Last June , the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) published a harmonized draft drug-drug interaction (DDI) guideline (ICH M12), providing recommendations for in vitro and in vivo DDI studies for new medicinal products (read more about DDIs in this blog post). After being made available for public consultation globally until November 2022, the document is now being reviewed and potentially updated. The guideline is generally relevant to small molecule drugs, but some consideration is also given to therapeutic proteins and antibody-drug conjugates (ADCs). The document is not as comprehensive as some of the regional guidelines, such as the EU one, which also considers food effects, DDIs with herbal medicines and absorption-related DDIs including pH-mediated ones. Thus, regional guideline(s) remain valid and will still need to be consulted for topics such as the aforementioned ones.
The ICH M12 remains a draft guideline. Although it reflects the current regulatory thinking, it is not likely to be enforced or fully implemented until its finalisation and adoption by regional agencies, which is likely to occur in 2024. Despite this, the ICH M12 indicates how the data-driven requirements for in vitro and in vivo DDI studies are likely to change and as such should be used as a reference point from here on, especially as there are likely to be minimal changes to the guideline during the revision process.
Time to review and update your DDI packages!
We recommend a review of all available in vitro (and in vivo) DDI data with “fresh eyes” and perspective.
- Do your in vitro studies fulfil the requirements of the ICH M12 guideline?
- After implementation of the ICH M12 guideline, will a negative DDI risk remain so or be considered positive or inconclusive? Or will your planned in vivo DDI study no longer be required as your assumed positive in vitro signal is now considered negative?
- Are the upcoming changes already factored into your program timelines, or could the program be put on hold next year due to lack of relevant in vitro data?
For some scenarios, the draft guideline has less strict criteria (cutoffs, R-values) i.e. for when an in vitro signal is considered to be relevant in vivo. For example, a positive in vitro signal previously identified for a time-dependent-inhibitor (TDI) may now lose its in vivo relevance. However, the requirements for in vitro studies may have intensified; for example, % recoveries which reflect the reliability of the study. Thus, take a closer look at the draft ICH M12 DDI guideline to determine whether your in vitro data or planned studies will reach the desired standard!
Proposed changes in the ICH guideline
The DDI guideline is detailed. Hence, we have provided an overview of the key changes below and a summary in the table for quick reference.
Timing: The availability of data to inform DDI decision making during development is key. Timing is of the essence! Whilst generation of in vitro metabolism data including reaction phenotyping, assessment of perpetrator effect, and conduct of the mass balance study remains as before, DDI assessment of metabolites can now be conducted downstream in drug development.
Risk assessment: In the “in vitro” section of the guideline, less strict criteria may be used to indicate when a perpetrator signal is positive. The “cutoffs” are to a significant extent, data driven and based on current knowledge. The expectation is that they will be informed by high quality in vitro data. Hence, recommendations on in vitro study design and data interpretation are discussed in detail in the guideline.
Table: Summary of key changes in ICH M12 guideline
| In vitro studies | |
| Topic/Investigation | New in draft ICH M12 |
| General Principles (Timing) |
|
| Substrate of Metabolizing Enzymes |
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| CYP Reversible Inhibition |
|
| CYP450 Time-dependent Inhibition (TDI) |
|
| UGT Inhibition |
|
| CYP Induction |
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| Substrate of Transporters |
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| Transporter Inhibition |
|
| DDI of Metabolites |
|
| Assay Conditions |
|
| In vivo studies | |
| General Principles (Timing) |
|
| In vivo studies |
|
In conclusion, although the ICH M12 guideline is a draft, you should plan for its finalization and implementation. Are your DDI data ready for prime time?
If you’d like to read more of our thoughts on regulatory expectations and modeling & simulation approaches for assessing DDIs for therapeutic proteins, please read this white paper.
