Masterarbeit

International Regulatory Lifecycle Management of Gadolinum-based Contrast Agents ***

Dr. Larissa Maier (2018)

Summary
Language: English
Since the introduction of Magnevist® in the late 1980s, gadolinium-based-contrast agents (GBCAs) have been used in millions of MRI examinations with a high benefit-to-risk ratio. But in 2008, a new finding raised concern in clinicians, patients, and health authorities: specific GBCAs have been linked to the occurrence of nephrogenic systemic fibrosis (NSF) in patients with severe renal insufficiency. Consequently, the Food and Drug Administration (FDA), followed by the European Medicines Agency (EMA), issued alerts concerning the use of GBCAs in patients with renal impairment, stratified the agents by risk, and contraindicated specific GBCAs in that patient population. New guidelines and practice recommendations were released by scientific organizations at that time to reduce the occurrence of NSF. These measures led to no new cases being reported in Europe and the United States.
In 2014, a report of a Japanese working group again drew attention of the scientific community to GBCAs: an enhanced MRI signal intensity was detected in deep brain tissues of patients with normal renal function who had received multiple doses of GBCAs. Further studies in humans and animals confirmed the observations associated with gadolinium deposition in certain tissues including dentatus nucleus (DN) and globus pallidus (GP) in the brain, even years after several administrations of GBCAs. These findings, and unknown clinical long-term effects in patients, gave rise to a suspension of four marketing authorizations of linear GBCAs in the European Union- specifically Magnevist®, Omniscan®, Optimark® and MultiHance®, whereas the Food and Drug Administration and other regulatory agencies required precautionary measures including changes to all GBCA labels, a thorough choice of GBCA agents, and an improved patient education.
Regulatory authorities have to ensure the availability of necessary pharmaceuticals and their efficacy, safety, and quality throughout the lifecycle. Other stakeholders, such as radiologists want an exact visualization of pathological structures in imaging for precise diagnosis. Patients want safe therapeutics, while contrast media manufacturers want to achieve a profit due to high development costs. Despite these different perspectives, a continuous assessment of GBCAs in regard to a benefit-risk-ratio is crucial for all stakeholders.
This thesis outlines the current knowledge, gives an overview of developments in contrast media and characterizes the differences of approvals and usages of GBCAs in the ICH region, Australia and New Zealand. Moreover, further necessary investigations and limitations are considered as well as their impact on contrast media manufacturers on an international level.
Pages: 96
Annexes: 2, Pages: 18