In May 2024, the International Council of Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) published a final draft of the newly developed scientific guidance on drug-drug interaction (DDI) studies, ICH M12, that will be adopted by ICH-abiding regulatory agencies (FDA, EMA, Japan). Read on to discover what is new about this DDI guidance and how it affects your drug development program.

Background

A harmonized approach to assessing DDI is long overdue. Until now, regulatory guidance has been agency-specific with variations in recommendations and expectations. The US Food and Drug Administration (FDA) has two main DDI guidances, published in 2020, one for in vitro studies and one for clinical DDI studies. The European Medicines Agency (EMA) has their own guidance finalized in 2013 and so does Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), finalized in 2018. ICH M12 consolidates DDI recommendations from all three regulatory agencies, providing a consistent approach in designing, conducting, and interpreting in vitro and clinical DDI studies during the development of a therapeutic product in order to facilitate patient access to needed therapies and streamline global drug development.

Highlights

• ICH M12 is a comprehensive guidance on pharmacokinetic DDI, covering both in vitro and clinical DDI study recommendations and designs, with a focus on enzyme- and transporter-mediated interactions.
  • It also includes lists of recommended substrates and inhibitors for both in vitro and clinical DDI studies which is not included in the FDA guidances.
• Important timelines for when to conduct in vitro assays in relation to the clinical drug development program.
  • ICH M12 outlines which in vitro DDI studies/assessments should be available prior to initiation of each clinical phase.
  • There was minimal guidance on timing in the FDA guidances, more information was provided in the EMA guidance.
• The new guidance contains a discussion of DDI considerations for protein therapeutics, such as considering implications on P450 activity if cytokines are modulated and about studies appropriate for antibody-drug conjugates.
  • These are similar to that discussed in FDA’s therapeutic protein guidance but was not addressed in the FDA’s in vitro DDI guidance.
• Phase II glucuronidation enzymes got a special shoutout; in the FDA’s in vitro DDI guidance, there was minimal guidance on the evaluation of UDP-glucuronosyltransferase enzymes.
  • ICH M12 provides a detailed discussion of when to evaluate UDP-glucuronosyltransferase enzymes and a list of recommended substrates and inhibitors to use for in vitro and clinical studies.
• Clarity on when to evaluate metabolite DDI:
  • As a substrate: In ICH M12, considerations for evaluating DDI of metabolites is consolidated, as in FDA’s in vitro DDI guidance. The recommendation remains the same as in previous guidances: the metabolite’s role as a substrate for metabolic enzymes and transporters should be investigated if there is data suggesting changes in metabolite exposure may affect efficacy or safety. In vitro studies should also be conducted if the metabolite has in vivo pharmacological effects similar to or greater than the parent compound.
  • As an inhibitor: The metabolite’s ability to inhibit metabolism and transporters should be assessed if the AUC_metab ≥ 25 % of the AUC_parent and accounts for at least 10% of drug-related material in circulation (ie, considered a major metabolite per ICH M3). In vitro studies may not be needed if clinical DDI studies that can capture the DDI potential of the metabolite are planned. This change is more consistent with the approach in the EMA guidance.
  • As an inducer: Induction studies of the metabolite are typically not needed as they are evaluated in assays with the parent drug. If the metabolite is formed extra-hepatically, then in vitro evaluation of the metabolite is recommended using the same threshold as for inhibition. Previously, the FDA guidance did not specify assessment of metabolites as inducers.
• Clinical DDI recommendations in ICH M12 generally parallel FDA’s previous clinical DDI guidance. ICH M12 discusses various aspects of clinical DDI studies, including:
  • Study design (eg, standalone vs nested design, crossover vs parallel)
  • Study population (eg, healthy volunteers vs patients)
  • Dose and dose regimen of study drug (eg, timing of administration, co-medications)
  • Index substrates
  • Assessing influence of pharmacogenetics
  • Route of drug administration
  • Model-informed drug development approaches (eg, population PK models, mechanistic static)
  • Study reporting and interpretation
• ICH M12 also provides risk assessment and management considerations that are critical in the clinical development program.
  • Risk assessment should inform the use of DDI management strategies that will evaluate how clinically relevant concomitant use of the drugs leads to safety, effectiveness, or tolerability concerns compared to those present when the drugs are administered alone.

What This Means for Your Program

The ICH M12 guidance provides a one-stop shop for understanding how to evaluate DDIs during drug development. Make sure your drug development plan/program is in line with the latest recommendations: Are you evaluating the most appropriate P450 enzymes and transporters using the latest thresholds? Do your metabolites need to be evaluated for DDI? Is your DDI risk mitigation plan appropriate? How can the recommended approaches be leveraged to optimize your drug development program? How can you incorporate model-informed drug development into your clinical program with the relevant clinical DDI considerations? How do the recommendations in this guidance apply to your 505(b)(2) program? Our experts at Premier can help you identify what DDI approach your program needs to be up to date with regulatory expectations to achieve your corporate goals.

Authors: Mimi Huang and Isaac Asante