Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “FDA clinical trials”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

14 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Graph-based featurization methods for classifying small molecule compounds

For over a decade, drug-induced liver injury (DILI) has posed significant drawbacks in the synthesis and development of drugs and remains a consequential concern. With finite success within the existing preclinical models, DILI is one of the main causes of drug withdrawal or termination from the market. Particularly, this withdrawal occurs during the late stages of drug development (Kullak-Ublick, 2017). Since DILI is difficult to diagnose and treat, it has become an obstacle in the drug production market that in turn affects clinicians, pharmaceutical companies, and consumers. We propose a method for learning features of DILI-positive drugs based on the graphical relationships and patterns they possess within a network of biological databases. We also train various statistical and machine learning models on these learned features in order to classify the drugs as DILI-positive or negative. Our methods include Random Forest, Neural networks, and logistic regression classification. We utilize labeled DILI-positive and DILI-negative datasets, which were developed by the FDA and the National center for toxicological research, as well as additional literature datasets (Thakkar, 2020) in order to validate our results and assess our featurization and model accuracy.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

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

Our research supported the dose selection recommendations for adolescents in the US Food and Drug Administration (FDA) Guidance on Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. The FDA Guidance states that for drugs administered as a flat dose in adults and data showing no clinically meaningful effect of body size on drug exposure and toxicity in adults, a minimum body weight threshold may need to be defined to prevent adolescents who have a lower body weight from exceeding adult exposures. Our review of adult population pharmacokinetic analyses of new molecular entities approved for oncology between January 2015 and March 2021 suggested that 40 kg (the approximate median body weight of a 12-year-old) is generally the lower end of the body weight range that has no clinically relevant effect on drug pharmacokinetics or safety. In conclusion, the minimum body weight threshold and selection of an appropriate dose for adolescents in relevant adult oncology clinical trials should ultimately be determined based on available data on pharmacokinetics or pharmacodynamics of the investigational drug with consideration of body size effect on drug exposure, toxicity, and efficacy data (if available), the therapeutic index of the drug, and dose- and exposure-response relationships in adults.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

NIRDye 812: A molecular platform tailored for multimodal bioimaging applications of targeted fluorescence- and photoacoustic-guided surgery

The primary treatment for malignant tumors remains to be surgical removal of the diseased tissue. The presence or absence of residual diseased tissue at the tumor margin is the strongest predictor of postoperative prognosis and recurrence. Accordingly, reliance on the ability of surgeons to visually distinguish diseased tissue from healthy tissue unambiguously in real time is crucial. Near infrared-I (NIRsingle bondI) fluorescence-emitting targeting biomolecular constructs such as anticancer antibody-fluorophore conjugates, namely cetuximab-IRDye® 800CW (CTB-IRDye® 800CW), are FDA-approved for clinical trial usage in the fluorescence-guided resection of diseased tissue due to affording improved direct visualization of tumor tissue when compared to the use of either the unaided eye under standard white light illumination (WLI) surgical techniques or non-targeting fluorophores. Unfortunately, though helpful, CTB-IRDye® 800CW affords limited (i) identification of diseased tissue and (ii) tumor margin delineation, because the immunoconjugate generates suboptimal tumor-to-background ratios (TBRs) as a result of its spectral/photophysical profiles poorly aligning with the fixed optical windows of pre-/clinical setups. As such, CTB-IRDye® 800CW is more prone to affording incomplete resection compared to if TBRs were higher due to otherwise. Here, to aid in accurately identifying deep-seated diseased tissue, photoacoustic (PA) tomography has been implemented alongside CTB-IRDye® 800CW to achieve PA signals that could result in higher TBRs. However, in clinical trial practice, using IRDye® 800CW for PA imaging also yields subpar TBRs due to it affording low PA signals. To overcome such limitations, we developed NIRDye 812, a structurally-modified topological equivalent of IRDye® 800CW, to confer it the capability to yield both higher TBRs and superior PA signal than that of the equivalent CTB-conjugate and fluorophore IRDye® 800CW itself, respectively. To do so, we substituted the oxygen atom at its meso-position with a sulfur atom. CTB-NIRDye 812 demonstrated a red-shifted absorption wavelength at 796 nm and a peak NIR-I fluorescence emission wavelength at 820 nm, which better dovetails with the fixed windows of preinstalled fixed emission filters within commercial pre-/clinical NIR-I fluorescence imaging instruments. Overall, CTB-NIRDye 812 provided a ~ 2-fold increase in TBRs compared to those of CTB-IRDye® 800CW in vivo. Also, NIRDye 812 displayed an ~60% higher PA signal than that of IRDye® 800CW. Collectively, we achieved our goal of improving upon the spectral/photophysical and PA properties of IRDye® 800CW via introducing a subtle modification to its electronic core such that its CTB immunoconjugate could potentially allow for fast track or breakthrough designation by the FDA due to its near-identical structure displaying considerably improved efficacy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non–Small Cell Lung Cancer Treated With a PD –1/PD– L1 Blocking Antibody Using Real–World and Trial Data

Clinical trials have demonstrated the benefit of PD-1/PD-L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1/PD-L1 blocking antibodies in real-world data (RWD; patient-level data from electronic health records) and pooled clinical trial data submitted to the US Food and Drug Administration (FDA). The Kaplan–Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis-generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and hold promise to complement trial data in better understanding populations not represented in clinical trials.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Regulatory Considerations in the Development of Radiation-Drug Combinations

Radiation therapy remains a fundamental treatment for patients with cancer. Despite an increasing number of targeted molecular therapies that are US Food and Drug Administration (FDA)-approved for the treatment of patients with metastatic disease, there has been very little progress made in terms of drugs used concurrently with radiation. This article reviews the existing regulatory framework in which cancer drugs may be developed for use in combination with radiation therapy from the perspective of the FDA. To briefly summarize: (1) nonclinical studies are a critical first step to ensure that drugs are safe for use in humans; however, additional nonclinical studies of a drug with radiation may not be required before a clinical trial in combination with radiation as long as the safety profile of the drug has been characterized in humans. The FDA determines the quality of evidence required before studying a drug in combination with radiation on a case-by-case basis. (2) Although often impractical to consider late toxicities during dose-escalation, late adverse events should be captured and taken into consideration when determining the final dose and schedule to take forward during drug development. (3) There are a number of expedited programs for cancer drug development, including accelerated approval, a conditional approval that allows for use of earlier clinical endpoints when the data suggests a clinically meaningful improvement over available therapy. (4) The Agency encourages sponsors to discuss their development plan with the appropriate FDA review division in formal regulatory meetings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Supervised learning with word embeddings derived from PubMed captures latent knowledge about protein kinases and cancer

Abstract Inhibiting protein kinases (PKs) that cause cancers has been an important topic in cancer therapy for years. So far, almost 8% of >530 PKs have been targeted by FDA-approved medications, and around 150 protein kinase inhibitors (PKIs) have been tested in clinical trials. We present an approach based on natural language processing and machine learning to investigate the relations between PKs and cancers, predicting PKs whose inhibition would be efficacious to treat a certain cancer. Our approach represents PKs and cancers as semantically meaningful 100-dimensional vectors based on word and concept neighborhoods in PubMed abstracts. We use information about phase I-IV trials in ClinicalTrials.gov to construct a training set for random forest classification. Our results with historical data show that associations between PKs and specific cancers can be predicted years in advance with good accuracy. Our tool can be used to predict the relevance of inhibiting PKs for specific cancers and to support the design of well-focused clinical trials to discover novel PKIs for cancer therapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Insights into the Structure of Ultrasmall Fluorescent Core–Shell Silica Nanoparticles

Ultrasmall fluorescent core–shell nanoparticles (NPs) with a silica core and poly(ethylene glycol) ligand shell are the earliest example of hybrid NPs that have received U.S. investigational new drug FDA approval. They are among only a few inorganic NPs translated to safety, diagnostic, and therapeutic human clinical trials. Despite these achievements, little is known about the exact structure of their 3–4 nm sized silica cores. We report the surprising discovery of a well-defined pentagonal bipyramidal core structure preferentially formed in the aqueous synthesis built from seven primary silica NPs. A combination of reverse-phase high-performance liquid chromatography, cryogenic transmission electron microscopy, and coarse-grained simulations provides fundamental insights into this magic-size cluster formation and its unusual stability. Here, results rationalize the successful NP synthesis scale-up from 1 mL to 50 L, provide clues to the recent discovery of their self-therapeutic properties in oncology via ferroptosis, an iron-dependent cell death mechanism, and promise improved control of particle size distribution via chromatographic separations.

cluster chemistry↗
DOE OSTI2024

Verazine biosynthesis from simple sugars in engineered Saccharomyces cerevisiae

Steroidal alkaloids are FDA-approved drugs (e.g., Zytiga) and promising drug candidates/leads (e.g., cyclopamine); yet many of the ≥697 known steroidal alkaloid natural products remain underutilized as drugs because it can be challenging to scale their biosynthesis in their producing organisms. Cyclopamine is a steroidal alkaloid produced by corn lily (Veratrum spp.) plants, and it is an inhibitor of the Hedgehog (Hh) signaling pathway. Therefore, cyclopamine is an important drug candidate/lead to treat human diseases that are associated with dysregulated Hh signaling, such as basal cell carcinoma and acute myeloid leukemia. Cyclopamine and its semi-synthetic derivatives have been studied in (pre)clinical trials as Hh inhibitor-based drugs. However, challenges in scaling the production of cyclopamine have slowed efforts to improve its efficacy and safety profile through (bio)synthetic derivatization, often limiting drug development to synthetic analogs of cyclopamine such as the FDA-approved drugs Odomzo, Daurismo, and Erivedge. If a platform for the scalable and sustainable production of cyclopamine were established, then its (bio)synthetic derivatization, clinical development, and, ultimately, widespread distribution could be accelerated. Ongoing efforts to achieve this goal include the biosynthesis of cyclopamine in Veratrum plant cell culture and the semi-/total chemical synthesis of cyclopamine. Herein, this work advances efforts towards a promising future approach: the biosynthesis of cyclopamine in engineered microorganisms. We completed the heterologous microbial production of verazine (biosynthetic precursor to cyclopamine) from simple sugars (i.e., glucose and galactose) in engineered Saccharomyces cerevisiae (S. cerevisiae) through the inducible upregulation of the native yeast mevalonate and lanosterol biosynthetic pathways, diversion of biosynthetic flux from ergosterol (i.e., native sterol in S. cerevisiae) to cholesterol (i.e., biosynthetic precursor to verazine), and expression of a refactored five-step verazine biosynthetic pathway. The engineered S. cerevisiae strain that produced verazine contains eight heterologous enzymes sourced from seven different species. Importantly, S. cerevisiae-produced verazine was indistinguishable via liquid chromatography-mass spectrometry from both a commercial standard (Veratrum spp. plant-produced) and Nicotiana benthamiana-produced verazine. To the best of our knowledge, this is the first report describing the heterologous production of a steroidal alkaloid in an engineered yeast. Verazine production was ultimately increased through design-build-test-learn cycles to a final titer of 83 ± 3 μg/L (4.1 ± 0.1 μg/g DCW). Finally, this research lays the groundwork for future microbial biosynthesis of cyclopamine, (bio)synthetic derivatives of cyclopamine, and other steroidal alkaloid natural products.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Drug-induced kidney injury: challenges and opportunities

Abstract Drug-induced kidney injury (DIKI) is a frequently reported adverse event, associated with acute kidney injury, chronic kidney disease, and end-stage renal failure. Prospective cohort studies on acute injuries suggest a frequency of around 14%–26% in adult populations and a significant concern in pediatrics with a frequency of 16% being attributed to a drug. In drug discovery and development, renal injury accounts for 8 and 9% of preclinical and clinical failures, respectively, impacting multiple therapeutic areas. Currently, the standard biomarkers for identifying DIKI are serum creatinine and blood urea nitrogen. However, both markers lack the sensitivity and specificity to detect nephrotoxicity prior to a significant loss of renal function. Consequently, there is a pressing need for the development of alternative methods to reliably predict drug-induced kidney injury (DIKI) in early drug discovery. In this article, we discuss various aspects of DIKI and how it is assessed in preclinical models and in the clinical setting, including the challenges posed by translating animal data to humans. We then examine the urinary biomarkers accepted by both the US Food and Drug Administration (FDA) and the European Medicines Agency for monitoring DIKI in preclinical studies and on a case-by-case basis in clinical trials. We also review new approach methodologies (NAMs) and how they may assist in developing novel biomarkers for DIKI that can be used earlier in drug discovery and development.

Connor, Skylar (ORCID:0000000233479180)↗
DOE OSTI2022

Extrapolation of Efficacy from Adults to Pediatric Patients of Drugs for Treatment of Partial Onset Seizures: A Regulatory Perspective

The US Food and Drug Administration (FDA) has concluded that the efficacy of drugs approved for the treatment of partial onset seizures (POS) in adults can be extrapolated to pediatric patients 1 month of age and above and that independent efficacy trials in this pediatric population are no longer needed. This paper focuses on the dosing, pharmacokinetic (PK), exposure‐response, and clinical information that were leveraged from the approved drugs for the treatment of POS to conduct analyses that supported extrapolation of efficacy in pediatric patients. Clinical data from trials for eight drugs (levetiracetam, oxcarbazepine, topiramate, lamotrigine, gabapentin, perampanel, tiagabine, and vigabatrin) approved in both adults and pediatric patients for the treatment of POS were analyzed. Comparisons of exposures at approved doses, placebo response, and model‐based exposure‐response relationships were performed. Based on disease similarity, similar response to intervention, and similar exposure‐response relationships in adults and pediatric patients, it was concluded that extrapolation of efficacy in pediatric patients aged 1 month and above is acceptable. PK analysis to determine pediatric dose and regimens that provide drug exposure similar to that known to be effective in adult patients with POS will be required, along with long‐term open‐label safety data in pediatric patients.

Pharmacology & Pharmacy↗
DOE OSTI2025

Emerging Tools to Support DILI Assessment in Clinical Trials with Abnormal Baseline Serum Liver Tests or Pre-existing Liver Diseases

Abstract Based on the late Dr. Hyman Zimmerman’s observation that hepatocellular drug-induced liver injury (DILI) leading to jaundice carries a ≥ 10% fatality risk (coined as Hy’s law by others), evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) continues to play a central role in the assessment of a study drug’s liability for acute hepatocellular DILI. The eDISH identifies drugs in clinical trials with DILI fatality (death or transplant) risk that may be unacceptable in a post-market setting. As a two-dimensional graph that plots peak total bilirubin (TB) versus peak serum aminotransferase levels for each patient during study drug or comparator treatment, eDISH identifies potential cases of acute, modest, and serious hepatocellular DILI for in-depth analysis of liver tests (LT) and clinical course so that the likelihood of causal association with the study drug can be determined. Unfortunately, the generalizable utility of this tool only pertains to trials enrolling patients with normal or near normal (NNN) baseline (BL) serum LTs. The eDISH does not necessarily apply to trials of patients with abnormal baseline (ABN-BL) LTs that often coincide with underlying liver disorders. Because drug development programs being reviewed by the FDA increasingly target liver disorders, we are often challenged to evaluate DILI risk in trials of patients with ABN-BL LTs. Also, the high background prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) means patients with LTs above NNN may need to be enrolled in trials treating non-liver disorders to reflect the target population. Such study populations create challenges for industry and regulators because eDISH may not reliably categorize or identify potential cases of DILI for further analysis, as it so efficiently does in NNN-BL trials. We describe the main functionalities of eDISH in NNN-BL trials to understand what should be emulated by new tools or eDISH modifications. We then discuss non-eDISH–based plots that may be useful in ABN-BL trials.

Amirzadegan, Jasmine↗
DOE OSTI2024

Exploration of a Potential DOOR Endpoint for Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs

Abstract Background Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). Methods Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator. Results DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Although infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar. Conclusions Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design.

Immunology↗
DOE OSTI2024

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

While many researchers can design knockdown and knockout methodologies to remove a gene product, this is mainly untrue for new chemical inhibitor designs that empower multifunctional DNA Damage Response (DDR) networks. Here, we present a robust Goldilocks (GL) computational discovery protocol to efficiently innovate inhibitor tools and preclinical drug candidates for cellular and structural biologists without requiring extensive virtual screen (VS) and chemical synthesis expertise. By computationally targeting DDR replication and repair proteins, we exemplify the identification of DDR target sites and compounds to probe cancer biology. Our GL pipeline integrates experimental and predicted structures to efficiently discover leads, allowing early-structure and early-testing (ESET) experiments by many laboratories. By employing an efficient VS protocol to examine protein-protein interfaces (PPIs) and allosteric interactions, we identify ligand binding sites beyond active sites, leveraging in silico advances for molecular docking and modeling to screen PPIs and multiple targets. A diverse 3,174 compound ESET library combines Diamond Light Source DSI-poised, Protein Data Bank fragments, and FDA-approved drugs to span relevant chemotypes and facilitate downstream hit evaluation efficiency for academic laboratories. Two VS per library and multiple ranked ligand binding poses enable target testing for several DDR targets. This GL library and protocol can thus strategically probe multiple DDR network targets and identify readily available compounds for early structural and activity testing to overcome bottlenecks that can limit timely breakthrough drug discoveries. By testing accessible compounds to dissect multi-functional DDRs and suggesting inhibitor mechanisms from initial docking, the GL approach may enable more groups to help accelerate discovery, suggest new sites and compounds for challenging targets including emerging biothreats and advance cancer biology for future precision medicine clinical trials.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Clinical pharmacology information in regulatory submissions and labeling: A comparative analysis of orphan and non-orphan drugs approved by the FDA

Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non-orphan drugs, were analyzed for recommendations and information available related to food–drug interaction, drug–drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non-orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non-orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non-orphan drugs were established; with most difference observed for drug–drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non-orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non-orphan drugs.

60 APPLIED LIFE SCIENCES↗