***New Revision 2 FDA MIST guidance issued March 2020 - see Resources for direct link***

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Over the past two decades considerable industry and regulatory discussion has focused around the importance of drug metabolites as potential sources of drug toxicity. In 2008, the FDA published draft guidance on this issue entitled “Safety Testing Of Metabolites” with an updated guidance issued more recently in 2016 and 2020. Collectively, the issue of metabolite-mediated toxicity, and when it should be assessed, has become known as Metabolites in Safety Testing or MIST within the industry.

The principal recommendations of the FDA’s guidance regarding the concept of MIST guidance are:
 

+ To encourage the identification of differences in drug metabolism between animals used in nonclinical safety assessments and humans as early as possible during the drug development process

+ 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.The clearance pathways of a new molecule need to be defined in animal species used for safety assessment and ulitmately humans. These data are obtained using ADME studies. 

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If you have a human-specific [disproportionate] metabolite:

 

+Possible important human toxicities may be missed

+Requirement to synthesize human metabolite(s) in large quantities

+Expensive

+Time-consuming

+Additional toxicity testing

+Possible termination of drug if human-specific toxicity observed

+Metabolites can cause DDIs

+Delay to NDA

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The key to MIST

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What is your definitive Human data set? [Still] the human 14C AME study!

 

+ Therefore, knowing when to conduct this study is pivotal

+ Too early and your study design might not be optimal for your molecule

+ Too late and your NDA and/or licensing can be delayed

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An appropriate MIST strategy should be designed to inform you if your drug has a potential MIST issue (human-specific metabolism) and therefore if you should conduct the MIST-critical human 14C-AME study early: 

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