Gadolinium Retention as a Safety Signal: Experience of a Manufacturer

Abstract

Objectives: The purpose of this manuscript is to review the successive regulatory actions and decisions following the initial publication by Kanda and colleagues in 2014 regarding gadolinium retention in the human brain after multiple gadolinium-based contrast agents (GBCAs) administrations.

Materials and methods: Starting from 2014, the actions and decisions made by all regulatory authorities were collected and summarized region by region. Volumes of GBCA sales in 2018 per region and main countries are also presented as an indicator of patients' exposure to those products.

Results: All regulatory authorities agreed on the absence of evidence of any harmful effect of gadolinium retention in humans. However, based on the same amount of preclinical and clinical evidence available in adults and children, regulatory authorities used different approaches resulting in different actions and decisions regarding the labeling and market authorizations of GBCAs, as well as the specific actions requested to the manufacturers.

Conclusions: The manufacturers of GBCAs had to face different situations according to the countries, due to the different positions and expectations from regulatory agencies. They have adapted their responses to the different positions of the regulatory agencies and conducted specific preclinical and clinical investigations to provide the expected evidence. It is also their responsibility to continuously monitor the benefit-risk balance of the products and to propose risk minimization measures to the regulatory agencies.

FIGURE 1

Timelines of the EU referral procedures on GBCAs. LoQ indicates list of questions; AR, assessment report; EGM, expert group meeting; OE, oral explanation; PRAC, Pharmacovigilance Risk Assessment Committee; CHMP, Committee for Human Health and Medicinal Products; SC, Standing Committee; EC, European Commission.