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Neurology May 2021Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3... (Review)
Review
Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.
Topics: Alzheimer Disease; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dementia; Drug Development; Frontotemporal Dementia; Humans; Neurodegenerative Diseases; Outcome Assessment, Health Care; Proof of Concept Study; Research Design; Treatment Failure; Treatment Outcome
PubMed: 33674360
DOI: 10.1212/WNL.0000000000011774 -
Osteoarthritis and Cartilage Mar 2021
Topics: Cognitive Behavioral Therapy; Humans; Low Back Pain; Mediation Analysis; Patient Satisfaction; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 33429055
DOI: 10.1016/j.joca.2020.12.011 -
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 -
Annals of Clinical and Translational... Jul 2021The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature of progressive cerebellar ataxia. The disease process,... (Review)
Review
The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature of progressive cerebellar ataxia. The disease process, however, is not confined to the cerebellum; other areas of the brain, in particular, the brainstem, are also affected, resulting in a high burden of morbidity and mortality. Currently, there are no disease-modifying treatments for the SCAs, but preclinical research has led to the development of therapeutic agents ripe for testing in patients. Unfortunately, due to the rarity of these diseases and their slow and variable progression, there are substantial hurdles to overcome in conducting clinical trials. While the epidemiological features of the SCAs are immutable, the feasibility of conducting clinical trials is being addressed through a combination of strategies. These include improvements in clinical outcome measures, the identification of imaging and fluid biomarkers, and innovations in clinical trial design. In this review, we highlight current challenges in initiating clinical trials for the SCAs and also discuss pathways for researchers and clinicians to mitigate these challenges and harness opportunities for clinical trial development.
Topics: Biomarkers; Clinical Trials as Topic; Humans; Neuroimaging; Prevalence; Spinocerebellar Ataxias
PubMed: 34019331
DOI: 10.1002/acn3.51370 -
The Lancet. Oncology Nov 2021
Topics: Clinical Trials as Topic; Congresses as Topic; Humans; Medical Oncology; Neoplasms; Treatment Outcome
PubMed: 34563314
DOI: 10.1016/S1470-2045(21)00567-2 -
Contemporary Clinical Trials Jun 2024Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last... (Review)
Review
BACKGROUND
Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last steps in the evaluation process for a new drug, have been recommended to all be RCTs. Nevertheless, single-arm phase 3 trials still appear to be in use.
METHODS
We performed a PubMed search to identify the use of a single-arm design in phase 3 trials, excluding only non-English articles. Three categories were distinguished: past use of an RCT, of any other trial design, or no previous trial; and according to diagnosis (oncology, infection, others).
RESULTS
A total of 176 single-arm phase 3 trials (19 oncology, 43 infections and 114 others) were identified by the search, with exponential growth since 1994, in parallel with that of RCTs. Among them, 64 (36%) were preceded by an RCT, 58 (33%) by a non-randomized trial, and 54 (31%) had no previous trial, with no main influence of the diagnosis setting. Justification of the design was reported in 30 (18%) of those trials, with ethical concerns comprising one-third of those justifications. This was similar in the 14 single-arm phase 2-3 trials, with about one-third in each group, and 17% justification of a non-comparative design.
CONCLUSION
The use of a single-arm phase 3 trial is heterogeneous, ranging from first trials up to confirmatory trials after a previously conducted RCT. Justification for these single-arm designs as confirmatory evidence should be more clearly reported, along with potential sources of bias.
Topics: Humans; Research Design; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic; Non-Randomized Controlled Trials as Topic
PubMed: 38508234
DOI: 10.1016/j.cct.2024.107506 -
Gan To Kagaku Ryoho. Cancer &... Apr 2022Like most complex(or multifactorial)diseases, cancer results not from a single factor, but rather from the interaction of multiple genes and environmental factors. Thus... (Review)
Review
Like most complex(or multifactorial)diseases, cancer results not from a single factor, but rather from the interaction of multiple genes and environmental factors. Thus patients can experience different signs and symptoms that reflect more than one consequence of suffering the disease. When evaluating the effects of new treatments in cancer clinical trials, the multidimensional assessment using multiple outcomes to measure improvements in the patients' signs and symptoms associated with treatments would be preferred. Most cancer clinical trials use more than one clinical outcome as multiple primary, or primary and(key)secondary endpoints, such as overall survival, endpoints based on tumor assessments(e.g., disease-free survival, event-free survival, objective response rate, time to progression, progression-free survival), and endpoints involving symptom assessment. Utilizing multiple endpoints may provide the opportunity for characterizing the intervention's multidimensional effects, but also creates challenges, specifically controlling the Type Ⅰ and/or Type Ⅱ errors in hypotheses testing and trial designs associated with multiple endpoints. In this article, we review issues in design, monitoring, analysis and reporting of clinical trials with multiple endpoints, with illustrating examples in oncology disease settings. We outline several methods for controlling the Type Ⅰ error associated multiple tests, which have been commonly used in clinical trials. We also briefly discuss issues in interim analyses and group sequential designs for clinical trials with multiple endpoints.
Topics: Clinical Trials as Topic; Disease-Free Survival; Humans; Neoplasms; Progression-Free Survival; Research Design
PubMed: 35444117
DOI: No ID Found -
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 -
Drug Discovery Today Apr 2020Passive microwave radiometry (MWR) measures natural emissions in the range 1-10GHz from proteins, cells, organs and the whole human body. The intensity of intrinsic... (Comparative Study)
Comparative Study Review
Passive microwave radiometry (MWR) measures natural emissions in the range 1-10GHz from proteins, cells, organs and the whole human body. The intensity of intrinsic emission is determined by biochemical and biophysical processes. The nature of this process is still not very well known. Infrared thermography (IRT) can detect emission several microns deep (skin temperature), whereas MWR allows detection of thermal abnormalities down to several centimeters (internal or deep temperature). MWR is noninvasive and inexpensive. It requires neither fluorescent nor radioactive labels, nor ionizing or other radiation. MWR can be used in early drug discovery as well as preclinical and clinical studies.
Topics: Animals; Body Temperature; Clinical Trials as Topic; Drug Discovery; Drug Evaluation, Preclinical; Humans; Microwaves; Radiometry; Thermography
PubMed: 32004473
DOI: 10.1016/j.drudis.2020.01.016 -
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