The US Food and Drug Administration (FDA) on Tuesday released revised guidance on recommendations to industry on when and how to identify and characterize drug metabolites whose nonclinical toxicity needs to be evaluated.

The revisions mean the new guidance supersedes guidance from February 2008. The guidance has been revised to be in alignment with ICH guidance, known as M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.

According to ICH, the recommendations in that 2010 guidance further harmonize the nonclinical safety studies to support the various stages of clinical development among the EU, Japan and the US.

The guidance represents the consensus that exists regarding the type and duration of nonclinical safety studies and their timing to support the conduct of human clinical trials and marketing authorization for pharmaceuticals.

FDA Guidance

Nonclinical evaluation of drug safety usually consists of standard animal toxicology studies, including assessment of drug exposure, primarily, according to FDA, parent drug plasma concentration.

Generally, drug plasma concentration and systemic exposure in the nonclinical studies are compared with systemic exposure in humans to assess the potential risks from nonclinical findings and guide monitoring in trials.

This testing paradigm “usually is sufficient” when the human metabolic profile is similar to at least one animal species used in nonclinical studies, FDA says, but metabolic profiles can vary across species, and “there are cases when clinically relevant metabolites have not been identified or adequately evaluated during nonclinical safety studies.

“It is not standard practice for drug metabolites to be evaluated separately in a cross-species safety assessment. As a result, their specific contribution to the overall toxicity of the parent drug has often remained unknown,” FDA says. “This lack of appreciation of the role of metabolites in drug toxicity may be partly because of the inadequate sensitivity of the analytical methods used to detect and characterize metabolites derived from the parent drug.”

FDA acknowledges that technological advances have improved the analytical capabilities to detect, identify and characterize metabolites and allow for a better understanding of the role metabolites play in drug safety assessment.

The agency also says it encourages the identification of any differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible in a drug’s development.

“The discovery of disproportionate drug metabolites late in drug development can potentially cause development and marketing delays. Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher levels in humans than in any of the animal test species should be considered for safety assessment. Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug-related exposure at steady state. The choice of a level of greater than 10 percent for characterization of drug metabolites reflects consistency with FDA and Environmental Protection Agency guidances.”