The process of drug discovery and early development occurs in a staged manner. It starts with considerable safety screening and potential efficacy assessment of new compounds. A blend of in vitro and in vivo models is used to assess the pharmacological action and toxicity of a drug, as well as its pharmacokinetics. Risk assessment in this phase utilizes several quantitative thresholds for evaluating toxicity in a tiered approach, such as the no observed adverse effect level (NOAEL), median lethal dose (LD50), half maximal inhibitory concentration (IC50), and effective concentration 50 (EC50). These thresholds are pivotal to inform important safety decision requirements for further testing in first-in-human (FIH) clinical trials. FIH trial is the first test in humans, marking a key checkpoint in the drug development process. These studies focus on safety, tolerability, pharmacokinetics, and pharmacodynamics, evaluating all these in dose-escalation frameworks of single ascending dose (SAD) and multiple ascending dose (MAD). The preclinical studies NOAEL, human equivalent dose (HED) and maximum recommended starting dose (MRSD) derivations provide baseline estimates for FIH dosing levels, which depend on a safe and effective dose to commence. These estimates come from allometric scaling and application of safety factors. In early-phase development, the concepts of minimal clinically important difference (MCID) or minimal important difference (MID) usually come into play in much later-stage trials due to their focus on patient-reported outcomes (PROs) and effectiveness measures. Nonetheless, incorporating MCID reasoning into first-in-human (FIH) studies can enhance dose selection and pharmacodynamic (PD) predictive models. When PD models detect validated clinical milestones early, forecasting which drug candidates to de-risk becomes more precise. This is crucial in oncology, where surrogate markers like tumor size reduction or progression-free survival (PFS) are often linked to established MCID thresholds. Organ-on-a-chip and 3D microtissues, such as human liver models, have advanced the in vitro to in vivo translation of toxicity thresholds into clinical relevance. These models help define important clinical thresholds for metrics such as drug-induced liver injury (DILI), which is critical in the safety evaluation of new drugs. While referred to as ROC curve analysis, predictive validity and optimization of sensitivity/specificity, reasoning similar to MCID estimation is employed, though often not labeled as such. In summary, early drug discovery and development steadily appreciates the necessity of defining MCIDs, as they build on concepts that surpass simple statistically significant thresholds. Implementing patient-centric principles such as MCID during preclinical and FIH stages represents a dramatic change toward more responsible and streamlined drug development frameworks.

The Role of Minimal Important Difference (MID) in Drug Development Process

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发表日期：

2025年

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István Fekete

摘要

The process of drug discovery and early development occurs in a staged manner. It starts with considerable safety screening and potential efficacy assessment of new compounds. A blend of in vitro and in vivo models is used to assess the pharmacological action and toxicity of a drug, as well as its pharmacokinetics. Risk assessment in this phase utilizes several quantitative thresholds for evaluating toxicity in a tiered approach, such as the no observed adverse effect level (NOAEL), median lethal dose (LD50), half maximal inhibitory concentration (IC50), and effective concentration 50 (EC50). These thresholds are pivotal to inform important safety decision requirements for further testing in first-in-human (FIH) clinical trials. FIH trial is the first test in humans, marking a key checkpoint in the drug development process. These studies focus on safety, tolerability, pharmacokinetics, and pharmacodynamics, evaluating all these in dose-escalation frameworks of single ascending dose (SAD) and multiple ascending dose (MAD). The preclinical studies NOAEL, human equivalent dose (HED) and maximum recommended starting dose (MRSD) derivations provide baseline estimates for FIH dosing levels, which depend on a safe and effective dose to commence. These estimates come from allometric scaling and application of safety factors. In early-phase development, the concepts of minimal clinically important difference (MCID) or minimal important difference (MID) usually come into play in much later-stage trials due to their focus on patient-reported outcomes (PROs) and effectiveness measures. Nonetheless, incorporating MCID reasoning into first-in-human (FIH) studies can enhance dose selection and pharmacodynamic (PD) predictive models. When PD models detect validated clinical milestones early, forecasting which drug candidates to de-risk becomes more precise. This is crucial in oncology, where surrogate markers like tumor size reduction or progression-free survival (PFS) are often linked to established MCID thresholds. Organ-on-a-chip and 3D microtissues, such as human liver models, have advanced the in vitro to in vivo translation of toxicity thresholds into clinical relevance. These models help define important clinical thresholds for metrics such as drug-induced liver injury (DILI), which is critical in the safety evaluation of new drugs. While referred to as ROC curve analysis, predictive validity and optimization of sensitivity/specificity, reasoning similar to MCID estimation is employed, though often not labeled as such. In summary, early drug discovery and development steadily appreciates the necessity of defining MCIDs, as they build on concepts that surpass simple statistically significant thresholds. Implementing patient-centric principles such as MCID during preclinical and FIH stages represents a dramatic change toward more responsible and streamlined drug development frameworks.