Regulatory Decision Summary for ProHance

Health Canada considers that the benefit-harm-uncertainty profile of ProHance (gadoteridol, 0.1 mmol/kg) is favourable for contrast-enhanced MRI of CNS (brain, spine and surrounding tissues) in pediatric subjects less than 2 years of age, including term neonates, in conditions with expected vascular abnormality or defective blood-brain barrier. ProHance is currently approved in Canada at the same dose regimen for contrast-enhanced MRI of CNS in adults and pediatric patients 2 to 18 years of age. ProHance is also indicated for contrast-enhanced MRI of extracranial and extraspinal head and neck pathology in adults.

The proposed indication is supported by the results from a Phase 3, retrospective study (Study PH-108) in 125 pediatric patients (1 day to 24 months of age) with known or highly suspected disease of the CNS (brain/spine) and who had undergone MRI examination with intravenously injected ProHance at a dose of 0.1 mmol/kg as part of their medical workup. The study was conducted at 5 sites in North America and Europe. Efficacy was prospectively evaluated, comparing blinded readings of pre-dose, post-dose, and paired (pre + post-dose) MR image sets. Three co-primary efficacy endpoints were used to reflect the level of lesion visualization (lesion border delineation, visualization lesion internal morphology and lesion contrast enhancement). Each lesion was assigned a grade on a 5-point scale from 0 to 4 for each endpoint, where a score of 0 means no visualization, 1 is poor, 2 is moderate, 3 is good, and 4 is excellent visualization.

The primary analysis based on lesions detected across all image sets demonstrated that paired visualizations were statistically and clinically significantly superior to visualizations without ProHance (p values <0.0001); mean improvements in visualization scores ranged from 0.8 to 1.1 for lesion border delineation, from 0.9 to 1.2 for visualization of lesion's internal morphology, and 0.9 to 1.1 for lesion contrast enhancement. The secondary analyses investigating lesion-level and patient-level changes supported the results of the primary analysis, demonstrating that paired and post-dose visualizations were significantly superior to visualizations without ProHance for all 3 co-primary visualization endpoints (p values <0.009 to <0.0001). Furthermore, key endpoints supportive of the primary and secondary efficacy outcomes showed statistical significance, including a significant increase in the number of lesions detected (mostly 1 extra lesion) and better visualization scores (60-70%) for paired versus pre-dose assessments, and significant improvements in contrast-to-noise ratio (CNR) (24.6 to 96.7) and lesion-to-brain ratio (LBR) (0.74 to 2.4) on post-dose image sets compared to pre-dose image sets for up to 3 largest lesions.

A Population (PoP)-Pharmacokinetic (PK) model was provided to support the proposed dosing regimen in the proposed population. The PoP-PK model allowed the PK parameters derived from the model to be extrapolated from existing PK data in subjects 2 years of age and older to subjects younger than 2 years, based on established principles for the changes in body weight and glomerular filtration rate (GFR)/creatinine clearance with age. The simulations demonstrated that using weight-based dosing for patients less than 2 years old, the gadoteridol exposures were expected to be approximately within the range of the exposure in adults and pediatric patients 2 to 18 years of age. Therefore, no dose adjustments are deemed necessary for the pediatric population less than 2 years of age.

The safety of ProHance in patients younger than 2 years of age was derived from the Sponsor’s clinical trial database, post-marketing surveillance database and the peer-reviewed literature. There was no change in the expected safety profile of ProHance based on cumulative results of safety evaluations from 3,174 subjects receiving ProHance in clinical trials, including 2,896 adults and 278 pediatric subjects aged 0 to 17 years. There were no deaths, serious adverse events (SAEs), or discontinuation due to an adverse event (AE) in the pediatric population. The identified or potential risks of ProHance in children under 2 years of age included 13 mild to moderate AEs related to changes in clinical laboratory parameters outside the normal range reported in 7 patients, which resolved without sequelae. All AEs across different age groups are adequately presented in the ProHance Product Monograph (PM).

The main class-specific risks associated with GBCAs are NSF and gadolinium brain deposition. The risks are considered particularly relevant for very young infants (less than 2 months of age) given the immaturity of renal clearance and blood-brain barrier. Based on the chemical structure of ProHance (macrocyclic), the risk of NSF and gadolinium deposition in the brain is less prominent than with linear GBCAs. Notably, there were no reported cases of NSF in pediatric subjects of any age in ProHance clinical trials, post-marketing data, and peer-reviewed literature, and although long-term retention of small quantities of administered gadolinium has been measured in adult human tissues, including the brain, no adverse neurological health effects have been associated with it. The Product Monograph is adequately labelled about these risks.

Overall, the anticipated benefits of an intravenous dose of 0.1 mmol/ kg ProHance in pediatric subjects <2 years of age, is expected to outweigh its risks under the conditions of use recommended in the ProHance Product Monograph at this time.