Regulatory Decision Summary for Gadovist

In support of this indication, the sponsor submitted one pivotal Phase I pharmacokinetics (PK) study to show similarity of PK parameters in children aged 0 to < 2 years as compared to older subjects using population PK modelling. Typically, in support of a new indication, an acceptable Phase III clinical study is required. However, given the study population [that is (i.e.), vulnerable children], and as per International Conference on Harmonisation (ICH) guideline E11, it is acceptable, for the same indication studied and approved in adults with a comparable outcome therapy, to extrapolate adult safety and efficacy data to children provided that PK parameters are also similar.

The early plasma concentrations at 20 and 30 minutes (C₂₀-C₃₀) are relevant for magnetic resonance imaging (MRI). As the C₂₀-C₃₀ was 24-30% lower in children < 2 years of age as compared to adults and older children, the efficacy conclusion was based on the totality of the evidence, i.e., PK data (primary efficacy) and qualitative evaluation of images (secondary). In the combined images (enhanced MRI + non-enhanced), the degree of contrast-enhancement was “good or excellent” in 93.2% of the subjects. Border delineation of the lesions/vessels was more often rated good and excellent (97.7%) in combined MRIs, as compared to unenhanced MRI (75.0%). Similar results were noted for lesion characterization. Therefore, even though the C₂₀-C₃₀ in children < 2 years of age was 24-30% lower than in adults, the quality of imaging with Gadovist-enhanced MRI provided acceptable evidence of efficacy for the proposed dose of 0.1 µmol/kg. The individual PK data showed differences in children < 2 months of age, as compared to adults, however, the area under the curve (AUC) was not significantly different.

The safety data was derived from the pivotal study [Number of patients (N) = 44], post-marketing data (1999-2014), an observational study, and a Phase IV safety study. In the pivotal study, there was only one case of drug-related adverse events (mild vomiting) and most adverse events (AEs) were mild to moderate, with no drug related serious AEs. Overall, this limited safety data in children less than 2 years of age showed no new or significant safety findings.

In the adult population, the most frequently reported treatment-related AEs were headache (1.5%), nausea (1.2%), and dizziness (0.5%).

Two non-clinical studies in juvenile animals were submitted with a finding of fully reversible increased number of microglia in the brain only at a high dose in the single-dose study, but not in the repeated-dose study. However, given the possible risk of gadolinium penetration through the immature blood brain barrier (BBB) in this population, especially after repeated exposure, it is difficult to conclude categorically on the clinical significance of such finding and on the effect of the contrast agent in term infants (or if the drug was to be used off-label in preterm infants). This possibility is probably remote as there are no known cases reported in this pediatric population, therefore, for now it is still acceptable given the benefit of the drug.

The major known risk associated with gadolinium (Gd)-based contrast agents is nephrogenic systemic fibrosis (NSF), however, no such findings were reported in juvenile animals studies, or in the pediatric clinical safety data. Even though some residual uncertainty remains on the long term safety related to NSF due to the immature renal function in very young children, these relative uncertainties are adequately addressed in the labelling at this time, and do not change the risk-to-benefit profile of Gadovist, which remains favourable in the pediatric population 0 to 23 months of age.