EMA consults on ICH M12 guideline for drug-drug interaction studies

Regulatory NewsRegulatory News
| 25 July 2022 | By Jeff Craven 

The International Council for Harmonisation (ICH) has released a draft guideline with recommendations on designing, conducting and interpreting drug-drug interaction (DDI) studies involving interactions mediated by enzymes and/or transporters that occur in vitro during the development of an investigational therapeutic drug.
ICH’s draft M12 guideline, which was adopted by the European Medicines Agency’s Committee for Medicinal Products for Human Use and released for public consultation this week, is intended to bring together recommendations for in vitro and clinical evaluation of DDIs, which have been mostly similar across regions and updated as scientific progress has improved. The draft guideline provides general recommendations for DDI evaluation due to the many possible combinations of drugs, patient populations and therapeutic contexts, but also contains specific recommendations in well-established areas. EMA is accepting comments on the guideline through 21 November 2022.
“The occurrence of DDIs is a common clinical problem that can increase the risk of adverse events, sometimes leading to hospital admissions. Alternatively, some DDIs can reduce treatment efficacy,” the authors of the guideline wrote. “Hence, it is important to consider an investigational drug’s potential to interact with other drugs.”
General principles
Evaluation of whether an investigational drug causes a DDI (perpetrator drug) or is affected by other drugs (victim drug) is important, the authors wrote. An investigational drug that causes a DDI is often investigated through in vitro experiments to determine DDI mechanisms followed by clinical studies. Drugs that cause a DDI when interacting with an investigational drug should be evaluated in a clinical mass balance study to identify principal elimination routes of the drug.
“For quantitatively important elimination pathways, in vitro and clinical studies should be used to identify the main enzymes or transporter proteins involved in these pathways,” the authors explained. “The ability to predict interactions affecting the investigational drug is dependent on the identification of these proteins.”
In general, these studies should be conducted as early as possible in a stepwise approach to inform clinical studies with patients and ensure patient safety and limit restrictions of use of other medications in later trial phases, according to the guideline, but the timing of these non-clinical and clinical studies can vary. For example, in vitro data on the potential metabolic pathways and what enzymes an investigational drug uses to metabolize should be gathered before Phase 1 trials, while mass balance study data can be obtained before Phase 3 trials.
Entities involved in developing investigational drugs should also collect data on absorption, distribution, metabolism and excretion (ADME) properties to determine whether in vitro studies are needed. “If a drug has limited absorption or is expected to undergo significant active hepatic uptake, biliary excretion or active renal secretion as unchanged drug, the relevant transporters should be identified in vitro before initiating clinical studies in patients to avoid protocol restrictions,” the guideline states.
Types of in vitro evaluations, DDI clinical study types
Specifically, ICH details when stakeholders should conduct studies for situations where inhibition of cytochrome P450 (CYP) enzymes are reversible, when CYPs are inhibited intestinally, time-dependent inhibition of CYPs, CYP induction, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibition, organic anion transporting polypeptide (OATP)1B1 and OATP1B3 inhibition, OAT1/3, OCT2, and MATEs renal transporter inhibition, and the contribution of metabolites to inhibition and induction.
The guideline also describes the types of clinical DDI studies that can be conducted, such as standalone and nested studies, studies with index perpetrators and index substrates, concomitant drug use studies, and cocktail studies. ICH noted that use of the different clinical DDI studies is not mutually exclusive.
“Regulatory decision-making generally relies upon prospective studies specifically designed to evaluate the potential for DDIs,” the guideline states. “Retrospective evaluation of drug concentrations from studies not designed to evaluate DDIs rarely includes sufficient accuracy and precision to provide an adequate assessment. DDIs identified or ruled out using a retrospective analysis may need to be confirmed using a prospective evaluation.”
Pharmacogenetics, therapeutic protein DDIs
The M12 guideline also mentions how pharmacogenetic information can impact DDIs and the potential benefits of using prospective genotyping in DDI studies. Additionally, among polymorphisms in metabolizing enzymes that are poor metabolizers (PMs) with a well-defined PM phenotype such as CYP2D6 or CYP2C19, “exposure in PM is expected to be similar to the effect of a strong inhibitor of that pathway,” the authors noted.
Regarding therapeutic proteins, there is a lower risk for pharmacokinetic DDIs, and in vitro assays for small molecules are “generally not applicable for proteins.”
“When evaluating the potential for a DDI between monoclonal antibodies and small molecules or between monoclonal antibodies, the mechanisms of a potential DDI should be considered, taking into account the pharmacology and clearance of the monoclonal antibodies as well as any co-administered medications in the patient population,” the guideline states.
Reporting of data
Data analysis should be a cornerstone of reporting and interpreting clinical DDI results, according to the guideline. “A DDI study report should include and justify the study design and data analysis method based on what is known about the mechanism of the DDI and the PK properties of the perpetrator and victim drugs,” the authors wrote.
Entities creating these data analyses should determine no-effect boundaries with a focus in the interpretation on the boundaries of the drug as a victim. If the investigational drug is causing the DDI, a classification system can be used for CYPs to categorize the drug as being strong, moderate, or weak based on whether it is inhibiting or inducing an index CYP substrate.
The authors acknowledged that clinical testing of every drug combination is not possible. “When possible, results from DDI studies should be extrapolated to other drugs and clinical situations,” they wrote. “Results from DDI studies with index drugs generally represent the largest magnitude interaction by a specific mechanism and can be used to predict the magnitude of other interactions by the same mechanism.”
Risk management
DDI prevention and risk management involves considering exposure-response relationships, variability of observed data, concomitant drug use duration and timing, DDI mechanism, monitoring parameter availability, investigational or concomitant drug interruption and potential adverse outcomes compared with the clinical benefit.
“Risk assessment should inform the use of DDI management strategies,” the authors wrote. “A DDI is clinically relevant if concomitant use of the drugs leads to safety, effectiveness, or tolerability concerns greater than those present when the drugs are administered alone.”
ICH M12 on drug interaction studies


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