How Qualification of 3D Disease Models Cuts the Gordian Knot in Preclinical Drug Development

Preclinical research struggles with its predictive power for drug effects in patients. The clinical success of preclinically approved drug candidates ranges between 3% and 33%. Regardless of the approach, novel disease models and test methods need to prove their relevance and reliability for predicting drug effects in patients, which is usually achieved by method validation. Nevertheless, validating all models appears unrealistic due to the variety of diseases. Thus, novel concepts are needed to increase the quality of preclinical research.Herein, we introduce qualification as a minimal standard to establish the relevance of preclinical models and test methods. Qualification starts with prioritizing and translating scientific requirements into technical parameters by quality function deployment. Qualified models use authenticated cells, which resemble the corresponding cells in humans in morphology and drug target expression. Moreover, disease models differ from normal models in the expression of relevant biomarkers. As a result, qualified test methods can discriminate effects of treatment standards and the effects of weakly effective or ineffective substances. Observer-blind readout, adequate data documentation, dropout inclusion, and a priori power studies are as crucial as realistic dosage regimens for qualified approaches. Here, we showcase the implementation of qualification. Adjusting the level of model complexity and qualification to three defined phases of preclinical research assures the optimal level of certainty at each step.In conclusion, qualification strengthens the researchers' impact by defining basic requirements that novel approaches must fulfill while still allowing for scientific creativity. Qualification helps to improve the predictive power of preclinical research. Applied to human cell-based models, qualification reduces animal testing, since only effective drug candidates are subjected to final animal testing and subsequently to clinical trials.