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Clinical and Translational Science Mar 2021The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the... (Review)
Review
The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the clinical trial paradigm from a site-centric to a patient-centric model. Merck's (Kenilworth, NJ) digitally enabled clinical trial initiative is focused on introduction of digital technologies into the clinical trial paradigm to reduce patient burden, improve drug adherence, provide a means of more closely engaging with the patient, and enable higher quality, faster, and more frequent data collection. This paper will describe the following four key areas of focus from Merck's digitally enabled clinical trials initiative, along with corresponding enabling technologies: (i) use of technologies that can monitor and improve drug adherence (smart dosing), (ii) collection of pharmacokinetic (PK), pharmacodynamic (PD), and biomarker samples in an outpatient setting (patient-centric sampling), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) use of data platforms that integrate digital data streams, visualize data in real-time, and provide a means of greater patient engagement during the trial (digital platform). Furthermore, this paper will discuss the synergistic power in implementation of these approaches jointly within a trial to enable better understanding of adherence, safety, efficacy, PK, PD, and corresponding exposure-response relationships of investigational therapies as well as reduced patient burden for clinical trial participation. Obstacle and challenges to adoption and full realization of the vision of patient-centric, digitally enabled trials will also be discussed.
Topics: Ambulatory Care; Clinical Trials as Topic; Drug Development; Humans; Monitoring, Ambulatory; Patient Participation; Patient-Centered Care; Telemedicine; Wearable Electronic Devices
PubMed: 33048475
DOI: 10.1111/cts.12910 -
Neurotherapeutics : the Journal of the... Jul 2021The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies. They usually begin in infancy or childhood with drug-resistant seizures,... (Review)
Review
The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies. They usually begin in infancy or childhood with drug-resistant seizures, epileptiform EEG patterns, developmental slowing or regression, and cognitive impairment. DEEs have a high mortality and profound morbidity; comorbidities are common including autism spectrum disorders. With advances in genetic sequencing, over 400 genes have been implicated in DEEs, with a genetic cause now identified in over 50% patients. Each genetic DEE typically has a broad genotypic-phenotypic spectrum, based on the underlying pathophysiology. There is a pressing need to improve health outcomes by developing novel targeted therapies for specific genetic DEE phenotypes that not only improve seizure control, but also developmental outcomes and comorbidities. Clinical trial readiness relies firstly on a deep understanding of phenotype-genotype correlation and evolution of a condition over time, in order to select appropriate patients for clinical trials. Understanding the natural history of the disorder informs assessment of treatment efficacy in terms of both clinical outcome and biomarker utility. Natural history studies (NHS) provide a high quality, integrated, comprehensive approach to understanding a complex disease and underpin clinical trial design for novel therapies. NHS are pre-planned observational studies designed to track the course of a disease and identify demographic, genetic, environmental, and other variables, including biomarkers, that correlate with the disease's evolution and outcomes. Due to the rarity of individual genetic DEEs, appropriately funded high-quality DEE NHS will be required, with sustainable frameworks and equitable access to affected individuals globally.
Topics: Biomarkers; Brain Diseases; Clinical Trials as Topic; Epilepsy; Humans; Medical History Taking; Neurodevelopmental Disorders
PubMed: 34708325
DOI: 10.1007/s13311-021-01133-3 -
Contemporary Clinical Trials Mar 2021This paper describes the need to prepare for the development of antiviral therapeutics for the next pandemic. Preparation would consist of a stockpiling of best...
This paper describes the need to prepare for the development of antiviral therapeutics for the next pandemic. Preparation would consist of a stockpiling of best practices for clinical trial design, analysis and operations during the current SARS-CoV-2 pandemic as well as continuous development of treatments and methodology between pandemics. This development would be facilitated by a global clinical trial pandemic reserve similar to the military reserves consisting of medical and quantitative methods professionals who would remain engaged between pandemics. Continuous identification of potential antiviral drugs and diagnostic methods would also be needed. Specific methodology addressed includes the importance of large simple trials, follow up time, efficacy endpoint, appropriate estimands, non-inferiority trials, more sophisticated patient accrual models and procedures for data sharing between clinical trials.
Topics: Antiviral Agents; COVID-19; Clinical Trials as Topic; Diagnostic Techniques, Cardiovascular; Drug Development; Humans; Pandemics; Research Design; SARS-CoV-2; Time Factors; COVID-19 Drug Treatment
PubMed: 33515783
DOI: 10.1016/j.cct.2021.106292 -
Neurotherapeutics : the Journal of the... Oct 2020Four-repeat tauopathies are a neurodegenerative disease characterized by brain parenchymal accumulation of a specific isoform of the protein tau, which gives rise to a... (Review)
Review
Four-repeat tauopathies are a neurodegenerative disease characterized by brain parenchymal accumulation of a specific isoform of the protein tau, which gives rise to a wide breadth of clinical syndromes encompassing diverse symptomatology, with the most common syndromes being progressive supranuclear palsy-Richardson's and corticobasal syndrome. Despite the lack of effective disease-modifying therapies, targeted treatment of symptoms can improve quality of life for patients with 4-repeat tauopathies. However, managing these symptoms can be a daunting task, even for those familiar with the diseases, as they span motor, sensory, cognitive, affective, autonomic, and behavioral domains. This review describes current approaches to symptomatic management of common clinical symptoms in 4-repeat tauopathies with a focus on practical patient management, including pharmacologic and nonpharmacologic strategies, and concludes with a discussion of the history and future of disease-modifying therapeutics and clinical trials in this population.
Topics: Clinical Trials as Topic; Disease Management; Forecasting; Humans; Motor Disorders; Tauopathies; Treatment Outcome
PubMed: 32676851
DOI: 10.1007/s13311-020-00888-5 -
Journal of Nuclear Medicine : Official... Jun 2021This article explores basic statistical concepts of clinical trial design and diagnostic testing, or how one starts with a question, formulates it into a hypothesis on... (Review)
Review
This article explores basic statistical concepts of clinical trial design and diagnostic testing, or how one starts with a question, formulates it into a hypothesis on which a clinical trial is then built, and integrates it with statistics and probability, such as determining the probability of rejecting the null hypothesis when it is actually true (type I error) and the probability of failing to reject the null hypothesis when it is false (type II error). There are a variety of tests for different types of data, and the appropriate test must be chosen for which the sample data meet the assumptions. Correcting type I error in the presence of multiple testing is needed to control the error's inflation. Within diagnostic testing, identifying false-positive and false-negative results is critical to understanding the performance of a test. These are used to determine the sensitivity and specificity of a test along with the test's negative predictive value and positive predictive value. These quantities, specifically sensitivity and specificity, are used to determine the accuracy of a diagnostic test using receiver-operating-characteristic curves. These concepts are briefly introduced to provide a basic understanding of clinical trial design and analysis, with references to allow the reader to explore various concepts at a more detailed level if desired.
Topics: Clinical Trials as Topic; Diagnostic Techniques and Procedures; Humans; Predictive Value of Tests; ROC Curve; Sensitivity and Specificity; Statistics as Topic
PubMed: 33608427
DOI: 10.2967/jnumed.120.245654 -
Neurosurgery Mar 2021Cell therapy has been widely recognized as a promising strategy to enhance recovery in stroke survivors. However, despite an abundance of encouraging preclinical data,... (Review)
Review
Cell therapy has been widely recognized as a promising strategy to enhance recovery in stroke survivors. However, despite an abundance of encouraging preclinical data, successful clinical translation remains elusive. As the field continues to advance, it is important to reexamine prior clinical trials in the context of their intended mechanisms, as this can inform future preclinical and translational efforts. In the present work, we review the major clinical trials of cell therapy for stroke and highlight a mechanistic shift between the earliest studies, which aimed to replace dead and damaged neurons, and later ones that focused on exploiting the various neuromodulatory effects afforded by stem cells. We discuss why both mechanisms are worth pursuing and emphasize the means through which cell replacement can still be achieved.
Topics: Cell Survival; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Humans; Neurons; Stroke
PubMed: 33370810
DOI: 10.1093/neuros/nyaa531 -
Epilepsy & Behavior : E&B Dec 2019Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of... (Review)
Review
Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
Topics: Adult; Anticonvulsants; Benzodiazepines; Child, Preschool; Clinical Trials as Topic; Diagnostic Tests, Routine; Double-Blind Method; Emergency Service, Hospital; Female; Humans; Levetiracetam; Male; Status Epilepticus; Treatment Outcome; Valproic Acid
PubMed: 31653603
DOI: 10.1016/j.yebeh.2019.04.049 -
Biomedical Engineering Online Jan 2021Novel endoscopic biophotonic diagnostic technologies have the potential to non-invasively detect the interior of a hollow organ or cavity of the human body with... (Review)
Review
Novel endoscopic biophotonic diagnostic technologies have the potential to non-invasively detect the interior of a hollow organ or cavity of the human body with subcellular resolution or to obtain biochemical information about tissue in real time. With the capability to visualize or analyze the diagnostic target in vivo, these techniques gradually developed as potential candidates to challenge histopathology which remains the gold standard for diagnosis. Consequently, many innovative endoscopic diagnostic techniques have succeeded in detection, characterization, and confirmation: the three critical steps for routine endoscopic diagnosis. In this review, we mainly summarize researches on emerging endoscopic optical diagnostic techniques, with emphasis on recent advances. We also introduce the fundamental principles and the development of those techniques and compare their characteristics. Especially, we shed light on the merit of novel endoscopic imaging technologies in medical research. For example, hyperspectral imaging and Raman spectroscopy provide direct molecular information, while optical coherence tomography and multi-photo endomicroscopy offer a more extensive detection range and excellent spatial-temporal resolution. Furthermore, we summarize the unexplored application fields of these endoscopic optical techniques in major hospital departments for biomedical researchers. Finally, we provide a brief overview of the future perspectives, as well as bottlenecks of those endoscopic optical diagnostic technologies. We believe all these efforts will enrich the diagnostic toolbox for endoscopists, enhance diagnostic efficiency, and reduce the rate of missed diagnosis and misdiagnosis.
Topics: Clinical Trials as Topic; Endoscopy; Humans; Optical Phenomena
PubMed: 33407477
DOI: 10.1186/s12938-020-00845-5 -
Tomography (Ann Arbor, Mich.) Jun 2020The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and... (Review)
Review
The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and harmonization of quantitative imaging (QI) methods and tools for use in cancer clinical trials. In the past 10 years, the Group has been working in several areas to identify challenges and opportunities in clinical trials involving QI and radiation oncology. The Group has been working with Quantitative Imaging Network members and the Quantitative Imaging Biomarkers Alliance leadership to develop guidelines for standardizing the reporting of quantitative imaging. As a validation platform, the Group led a multireader study to test a semi-automated positron emission tomography quantification software. Clinical translation of QI tools cannot be possible without a continuing dialogue with clinical users. This article also highlights the outreach activities extended to cooperative groups and other organizations that promote the use of QI tools to support clinical decisions.
Topics: Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Diagnostic Imaging; Humans; Neoplasms; Positron-Emission Tomography; Radiation Oncology; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed
PubMed: 32548281
DOI: 10.18383/j.tom.2019.00022 -
Cardiovascular and Interventional... Nov 2022
Topics: Humans; Embolization, Therapeutic; Liver Neoplasms; Longitudinal Studies; Radiopharmaceuticals; Treatment Outcome; Clinical Trials as Topic
PubMed: 36184696
DOI: 10.1007/s00270-022-03270-4