Surviving the Moly shortage: Investing in Alternatives

Over the past few years, the global nuclear medicine community has been plagued with shortages of medical radioisotopes, which is particularly detrimental for the oft-used molybdenum-99 (Mo-99)—the parent isotope of technetium-99m (Tc-99m), the most widely utilized radioisotope in the world for molecular and nuclear diagnostic imaging studies. Forced reliance upon aging, less reliable nuclear reactors consistently causes much of the instability and turmoil to the supply. This is a global issue being addressed locally. Molecular imaging physicians, clinicians and administrators, along with industry, are seeking short- and long-term clinical alternatives for diagnosis and treatment. Yet, most agree that long-term solutions need to be crafted to provide the much-needed tests patients will require in the future.

The Problem

Approximately 80 percent of worldwide clinical nuclear medicine is dependent on the availability of Mo-99, the parent isotope of Tc-99m—which is used in approximately 16 million patient procedures annually in the United States alone. However, this crisis is clearly global. Recent shortages around the world have resulted from the unexpected and scheduled shutdowns of the largest—albeit aging—producers of Mo-99: the National Reactor Universal (NRU) reactor in Chalk River, Ontario, and the High Flux Reactor (HFR) in Petten, Netherlands. Together, these reactors produce two-thirds of the world’s Mo-99 supply. In August, the shutdown of NRU was extended into the first quarter of 2010. To date, based on their proximity, the U.S. and Canadian medical communities have been most affected by the current shortage.

Until this year, 95 percent of the world’s Mo-99 has been produced by five commercial nuclear reactors—NRU, HFR, Safari-1 in Pelindaba, South Africa, BR-2 in Mol, Belgium, and Osiris in Saclay, France—all of which are more than 40 years old. However, the Australian Nuclear Science and Technology Organization (ANSTO) is scheduled to begin distribution by year’s end from the OPAL reactor in Sydney. Health Canada and the U.S. FDA this summer fast-tracked the reactor’s approval as a valid supplier for low-enriched uranium (LEU)-derived Mo-99 to their respective countries. Canada also approved South Africa’s Safari reactor as an alternative supply of the isotope Iodine 131 to treat thyroid cancer. And a fast approval of sodium fluoride for bone scans has made it available in Canada through the University of Sherbrooke Hospital in Quebec, McMaster University in Ontario and the Cross Cancer Institute in Alberta.

The 52-year-old NRU reactor in Ontario—the world’s largest medical isotope manufacturer—produces about one-third of the global supply, and approximately 50 percent of Mo-99 used in North America. The 47-year-old HFR in the Netherlands supplies another one-third of the global supply. Together, the South African and European reactors supply about 15 percent of the world’s needs. Typically, the United States uses about half of the world Mo-99 supply.

When crisis hits

When HFR closed for its scheduled four-week maintenance starting in July, the three remaining reactors increased their isotope supply. And even though South Africa ramped up its Mo-99 output with round-the-clock, seven-day-a-week production— increasing its output by 15 percent—the three remaining reactors are unable to match normal supply levels, without at least HFR or NRU operational. To add to the complications, production problems have delayed the Australian reactor’s distribution of Mo-99.

As a result, some cancer and heart patients across the world could not receive the tests that their physicians had ordered. The province of Quebec reported that 27,000 cancer and heart tests had been delayed as of early August. Delayed studies are plaguing Europe as well. Some 20 percent to 40 percent of nuclear medicine procedures have been delayed at St. Vincent’s Hospital in Linz, Austria, says Werner Langsteger, MD, director of nuclear medicine and endocrinology.

The global crisis has been less felt down under, says Rodney J. Hicks, MD, director at the Centre for Molecular Imaging at the Peter MacCallum Cancer Centre in Melbourne, Australia. The Australian Mo-99 supply was “relatively protected during the most recent global crisis due to a significant local production”—but he expresses concern about early 2010 if the NRU’s closure gets extended again, simultaneous to longer HFR closure.

During normal times, Dublin, Ireland-based Covidien supplies about half of the U.S. technetium supply. The company receives the majority of its Mo-99 from HFR, and maintains supply of additional Mo-99 from NRU, BR-2 in Belgium, Osiris in France and the Safari-1 in South Africa, routinely during scheduled shutdowns, says Elaine Haynes, Covidien’s group director of marketing for U.S. imaging solutions. “However, with the two largest [HFR and NRU] both shuttered, we struggle to meet the increased demands, even with the augmented production,” she says.

Lantheus Medical Imaging of North Billerica, Mass., U.S, supplies the other half of the U.S. technetium supply when all the reactors are operational. They also receive supplies from the South African, Belgian and French reactors when both HFR and/or NRU are closed, according to Bill Dawes, vice president of manufacturing and supply chain at Lantheus. Additionally, the company formed an agreement with the Australian reactor. Dawes anticipates that “those supplies will be realized over the coming weeks and months.” However, he adds that Lantheus’ ability to maintain its Mo-99 supply is difficult with the closure of the two largest suppliers.

Haynes stresses that during these more extreme shortages the focus needs to be on equal and fair distribution to patients globally, in particular in Japan, Canada and underserved U.S. rural areas—the latter of which were particularly reliant on the NRU reactor.

While temporary solutions are implemented, long-term challenges remain. For example, in June, the Canadian government announced it will stop producing radioisotopes by 2016, declaring its intentions to sell off the government-owned Atomic Energy of Canada Limited, which operates the Chalk River facility. This decision has the fate of the reactor unclear, and led some, including SNM President Michael M. Graham, MD, PhD, to speculate whether it will reopen at all.

Unfortunately, the ability to properly care for patients is what suffers most during these crises. “We don’t know from week to week what our supply will be,” says Graham, who also is the director of nuclear medicine at the University of Iowa Carver College of Medicine in Iowa City.

Even high-profile U.S.-based healthcare providers, such as the Cleveland Clinic, have to hold off scheduling patients during the shortages, according to Manuel D. Cerqueira, MD, chairman of its nuclear medicine division. In fact, about 91 percent of U.S. nuclear medicine physicians suffered shortages during the most recent crisis. Meanwhile, referring physicians are seeking alternative tests.

Clinical alternatives for nuclear cardiology

So what are the alternatives? Nuclear cardiology has the significant alternative of thallium 201 for myocardial perfusion imaging, and many sites made the switch from technetium-labeled agents.

Both Covidien and Lantheus say they have “significantly” increased their production of thallium 201 to meet burgeoning demand. In fact, Lantheus ramped up its thallium 201 production to approximately three times its normal amount during the recent global shortage.

“While the image quality with thallium 201 isn’t quite on par with Tc-99m studies,” Graham says, “the biggest caveat is physician experience.”

Twenty years ago, thallium 201 was the gold standard, as the initial myocardial perfusion agent, and became commonly used in the late 1970s and early 1980s. As a result, older practitioners are comfortable with the test. However, those who have trained in the last 10 years have much less experience, if any. “The way you read and interpret these studies is quite different—not that huge mistakes will be made, but it will have a bit of a learning curve for new adopters,” Graham says.

Cerqueira, who is a practicing nuclear cardiologist, also notes that thallium carries a higher radiation dose than technetium-based cardiac agents.

In July, the Ontario Association of Nuclear Medicine called on the Ontario government to fund PET scans to reduce dependency on SPECT isotopes. Hicks and Langsteger also suggest that these crises will encourage a progressive move to PET, instead of technetium myocardial perfusion or thallium 201 imaging.

However, that poses a problem in the United States. Cerqueira estimates that currently approximately eight million nuclear cardiology studies are performed with Tc-99m, and only about 100,000 with PET agents annually in the United States. He is skeptical that the number of PET scanners could fill the large gap left by the isotope void, noting that there are about 10 times as many gamma cameras as PET scanners.

Clinical alternatives for other 'ologies

There are other alternative studies as well. 18F-Flourine is an available alternative for bone scans. In fact, Canadian authorities promptly recognized this need during the recent shortage, and approved its reimbursement. And this could be a game-changer. Hicks says that any clinician who has experience with 18F-Flourine PET bone scans “will be reluctant to return to the Tc-99m variety.”

18F-Flourine PET bone scans are under consideration for reimbursement by the U.S.’s Centers for Medicare & Medicaid Services, with an expected NCA (national coverage determination) completion date of March 4, 2010. “With all the bureaucratic delays, the U.S. process takes months, which is very frustrating,” Graham says. “In the meantime, the lack of reimbursement will mean that it will not be performed routinely, except in emergency settings.”

Also, Graham concurs with Cerqueira that PET does not present an easy alternative in the U.S. because PET scanners are such a limited commodity across the nation. “Most providers could not perform an extra 10 scans a day for bone scanning, which is about what it would take to fill the national need,” Graham says. “So, even if [18F-Flourine] does receive CMS approval, we will not be able to perform all the necessary bone scanning due to a lack of PET machines.”

Europe has more options, notes Langsteger, who recommends PET imaging as an alternative for a variety of conditions. For instance: 18F-Choline PET/CT for neuroendocrine tumor and prostate cancer imaging; FDG-PET/CT for inflammation imaging, instead of a three-phase bone scan; and FDG-PET/CT in general for tumor staging, in addition to follow up and therapy management, namely in breast, colorectal, head and neck and lung cancer.

Hicks supports Langsteger’s recommendations of PET alternatives. “There is hardly a conventional nuclear medicine test that we couldn’t replace with a PET version with an appropriate will and regulatory environment using F-18, Ga-68, Zr-89 or I-124,” Hicks says.

Unfortunately, these same aging nuclear reactors create Iodine-131, which is critical for treating hyperthyroidism and thyroid cancer. Fortunately, it has a longer half-life at eight days, so the supply does not dwindle as rapidly. “In most of these cases, treatment will have to be postponed, which could mean worse outcomes for the patient,” Graham notes.

Presently, there are no reasonable substitutes for the bilary and lung scans, as well as the renal studies. “The alternative tests for these conditions are less accurate, involve more radiation dose, are typically more invasive,” Graham says.

Medium-term solutions

There have been many calls to action across the globe, but no concrete solutions to the current shortage. In the United Kingdom, President of the British Nuclear Medical Society Alan Perkins, MD, recommended in March that the U.K. government start producing medical isotopes or “face a dangerous shortage that threatens to compromise patient healthcare.” He added that the recent supply disruptions have “adversely affected patient services in many countries including the U.K., the majority of Europe, the U.S. and Canada and beyond.”

In Germany, the Technical University of Munich is seeking funding to upgrade its FRM II neutron source to produce Mo-99, which could “cover all of Europe's needs,” according to the university. Winfried Petry, scientific director of the FRM II, says this strategy would be far cheaper and quicker than building a new facility from scratch. He speculates that new reactor in Europe would cost €300 million and take 12 to 15 years, “if you started the project now.”

The Canadian government, lead by Natural Resources Canada, has been mobilizing an international approach to the problem, bringing together global stakeholders in meetings that have resulted in both the Netherlands and South Africa temporarily increasing Mo-99 production, Australia accelerating efforts to ramp-up isotope production and better coordination among the five major international producers to coordinate operations and shutdowns.

Canada also has put in place regulations to ensure that alternatives to the current production of Mo-99 deemed safe and effective can be provided to the medical community quickly. In mid-June, the Minister of Natural Resources launched a process to solicit ideas for the alternative production of Moly-99/Tc-99m for the Canadian market in the medium to long term. An Expert Review Panel, named to assess these options, is due to complete its final report by November 30.

With an eye toward the future, the Minister of Health with the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada has earmarked $6 million to find alternatives to nuclear-produced Tc-99m.

In the U.S., a bill has been proposed by Rep. Edward J. Markey, D-Mass., chair of the House Subcommittee on Energy and the Environment seeking the establishment of a medical isotope production in the United States. Markey proposes that isotopes can be made effectively with low-enriched uranium (LEU). Earlier this year, the National Academy of Sciences concluded that there are “no technical reasons that adequate quantities cannot be produced” without the use of highly enriched uranium.

The bill also seeks to provide resources to the Department of Energy (DoE) to bring U.S. production of Mo-99 online as soon as possible, authorizing $163 million over five years, to fund the current DoE cost projection for creating a Mo-99 production. The DoE would be required to use the money to support private sector or research sector projects.

Cerqueira notes that a U.S. reactor would be subject to all the rules and regulations of the Nuclear Regulatory Commission (NRC). “Even if the bill was passed, it would probably take about five years to begin distributing production,” he estimates.

However, Damien LaVera, director of public affairs at the DoE’s National Nuclear Security Administration, confirms that the U.S. government, through the White House Office of Science & Technology Policy, is actively seeking a sustainable means of domestic production using LEU. He adds that the primary focus is to establish a system that could not be undermined by a malfunction at a single reactor.

Another mid-term solution for the U.S. and potentially the world, which could come to fruition sooner if approved and funded, is an upgrade to the Missouri University Research Reactor (MURR). This would create a molybdenum processing facility, adjacent to the reactor, which is another component of the Markey bill. If they receive full funding, it would likely be three years before MURR is functional to distribute Mo-99.

“That would be a huge improvement in the overall global situation because they would be able to produce about 50 percent of U.S. needs. In reality, we could probably limp long quite easily with that supply,” Graham says. “It would be terrific, although not a true long-term solution because MURR also is a fairly old reactor.”

The most viable U.S. solution in the next five years could emerge from an industry plan presented by Covidien and Babcox & Wilcox. They are working on a design to build a different kind of reactor that would seek to optimize Mo-99 production through LEU. The plan involves using a liquid core, allowing them to withdraw an aliquot from the fuel periodically, which would then be processed for the efficient separation of byproducts, including the Mo-99. Ideally, the users could return the processed material, which still contains uranium, back into the core, therefore, reducing nuclear waste generation.

“This entirely LEU-based solution could be up and running in approximately five years, and could potentially supply approximately 50 percent of U.S. demand for Mo-99,” Covidien’s Haynes says.

While a U.S. reactor may be created through a private enterprise, they may be able to obtain government funding for the $250 million to $300 million project, according to SNM estimates.

However, the process to building a new U.S.-based reactor would be confronted with a great deal of political and regulatory difficulties—not the least of which is the location. Graham says the reticence about having a nuclear reactor in a particular area could be combated through education.

Meanwhile, there is some hope of help from Australia. Dawes suggests that the Australian reactor, which is less than two years old and relies upon LEU, could help to offset future shutdowns over the next several years. Hicks notes: “Although our national reactor has been troubled by its own problems, there is certainly an expectation that it will be able to ameliorate the shortfall as other international suppliers go off-line.”

In the long term

Many challenges remain in insuring and maintaining an adequate global supply of Mo-99. Old reactors must be maintained and monitored for realistic production expectations, and new reactors will require significant time, government support, investment and security. Through this global and local crisis, healthcare professionals and industry have realized the value of international collaboration to meet the challenges of this complex supply chain, the best methods to utilizing limited supplies and that clinical alternatives offer a viable and perhaps long-term solution to meet the needs of patients.