Search

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration's Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

This study reviews the participation of racial and ethnic populations at US sites in 2015-2019 to understand the extent to which US trial participation represents the diversity of the US population.

Neuroinflammation, a key early pathomechanistic alteration of Alzheimer’s disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer’s disease exploring whether age, sex, and the apolipoprotein E e4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis.

Bridging the Gap at Warp Speed In addition to its goal of delivering safe and effective vaccines quickly, Operation Warp Speed aims to combat Covid-19 by improving the use of existing therapies and...

Introduction Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods We investigated whether plasma concentrations of the Aβ 1–40 /Aβ 1–42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. Results The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ 1–40 /Aβ 1–42 ratio. The accuracy is not affected by the apolipoprotein E ( APOE ) e4 allele, sex, or age. Discussion Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ 1–40 /Aβ 1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design.

Background: Abacavir drug hypersensitivity in HIV-treated patients is associated with HLA-B� 57:01 expression. To understand the immunochemistry of abacavir drug reactions, we investigated the effects of abacavir on 1) HLA-B� 57:01 epitope-binding in vitro and 2) the quality and quantity of self-peptides presented by HLA-B� 57:01 from abacavir-treated cells. Design and methods: An HLA-B� 57:01 specific epitope binding assay was developed to test for effects of abacavir, didanosine or flucloxacillin on self-peptide binding. To examine whether abacavir alters the peptide repertoire in HLA-B� 57:01, a B-cell line secreting soluble HLA (sHLA) was cultured in the presence or absence of abacavir, peptides were eluted from purified HLA, and the peptide epitopes comparatively mapped by mass spectroscopy to identify drug-unique peptides. Results: Abacavir, but not didansosine or flucloxacillin, enhanced binding of the FITC labeled self-peptide LF9 to HLA-B� 57:01 in a dose dependent manner. Endogenous peptides isolated from abacavir-treated HLA-B� 57:01 B-cells showed amino acid sequence differences compared with peptides from untreated cells. Novel druginduced (DI)-peptides lacked typical carboxyl(C)-terminal amino-acids characteristic of the HLA-B� 57:01 peptide motif and instead contained predominantly Isoleucine or Leucine residues. DI-peptides bind to soluble HLA-B� 57:01 with high affinity that was not altered by abacavir addition. Conclusion: Our results support a model of drug-induced autoimmunity in which abacaviraltersthequantity andquality of self-peptideloadinginto HLA-B� 57:01.Druginduced loading of novel self-peptides into HLA, possibly by abacavir either altering the binding cleft or modifying the peptide loading complex, generates an array of neo

The Institute of Medicine (IOM) Forum on Drug Discovery, Development, and Translation commissioned a series of papers to tackle the grand challenges facing drug discovery for psychiatric disorders, and to identify novel strategies for the development of new therapeutics. The three papers authored by Conn and Roth {Conn, 2008 #24}, Carpenter and Koenig {Carpenter, 2007 #26}, and Mathew and colleagues {Mathew, 2008 #25} identify opportunities and challenges to translate advances in basic and clinical neuroscience into novel medications to treat mood and anxiety disorders and schizophrenia. Some common themes emerge from these papers. The authors identify the need to develop novel mechanism of action therapeutics based on validated molecular targets. They observe a high degree of variability in the predictive value of existing preclinical models to assess drug efficacy, and call for more rigorous target validation at each stage along the pathway—from target identification to clinical validation—through clinical trials with appropriate levels of statistical power. The authors summarize the variable degree of predictive value that existing preclinical models have in assessing efficacy in the majority of psychiatric disorders. With the lack of congruence between disease models and symptoms in psychiatric disorders, the development of a strong mechanistic foundation for efficacy and toxicity biomarkers, both preclinical and clinical, is considered crucial for subsequent therapeutic development. The authors identify the pressing need not only for novel, pre-validated molecular and cellular targets, but also drug targets that are clinically established. The authors suggest targeting core phenotypic domains of dysfunction within and across psychiatric disorders, such as cognitive deficits in schizophrenia, sleep disturbances in post-traumatic stress disorder, and suicide across multiple disorders. This approach calls for developing and validating models that translate these clinical phenotypes into experimental endpoints to assess drug efficacy in animals and humans. One example of such an experimental endpoint is fear extinction, which has been successfully modeled in both animals and humans. The papers cite significant opportunities as well as challenges for systems levels approaches to facilitate the translation of basic discoveries into validated drug targets and new models of impaired domains of function. These opportunities have the potential to introduce innovation along the critical path for psychiatric drug discovery.