Bioequivalence and Bioavailability Forum

Hello all,

as per guideline ICH M12 Drug Interaction Studies in Section 5.3 Interpreting DDI Study Results and subsection 5.3.1 Determination of No-Effect Boundaries it says that (my emphases):
"The results of a DDI study should be interpreted based on the no-effect boundaries for the substrate drug. No effect-boundaries represent the interval within which a change in systemic exposure measure is considered not significant enough to warrant clinical action (e.g., avoiding coadministration, dose or schedule adjustment, or additional therapeutic monitoring).
It is preferable for no-effect boundaries to be developed based on exposure-response relationships derived from clinical trial results, as well as other relevant information for the substrate drug (e.g., safety data and the maximum-tolerated dose). A good understanding of exposure-response relationships for desirable and undesirable drug effects, as well as knowledge of the variability of exposures in the indicated population, facilitates data interpretation. In the absence of a defined exposure-response relationship, the totality of evidence should be considered when determining the clinical impact of a DDI. Sometimes, a 90% confidence interval of 80%-125% is proposed as a default no-effect boundary. This is in general an acceptable approach but is considered overly conservative for most drugs, where small changes in exposure are unlikely to be of clinical consequence.
In general, the point estimate for the ratio between the exposure of the substrate with and without the precipitant can be used to describe the magnitude of the interaction and to determine whether interventions such as dose adjustments should be considered. Sponsors should also consider the variability of the interaction. The number of subjects included in the study should be sufficient to provide a reliable estimate of the magnitude and variability of the interaction (See ICH M12 Questions and Answers Document)."

My question is: has anyone ever submitted a DDI study where the acceptance criterion was that only the point estimate (not the confidence interval) needed to fall within a predefined no-effect boundary, and that this boundary was wider than the conventional 80-125% range? If so, was this approach accepted by the regulatory agencies? Did the submission include any additional justifications, such as PK/PD relationship?

Regards
BEQool