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All quiet at the MR contrast agent front?

Rinckside 2021; 32,3: 7-9.


here is not much innovation in the clinical use of MR contrast agents, but numer­ous “market re­ports” have been released during recent years predicting a roaring future — although they were mostly written by people without deep insight into the field. These reports are being offered at prices of several thousand dollars each. According to them, the future of the MRI contrast agent market is bright, most of the big companies have just introduced new agents, and at least a 4% an­nual increase in sales can be expected. Thus, they are as accurate as today’s weather forecast for February 2031. It is rumored that their publishers also sell market forecasts for bitter orange mar­malade for 2022-2031, same predictions, same bitter off-taste.

The so-called “new” agents according to these reports are generics, mostly copies of Gd-DOTA, the “Dotarem” the French company Guerbet brought out more than thirty years ago. The novel trade names are different, but this is how far novelty goes.

Ongoing research in the field of MRI contrast agents at universities and other research institutions paint a different picture: there are plenty of ideas and developments — applicable for biomedical re­search, but not for clinical life. Among them are compounds capable of being activated by outside factors and targeted ones; they all seem to function nicely in animal models. An excellent 100-page overview was given by a research group at MGH / Harvard Medical School in 2019 [1], a shorter and more clinical basic introduction to MR contrast agents was published by TRTF/EMRF in 2021 [2].

Still, no new products have reached the market; on the contrary, a number of approved compounds were withdrawn because they didn’t sell. Others — linear gadolinium based agents — had to be re­moved because they were considered a risk for patients after the overdosing of gadolinium com­pounds led to the NSF (nephrogenic systemic fibrosis) scandal [3].

Gadolinium deposits have also been found in other body tissues. Yet, there is currently no evidence that gadolinium deposition in the brain has caused any harm to patients. In 2019, a major study pro­vided evidence from a large animal model that linear gadolinium-based contrast agents leave traces of gadolinium within the deep cerebellar nuclei, while there was no significant difference of gadolinium residue between three macrocyclic agents marketed in Europe and a saline control group [4].

The European Medicines Agency (EMA) recommended restrictions and suspensions for some intravenous linear agents in order to prevent any risks that could potentially be associated with gadolinium brain deposition. EMA stated that the intravenous linear agents gadoxetic acid and gadobenic acid can continue to be used for liver scans because they are taken up in the liver and meet an important diagnostic need. All other intravenous linear products (gadodiamide, gadopentetic acid and gadoversetamide) are suspended in the EU [5].

On the other hand, the US Food and Drug Administration did not restrict any Gd-containing agents [6]. Only the intravenous linear blood pool agent Gadofosveset trisodium (also known as Ablavar or Vasovist) was withdrawn from the US-market; the manufacturer discontinued production in 2017 due to poor sales.


Gadolinium contrast agents are still the safest contrast agents one can use in diagnostic imaging, far safer than x-ray agents.



Gadolinium contrast agents are still the safest contrast agents one can use in diagnostic imaging, far safer than x-ray agents. The dream of some of the early developers to create outstanding and safe contrast enhancers was destroyed by corruption sprees and greedy abuse of the gadolinium agents. Their reputation was severely damaged by avarice and depravity on the one hand and, on the other, by cheap sensationalism in the press [7,8].

The main question is if there is room for a new agent today or in the future — and if so, how and why — when the remaining Gd chelates are so uni­versal in terms of their application. Gadolinium extra-cellular fluid agents are the only ones that have grown into a realistic market size. Thus, it will be extremely dif­ficult to develop a new MR contrast agent that fulfills unsatisfied clinical needs and has a large enough range of application to justify development [9]. New agents for e.g. liver or pancreas imaging may have difficulties to gain a foothold.

The global market value of gadolinium contrast agents still is in the billions of dollars per year al­though it shrunk in the U.S.A. between 2019 and 2020 from more than 500 million USD to about the half — it contracted significantly during the Covid-19 lockdowns and the market has not yet re­turned to pre-pandemic levels.

There is, of course, the financial in­duce­ment. The American market is huge and the retail prices of contrast agents are high. Generally speaking, prescription drug prices in the United States are two and a half times the prices elsewhere, the gap between prices in the United States and other coun­tries is even larger for brand-named drugs, with U.S. prices averaging 3.44 times those in compari­son nations. A recent study by the Rand Corporation found that among G7 nations, the United King­dom, France, and Italy generally have the lowest prescription drug prices, while Canada, Germany, and Japan tend to have higher prices, still far below those in the U.S. [10].

For connoisseurs and lovers of obscure statistics: average life expectancy in years in these countries is as follows: Japan 85.0, Italy 84.1, France 83.1 Canada 83.0, Germany 81.9, United Kingdom 81.8, and the United States 79.1. In other words, one lives longer where drugs are cheaper.


Reimbursement

Until some five years ago, reimbursement of contrast agents by health agencies and insurance com­panies was generally generous — a number of people took advantage of this behavior. The sums involved were horrendous. Then the evidence trickled down to the media and the public. One corruption scandal followed the next.

As a result in Germany, for instance, reimbursement by the local Statutory Health Insurances dropped substan­tially. Originally these insurance companies used to reimburse between 3900 and 6000 Euros per one liter of contrast agent (50 doses) to the manufacturer or wholesaler; since 2019, only 970 Euros are reimbursed. Probably only 700 Euros per liter will be paid in the future. However, the ten per­cent of the population who are not members of the national insurance scheme and are covered by private insurance coverage continue paying substantially more per contrast-enhanced MR examina­tion.

In some parts of Germany, radiologists are not allowed to decide which contrast agent they can use and they are not told how much it costs. It’s a secret between the local Statutory Health Insurance and the company delivering the agent. Again, venality is part of the game.

Lower reimbursement discourages the clinical development of new agents since it requires tens, perhaps hundreds of millions of euros for the pre-clinical and clinical studies in humans. More so, compared to thirty years ago, the registration authorities demand far more stringent safety studies. There is also a simple rule: The better the specificity, the smaller the market will be — and the smaller the market, the higher the price per dose has to be — and higher prices might be an insur­mountable obstacle.

Thus there is the attractive idea of applying new paradigms to already approved agents that were withdrawn from the market before the gadolinium phobia, such as the use of Mn-DPDP for cardiac and brain applications and ferumoxtran for the enhance­ment of metastases. New patents cover these new applications. In these cases re-introduction should be less complicated — but apparently, it still is rather expensive and very time consuming.

At the same time, the equipment manufacturers are doing everything they can to come up with non-contrast agent alternatives. In addition, AI applied to imaging looks set to change the goal posts both in terms of diagnosis and also in highlighting subtle differences and abnormalities. This tech­nology will be fully integrated with the equipment.

Another question is what will be the clinical need for imag­ing agents when in vitro diagnostics will begin to pro­vide useful information. Advances in gene sequencing and in molecular biology under­line the significance and impact of linking diagnostics and biotechnology, for instance in identification of can­cer from blood samples. Long-term thinking is not the business approach of many companies, but some in­vest in innovative lateral thinking, hoping and already seeing commercial success.



References

1. Wahsner J, Gale EM, Rodríguez-Rodríguez A, Caravan P. Chemistry of MRI contrast agents: Current challenges and new frontiers. Chem Rev. 2019; 119(2): 957-1057. doi:10.1021/acs.chem­rev.8b00363.
2. Rinck PA. Contrast agents in magnetic resonance imaging. Free offprint from: Magnetic Resonance in Medicine. A Critical Introduction. The Basic Textbook of the European Magnetic Resonance Forum. Preprint of the 13th edition. 2021.
3. Rinck PA. Gadolinium — will anybody learn from the debacle? Rinckside 2015; 26,9: 23-26.
4. Radbruch A, Richter H, Fingerhut S, Martin LF, Xia A, Henze N, Paulus W, Sperling M, Karst U, Jeibmann A. Gadolinium deposition in the brain in a large animal model – Comparison of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol 2019; 54: 531–536.
5. European Medicines Agency. EMA’s final opinion confirms restrictions on use of linear gadolin­ium agents in body scans. Recommendations conclude EMA’s scientific review of gadolinium depo­sition in brain and other tissues. 20 July 2017.
6. FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue. 19 December 2017.
7. Rinck PA. Adding fuel to the flames: Gadolinium – the German follow-up. Rinckside 2016; 27,1: 1-3.
8. Rinck PA. German newspapers and the gadolinium controversy. Rinckside 2018; 29,3: 7-8.
9. Rinck PA. MR Imaging: Quo Vadis? Rinckside 2019; 30,3: 5-8.
10. The Rand Corporation (Mulcahy AW). Prescription drug prices in the United States are 2.56 times those in other countries.



Citation: Rinck PA. All quiet at the MR contrast agent front?. Rinckside 2021; 32,3: 7-9.

An edited digest version of this column was published as:
Where do we really stand now with MRI contrast agents?
Aunt Minnie Europe. Maverinck. 7 July 2021.


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