Science Pool

ICH M12 2024 vs EMA 2013 DDI Guidance. What’s New?


The new ICH M12 guideline on drug interaction studies provides a harmonised approach which is expected to be implemented by the major regulatory authorities including the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), and presumably replace their respective existing guidelines/guidance. In this blog, we explore the differences between the new ICH M12 guideline adopted in 2024 and the previous EMA guideline which came into effect in 2013. You may also be interested in our blog comparing the US FDA 2020 guidance to the ICH M12 2024 harmonised guideline (LEARN MORE). Our comparison of the Japanese PMDA 2018 guideline with the ICH M12 guideline will follow shortly.

Reaction Phenotyping

The new M12 ICH and the EMA guidelines are similar in terms of their recommendations. Both the ICH M12 and the EMA guideline have the same cut-off of ≥25% of total elimination for determining if the enzyme needs further investigation in a clinical study.

Enzyme Inhibition

For enzyme inhibition, both the ICH M12 and EMA 2013 guidelines recommend evaluating the main seven CYP isoforms for enzyme inhibition. For reversible inhibition, the cut-off for determining if a clinical study is required is the same in both guidelines using the basic model. However, for time dependent inhibition, 5x Cmax is used in the calculation in the ICH M12 whereas 1x Cmax was used in the EMA 2013 guideline, suggesting a more conservative approach is now being used in the new ICH M12 guidance. Furthermore, in the ICH M12, only a single cut-off is provided for time dependent inhibition whereas the EMA has cut-offs for intestinal enzymes for orally administered drugs as well as systemic enzymes. The EMA currently suggest drug interactions in the GI tract will be addressed with accompanying EMA documentation.

Both guidelines suggest evaluating UGT inhibition if one of the major elimination pathways of the investigational drug is direct glucuronidation, however, the ICH M12 references a larger panel of UGT isoforms including UGT1A1, UGT1A4, UGT1A9, UGT2B7 and UGT2B15 whereas the EMA 2013 references only UGT1A1 and UGT2B7.

Enzyme Induction

The ICH M12 and the EMA 2013 guidelines are similar in terms of CYP induction. The cut-offs for the basic fold-change method and the relative induction score (RIS) are the same. For the correlation method, the ICH M12 guideline gives better clarity on the cut-off value to be used compared to the EMA guideline. The ICH M12 provides clearer guidance on how to interpret the basic kinetic model whereas the EMA 2013 guideline incorporates the model into a mechanistic static equation.

Transporter Substrate Identification

Both guidelines recommend the same transporters are assessed. The method for testing and cut-offs for clinical assessment are very similar between the ICH M12 and EMA guidelines. However, once again the ICH M12 provides more clarity on interpretation of the results especially in the case of the uptake transporters.

Transporter Inhibition

For transporter inhibition, the EMA 2013 guideline recommends screening for OCT1 and BSEP inhibition in addition to the standard transporters recommended by the ICH M12. Although these transporters are not in the standard list for the ICH M12 guideline, it is suggested they may be assessed on a case-by-case basis with other transporters such as OATP2B1 and MRP2. The cut-off values also differ between the two guidelines with the EMA 2013 guideline tending to be more conservative for certain transporters. One final difference is that the ICH M12 recommend a pre-incubation with test article for transporters such as OATP1B1 and OATP1B3 whereas the EMA 2013 guideline does not refer to a pre-incubation as the scientific literature and consensus concerning this topic only started to appear later around 2017.


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