Updated Nov. 6th, 2017
The FDA has released its long-awaited new draft guidance for industry on drug-drug interaction (DDI) studies. There are two guidance documents, one for in vitro DDI studies, and the other for clinical DDI studies. The documents are available here, and industry comments are due Jan. 23, 2018. We have completed our initial review, focusing on in vitro DDI studies. There are several significant changes from the 2012 draft guidance, some of which we have been anticipating and including in our studies for some time now, including the following:
- CYP inhibition: Use validated analytical methods for the marker substrate. SEKISUI XenoTech has used validated LC-MS/MS methods for many years.
- Reaction phenotyping: Demonstrate specificity of chemical inhibitors under the conditions used in incubations (see SEKISUI XenoTech poster)
- CYP Induction: the endpoint can be mRNA or enzyme activity if the inhibition profile is known first. SEKISUI XenoTech has used both endpoints for many studies for many years.
- CYP induction: Evaluate CYP2C enzymes if CYP3A4 is induced. SEKISUI XenoTech has been recommending this approach for several years.
- CYP Induction: Include a clinically used negative control. SEKISUI XenoTech has been including a negative control for several years.
- Transporter studies: The addition of interaction studies with MATE1 and MATE2‑K. SEKISUI XenoTech has been recommending these transporters for most studies for several years.
- Transporter studies: keep organic solvent <1% (preferably <0.5%). SEKISUI XenoTech has been taking this approach for many years.
As the FDA’s previous draft DDI guidance was issued in 2012, stakeholders will need to adapt quickly to meet the FDA’s new expectations. Needed changes, however, cannot occur immediately. Relevant questions such as strategies to ensure utility of recently conducted studies on clinical-stage candidates are paramount. For candidates under development for which definitive in vitro DDI studies have already been performed, it is recommended to first perform a gap analysis with respect to the differences between the 2012 and 2017 draft FDA guidance documents. Based on the extent of the gaps and the stage of development (e.g., pre- or early-clinical), additional in vitro studies or re-interpretation of existing data may be needed for inclusion in upcoming new drug applications. For programs that are far along in clinical development, it may be possible to negotiate post-marketing requirements or commitments to address any gaps. Please contact us with questions pertaining to this topic.
We offer this late-breaking update to interested stakeholders in the candidate development field and will provide additional considerations and updates shortly:
Watch our Nov. 21st webinar “Essential Considerations on the New FDA In Vitro DDI Guidance (the What, the Why, and the Wow).”
Watch our Dec. 19th webinar “Comparison Between the New US FDA and Japan PMDA In Vitro DDI Guidance Documents: Are We Close to Harmonization?“
Download our convenient and informative Poster on the New US FDA and Japan PMDA In Vitro DDI Guidance Documents
Register here to receive more valuable insights as they become available.
View guidance documents and other resources here.
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