Supplying Demand
By Beth W. Orenstein
Radiology Today
Vol. 26 No. 1 P. 12
As medical isotope use increases, radiopharmaceutical companies expand to meet the need.
Hospitals and imaging clinics in the United States currently perform about 20 million nuclear medicine procedures for diagnosis and treatment every year, according to the World Nuclear Association. Six reactors in the world are responsible for much of the supply of radioisotopes needed for these studies. Of the three major isotopes used in nuclear medicine that are produced by reactors, one is molybdenum-99 (Mo-99), the parent of technetium-99m (Tc-99m)—the most frequently used diagnostic radionuclide.
Tc-99m is used in about 80% of all diagnostic scans, according to SNMMI. The other two are iodine 131 (I-131), used to diagnose and treat thyroid and other conditions, and lutetium-177 (Lu- 177), a medical isotope used in targeted cancer therapies.
“Demand for radiopharmaceuticals is increasing, particularly for cardiac, neurology, and oncology, due to an aging population and the success of theranostics,” says SNMMI President Cathy Sue Cutler, PhD. While demand is up, supply has tended to fluctuate. Reactor shutdowns for maintenance and repairs have sometimes rattled the markets, but the future is looking more promising as new facilities are set to open. The worldwide nuclear medicine community has also taken steps to mitigate issues when shutdowns occur—planned or otherwise.
Maintenance Required
Reactors require maintenance and, even when scheduled well in advance and customers are notified, maintenance shutdowns can cause disruptions. Doctors are warned they may have to delay nuclear imaging tests for nonurgent cases. Also, unexpected shutdowns may occur when safety concerns arise that must be addressed immediately or sooner than planned.
More than 15 years ago, in May 2009, the world’s largest medical isotope producer, the National Research Universal in Chalk River, Ontario, Canada, was shut down for several months. The shutdown caused a medical isotope shortage that left hospitals in more than 80 countries with costlier and less effective procedures. “It was very serious,” Cutler says. Similar supply issues also had arisen the year before—in August 2008—when a temporary shutdown at the High Flux Reactor (HFR) in Petten, the Netherlands, was extended unexpectedly.
After those shutdowns, the Organisation for Economic Co-operation and Development’s Nuclear Energy Agency, an intergovernmental agency that facilitates co-operation among countries with advanced nuclear technology infrastructures, evaluated the issue and recommended that an excess of material be produced at other facilities that could be utilized if the HFR shutdown caused a shortage. Unfortunately, this is costly and has been difficult to implement, Cutler says.
Unplanned shutdowns are inevitable. As recently as late October 2024, for example, the HFR was shut down for maintenance earlier than expected. The reactor is operated by the Nuclear Research and Consultancy Group. Letters were written to the South African authorities requesting their Safari-1 research reactor be allowed to increase production, and the Maria reactor in Poland, a research reactor operated in NCBJ Świerk near Warsaw, was requested to begin its startup a few days earlier than planned to help mitigate the shortage, Cutler says.
“The agency did successfully implement a high-level group to coordinate production schedules and down periods to mitigate shortages,” she says. “They further alert the public when a shortage is imminent to mitigate the impact.” (The HFR reactor restarted the week of November 4, and the normal global supply of Mo-99 was restored soon after.)
New Facilities
Not all radiopharmaceuticals are made by reactors. Many are made by cyclotrons or accelerators. While only six reactors supply Mo-99 to the world, about 1,500 cyclotrons produce many of the other radionuclides used in radiopharmaceuticals. If any of these cyclotrons shut down for any reason, they can often be backed up by other sites, Cutler explains. If shortages occur, they likely will be short-term because cyclotrons are more easily repaired than reactors. “That being said,” Cutler adds, “We still can expect to see reactor shutdowns and shortages continue from time to time.”
A number of new facilities are expected to open in the United States and around the world within the next decade. Canada has announced a number of new reactors expected to come online in the next few years. They include a small modular reactor (SMR) at the Chalk River Laboratories site that is expected to open by 2028. SMRs are also planned for New Brunswick in 2030 and in Saskatchewan by the mid-2030s. Cutler sees the use of Canadian power reactors for isotope production as “game changers” and has confidence that they will help meet the growing supply demands.
Others also have projects in the works. Fusion tech company SHINE Technologies recently announced the opening of the largest facility in North America dedicated to the production of noncarrier-added Lu-177. The facility, which operates at the company’s headquarters in Janesville, Wisconsin, has an initial production capacity of 100,000 doses of Lu-177 per year, with the ability to further expand production capacity to 200,000 doses per year in the future.
In addition, the Department of Energy (DOE) Isotope Program is developing stable isotope production at Oak Ridge National Laboratory in Tennessee and increasing production capabilities at other national laboratories such as Brookhaven National Laboratory in Upton, New York, and Los Alamos National Laboratory in New Mexico. SHINE is also still pursuing an accelerator-driven system to supply Mo-99 and may become the only domestic supplier in the US. SHINE has received the support of the DOE National Nuclear Security Administration for production of Mo-99, Cutler notes.
The University of Missouri is also seeking to build a new 20-megawatt state-ofthe- art reactor, NEXTGEN, to help meet the need for radionuclides in the US. The project will take 10 to 12 years and cost around $1 billion. The University of Missouri already has a research reactor called MURR (Missouri University Research Reactor), which is the only US producer of four medical isotopes used in lifesaving treatments for liver, thyroid, pancreatic, and prostate cancer.
Increasing Production
NorthStar Medical Radioisotopes in Beloit, Wisconsin, was originally given funding to establish Mo-99 production in the US but it suspended production last year, citing that it could not compete with the subsidization of foreign reactors. NorthStar is currently focusing on producing therapeutic isotopes copper-67 and actinium-225 (Ac-225). In October, it opened a 52,000-square-foot facility on its Beloit campus to provide additional therapeutic radioisotopes. In addition to Ac-225 and Lu-177, the new facility also provides development services and dose manufacturing capacity for copper-64, copper-67, indium-111, and others, the company says. Frank Scholz, president and CEO of NorthStar, says the company expects to be able to supply as much as 40% of the global projected demand for Ac-225 in the early 2030s.
“We expect other companies to increase their capacity during that same period, but a variety of factors such as the success or failure of specific clinical trials or regulatory review processes could affect demand,” Scholz says. “We and others in the industry will continue to closely watch the market and we have the space and ability to construct additional facilities if there is a need.”
Scholz notes that NorthStar’s Ac-225 process uses a source farm of generators growing Ac-225 in multiple generators so multiple radium solutions are online simultaneously, even if the accelerator is undergoing planned maintenance. “We have the ability to consistently ship Ac-225 product even during accelerator downtime,” he says.
Scholz says NorthStar believes that enhanced supply and more mature, resilient production and distribution for radiopharmaceuticals will further increase interest and exploration into novel radiotherapeutics, as well. These innovative targeted medicines have the potential “to bring new hope to millions of patients suffering from cancer and other serious diseases who have long needed more and better treatments,” he says.
Cutler says the US does rely heavily on foreign suppliers for their isotopes, as well as the cold target materials used to make the isotopes. “This is not unique to the US but, based on the fact that the US uses 50% of the world’s isotopes, it does put us in a risky situation,” she says. The challenge, Cutler says, is meeting the low costs of isotopes from other countries that don’t have to follow the same guidelines and regulations “that we do in the US. Because of the shortages, some customers have been stepping away from foreign supply and paying the higher costs to ensure domestic supply.”
New CMS Policy
A new CMS policy for reimbursement may increase access to radiopharmaceuticals to patients across the country and could affect demand and, thus, supply. The policy was announced on November 1 and took effect at the start of the new year.
Previously, diagnostic radiopharmaceuticals were bundled as “supplies,” which limited access in several ways, SNMMI says. Patients frequently lacked access to nuclear medicine scans that could alter their course of treatment because of cost barriers. Physicians were less likely to administer these procedures because reimbursements were inadequate. Hospitals were sometimes forced to discontinue certain nuclear medicine procedures because reimbursements from Medicare did not cover the full cost of these high-value radiopharmaceuticals. Pharmaceutical companies struggled to sustain production of innovative nuclear medicine radiopharmaceuticals because they were not sufficiently reimbursed.
SNMMI and other groups lobbied for a more equitable reimbursement structure. Under the new policy, CMS will unpackage and pay separately for diagnostic radiopharmaceuticals with per-day costs exceeding $630. Cutler says the new policy removes financial barriers that have long hindered patient access to essential nuclear medicine diagnostic procedures. She believes that the adjustment in CMS policy is a “critical advancement, as it increases patient access to radiopharmaceuticals and shows companies that investing in diagnostics is a viable business model.”
Cutler says SNMMI has been working for more than 10 years to get CMS to update its reimbursement policy on radiopharmaceuticals. Partner organizations provided vital support, she says. Cutler also says that SNMMI will continue to work closely with CMS to refine and enhance the reimbursement models, ensuring sustained and equitable access to advanced diagnostic care for all patients.
Scholz adds that the new CMS rules on reimbursement for diagnostic radiopharmaceuticals “are likely to significantly benefit the radiopharmaceutical industry as a whole.” They will do that by increasing access to best-in-class advanced imaging agents that will make diagnosis easier and more precise for doctors and their patients, he says.
The new CMS reimbursement policy could spur innovation in the field, as well, by providing better financial incentives for developing new radiopharmaceutical agents, Scholz says. The financial incentives will help encourage those who supply the radiopharmaceuticals to continue to build their businesses.
“As diagnostic radiopharmaceuticals are increasingly prescribed and used, the supply chain to produce and deliver these complex agents to patients will grow and mature, as well,” he says.
NorthStar and others in the industry will continue to closely watch the market, Scholz says. “We have the space and the ability to construct additional facilities if there is a need,” he adds.
— Beth W. Orenstein of Northampton, Pennsylvania, is a freelance medical writer and regular contributor to Radiology Today.