Gaps and challenges in nonclinical assessments of pharmaceuticals: An FDA/CDER perspective on considerations for development of new approach methodologies

Avila, Amy M.; Bebenek, Ilona; Mendrick, Donna L.; Peretz, Jackye; Yao, Jia; Brown, Paul C.

doi:10.1016/j.yrtph.2023.105345

Cited by 19 publications

(9 citation statements)

References 10 publications

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“…Therefore, the studies detailed herein aimed to evaluate the PhysioMimix™ T12 plate, a 28 commercially available flow-enabled transwell system. In this study, the platform was characterized with respect to its reproducibility, robustness, and human translational relevance as a flow-enabled model of the renal proximal tubule in several regulatory-focused contexts of use (Avila et al, 2023). These included testing of the effects of shear stress and RPTEC cell sources on barrier formation, directional transport of water and small molecules, and similarity to human kidney gene expression profiles.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of the physiological and transport functions of various sources of renal proximal tubule cells under static and fluidic conditions in PhysioMimix T12 platform

Sakolish,

Moyer,

Tsai

et al. 2025

Drug Metabolism and Disposition

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In vitro models that can faithfully replicate critical aspects of kidney tubule function such as directional drug transport are in high demand in pharmacology and toxicology. Accordingly, development and validation of new models is underway. The objective of this study was to characterize physiological and transport functions of various sources of human renal proximal tubule epithelial cells (RPTECs). We tested TERT1-immortalized RPTEC, including OAT1-, OCT2-or OAT3-overexpressing variants, and primary RPTECs. Cells were cultured on transwell membranes in static (24-well transwells) and fluidic (transwells in PhysioMimix™ T12 organ-onchip with 2 L/s flow) conditions. Barrier formation, transport, and gene expression were evaluated. We show that two commercially available primary RPTECs were not suitable for studies of directional transport on transwells because they formed a substandard barrier even though they exhibited higher expression of transporters, especially under flow. TERT1-parent, -OAT1 and -OAT3 cells formed robust barriers, but were unaffected by flow. TERT1-OAT1 cells exhibited inhibitable para-aminohippurate transport, it was enhanced by flow. However, efficient tenofovir secretion and perfluorooctanoic acid reabsorption by TERT1-OAT1 cells were not modulated by flow. Gene expression showed that TERT1 and TERT1-OAT1 cells were most correlated with human kidney than other cell lines, but that flow did not have noticeable effects.Overall, our data show that addition of flow to in vitro studies of the renal proximal tubule may afford benefits in some aspects of modeling kidney function, but that careful consideration of the impact such adaptations would have on the cost and throughput of the experiments is needed.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of the physiological and transport functions of various sources of renal proximal tubule cells under static and fluidic conditions in PhysioMimix T12 platform

Sakolish,

Moyer,

Tsai

et al. 2025

Drug Metabolism and Disposition

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“…These translational gaps have contributed to concerns that animal studies are leading us astray. A number of these predictive challenges were recently represented by Avila et al (2023) , which included several neurobehavioral gaps in our current approaches including the need for more standardization of safety pharmacology protocols, more quantitative and objective measures in core neurological screens, and improved prediction of human-relevant seizure risk. These translational challenges have several possible contributors.…”

Section: Problem Statementmentioning

confidence: 99%

Digitalization of toxicology: improving preclinical to clinical translation

Berridge,

Baran,

Kumar

et al. 2024

Front. Toxicol.

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Though the portfolio of medicines that are extending and improving the lives of patients continues to grow, drug discovery and development remains a challenging business on its best day. Safety liabilities are a significant contributor to development attrition where the costliest liabilities to both drug developers and patients emerge in late development or post-marketing. Animal studies are an important and influential contributor to the current drug discovery and development paradigm intending to provide evidence that a novel drug candidate can be used safely and effectively in human volunteers and patients. However, translational gaps—such as toxicity in patients not predicted by animal studies—have prompted efforts to improve their effectiveness, especially in safety assessment. More holistic monitoring and “digitalization” of animal studies has the potential to enrich study outcomes leading to datasets that are more computationally accessible, translationally relevant, replicable, and technically efficient. Continuous monitoring of animal behavior and physiology enables longitudinal assessment of drug effects, detection of effects during the animal’s sleep and wake cycles and the opportunity to detect health or welfare events earlier. Automated measures can also mitigate human biases and reduce subjectivity. Reinventing a conservative, standardized, and traditional paradigm like drug safety assessment requires the collaboration and contributions of a broad and multi-disciplinary stakeholder group. In this perspective, we review the current state of the field and discuss opportunities to improve current approaches by more fully leveraging the power of sensor technologies, artificial intelligence (AI), and animal behavior in a home cage environment.

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“…45 For each individual drug project, sponsors can put forward a sound scientific plan that might not contain all studies mentioned in the relevant ICH guideline but nonetheless addresses human risk-benefit. Within this, the use of NAMs is encouraged wherever possible as outlined in the FDA Modernization Act 2.0 46 with a thorough assessment of gaps and challenges, 47 and in the European Medicines Agency (EMA) workplan. 30…”

Section: Regulatory and Legal Barriersmentioning

confidence: 99%

New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption

Sewell,

Alexander-White,

Brescia

et al. 2024

Toxicology Research

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New approach methodologies (NAMs) can deliver improved chemical safety assessment through the provision of more protective and/or relevant models that have a reduced reliance on animals. Despite the widely acknowledged benefits offered by NAMs, there continue to be barriers that prevent or limit their application for decision-making in chemical safety assessment. These include barriers related to real and perceived scientific, technical, legislative and economic issues, as well as cultural and societal obstacles that may relate to inertia, familiarity, and comfort with established methods, and perceptions around regulatory expectations and acceptance. This article focuses on chemical safety science, exposure, hazard, and risk assessment, and explores the nature of these barriers and how they can be overcome to drive the wider exploitation and acceptance of NAMs. Short-, mid- and longer-term goals are outlined that embrace the opportunities provided by NAMs to deliver improved protection of human health and environmental security as part of a new paradigm that incorporates exposure science and a culture that promotes the use of protective toxicological risk assessments.

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Gaps and challenges in nonclinical assessments of pharmaceuticals: An FDA/CDER perspective on considerations for development of new approach methodologies

Cited by 19 publications

References 10 publications

Comparative analysis of the physiological and transport functions of various sources of renal proximal tubule cells under static and fluidic conditions in PhysioMimix T12 platform

Comparative analysis of the physiological and transport functions of various sources of renal proximal tubule cells under static and fluidic conditions in PhysioMimix T12 platform

Digitalization of toxicology: improving preclinical to clinical translation

New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption

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