Nonclinical abuse liability testing of new CNS-active drugs: Role of sex as a critical factor for drug scheduling

Abstract

All new drugs targeting or influencing the central nervous system (CNS) must be screened for Drug Abuse Liability (DAL) prior to license approval by the FDA. Drug discrimination, self-administration, and drug dependence potential study designs are three core behavioral assays proposed in the 2017 FDA Guidance to Industry on Abuse Liability Testing for submission to the agencies for review at the time of the NDA submission. There are no international or federal drug control agency requirements for which animal species to use and selection of the test parameters for the sex, strain, age, dose range, study duration, systemic drug exposure thresholds or positive comparators to use in the conduct of these studies. In pre-IND and pre-NDA discussions with sponsor representatives, it is the FDA that has placed the financial burden on the industry to conduct these studies in both sexes in, what appears to be, a direct conflict with the intent of the Animal Welfare Act (1996). There is no single drug-of-abuse that is self-administered exclusively by one sex and there are no differential schedule controls placed on any drug substance based on any sex- or gender-based pharmacokinetic parameter. These nonclinical assays used for drug control scheduling actions should be conducted in only one sex unless there is a strong indication that sex is an important factor in the therapeutic use of the new drug or the mechanism of action.