PreS/MD: Predictor of Sensitization hazard for chemical substances released from Medical Devices

Abstract In the United States, a pre-market regulatory submission for any medical device that comes into contact with either a patient or the clinical practitioner must include an adequate toxicity evaluation of chemical substances that can be released from the device during its intended use. These substances, also referred to as extractables and leachables, must be evaluated for their potential to induce sensitization/allergenicity, which traditionally has been done in animal assays such as the guinea pig maximization test (GPMT). However, advances in basic and applied science are continuously presenting opportunities to employ New Approach Methodologies (NAMs), including computational methods which, when qualified, could replace animal testing methods to support regulatory submissions. Herein, we developed a new computational tool for rapid and accurate prediction of the GPMT outcome that we have named PreS/MD (Predictor of Sensitization for Medical Devices). To enable model development, we (i) collected, curated, and integrated the largest publicly available dataset for GPMT results; (ii) succeeded in developing externally predictive (balanced accuracy of 70-74% as evaluated by both 5-fold external cross-validation and testing of novel compounds) Quantitative Structure-Activity Relationships (QSAR) models for GPMT using machine learning algorithms, including Deep Learning; and (iii) developed a publicly accessible web portal integrating PreS/MD models that can predict GPMT outcomes for any molecule of interest. We expect that PreS/MD will be used by both industry and regulatory scientists in medical device safety assessments and help replace, reduce, or refine the use of animals in toxicity testing. PreS/MD is freely available at https://presmd.mml.unc.edu/.