Do we need so many gadolinium chelates?
his column has the same title as two refresher courses at the European Congress of Radiology in Vienna 1995 and 1997. It is a provocative question because whatever your answer, you either lie or step on somebody’s toes. It would be easy to respond “yes” or “no” or “of course, because all pharmaceutical companies want to make a profit”. But first it is essential to look at the facts.
Gadolinium is a rare earth metal that offers an extremely strong degree of relaxation enhancement, and therefore seems to be the best foundation for paramagnetic contrast agents. It has to be chelated to organic ligands to decrease its toxicity and facilitate delivery to the desired region of the body.
The gadolinium class of magnetic resonance contrast agents consists of a number of chelates. Chelates come as stretched, or linear, or cyclic or macrocyclic molecules. Their number is increasing every year. It is this expansion that leads to our question. Before attempting to determine whether we need so many gadolinium chelates, however, a far more important question must be addressed: Do we need gadolinium chelates at all?
Ten years ago the response to this question was equivocal, but today it is clearly affirmative. Administration of a gadolinium contrast agent often renders an MR examination conclusive, delivering a straight diagnostic answer. Nonetheless, there are only a few publications dealing with this topic that include a large patient population.
In one of the few prospective studies, Elster et al. reported in 1989 that in 3% of all patients enrolled, lesions were detected after contrast that were not otherwise apparent in precontrast T1- or T2-weighted images . Contrast-enhancing lesions were seen in 20% of patients, and in 75% of those cases radiologically useful information was revealed. Lack of enhancement was found useful in an additional 22% of cases. A number of other papers have underlined the added benefit of gadolinium-containing contrast agents.
The first gadolinium chelate was brought to the market in the late 1980s. It was Gd-DTPA, Schering’s Magnevist. It enjoyed a kind of monopoly position in most countries of the world. Between 1988 and 1991 more than 5 million patients underwent examinations with Magnevist. The only competitor was Gd-DOTA, which was marketed in some countries by Guerbet as Dotarem.
For some years there was no other competitor. In Spain, Schering competed with itself by selling Gd-DTPA through the Spanish company, Juste, under the trade name Magnograf. And in China, Gd-DTPA is available as a copied product, with the Chinese apparently not paying license fees to Schering.
Two new products were introduced in 1993, both slightly different from the first ones. Nycomed’s Omniscan, or Gd-DTPA-BMA, and Squibb Diagnostics' (now Bracco's) ProHance, or Gd-HP-DO3A, possess a lower osmolality and are neutral or nonionic. Their manufacturers claim that the safety indexes of their nonionic products are better than those of the earlier products. This will be difficult to prove, however, because even Magnevist seems to be at least one order, perhaps even two orders, of magnitude safer than ionic x-ray contrast agents. In other words, hundreds of millions of examinations are needed to prove the manufacturers' claim because all these agents are safe in the first place.
New Agents on the Way
At least three more gadolinium-based contrast agents will hit the market in the foreseeable future. Mallinckrodt will have a gadolinium compound of its own called Optimark, Bracco will introduce its Gd-BOPTA as MultiHance, and Schering its Gd-EOB-DTPA as Eovist. The latter two agents will be used not only for the same indications of the compounds sold today, but also for liver and myocardial examinations, for example, because of their specific distribution to these organs.
Gd-BOPTA combines hepatocyte specificity with plasma kinetics similar to that of the four traditional gadolinium agents and relaxivity modulated by serum protein concentration. The latter behavior may have implications for the detection of blood-brain barrier disruption after ischemic insults and in tumors.
Even more gadolinium agents are on their way. Gd-DTPA-albumin, GD-DTPA-dextran, and Gd-DTPA-polylysine could facilitate MR angiography and help to assess myocardial and cerebral ischemia, pulmonary embolism, vascularization of tumors, and tumor perfusion. Altogether, today, some ten compounds are sold for routine use or are on their way to the market. There are numerous other gadolinium chelates still in the laboratories of their developers.
To my knowledge, to date none of the new contrast agents has so far been rejected by the regulatory and licensing authorities. In the future, however, approval might become more difficult to obtain because the regulators will require proof of additional diagnostic benefit of the new compounds compared to those already on the market.
New contrast agents must be innovative, yet the initial four already competing on the market, and some of those still to come are very similar. Three major factors influence the evaluation of these products: firstly, efficacy; secondly, relative biological tolerance profiles; and thirdly, price.
There is a general consensus that Magnevist, Dotarem, ProHance, and Omniscan are similar in their efficacy; this consensus exists because there is no proof to the contrary.
Furthermore, it is difficult to test two different contrast agents in the same patient at, more or less, the same time. It even might be considered unethical. I have heard about some such comparative studies being conducted and about results giving preference to a particular contrast agent. However, nobody has dared to publish them.
In terms of acute safety aspects and relative tolerance profiles, the agents do not differ substantially. So the basic difference between these contrast agents is price, and a subtle price war is already going on.
Undoubtedly, today’s unspecific agents were a big step forward in MR imaging and medical diagnostics in general. However, the development of new ligands for these traditional unspecific indications is not worthwhile. What is both desirable and necessary are new compounds with higher specificity.
However, there seems to be a simple rule: The better the specificity, the smaller the market will be.
There might be one exception: blood pool, i.e., angiographic agents, should be introduced as soon as possible because there is a need for MR angiography with less pitfalls, which means with an MR angiographic contrast agent.
In this case, there is a substantial market because contrast-enhanced MR angiography will cut a big slice out of the conventional and CT angiography cake.
Nuclear Medicine Connection
For other specific applications, new impulses will come from nuclear medicine. Always remember that DTPA was a ligand used first in nuclear medicine, yet researchers in MR imaging have only looked into radiopharmaceuticals with a half-opened eye.
For a long time nuclear medicine was considered a discipline that was “supposed to die” – but it appears to be expiring very slowly. Many observers thought nuclear medicine would be replaced by MR imaging and MR spectroscopy, but it looks instead as if MR spectroscopy has been replaced by nuclear medicine.
In the meantime, spatial resolution in nuclear medicine has improved and new radiopharmaceuticals have been introduced. I still believe that MR imaging has a more important future for mankind than nuclear medicine, but this should not prevent us from trying to learn from nuclear medicine and to develop higher-specificity MR contrast agents based on the results of nuclear medicine research.
There is another aspect to the debate about whether we really need so many gadolinium chelates. Just as the automobile, the electronic, and the tourist industries have to some extent developed into consumer industries, so has medicine.
New products are developed and sold, many of them are hardly essential for the survival of mankind. However, they do create income and employment for thousands of physicians, scientists, clerks, and workers. As long as they do not harm people, they are welcome. In the case of gadolinium contrast agents, the new products may have a positive impact on cost-containment, because prices are likely to fall as competition intensifies.
In the end, whether we need so many gadolinium chelates depends on where we live. In socialist societies or those with restrictive healthcare systems the policy followed is “That’s what we have, that’s what you get”. In many Central and Western European countries, in the U.S.A., in Japan, and in some other nations the answer is (still) different: You get a selection of goods, which also include contrast agents. If a product is not good or too expensive it will be eliminated.
PS. Within a few years, the landscape in MR contrast agents has completely changed. A number of companies has disappeared and the aftermath of the NSF scandal has left its traces.
1. Elster AD, Moody DM, Ball MR, Laster DW. Is Gd-DTPA required for routine cranial MR imaging? Radiology 1989; 173: 231-238.