A general procedure to select calibration drugs for lab-specific validation and calibration of proarrhythmia risk prediction models: An illustrative example using the CiPA model
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INTRODUCTION: In response to the ongoing shift of the regulatory cardiac safety paradigm, a recent White Paper proposed general principles for developing and implementing proarrhythmia risk prediction models. These principles included development strategies to validate models, and implementation strategies to ensure a model developed by one lab can be used by other labs in a consistent manner in the presence of lab-to-lab experimental variability. While the development strategies were illustrated through the validation of the model under the Comprehensive In vitro Proarrhythmia Assay (CiPA), the implementation strategies have not been adopted yet. METHODS: The proposed implementation strategies were applied to the CiPA model by performing a sensitivity analysis to identify a subset of calibration drugs that were most critical in determining the classification thresholds for proarrhythmia risk prediction. RESULTS: The selected calibration drugs were able to recapitulate classification thresholds close to those calculated from the full list of CiPA drugs. Using an illustrative dataset it was shown that a new lab could use these calibration drugs to establish its own classification thresholds (lab-specific calibration), and verify that the model prediction accuracy in the new lab is comparable to that in the original lab where the model was developed (lab-specific validation). DISCUSSION: This work used the CiPA model as an example to illustrate how to adopt the proposed model implementation strategies to select calibration drugs and perform lab-specific calibration and lab-specific validation. Generic in nature, these strategies could be generally applied to different proarrhythmia risk prediction models using various experimental systems under the new paradigm.
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DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- A general procedure to select calibration drugs for lab-specific validation and calibration of proarrhythmia risk prediction models: An illustrative example using the CiPA model
- Date Crossref
- 01/09/2020
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Center for Drug Evaluation and Research pays non établi dans la noticeStructure de recherche
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Nanion (Germany) pays non établi dans la noticeEntreprise
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Charles River Laboratories (United States) pays non établi dans la noticeEntreprise
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Office of Clinical Pharmacology Division of Applied Regulatory Science pays non établi dans la noticeÉtablissement de santé
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CiPA LAB pays non établi dans la noticeStructure de recherche
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Nanion Technologies Munich pays non établi dans la noticeInstitution
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Nanion Technologies USA pays non établi dans la noticeInstitution
Center for Drug Evaluation and Research, Nanion (Germany) et Charles River Laboratories (United States), avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.