Clinical Pharmacology Corner: FDA Announces Two New Draft DDI Guidances

FDA Announces Availability of Two Draft Guidances, “In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies” and “Clinical Drug Interaction Studies -- Study Design, Data Analysis, and Clinical Implications”

On October 25, 2017, the U.S. Food and Drug Administration (FDA) announced the availability of two drug-drug interaction (DDI) draft guidances for industry titled “In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies” (in vitro DDI guidance) and “Clinical Drug Interaction Studies -- Study Design, Data Analysis, and Clinical Implications” (clinical DDI guidance).  These two draft guidances describe a systematic, risk-based approach to the assessment of DDIs, and update and replace the one draft guidance for industry titled “Drug Interaction Studies -- Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations” issued February 21, 2012.  

Concomitant use of two or more medications in a patient is common and can lead to DDIs.  Unanticipated, unrecognized, or mismanaged DDIs are an important cause of morbidity and mortality associated with prescription drug use, therefore clinically relevant DDIs between an investigational drug and other drugs should be defined during drug development as part of an adequate assessment of the drug’s overall benefit/risk profile. These draft guidances are intended to help drug developers plan and evaluate studies to determine the DDI potential of an investigational drug product.  The primary focus of these draft guidances is DDIs related to metabolic pathways and transporter systems.

The in vitro DDI guidance focuses on in vitro experimental approaches for evaluating metabolizing enzyme- and transporter-based drug interaction potential, and how to extrapolate in vitro data to determine the need for clinical DDI studies. Considerations in the choice of in vitro experimental systems, key issues regarding in vitro experimental conditions, and a detailed explanation of model-based DDI prediction strategies (e.g. physiologically based pharmacokinetic modeling (PBPK)) are presented. If an in vitro assessment suggests that the sponsor should conduct a clinical DDI study, the sponsor should refer to the clinical DDI guidance that addresses the conduct and interpretation of clinical drug interaction studies.  The clinical DDI guidance focuses on clinical studies that evaluate the potential for DDIs which alter a drug’s pharmacokinetics by modulating the effects of drug metabolizing enzymes and transporters. It advises sponsors on the timing and design of the clinical studies, interpretation of the results, and options for managing DDIs in patients.

The “In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies” guidance is available at https://go.usa.gov/xngDs, and the “Clinical Drug Interaction Studies -- Study Design, Data Analysis, and Clinical Implications” guidance is available at https://go.usa.gov/xngDH.  Please refer to the guidances for more details.

FDA is publishing the two draft guidances to collect additional public comments.  You may submit your comments to this guidance by January 23, 2018 to the Docket No. FDA-2017-D-5961-0001 available athttps://www.regulations.gov. Your comments do make a difference and can impact the outcomes of FDA regulatory policy. Share your knowledge and experience, and make your voice count.

Read a CDER Conversation available at https://go.usa.gov/xngZV with Issam Zineh, Pharm.D., MPH, FCP, FCCP, Director of the Office of Clinical Pharmacology, on how drug interactions affect patients, and how the FDA addresses the issue.