From Paper to Practice: The First Year of ICH M12

In May 2024, the ICH released the final version of their M12 guidelines for Drug Interaction Studies¹, after a multi-step development process including publishing a draft version and a public consultation phase. The aim of this new regulatory guidance was to harmonize drug-drug interaction (DDI) assessment requirements internationally and supersede the various regional guidelines previously in place. The M12 guidelines were adopted by the FDA in August 2024, replacing the agency’s DDI guidance published in 2020. In several other regions, including the EU (EMA), Japan (PMDA) and China (NMPA), the new guidelines came into effect at the end of 2024.

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The changes in this new M12 guidance compared to its major regional predecessors have been extensively discussed, as explained in our webinar. The rationale behind these changes, however, has been subject to speculation, including some comments submitted during the public consultation phase.

The Expert Working Group authoring the guidelines recently published a follow-up paper² where several of these changes are explained in detail. Overall, the team confirms that the primary objective of the guidelines remains to minimize the chance of false-negative predictions of DDI, although reducing the false-positive rate is also a key aim, as it allows eliminating unnecessary clinical studies. Our Regulatory DDI page contains the list of in vitro metabolic enzyme interaction and transporter assays required by the ICH M12.

For enzyme- and transporter-mediated DDI assessment, the ICH M12 provide clear recommendations for most aspects of in vitro and clinical studies; however, there are areas of DDI assessment not fully covered in the new guidelines, requiring further discussion. The long-term implications of the changes introduced in the M12; on DDI studies in general and on certain broader areas of DMPK studies are also yet to be understood.

This article highlights several key areas where lively, industry-wide discussion has arisen around the contents, scope, and limitations of the ICH M12, illustrating how its impact goes beyond "traditional" DDI assessment.

Beyond M12: Insights from the EMA Implementation Strategy

At the same time of adopting the ICH M12, the EMA released its official implementation strategy for the new guidelines³. The document addresses differences in scope between the 2013 EMA DDI guidance previously in use and the new harmonized version. It highlights areas not covered by the M12 where new regulatory documents may need to be prepared, which include:

• Food effect
• Contraceptives
• Enterohepatic circulation
• Complex binding
• Mass balance studies
• Interactions affecting solubility
• Drugs modulating gastrointestinal motility or gastric emptying
• Displacement from protein binding
• Special populations, paediatric in particular
• Translation into SmPC
• Herbal products

For these areas, their respective sections of the existing EMA Guideline on drug interaction studies will continue to apply until they are replaced by a new specific EMA guidance for each area.

The first in the series of new documents in development is a Guideline on the investigation of drug interactions in the gastrointestinal tract, with a concept paper⁴ published in April 2025. The document focuses on gastrointestinal drug interactions not mediated by enzymes or transporters, including:

• Food effect for new, orally administered medicines
• Interactions affecting solubility caused by complex formation changes in gastric pH or excipients
• Interactions impairing enterohepatic circulation,
• Interactions affecting gastric emptying and gastrointestinal motility.

While the FDA has not explicitly expressed such intent for gap-filling, they have already published guidelines or draft documents for several areas also listed by the EMA, including:

• Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations⁵
• Clinical Drug Interaction Studies With Combined Oral Contraceptives Guidance for Industry⁶
• Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies⁷
• Evaluation of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications Guidance for Industry⁸
• General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products (draft)⁹
• Drug Interaction Information in Human Prescription Drug and Biological Product Labeling (draft)¹⁰
• Botanical Drug Development Guidance for Industry¹¹

Additionally, the ICH is also developing and applying further harmonized guidelines, including:

• ICH M10 for bioanalytical method validation¹²
• ICH M15 draft guidelines for model-informed drug development¹³
• ICH E11A on pediatric extrapolation¹⁴

Paradigm Shift in Bioanalytical Applications

A seemingly small but high-impact update in the ICH M12 is that its authors acknowledge recent developments in bioanalytical sensitivity and allow the use of experimentally determined unbound fraction (f_u or f_u,p in plasma) data even if plasma protein binding (PPB) is > 99%. Previously for such compounds, 1% unbound fraction was assumed, which often led to overestimation of DDI risk and thus unnecessary follow-up studies. This more lenient approach may significantly reduce the occurrence of such false positives.

For experimentally determined PPB/f_u data to be admissible, the guidelines call for the demonstration of the "accuracy and precision" of the analytical method used. This entails, on the one hand, appropriate experimental setup and controls, and on the other hand, precision and accuracy of the bioanalytical method at the required sensitivity range. As an example of such accuracy, the example of "Calibration standards and Quality Controls at 15%; Lower Limit of Quantification at 20%" is provided. This example mirrors criteria from the ICH M10 guidelines for bioanalytical validation¹², although the level of rigor prescribed in this document is not required for in vitro studies (even if they are intended for regulatory submission).

The European Bioanalysis Forum (EBF) highlighted this ambiguity of the ICH M12, seemingly offering more lenience toward flexibly adapted methods for in vitro sample analysis while evoking (albeit subtly) a more strict ICH M10. In a passionate paper released after their most recent workshop¹⁵, EBF members call for the adoption of a "context of use" (CoU) approach for bioanalytical method validation over maximum rigor in all cases. The latter, they argue, may lead to an extent of rigidity in planning that can hinder progress, especially at the earlier stages of drug development, and could lead to unnecessary animal use.

While the interpretation of ICH M12 analytical criteria may pose a case-by-case challenge, it is precisely within this context that CoU-based practices may be proven especially valuable. As DDI data is often generated at multiple phases of drug development, depending on the context and intended use of these results, at every stage, a bioanalytical approach can be applied that is fit to support this purpose. One of the major challenges bioanalysts face in the application of ICH M12 is determining what qualifies as a "validated assay" for in vitro studies and how compliance may be achieved while avoiding over-validation. This may bring about a paradigm shift in how we apply bioanalysis and analytical validation at different stages along drug development, as stricter is not always better.

New Modalities: Out of Scope but Not Out of Sight

How the ICH M12 guidelines cover or do not cover drug modalities beyond small molecules has sparked widespread discussions, and the topic received several comments in the public consultation phase of the guidance development as well. The recent EWG publication reinforces that the main aim of the ICH M12 is to provide a framework for small molecule DDI assessment, aside from a few very specific examples:

• Proinflammatory cytokine-related mechanism,
• Antibody-drug conjugates (ADCs), with a focus on the small molecule component.

The range of new drug modalities in development and emerging new approaches goes significantly beyond these few examples, so drug developers were understandably awaiting guidance on how these new molecules should be assessed for drug interaction risk.

For many, however, the level of understanding, data generation, and industry-wide consensus necessary for developing long-lasting and sensible regulatory guidelines has not yet been achieved. As the M12 guidelines state: "The development and emergence of other modalities, such as oligonucleotides, small interfering ribose nucleic acids, and peptides, is acknowledged. However, these modalities are out of scope for this guideline. Where applicable, regional guidelines should be considered." These include, for example:

• FDA 2023 Drug-Drug Interaction Assessment for Therapeutic Proteins Guidance for Industry¹⁶
• FDA 2024 Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics¹⁷ 

For areas where regional guidelines have not yet been developed, papers published by dedicated expert working groups or IQ consortia can provide a good reference for risk assessment, study design, and industry best practices. Below are a few examples for strategic insight: 

• ADME and DMPK Considerations for the Discovery and Development of Antibody Drug Conjugates (ADCs)¹⁸
• Considerations and Recommendations for Assessment of Plasma Protein Binding and Drug–Drug Interactions for siRNA Therapeutics¹⁹
• Industry Perspective on Therapeutic Peptide Drug–Drug Interaction Assessments During Drug Development: A European Federation of Pharmaceutical Industries and Associations White Paper²⁰

Such collaborative industry-wide discussions can also ensure that proposed guidelines are being flexibly developed, responding to new developments and innovations in the rapidly evolving new modality landscape, which would not be possible within the confines of relatively conservative regulatory guidelines intended to stay relevant for years or decades.

While the lack of strict guidelines for DDI risk assessment for several new modalities may seem to introduce uncertainty in such development projects, it also means that through sharing experiences and best practices, we get to contribute to the development of cirteria that truly fit the purpose and context of these new drugs.

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