Drug-Drug Interactions: FDA Issues Guidance on Clinical, In Vitro Studies

Regulatory NewsRegulatory News | 23 January 2020 |  By 

The US Food and Drug Administration (FDA) on Thursday finalized two guidances providing recommendations to drugmakers on evaluating potential drug-drug interactions (DDIs) for new drugs through clinical and in vitro testing.
“Together, the two final guidances describe a systematic risk-based approach to evaluation and communication of DDIs,” FDA writes.
The two guidances finalize draft versions released in 2017 and have been revised to clarify their scope, provide additional considerations for conducting prospective studies and to explain “when DDI studies are needed for drugs identified as transporter substrates from in vitro studies.” Both guidances have been renamed from their draft versions to reflect an emphasis on investigating the cytochrome P450 (CYP) enzyme and transporter-mediated drug interactions.
FDA explains that DDIs are a critical factor in a drug’s overall benefit-risk profile and stresses that clinically relevant DDIs should be identified during drug development, known at the time of approval, included in labeling and monitored on an ongoing basis.
“The concomitant use of more than one medication in a patient is common. Unanticipated, unrecognized, or mismanaged DDIs are an important cause of morbidity and mortality associated with prescription drug use and have occasionally been the basis for withdrawal of approved drugs from the market. In some instances, understanding how to safely manage a DDI can allow approval of a drug that would otherwise have an unacceptable level of risk,” FDA writes.
In Vitro Drug Interaction Studies
FDA’s 43-page guidance on in vitro drug interaction studies discusses approaches to evaluate the DDI potential of investigational drugs and how those studies can inform clinical DDI studies down the road.
The guidance explains that “evaluating the DDI potential of an investigational new drug involves identifying the principal routes of the drug’s elimination; estimating the contribution of enzymes and transporters to the drug’s disposition; and characterizing the effect of the drug on enzymes and transporters.”
The results of in vitro DDI studies and pharmacokinetic (PK) data “provide mechanistic information that can inform the need for and proper design of potential future clinical studies.”
The guidance goes on to discuss approaches to evaluating metabolism-mediated and transporter-mediated drug interactions, as well as approaches to evaluate the DDI potential of metabolites.
Clinical Drug Interaction Studies
In the 24-page final guidance on clinical drug interaction studies, FDA explains when DDI studies should be conducted and provides recommendations for the design, conduct and interpretation of those studies.
Specifically, the guidance discusses different DDI study designs and considerations for prospective DDI studies, CYP-mediated interactions, transporter-mediated reactions and cocktail study approaches. The guidance also discusses other factors that could impact drug interactions, such as patient genetics, smoking and complex drug interactions.
Additionally, the guidance provides recommendations on what DDI information should be included in labeling and refers sponsors to four other relevant labeling guidances.
Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry
In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry
Federal Register Notice


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