Are targeted contrast agents realistically going to reach the clinic? Recent regulatory experience with targeted MRI contrast agents

Abstract

Developments in the visualization of molecular events in vivo are progressing at an unprecedented rate, a characteristic of rapidly developing or emergent technologies. The need to target the molecular mechanisms of disease has been the driving force behind this rapid growth in knowledge whilst the bridging of disciplines, such as imaging science, chemistry and biology, in some cases with a good deal of entrepreneurship, has made such technological advances possible. At the vanguard is the field of targeted molecular imaging agents. Targeted molecular imaging agents are now used in biological, medical and pharmaceutical research where they are proving to be powerful tools in the investigation of experimental in vivo systems. It is almost taken for granted that these technologies will translate readily into clinical practice, providing unique molecular information on disease. But will targeted molecular contrast agents reach the clinic and deliver the benefits expected of them? Journals, conferences and societies are now dedicated to molecular imaging and targeted contrast agents. But to make an agent available to widespread clinical use requires regulatory approval from either the Food and Drug Administration (FDA) in the USA or the European Agency for the Evaluation of Medicinal Products (EMEA) in Europe. The main purpose of these agencies is to ensure that safe and efficacious agents reach the market while denying access to agents that do not meet these standards. In defining targeted molecular imaging agents I am specifically referring to agents that will be used widely in the clinic and be prescribed because of their role in guiding clinical management. This is quite different from how such agents are currently used in, for example, probing cell biology or validating drug targets. Positron emission tomography (PET) tracers are making an impact in drug development and are likely to increase in use, but the widespread translation of these techniques into the clinic is unlikely to occur. Also excluded are the niche applications such agents might have in the manner of in vitro biomarkers [1]. Nevertheless, the medical community has high expectations of targeted molecular imaging. Witness the investment by national, private and business institutions across Europe and the USA. But if targeted contrast agents are increasingly viewed as potentially important clinical biomarkers, the role and value of using these agents remains to be established, and in this commentary I discuss in brief whether there is a realistic prospect of this occurring. Clinically, molecular imaging has been successfully applied for several decades via radionuclide imaging and, more recently, via modalities such as magnetic resonance [2, 3] and ultrasound. To address whether targeted contrast agents will reach the clinic requires an understanding of the process behind the development of a contrast agent. A contrast agent, despite rarely being administered more than once, is a drug and is treated as such by regulatory authorities. Prior to approval for clinical use, a contrast agent would have been guided through the discovery and development phases by a biotechnology or large pharmaceutical company, often in collaboration with academia. The processes require the coordination and cooperation of multidisciplinary teams. The financial outlay in bringing a contrast agent from the laboratory to the clinic is in the order of $100–150 million. This is a small sum compared with a therapeutic drug whose development costs, depending on the manner in which the data are interpreted, are reported to be on the order of $800 million [4]. However, the time required to develop such a contrast agent is no less than a therapeutic; it takes at least 8–10 years to bring any drug to market. More importantly, diagnostic imaging agents are very unlikely to return the type of profits seen with therapeutic drugs [5]. It is difficult to imagine how The British Journal of Radiology, 79 (2006), 870–872