Defining “Best Practices” For Critical Endpoints In Preclinical Screening of New Chemical Entities For Ototoxicity Liability

Abstract

CitationReview ABSTRACT Introduction: Ototoxicity has been defined as the tendency of certain therapeutic agents and other chemical substances to cause functional impairments and cellular degeneration of the tissues of the inner ear resulting in hearing loss. Objectives: This review is intended to provide details of a standardized preclinical assessment for ototoxicity under the current US FDA guidance documents that represents "industry best practices" for new drug application review of all new chemical entities being developed for human use. Methods: A literature review was conducted to assimilate study strategies that represent "Industry Best Practices" for the conduct of preclinical ototoxicity evaluation for submission to regulatory drug approval agencies. Conclusion: We have proposed a systems-approach and protocol criteria for the valid and reliable assessment of auditory function that can be easily included as a screening tool for ototoxicity within the Tiered Structure of preclinical assays required for approval of any chemical entity targeted for human use.

Use of Zebrafish in Drug Discovery Toxicology

“…Drug-induced ototoxicity is often reversible but sometimes is not, leading to a severe impact on the quality of life for patients faced with no alternative treatment, as is with aminoglycosides for life-threatening infection and cisplatin for cancer . Screening for ototoxicity in mammalian preclinical models is very difficult, and given few regulatory requirements, this is rarely done . A zebrafish model for ototoxicity may fill this gap in preclinical safety testing.…”

“…239 Screening for ototoxicity in mammalian preclinical models is very difficult, and given few regulatory requirements, this is rarely done. 240 A zebrafish model for ototoxicity may fill this gap in preclinical safety testing. Zebrafish and human auditory systems most likely share an evolutionary origin with those of all vertebrates.…”

In silico prediction of drug‐induced ototoxicity using machine learning and deep learning methods

“…There are currently no systematic or regulatory requirements for any standard preclinical studies conducted of new molecular entities for ototoxic potential before drug approval. This was due in large part to that screening for ototoxicity in mammalian preclinical models is very difficult (Cassar et al., 2020; Gauvin et al., 2016; Khoza‐Shangase, 2017; Sukardi et al., 2011). The experimental methods, as well as ototoxicity monitoring protocols, have not been standardized, thus, final analyses are not always entirely dependable or generalizable (Cassar et al., 2020).…”

“…The experimental methods, as well as ototoxicity monitoring protocols, have not been standardized, thus, final analyses are not always entirely dependable or generalizable (Cassar et al., 2020). In fact, the US FDA published a notice adopting its own guidance titled, “Non‐clinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route: Guidance for Industry and Review Staff; Good Review Practice”, in which specifically gives details on preclinical toxicology screening for “otic” products which includes auditory brainstem response and cytocochleogram evaluations (Gauvin et al., 2016). In the past decades, several in vitro and in vivo approaches have been proposed for estimation of drug‐induced ototoxicity (Yorgason et al., 2011).…”

“…There are currently no systematic or regulatory requirements for any standard preclinical studies conducted of new molecular entities for ototoxic potential before drug approval. This was due in large part to that screening for ototoxicity in mammalian preclinical models is very difficult (Cassar et al, 2020;Gauvin et al, 2016; Khoza-Shangase, 2017;…”