Consideration of Factors Affecting the Safety Index in Early Clinical Drug Development

In drug development, a safety index-the ratio of the highest exposure that does not induce toxicity to the exposure that exerts efficacy-is used to quantify the balance between the safety and efficacy of a test drug. Here, the phase 1 index (maximum area under the curve [AUC] in phase 1/therapeutic AUC) and no-observed-adverse-effect level (NOAEL) index (AUC at NOAEL/therapeutic AUC) of recently approved drugs in Japan were calculated and characterized by therapeutic areas and indications. A large variation within both indices was observed, with a median of 3.2 for the phase 1 index and 3.5 for the NOAEL index. Furthermore, the safety indices were affected by the therapeutic area, which might be attributed to the difference in unmet medical needs for certain diseases. This study provides a qualitative measure for interpreting the phase 1 index versus the NOAEL index and might help inform the decision-making process following phase 1 trials.