MR contrast agents reach
ne sunny day in late spring 1982, I stood on the public observatory
deck at the top of the Empire State Building in New York City with a visitor from Berlin in Germany. I recall being on crutches, my foot and ankle encased in a plaster cast, having stumbled awkwardly while walking on a Long Island beach. My visitor, Hanns-Joachim Weinmann, had traveled to New York to study a new chemical compound on our experimental MR machine. It came in a small vial directly from Berlin and was called Gd-DTPA. Gd stood for gadolinium, an element hardly any radiologist had ever heard of at that time. Today, gadolinium agents are well established, as if they had been with us forever.
The idea of using lanthanide compounds as contrast agents originated at State University of New York at Stony Brook, where I used to work. We knew that certain elements could shorten MRI relaxation times, so could they perhaps highlight certain tissues ? Researchers in Berlin quickly understood the theory of influencing relaxation times and the possible impact of MRI on radiology, despite the lack of any MRI system in Germany. Their high-risk gamble paid off .
In the end, we never tested the contents of the vial. The head of our university laboratory deemed that commercial cooperation was not desirable. As it subsequently turned out, the scientists at Schering had produced a compound with marginal acute toxicity and excellent contrast-enhancing properties. Schering's MR contrast agent Magnevist was launched in 1988. Guerbet followed some months later with Dotarem, Nycomed a little later with Omniscan, and then Squibb with ProHance.
Bracco's R&D department had something far better than all of the others: MultiHance, a compound with better relaxivity and higher contrast, enhancing both in the central nervous system and liver. But it took them far too long to bring this product to their customers. It came quite late to a market dominated by other products.
MR contrast agents are among the safest compounds in medical imaging, safer than x-ray contrast media. They have some common side effects ; severe side effects of at least one compound became publicly known only twenty years after their introduction . But what really makes these agents unsafe is ill-considered and careless use.
Indications for the original nonspecific gadolinium agents and reimbursement rules vary from country to country. Head and brain MR examinations are usually performed unenhanced and again after contrast injection so as not to miss any small metastases or leptomeningeal pathologies. Lesion characterization often requires a dynamic contrast series. This is particularly true when examining the liver and pancreas, though it is also the case for unclear soft-tissue masses. Most MR angiograms are performed following bolus injection as well.
Procedures and indications continue to be a subject for debate. Contrast-enhanced studies may show pathologies better than plain images or assist in diagnosis. Few will be truly decisive. But they facilitate treatment and mental comfort for patients and radiologists alike. The only clear and undisputed indication is breast MRI. Without a contrast agent, this examination is useless. With contrast, it is the best mammography technique we have.
"Contrast-enhanced studies facilitate treatment and mental comfort for patients and radiologists alike."
R&D associated with contrast agents suffers from the rapid, unpredictable development of imaging hardware and software. Eight to 12 years from idea to rollout is a long time. R&D has to be done conscientiously and thoroughly. Companies complain about the bureaucracy imposed by regulatory agencies, and their objections are partly justified, partly not. Many pencil pushers at many desks have to be fed – including those sitting in the companies themselves.
When all preclinical and clinical studies are finished and the paperwork is complete, the new compound can be submitted for approval in a European Union member state. If approved, as hoped, it may be mutually recognized by all other EU member states. Similar procedures are required for the U.S., Japan, and the rest of the world.
The contrast business can also involve infighting between companies. By this, I mean a patent war. Schering, for example, held a leading patent position for MR contrast. [Meanwhile, Schering does not exist any more; the company has been swallowed by another one.]
Contrast agents are drugs. They should be used only when necessary for the benefit of patients. Yet patent attorneys handle them as commodities. Some sales personnel have, unfortunately, done the same. A number of companies, their sales staff, and greedy radiologists have paid for this dearly. They were sentenced in court for buying and selling contrast agents like coffee or pork bellies, to the detriment of their patients. This has harmed their reputation and, by extension, the reputation of these agents.
Meanwhile we have seen many compounds come and go. Failures may be due to a bad product, incorrect marketing, absence of any market at all, an overconfident CEO, or developments in MR hardware and software that render the agent obsolete. The latter has an unpredictable impact on contrast development. New agents need several years from the first step of development to marketability. But if manufacturers suddenly adopt new technology that offers significant advantages over rival modalities and needs no contrast, the market for the new agent could collapse overnight.
Look Back, Move Forward?
The names of the original unspecific gadolinium agents may change and they may become available as generic drugs, but they will be with us for some time. Their concentration was determined empirically in the mid-1980s. Both tissue contrast and the relaxivity of contrast agents change independently of one another with field strength. These compounds were sufficiently good for low, midstrength and high-field MRI, though in hindsight, double concentration would have been appropriate. Adjusting the dose or concentration, or using a new class of agents with optimized relaxivity, would help improve contrast enhancement at these field strengths and hence aid diagnosis .
Concentration is also sufficient at ultrahigh-field strengths such as 3T, though standard contrast agents might not enhance properly at even higher field strengths. Particulate agents could work better for ultrahigh-field MRI.
The manufacturers' hardware branches want to sell ultrahigh-field machines because that is where the money is, both in sales and maintenance. Yet no synergy exists with the wishes of their brothers and sisters who are promoting contrast media. This is another nightmare for manufacturers, particularly those who have bought into contrast agent companies – and lost.
Some companies with a long-standing involvement in contrast agents seem to have learned from their mistakes of the past 20 years. The results are fairly cruel. Cuts have been made in research labs, and some big players have closed down their R&D facilities or disappeared from the scene altogether. Years ago, company executives were knowledgeable about their products, the pros and cons of agents, the diagnostic wishes of the medical community. Scientists, medical staff, management, and marketing personnel would all cooperate. Some companies today have a lack of trained researchers and – worse for customers and patients – few knowledgeable representatives. It is painful for customers to talk to clueless company managers who are untouched by medical reality.
"Greedy radiologists were sentenced in court for buying and selling contrast agents like coffee or pork bellies."
Every other year since 1988, the European Magnetic Resonance Forum (EMRF) arranges a conference on contrast agent research, mostly focusing on MRI and molecular imaging. The 14th meeting in this series took place in Valencia, Spain, in February 2013.
A fresh breeze was blowing from some of the university-based research groups; however, hardly any radiologist is involved. It seemed that we had returned to the times when contrast R&D was performed by a few academic groups, though without a link to economic reality and commercial concerns. Italy and Belgium excel in this area, with France, Germany, and the Netherlands following on. Research is aplenty in the U.S. as well.
We should return to the good old role of the radiologist; that is, trying to understand enough in many areas and combining this knowledge to deliver something useful. Regrettably, there is a problem. As a professor at one of the major Nordic university hospitals pointed out, young radiologists using contrast agents in their clinical routine have no background knowledge about how these agents function. They just ask technologists/radiographers to inject the agent according to agreed protocols and then read the images later.
So what does the future hold? Conventional demand for contrast agent R&D is focusing on "personalized" diagnosis. Fashionable "molecular imaging" is targeted at small patient groups, individual diagnosis, and, hopefully, treatment. Everybody, myself included, is fascinated by the possibilities molecular agents promise. Even some of the traditional hardware manufacturers are trying to move into molecular imaging on their own. The results of their involvement remain to be seen. Personalized contrast agents are economically and commercially difficult. They are not unfeasible, but there is no shareholder value. Today's megacompanies want and need blockbuster drugs.
Imaging is not only anatomy. The interaction between chemistry, physiology, metabolic processes, pathological changes on a cellular level, and the application of an enhancing imaging agent offers numerous diagnostic possibilities. Contrast agents can provide a plethora of additional, different information. New ideas should focus on medical, not technically feasible development. This can be achieved at a reasonable price, though perhaps only by small, dedicated companies.
1. Lauterbur PC, Mendonça Dias H, Rudin AM. Augmentation of tissue proton spin-lattice relaxation rates by in vivo addition of paramagnetic ions. In: Dutton PO, Leigh J, Scarpa A, eds. Frontiers of biological energetics. New York: Academic Press, 1978: 752-759.
2. Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. AJR 1984; 142: 619-624.
3. U.S. Food and Drug Administration. Public health advisory. Gadolinium-containing contrast agents for magnetic resonance imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. 8 June 2006 / 23 May 2007. http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm
4. for instance: Thakral C, Alhariri J, Abraham JL. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. CMMI 2007; 2: 199-205. • See also Rinckside - Radiologists meet with heavy collateral damage. Rinckside 2008; 19,3: 7-10
5. Rinck PA, Muller RN. Field strength and dose dependence of contrast enhancement by gadolinium-based MR contrast agents. Europ Radiol 1999; 9: 998-1004.