scholarly journals A Call for Objective Dose Selection to Increase Success in Pediatric Clinical Trials: A Perspective From NICHD and NIMH Program Staff

2021 ◽  
Vol 61 (S1) ◽  
Author(s):  
George Giacoia ◽  
Margaret C. Grabb ◽  
Aaron C. Pawlyk ◽  
Zhaoxia Ren ◽  
Lesly Samedy‐Bates ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Dose Selection ◽  
Program Staff

Direct Oral Anticoagulants in the Treatment of Venous Thromboembolism: Use in Patients with Advanced Renal Impairment, Obesity, or Other Weight-Related Special Populations

2021 ◽  
Author(s):  
Paul P. Dobesh ◽  
Molly M. Kernan ◽  
Jenni J. Lueshen
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Renal Impairment ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Safety Data ◽  
Special Populations ◽  
Dose Selection ◽  
Phase 3 ◽  
Optimal Drug

AbstractThere are currently more than 7 million patients taking a direct oral anticoagulant (DOAC), with more new prescriptions per year than warfarin. Despite impressive efficacy and safety data for the treatment of venous thromboembolism, patients with obesity or advanced renal impairment represented a small portion of the patients enrolled in the phase 3 clinical trials. Therefore, to evaluate the potential use of DOACs in these special populations, clinicians need to have an understanding of the pharmacokinetics and pharmacodynamics of these agents in these settings. Since data from randomized controlled trials are limited, data from observational trials are helpful in gaining comfort with the use of DOACs in these special populations. Selecting the appropriate dose for each agent is imperative in achieving optimal patient outcomes. We provide an extensive review of the pharmacokinetics, pharmacodynamics, phase 3 clinical trials, and observational studies on the use of DOACs in patients with advanced renal impairment, obesity, or other weight-related special populations to provide clinicians with a comprehensive understanding of the data for optimal drug and dose selection.

scholarly journals CURATE.AI: Optimizing Personalized Medicine with Artificial Intelligence

2019 ◽  
Vol 25 (2) ◽  
pp. 95-105
Author(s):  
Agata Blasiak ◽  
Jeffrey Khong ◽  
Theodore Kee
Keyword(s):  
Clinical Trials ◽  
Personalized Medicine ◽  
Standard Of Care ◽  
Small Data ◽  
Current Standard ◽  
Dose Selection ◽  
Support Tool ◽  
Combination Treatments ◽  
Multiple Challenges ◽  
Over Time

The clinical team attending to a patient upon a diagnosis is faced with two main questions: what treatment, and at what dose? Clinical trials’ results provide the basis for guidance and support for official protocols that clinicians use to base their decisions upon. However, individuals rarely demonstrate the reported response from relevant clinical trials, often the average from a group representing a population or subpopulation. The decision complexity increases with combination treatments where drugs administered together can interact with each other, which is often the case. Additionally, the individual’s response to the treatment varies over time with the changes in his or her condition, whether via the indication or physiology. In practice, the drug and the dose selection depend greatly on the medical protocol of the healthcare provider and the medical team’s experience. As such, the results are inherently varied and often suboptimal. Big data approaches have emerged as an excellent decision-making support tool, but their application is limited by multiple challenges, the main one being the availability of sufficiently big datasets with good quality, representative information. An alternative approach—phenotypic personalized medicine (PPM)—finds an appropriate drug combination (quadratic phenotypic optimization platform [QPOP]) and an appropriate dosing strategy over time (CURATE.AI) based on small data collected exclusively from the treated individual. PPM-based approaches have demonstrated superior results over the current standard of care. The side effects are limited while the desired output is maximized, which directly translates into improving the length and quality of individuals’ lives.

Dose selection in seamless phase II/III clinical trials based on efficacy and safety

2009 ◽  
Vol 28 (6) ◽  
pp. 917-936 ◽  
Author(s):  
Peter K. Kimani ◽  
Nigel Stallard ◽  
Jane L. Hutton
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Efficacy And Safety ◽  
Dose Selection

scholarly journals Allometric scaling models: history, use, and misuse in translating resveratrol from basic science to human clinical applications

2017 ◽  
Vol 7 (5) ◽  
pp. 338 ◽  
Author(s):  
James M. Smoliga ◽  
Otis L. Blanchard
Keyword(s):  
Clinical Trials ◽  
Allometric Scaling ◽  
Health Benefits ◽  
Clinical Applications ◽  
Pharmacokinetic Data ◽  
Rodent Models ◽  
Dose Selection ◽  
Allometric Models ◽  
Pharmacologically Active ◽  
Insight Into

Background: Determination of the first-in-human and pharmacologically active dosage for drugs and nutraceutical compounds is a critical step in study design and product development.  Allometric scaling is a form of mathematic modeling commonly used to convert dosages between species.  While allometric scaling allows for quick and straightforward conversions between species, it is often misunderstood and misused in translational clinical applications.  This is readily demonstrated in the case of resveratrol – a polyphenol which is found in red wine.  In the past decade, a considerable amount of research has emerged regarding the health benefits of the resveratrol supplementation.  Although data from rodent models suggests that resveratrol can have major effects on cardiometabolic and neurologic health, human clinical trials have had mixed results.  While some human clinical trials have yielded encouraging results, a few noteworthy trials have reported that seemingly appropriate allometry-derived dosages of resveratrol did not provide the expected health benefits reported in animal models.Here, we discuss the history of various models within allometry, including their advantages, disadvantages, and nuances from a clinical perspective.  This historical information will provide some insight into why dosages recommended from allometric scaling are appropriate in some circumstances and inappropriate in others.  We will then demonstrate how allometric models have been utilized to translate dosages of resveratrol from rodent models into the dosages recommended for human clinical trials.  Pharmacokinetic data from various human clinical trials will be summarized and compared to data predicted from allometric models.  Data from selected human clinical trials will then synthesized to demonstrate the dosage-dependent effects of resveratrol, and provide further insight into the appropriate use of allometric models for selecting resveratrol dosage.  Together, this information will promote a greater understanding of the role of allometric scaling in dose selection and provide an explanation for some of the apparent inconsistencies in translational research regarding resveratrol.Keywords: allometric scaling, dose conversion, bioavailability, pharmacokinetics, resveratrol

Recommendations for Dose Selection for Adolescent Patients in Relevant Adult Oncology Clinical Trials

2021 ◽  
Author(s):  
Ruby Leong ◽  
Qi Liu ◽  
Lingjue Li ◽  
Jiang Liu ◽  
Yunzhao R. Ren ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Dose Selection ◽  
Adolescent Patients ◽  
Oncology Clinical Trials ◽  
Selection For

scholarly journals Addressing the quality of submissions to ClinicalTrials.gov for registration and results posting: The use of a checklist

2020 ◽  
Vol 17 (6) ◽  
pp. 717-722
Author(s):  
Oswald Tetteh ◽  
Prince Nuamah ◽  
Anthony Keyes
Keyword(s):  
Quality Control ◽  
Clinical Trials ◽  
Success Rate ◽  
Program Staff ◽  
Medical Centers ◽  
Academic Medical ◽  
Protocol Registration ◽  
Timely Fashion ◽  
System Review

Background: US Federal regulations since the late 1990s have required registration of some clinical trials and submission of results for some of these trials on a public registry, ClinicalTrials.gov. The quality of the submissions made to ClinicalTrials.gov determines the duration of the Quality Control review, whether the submission will pass the review (success), and how many review cycles it will take for a study to be posted. Success rate for all results submitted to ClinicalTrials.gov is less than 25%. To increase the success of investigators’ submissions and meet the requirements of registration and submission of results in a timely fashion, the Johns Hopkins ClinicalTrials.gov Program implemented a policy to review all studies for quality before submission. To standardize our review for quality, minimize inter-reviewer variability, and have a tool for training new staff, we developed a checklist. Methods: The Program staff learned from major comments received from ClinicalTrials.gov and also reviewed the Protocol Registration and Results System review criteria for registration and results to fully understand how to prepare studies to pass Quality Control review. These were summarized into bulleted points and incorporated into a checklist used by Program staff to review studies before submission. Results: In the period before the introduction of the checklist, 107 studies were submitted for registration with a 45% (48/107) success rate, a mean (SD) of 18.9 (26.72) days in review, and 1.74 (0.78) submission cycles. Results for 44 records were submitted with 11% (5/44) success rate, 115.80 (129.33) days in review, and 2.23 (0.68) submission cycles. In the period after the checklist, 104 studies were submitted for registration with 80% (83/104) success rate, 2.12 (3.85) days in review, and 1.22 (0.46) submission cycles. Results for 22 records were submitted with 41% (9/22) success rate, 39.27 (19.84) days in review, and 1.64 (0.58) submission cycles. Of the 44 results submitted prior to the checklist, 30 were Applicable or Probable Applicable Clinical Trials, with 10% (3/30) being posted within 30 days as required of the National Institutes of Health. For the 22 results submitted after the checklist, 17 were Applicable or Probable Applicable Clinical Trials, with 47% (8/17) being posted within 30 days of submission. These pre- and post-checklist differences were statistically significant improvements. Conclusion: The checklist has substantially improved our success rate and contributed to a reduction in the review days and number of review cycles. If Academic Medical Centers and industry will adopt or create a similar checklist to review their studies before submission, the quality of the submissions can be improved and the duration of review can be minimized.

scholarly journals Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seth C. Hopkins ◽  
Nina Dedic ◽  
Kenneth S. Koblan
Keyword(s):  
Clinical Trials ◽  
Rem Sleep ◽  
Therapeutic Potential ◽  
Brain Activity ◽  
Plasma Concentrations ◽  
Dose Selection ◽  
Double Blind ◽  
Drug Concentrations ◽  
Sleep Parameters

AbstractSEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject’s pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials.

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