ICH M12 DRUG INTERACTION STUDIES

1. INTRODUCTION

1.1 Objective

This guideline provides recommendations to promote a consistent approach in designing,

conducting, and interpreting enzyme- or transporter-mediated in vitro and clinical drug-drug

interaction (DDI) studies during the development of a therapeutic product. A consistent approach

will reduce uncertainty for the pharmaceutical industry to meet the requirements of multiple

regulatory agencies and lead to more efficient utilization of resources. In addition, this approach

will lead to the effective and safe treatment for patients who take multiple medications.

1.2 Background

In clinical practice, patients are often prescribed more than one drug, which can result in a DDI.

Some patients, in particular fragile older patients or patients with serious or multiple health issues,

can be prescribed a large number of different drugs (i.e., polypharmacy). The occurrence of DDIs

is a common clinical problem that can increase the risk of adverse effects, sometimes leading to

hospital admissions. Alternatively, some DDIs can reduce or enhance efficacy of the treatment.

Hence, it is important to consider an investigational drug’s potential to interact with other drugs.

Regional guidelines for investigations of DDIs have been available for decades and have

undergone several updates as scientific progress has been made. In general, the proposed approach

to the evaluation of interaction potential of investigational drugs has been similar between regions,

but despite harmonization initiatives, some differences have remained. This ICH guideline aims

to harmonize recommendations for in vitro and clinical evaluation of DDIs.

This guideline provides general recommendations on how to evaluate the DDI potential of an

investigational drug. It is recognized that the DDI evaluation is generally tailored based on the

specific drug, intended patient population, and therapeutic context. Alternative approaches may be

acceptable if properly justified. The focus of the guideline is the development of new drugs, but if

new scientific information regarding the potential for DDIs is obtained after drug approval,

additional DDI evaluation should be considered.

1.3 Scope

The scope of the guideline is limited to pharmacokinetic interactions, with a focus on metabolic

enzyme- and transporter-mediated interactions. These aspects in general apply to the development

of small chemical molecules. DDI evaluation of biologics is covered briefly, with focus on

monoclonal antibodies and antibody-drug conjugates. Recommendations are provided on how to

investigate interactions mediated by inhibition or induction of enzymes or transporters, both in

vitro and in vivo (the terms ‘clinical’ and ‘in vivo’ are used interchangeably in this document), and

on how to translate the results to appropriate treatment recommendations. The guideline also

includes recommendations on how to address metabolite-mediated interactions. The use of modelbased data evaluations and DDI predictions are also covered. 

More details from:https://database.ich.org/sites/default/files/ICH_M12_Step4_Guideline_2024_0521_0.pdf

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