FDA issued final guidance on Safety Testing of Drug Metabolites on 05 March 2020. The guidance provides recommendations to industry on when and how to identify and characterize drug metabolites should nonclinical toxicity need to be evaluated. The guidance supersedes FDA guidance published in 2016 and aligns FDA guidance with the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.
This guidance applies to small molecule nonbiologic drug products and does not apply to some cancer therapies.
Nonclinical evaluation of drug safety usually includes standard animal toxicology studies in which drug exposure is assessed. Drug plasma concentration and systemic exposure in the nonclinical studies are compared with systemic exposure in humans to assess potential risks and guide monitoring in clinical studies. In some cases, however, a drug’s metabolic profile in humans is significantly different than in the animals used during standard testing. For example, the metabolite may only be formed in humans or be present at higher levels in humans than in the animal species used in the toxicology testing with the parent drug. FDA calls such a metabolite a disproportionate drug metabolite. Standard nonclinical testing does little to evaluate the toxicity of these metabolites to humans. Therefore, these metabolites, especially those that present at greater than 10 percent of total drug-related exposure at the steady state, should be considered for safety assessment.
The guidance states that there are two general approaches sponsors can consider to assess the effect of the drug metabolite. The first approach is to identify an animal species that routinely forms the metabolite at levels equivalent to or greater than the human exposure and investigate the drug’s toxicity in that species. The second approach, if the first approach is not possible, is to synthesize the metabolite and directly administer it to the animal for further safety evaluation. FDA acknowledges the difficulties of synthesizing a specific metabolite and the complexities that accompany direct administration but reaffirms the importance of identifying and evaluating the potential toxicity of the drug metabolite to ensure clinical safety.
Sponsors should identify the metabolic profile of the drug at different stages of the drug development process using in vitro and in vivo methods. In vitro studies, which should generally be conducted before initiating clinical trials, can use liver microsomes, liver slices, or hepatocytes from animals and humans. Those results will either be confirmed or reveal quantitative and/or qualitative differences in metabolism across species by in vivo metabolism studies in nonclinical test species. The latter situation may pose safety concerns, so FDA recommends sponsors conduct in vivo metabolic evaluation in humans “as early as feasible.”
The guidance also discusses general considerations, such as drug indication and patient population, when designing a nonclinical study for a disproportionate drug metabolite and recommended studies, including genotoxicity, embryo-fetal development toxicity, and carcinogenicity studies, for assessing the safety of metabolites.
The guidance also mention if toxicity studies of a drug metabolite are warranted, sponsors should complete studies and provide study reports to the FDA before beginning large-scale clinical trials.
To optimize and expedite drug development for serious or life-threatening diseases other than cancer (e.g., amyotrophic lateral sclerosis, stroke, human immunodeficiency virus), the number and type of nonclinical studies for the drug metabolites can be modified on a case-by-case basis for those drugs with major beneficial therapeutic advances and for drugs for illnesses that lack an approved effective therapy.