A review of criteria strictness in "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials".

To assess safety in vaccine development, stricter grading scales, such as the "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials" issued by the U.S. Food and Drug Administration (FDA grading scale), are required. However, concern exists that their strictness may lead to an overestimation of some adverse events (AEs). We analyzed the details of AEs in a phase I clinical trial of a preventive vaccine for infectious diseases. In this trial, we observed the high occurrence of Grade 1 or greater AEs in hemoglobin changes from baseline value, and hypernatremia, and hypokalemia by FDA grading scale. The range considered as non-AE according to the FDA grading scale shifted or became narrower when compared to reference intervals, especially for a Japanese cohort. For sodium grading, the criterion for hypernatremia was around 2 to mEq/L lower than the upper limit of most standards in several countries. Also, the criterion for hypokalemia was around 0.2 mEq/L higher than the lower limit of most standards. Regarding a decrease in hemoglobin from baseline, the criterion of "any decrease" used for a Grade 1 AE was too strict and we suggest this be omitted. Upper and lower limits of AE criteria for sodium and potassium should be equal to, or 10-20% above, the reference interval consistent with other toxicities determined by laboratory tests. Consideration should be given to the issues surrounding the criteria that determine AEs before conducting clinical trials.