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Annals of the New York Academy of... Jan 2022For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis,... (Review)
Review
For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.
Topics: Aging; Autophagy; COVID-19; Cardiovascular Diseases; Congresses as Topic; Geroscience; Humans; Longevity; Metabolomics; Nervous System Diseases; Research Report; Stem Cell Transplantation
PubMed: 34498278
DOI: 10.1111/nyas.14681 -
Clinical Pharmacology and Therapeutics Nov 2021On May 4, 2020, the US Food and Drug Administration (FDA) hosted an online public workshop titled "FY 2020 Generic Drug Regulatory Science Initiatives Public Workshop"... (Review)
Review
On May 4, 2020, the US Food and Drug Administration (FDA) hosted an online public workshop titled "FY 2020 Generic Drug Regulatory Science Initiatives Public Workshop" to provide an overview of the status of the science and research priorities and to solicit input on the development of Generic Drug User Fee Amendments fiscal year 2021 priorities. This report summarizes the podium presentations and the outcome of discussions along with innovative ways to overcome challenges and significant opportunities related to model-based approaches in bioequivalence assessment for breakout session 4 titled, "Data analysis and model-based bioequivalence (BE)." This session focused on the application of model-based approaches in the generic drug development, with a vision of accelerating regulatory decision making for abbreviated new drug application assessments. The session included both podium presentations and panel discussions with three topics of interest: (i) in vitro study evaluation methods and their clinical relevance, (ii) challenges in model-based BE, (iii) emerging expertise and tools in implementing new BE approaches.
Topics: Data Analysis; Drug and Narcotic Control; Drugs, Generic; Education; Humans; Research Report; Therapeutic Equivalency; United States; United States Food and Drug Administration
PubMed: 33236362
DOI: 10.1002/cpt.2120 -
CPT: Pharmacometrics & Systems... May 2023This workshop report summarizes the presentations and panel discussion related to the use of physiologically based pharmacokinetic (PBPK) modeling approaches for food... (Review)
Review
This workshop report summarizes the presentations and panel discussion related to the use of physiologically based pharmacokinetic (PBPK) modeling approaches for food effect assessment, collected from Session 2 of Day 2 of the workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches." The US Food and Drug Administration in collaboration with the Center for Research on Complex Generics organized this workshop where this particular session titled "Oral PBPK for Evaluating the Impact of Food on BE" presented successful cases of PBPK modeling approaches for food effect assessment. Recently, PBPK modeling has started to gain popularity among academia, industries, and regulatory agencies for its potential utility during bioavailability (BA) and/or bioequivalence (BE) studies of new and generic drug products to assess the impact of food on BA/BE. Considering the promises of PBPK modeling in generic drug development, the aim of this workshop session was to facilitate knowledge sharing among academia, industries, and regulatory agencies to understand the knowledge gap and guide the path forward. This report collects and summarizes the information presented and discussed during this session to disseminate the information into a broader audience for further advancement in this area.
Topics: Humans; Therapeutic Equivalency; Research Report; Models, Biological; Biological Availability; Drug Development; Drugs, Generic
PubMed: 36597353
DOI: 10.1002/psp4.12913 -
CPT: Pharmacometrics & Systems... May 2023This report summarizes the proceedings for day 2 sessions 1 and 3 of the 2-day public workshop entitled "Regulatory Utility of Mechanistic Modeling to Support... (Review)
Review
This report summarizes the proceedings for day 2 sessions 1 and 3 of the 2-day public workshop entitled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG). The aims of this workshop were: (1) to discuss how mechanistic modeling, including physiologically-based pharmacokinetic (PBPK) modeling and simulation, can support product development, and regulatory submissions; (2) to share the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (3) to establish a consensus on best practices for using PBPK modeling for BE assessment to help drive further investment by the generic drug industry into mechanistic modeling and simulation; and (4) to introduce the concept of a Model Master File to improve model-sharing. The theme of day 2 covered PBPK absorption model for oral products as an alternative BE approach and a tool for supporting risk assessment and biowaiver (session 1), oral PBPK for evaluating the impact of food on BE (session 2), successful cases, and challenges for oral PBPK (session 3). This report summarizes the topics of the presentations of day 2 sessions 1 and session 3 from FDA, academia, and pharmaceutical industry, including the current status of oral PBPK, case examples as well as the challenges and opportunities in this area. In addition, panel discussions on the utility of oral PBPK in both new drugs and generic drugs from regulatory and industry perspective are also summarized.
Topics: Humans; Therapeutic Equivalency; Research Report; Models, Biological; Computer Simulation
PubMed: 36530026
DOI: 10.1002/psp4.12907 -
Frontiers in Neurology 2022Developmental and epileptic encephalopathy 91 (DEE91; OMIM#617711) is a severe neurodevelopmental disorder caused by heterozygous variants. To the best of our...
INTRODUCTION
Developmental and epileptic encephalopathy 91 (DEE91; OMIM#617711) is a severe neurodevelopmental disorder caused by heterozygous variants. To the best of our knowledge, only a few DEE91 cases have been reported.
RESULTS
This study reports a boy who experienced recurrent afebrile convulsions and spasms at the age of 2 months. After being given multiple antiepileptic treatments with levetiracetam, adrenocorticotropic hormone (ACTH), prednisone, topiramate, and clonazepam, his seizures were not completely relieved. At the age of 4 months, the patient exhibited delayed neuromotor development and difficulty in feeding; at the age of 6 months, he was diagnosed with developmental regression with recurrent spasms and myoclonic seizures that could respond to vigabatrin. At the age of 1 year and 4 months, the patient showed profound global developmental delay (GDD) with intermittent absence seizures. Whole-exome sequencing (WES) identified a novel loss-of-function variant c.1258_1259insAGTG (p. Val420Glufs32) in .
CONCLUSION
This finding expands the genetic spectrum of the gene and reinforces the theory that DEE91-associated truncating variants cluster within a 26-amino acid region in the regulatory domain (RD) of .
PubMed: 36158964
DOI: 10.3389/fneur.2022.889167 -
Preventive Medicine Nov 2019In 2013 the U.S. Food and Drug Administration and National Institutes of Health established fourteen Tobacco Centers of Regulatory Science (TCORS) to advance scientific... (Review)
Review
In 2013 the U.S. Food and Drug Administration and National Institutes of Health established fourteen Tobacco Centers of Regulatory Science (TCORS) to advance scientific knowledge relevant to conducting evidence-based tobacco regulation. This report reviews TCORS-funded research with adult vulnerable populations. The literature search included a list of all TCORS-funded publications compiled by the TCORS coordinating center; all TCORS were requested to share publications not in the coordinating-center's list. Only TCORS-funded reports describing an empirical study with an adult vulnerable population published in a peer-reviewed journal between September 2013 and June 2018 were included. 71 reports met inclusion criteria; 39% (28/71) examined tobacco use among those with mental health and medical comorbidities, 34% (24/71) socioeconomic disadvantage, 31% (22/71) women of reproductive age, 30% (21/71) racial/ethnic minorities, 18% (13/71) rural residents, and 3% (2/71) each among active military/veterans and sexual/gender minorities. Regarding scientific domains, 63% (45/71) investigated behavior, 37% (26/71) addiction, 24% (17/71) health effects, 20% (14/71) impact analyses, 18% (13/71) toxicity, 8% (6/71) marketing influences, and 7% (5/71) communications. Totals exceed 100% because some reports addressed multiple populations/domains. TCORS funding has generated a substantial, multidisciplinary body of new scientific knowledge on tobacco use in adult vulnerable populations. However, considerable variability was noted in the amount of research conducted across the various vulnerable populations and scientific domains. Most notably, relatively few studies focused on active military/veterans or sexual/gender minorities, and the scientific domains of marketing influences and communications were conspicuously underrepresented. These are important knowledge gaps to address going forward.
Topics: Adult; Aged; Aged, 80 and over; Community-Based Participatory Research; Ethnicity; Female; Health Promotion; Humans; Male; Middle Aged; Minority Groups; Research Report; Socioeconomic Factors; Tobacco Products; Tobacco Use Disorder; United States; Vulnerable Populations; Young Adult
PubMed: 31054904
DOI: 10.1016/j.ypmed.2019.04.024 -
Epilepsia Nov 2022The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22-25, 2022 and was attended by 157 delegates from 26...
Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): II. Drugs in more advanced clinical development.
The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22-25, 2022 and was attended by 157 delegates from 26 countries representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK-001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients 2 years of age and older.
Topics: Humans; Anticonvulsants; Research Report; Pharmaceutical Preparations; Drugs, Investigational; Seizures
PubMed: 35950617
DOI: 10.1111/epi.17376 -
Circulation Research Oct 2019Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological... (Review)
Review
Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.
Topics: Animals; Cardiotoxicity; Cardiotoxins; Drug Evaluation, Preclinical; Education; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Research Report; United States; United States Food and Drug Administration
PubMed: 31600125
DOI: 10.1161/CIRCRESAHA.119.315378 -
Phlebology Mar 2024The aim was to retrieve and analyse the serious adverse events of venous occlusion systems used in cyanoacrylate adhesive closure (CAC) submitted to regulatory agencies.
OBJECTIVE
The aim was to retrieve and analyse the serious adverse events of venous occlusion systems used in cyanoacrylate adhesive closure (CAC) submitted to regulatory agencies.
METHODS
The (TPLC) database of the US Food and Drug Administration (FDA), the (DAEN) of the Australian Therapeutic Goods Administration (TGA), and the database of the UK Medicines and Healthcare Products Regulatory Agency (MHRA) were reviewed. Three Freedom of Information (FOI) requests had to be submitted to the MHRA to obtain data.
RESULTS
The TPLC contained 899 reports which included 13 cases of death, 7 strokes, 211 thromboembolic events, and 482 immune reactions. The DAEN recorded three reportable adverse events, and the MHRA recorded seven adverse incidents including one death.
CONCLUSION
CAC is associated with serious adverse events including death. These events are under-reported in the medical literature and only sub-optimally reported to the regulatory agencies.
Topics: Humans; Cyanoacrylates; Adhesives; Australia; Thromboembolism; Databases, Factual
PubMed: 37902099
DOI: 10.1177/02683555231211086