◽  
The Uk ◽  
Research Funding Body

ObjectivesTo evaluate compliance by researchers with funder requirements on clinical trial transparency, including identifying key areas for improvement; to assess the completeness, accuracy and suitability for annual compliance monitoring of the data routinely collected by a research funding body.DesignDescriptive analysis of clinical trials funded between February 2011 and January 2017 against funder policy requirements.SettingPublic medical research funding body in the UK.Data sourcesRelevant clinical trials were identified from grant application details, post-award grant monitoring systems and the International Standard Randomised Controlled Trial Number (ISRCTN) registry.Main outcome measureThe proportion of all Medical Research Council (MRC)-funded clinical trials that were (a) registered in a clinical trial registry and (b) publicly reported summary results within 2 years of completion.ResultsThere were 175 grants awarded that included a clinical trial and all trials were registered in a public trials registry. Of 62 trials completed for over 24 months, 42 (68%) had publicly reported the main findings by 24 months after trial completion; 18 of these achieved this within 12 months of completion. 11 (18%) trials took >24 months to report and 9 (15%) completed trials had not yet reported findings. Five datasets were shared with other researchers.ConclusionsCompliance with the funder policy requirements on trial registration was excellent. Reporting of the main findings was achieved for most trials within 24 months of completion; however, the number of unreported trials remains a concern and should be a focus for future funder policy initiatives. Identifying trials from grant management and grant monitoring systems was challenging therefore funders should ensure investigators reliably provide trial registries with information and regularly update entries with details of trial publications and protocols.

Accelerating clinical trial enrollment with comprehensive genomic profiling (CGP) and just-in-time clinical trial sites: An index case of a paradigm shift.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6539-6539
Author(s):  
Gaurav Singal ◽  
Deepu Madduri ◽  
Lara Yuan ◽  
David Luo ◽  
Aparna Upadhyay ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Therapeutic Option ◽  
Just In Time ◽  
Trial Participation ◽  
Community Settings ◽  
Patient Identification ◽  
Access Methods ◽  
Comprehensive Genomic Profiling

6539 Background: In many instances, trials may offer the best or only therapeutic option for patients with rare findings. However, conducting clinical trials of novel therapeutics targeting rare molecular variants is challenging. Patient populations are small, distributed, and predominantly in community settings where trial access remains limited by awareness and site availability. These challenges increase costs of drug development and approval, delaying widespread patient access. Methods: Foundation Medicine deployed a trial education and access program, “Precision Enrollment,” with Ignyta (a trial sponsor) and Pharmatech (a site management organization, or SMO, enabling “Just-In-Time” clinical trials) (Wiener, JCO 2007). Infrastructure and algorithms developed at Foundation Medicine (“SmartTrials Engine”) matched sequenced patients (avg n = 800/wk) with activating NTRK, ROS1, or ALK fusions to the phase II study of Entrectinib (NCT02568267). Oncologists at Foundation Medicine, through peer-to-peer outreach, facilitated trial access by providing trial and nearest site information to treating providers of matched patients. Results: 107 treatment-eligible patients with NTRK, ROS1, or ALK fusions were matched by the SmartTrials Engine; 36 (33%) expressed interest in trial participation. One such patient with NSCLC and a CD74-ROS1 fusion was unable to participate at an open trial site due to inability to travel. The patient’s site was part of the “Just-In-Time” network, with IRB and contract pre-approval, and was activated in only 3 days. Total time from patient identification to initiation of therapy was 7 days. Conclusions: We demonstrate a novel methodology for patient matching to trials targeting rare genomic findings, including in community settings. If extended, such innovative partnerships combined with computational matching infrastructure, could improve drug development and therapeutic access.

scholarly journals Clinical trial reporting performance of thirty UK universities on ClinicalTrials.gov—evaluation of a new tracking tool for the US clinical trial registry

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Sarai Mirjam Keestra ◽  
Florence Rodgers ◽  
Daphne Lenz ◽  
Rhiannon Osborne ◽  
Till Bruckner ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Median Number ◽  
World Health ◽  
Trial Registry ◽  
Clinical Trial Registry ◽  
Link Type ◽  
The Us ◽  
Health Organization ◽  
The Uk

AbstractClinical trial transparency forms the foundation of evidence-based medicine, and trial sponsors, especially publicly funded institutions such as universities, have an ethical and scientific responsibility to make the results of clinical trials publicly available in a timely fashion. We assessed whether the thirty UK universities receiving the most Medical Research Council funding in 2017–2018 complied with World Health Organization best practices for clinical trial reporting on the US Clinical Trial Registry (ClinicalTrials.gov). Firstly, we developed and evaluated a novel automated tracking tool (clinical-trials-tracker.com) for clinical trials registered on ClinicalTrials.gov. This tracker identifies the number of due trials (whose completion lies more than 395 days in the past) that have not reported results on the registry and can now be used for all sponsors. Secondly, we used the tracker to determine the number of due clinical trials sponsored by the selected UK universities in October 2020. Thirdly, using the FDAAA Trials Tracker, we identified trials sponsored by these universities that are not complying with reporting requirements under the Food and Drug Administration Amendments Act 2007. Finally, we quantified the average and median number of days between primary completion date and results posting. In October 2020, the universities included in our study were sponsoring 1634 due trials, only 1.6% (n = 26) of which had reported results within a year of completion. 89.8% (n = 1468) of trials remained unreported, and 8.6% (n = 140) of trials reported results late. We also identified 687 trials that contained inconsistent data, suggesting that UK universities often fail to update their data adequately on ClinicalTrials.gov. The mean reporting delay after primary completion for trials that posted results was 981 days, the median 728 days. Only four trials by UK universities violated the FDAAA 2007. We suggest a number of reasons for the poor reporting performance of UK universities on ClinicalTrials.gov: (i) efforts to improve clinical trial reporting in the UK have to date focused on the European clinical trial registry (EU CTR), (ii) the absence of a tracking tool for timely reporting on ClinicalTrials.gov has limited the visibility of institutions’ reporting performance on the US registry and (iii) there is currently a lack of repercussions for UK sponsors who fail to report results on ClinicalTrials.gov which should be addressed in the future.

scholarly journals Importance and role of independent data monitoring committees (IDMCs) in oncology clinical trials

BMJ Open ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. e047294
Author(s):  
P Schöffski
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Adverse Events ◽  
Stopping Rules ◽  
Data Monitoring ◽  
Independent Data ◽  
Oncology Clinical Trials ◽  
Life Threatening ◽  
Study Participants

The role and use of independent data monitoring committees (IDMCs) has evolved over the past decades. The Food and Drug Administration and European Medicines Agency have issued guidelines on the role and functioning of such committees. In general, data monitoring committees are recommended for large, often randomised clinical trials involving life-threatening diseases, studies performed in vulnerable populations or where the experimental intervention can potentially harm the trial participant. Such committees play an important role in trials evaluating treatments with the potential to prolong life or reduce the risk of major adverse health outcomes.Typically, oncology clinical trials fall within these recommendations, as they are often large, randomised, multicentric protocols aiming at improving survival outcomes by exploring the use of study treatments that may be associated with a significant risk of serious, even life-threatening adverse events. IDMCs are required for National Cancer Institute phase III randomised trials, European Organisation for Research and Treatment of Cancer phase II/III trials with formal interim analyses, early-stopping rules or adaptive studies. The primary role of an IDMC of ensuring the safety of study participants and maintaining clinical trial integrity is particularly important in oncology trials, due to the nature of the disease, the potential for treatment toxicity and for instilling confidence that the clinical trial data are reliable. A clear understanding by IDMC members of the natural course of the disease, treatment landscape, importance and relevance of certain adverse events in trial participants, clinical trial methodology in general and stopping rules for oncology trials in particular, is crucial for the functioning of an IDMC.It is recommended that IDMC members should be experienced trialists, have a track record of strong clinical, statistical and/or methodological expertise and the required level of independence, as they play a highly important role in the protection of study participants, and in commercially and strategically important go/no decisions. Ideally, IDMC members should have relevant experience or have some training, mentorship or guidelines.

scholarly journals Monitoring for Lack of Benefit: A Critical Component of a Randomized Clinical Trial

2009 ◽  
Vol 27 (4) ◽  
pp. 629-633 ◽  
Author(s):  
Boris Freidlin ◽  
Edward L. Korn
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Beneficial Effect ◽  
Randomized Clinical Trials ◽  
The Other ◽  
Data Monitoring ◽  
Complex Nature ◽  
Critical Component ◽  
Efficacy Data ◽  
Aggressive Approach

To balance patient interests against the need for acquiring evidence, ongoing randomized clinical trials are formally monitored for early convincing indication of benefit or lack of benefit. In lethal diseases like cancer, where new therapies are often toxic and may have limited preliminary efficacy data, monitoring for lack of benefit is particularly important. We review the complex nature of stopping a randomized trial for lack of benefit and argue that many cancer trials could be improved by a more aggressive approach to monitoring. On the other hand, we caution that some commonly used monitoring guidelines may result in stopping for lack of benefit even when a nontrivial beneficial effect is observed.

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