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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 -
The Journal of Molecular Diagnostics :... Nov 2016Molecular diagnostic tests with application to clinical diagnostics involve studies in infectious diseases, inherited diseases, oncology, predisposition to disease, or... (Review)
Review
Molecular diagnostic tests with application to clinical diagnostics involve studies in infectious diseases, inherited diseases, oncology, predisposition to disease, or the description of polymorphisms linked to disease states. General considerations in the design of evaluation of diagnostic test trials and statistical principles for reporting the results are discussed. A brief overview of the general statistical considerations related to the intent of use, test development versus validation, different types of biases, and issues with missing data are provided. Furthermore, issues related to commonly used but not necessarily correct methods to characterize the performance in the presence and absence of a clinical reference standard are discussed. These issues are broadly applicable to any molecular diagnostic test with a dichotomous result. This overview may help the clinical molecular diagnostic community to evaluate tests that provide a dichotomous result.
Topics: Clinical Trials as Topic; Humans; Molecular Diagnostic Techniques; Reproducibility of Results; Research Design; Sensitivity and Specificity
PubMed: 27639547
DOI: 10.1016/j.jmoldx.2016.06.008 -
Leukemia Research May 2018Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many... (Review)
Review
Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified α and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial's statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data.
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Remission Induction; Treatment Outcome
PubMed: 29524739
DOI: 10.1016/j.leukres.2018.02.002 -
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 -
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 -
Pediatric Research Nov 2017The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the... (Review)
Review
The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the small number of appropriate patients available for such studies. The American Society of Pediatric Nephrology Therapeutics Development Committee (TDC) was established to (1) identify the various stakeholders with interests and/or expertise related to clinical trials in children with kidney disease and (2) develop more effective partnerships among all parties regarding strategies for successful clinical trial development and execution. This article discusses the rationale, structure, and function of the TDC, the status of progress toward its goals, and the insights gained to date that may be useful for other subspecialties that face similar challenges.
Topics: Age Factors; Child; Clinical Trials as Topic; Consensus; Humans; Kidney Diseases; Nephrology; Pediatrics; Practice Guidelines as Topic; Research Design; Stakeholder Participation; Treatment Outcome; Workflow
PubMed: 28853726
DOI: 10.1038/pr.2017.180 -
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 -
Annals of the New York Academy of... Feb 2016Imaging of stroke and neurovascular disorders has profoundly enhanced clinical practice and related research during the last 40 years since the introduction of computed... (Review)
Review
Imaging of stroke and neurovascular disorders has profoundly enhanced clinical practice and related research during the last 40 years since the introduction of computed tomography (CT) and magnetic resonance imaging (MRI) enabled mapping of the brain. We highlight recent advances in neurovascular imaging. We describe how the convergence of readily available data and new clinical trial paradigms will recast our methods for studying the neurovascular patient. The application of a precision medicine approach to the collaterome, a comprehensive synthesis of neurovascular pathophysiology, will entail novel methods for clinical trial randomization, collection of routine and clinical trial imaging results, data archiving, and analysis.
Topics: Cerebrovascular Disorders; Clinical Trials as Topic; Collateral Circulation; Diagnostic Imaging; Humans; Magnetic Resonance Imaging; Precision Medicine; Tomography, X-Ray Computed
PubMed: 25922154
DOI: 10.1111/nyas.12765 -
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