Regulatory Decision Summary for Multihance

Health Canada considers that the benefits of Multihance outweigh the potential risks when used in adults for MRI of the breast for the detection of malignant lesions in patients where breast cancer is known or suspected on the basis of previous mammography or ultrasound results.

One pivotal Phase III, multicenter, double-blind, randomized, cross-over design clinical trial was submitted in support of this new indication. The objective of the Phase III clinical trial was to demonstrate superiority of a 0.1 mmol/kg dose of Multihance over a 0.1 mmol/kg dose of Magnevist for breast MRI in terms of sensitivity for the diagnosis of malignant lesions compared with histopathology. The superiority of Multihance over Magnevist in terms of sensitivity for detection of malignant lesions in subjects who underwent both exams (paired population) was demonstrated; for Multihance it ranged from 89.0% to 93.5%, which was significantly higher (p<0.0003) for all 3 blinded readers compared to Magnevist, for which the sensitivity ranged from 79.1% to 83.0%; therefore, the objective of the pivotal trial was met.

Numerically, more malignant lesions were detected with Multihance-enhanced MRI than with Magnevist-enhanced MRI for each type of cancer, i.e., invasive ductal carcinoma, invasive lobular carcinoma, non-invasive cancer, at lesion and region level for all 3 readers. Both the sensitivity and specificity were higher for Multihance as compared to Magnevist. Additionally, the number of both false negative and false positive results was higher with Magnevist than with Multihance.

The sensitivity, specificity and accuracy for detection of breast lesions with cancer was higher for Multihance-enhanced MRI than for mammography, ultrasound and mammography and ultrasound combined. Multihance-enhanced MRI of the breast outperformed all the other diagnostic modalities tested and comparator-enhanced MRI at lesion, region of the breast and patient level.

In terms of clinical utility, Multihance-enhanced MRI provided help in determining patient treatment for the majority of the patients in the efficacy population, mainly helping to determine the surgical approach. Multihance-enhanced MRI was preferred significantly more frequently over Magnevist-enhanced MRI (36.6% vs 16.3%). In particular, the number of patients needing potential changes in management was higher with Multihance-enhanced MRI compared to Magnevist-enhanced MRI, mammography, ultrasound or mammography and ultrasound combined.

The results of a Phase II dose-selection study demonstrated that there is a dose-dependent trend in diagnostic performance. The best diagnostic performance of Multihance-enhanced MRI was demonstrated with the highest dose 0.2 mmol/kg. Taking into consideration the lower risk of adverse events and demonstrated efficacy of Multihance at the lower dose of 0.1 mmol/kg compared to that of Magnevist at 0.1 mmol/kg in the pivotal clinical study, the 0.1 mmol/kg was considered acceptable for the proposed indication with a caveat that better performance of Multihance with the higher dose cannot be excluded.

No additional risks were identified in the pivotal study compared to the established safety profile, and the benefit-risk profile of Multihance remains favorable.