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The FDA has requested follow-up data… how do I fill in the gaps?

Because each new drug is unique in characteristics, such as chemical structure, mechanism of action, and physicochemical properties, there can never be one prescriptive preclinical path to properly evaluate all new chemical entities (NCEs).

While some components of an Investigational New Drug (IND) or Clinical Trial Application (CTA) data package submission to proceed past preclinical into Phase 1 trials are common and necessary for all or most small molecule drugs, the best way to access important information about how a drug will behave in a patient goes beyond ‘box checking’ standard studies. The FDA requires “pharmacological effects and mechanisms of action of the drug in animals, and information on the absorption, distribution, metabolism, and excretion of the drug.”[1] Investigators are expected to independently anticipate and respond to data showing metabolism pathways, drug-drug interaction (DDI) potential, and enzyme interactions in a way that gives insight to evaluating risk prior to human administration. The FDA has made especially clear the heightened focus on early and thorough DDI prediction in their most recent draft guidance update.[2] The associated activities may not be standard, so incorporating them into your preclinical development program demands careful consideration and scholarship.

Drug disposition encompasses absorption, distribution, metabolism, and excretion (ADME) and in conjunction with other pharmacokinetic information such as potential for DDI represent critical components of a drug’s overall disposition.

If you have received a request for more information, it may be time to reexamine DDI and ADME components of your data package and take a holistic approach to identifying areas of further investigation.

An example can be seen in a recent case study where a client proposed amending a clinical protocol to remove exclusion criteria for subjects receiving strong inhibitors or inducers of a P450 enzyme because the drug was almost entirely metabolized by conjugation with glucuronic acid in vivo (via UGT enzymes). The FDA did not agree to this proposal in large part because legacy in vitro reaction phenotyping data in human liver microsomes indicated that multiple P450 enzymes were involved in the metabolism. In consultation with SEKISUI XenoTech, the sponsor elected to provide additional in vitro data to the FDA. A study was designed with radiolabeled drug incubated in pooled cryopreserved human hepatocytes to provide definitive evidence that conjugation was the major pathway of metabolism and that drug-drug interactions with P450 inhibitors or inducers were unlikely.

Studies exploring transporter substrate/inhibition potential and drug-metabolizing enzyme induction and inhibitionplasma protein binding, and supporting mechanistic evaluations may all contribute valuable pieces to the puzzle. Ideally, including these into the preclinical development plan as robust and definitive studies can render data earlier in development, saving time and money by avoiding restrictive exclusion criteria in early clinical development, but some studies can also be performed later, concurrent with clinical trials.

Our experts have been working with drug developers for over 25 years and can provide you with the guidance necessary for planning your ADME and DDI studies to form a comprehensive profile. Instead of just handing you data and sending you on your way, our study directors and in-house experts put in the time and energy to ensure you understand the results of each in vitro or in vivo contracted study and, in some cases, can help plan next steps if necessary. We also have a pool of consultants available for package gap analysis to help you look for missing information or contextualize the information you do have to form a better understanding of metabolism and disposition.

View Our ADME and DDI Study Options
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[1] 21 CFR 312.23 (a)

About the Authors

Madison (Knapp) Esely-Kohlman received her BS from the University of Missouri – Columbia and is currently SEKISUI XenoTech’s Marketing Communication Specialist, developing scientific content that communicates the value and expertise of internal contract service and test system production teams. Madison joined SEKISUI XenoTech as the Scientific Communications Coordinator in 2019 after serving in similar positions at CropLife America, Bond Life Sciences Center and the University of Missouri CAFNR Office of Communications.

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