Isotope shortages are leading to mounting costs for hospitals and nuclear pharmacies. Experts agree that a domestic supply is the only answer.

Allegra DePietro Bruce, RPh, BCNP

The effects of well-documented isotope shortages have not yet reached critical mass, but experts agree that another prolonged reactor shutdown could trigger a chain reaction with devastating consequences. “It is critical that we take steps to stabilize the domestic supply of medically useful radionuclides, and how we do that is going to be the subject of much debate,” said Jeffrey P. Norenberg, PharmD, associate professor at the University of New Mexico College of Pharmacy, Albuquerque. “From every corner there is agreement that the current supply chain is flawed, unreliable, and irreparable.”

Radiologists and nuclear pharmacists remember the December 2007 Canadian reactor shutdown all too well. At that time, a scheduled 5-day maintenance break for the 50-year-old institution turned into a month out of action. Since nearly two-thirds of the US supply of molybdenum 99 (Mo-99) comes from the Canadian facility at Chalk River, making up the shortfall with material from Petten, The Netherlands, became problematic. As of press time, the Netherlands’ reactor remains shut down, as it has been since August 2008.

With Holland out of commission, the margin for error is uncomfortably slim. “If they are both down, there really is no one to turn to,” said Allegra DePietro Bruce, RPh, BCNP, nuclear pharmacy manager at Massachusetts General Hospital, Boston. “If the nuclear pharmacy that your hospital worked with did not have any radiopharmaceuticals, and another commercial nuclear pharmacy did, then you could try to get something from them if they had excess capacity. But they probably would charge a premium.”

US hospitals and nuclear medical facilities rely heavily on foreign sources of isotopes, a fact that motivated more than 70% of Society of Nuclear Medicine (SNM) survey respondents to affirm that the August 2008 Mo-99 shortage had impacted their practice or facility. Part of the problem stems from the parasitic nature of isotope production. Since reactors are operated for other purposes such as weapons or nuclear power, experts say that no one truly knows the free market economics surrounding Mo-99. Therefore, convincing private investors to build a reactor dedicated only to Mo-99 production is a highly unlikely proposition.

Currently, there are no facilities in the United States that are dedicated to manufacturing Mo-99 for Mo-99/Tc-99m generators. In the long term, experts agree that a brand-new, publicly financed American reactor would be ideal. However, issues such as cost, regulations, and politics all factor in to what would likely be a $250 million project. Industry activists will instead lobby for an upgrade to the University of Missouri Research Reactor in Columbia. “We are going to be pushing Congress to upgrade the Missouri facility, and my understanding is that for around $40 million it could be upgraded to provide as much as half the requirements for the United States,” said Michael M. Graham, MD, PhD, professor of radiology and radiation oncology, and director of nuclear medicine at the University of Iowa College of Medicine, Iowa City. “In the long term, we need a new reactor that is designed to work with low-enrichment uranium.”

Graham’s call for low-enrichment uranium is a nod to the concerns surrounding terrorism and weapons of mass destruction. Since 9/11, Homeland Security officials have kept a close eye on the amounts of highly enriched uranium flowing into and out of the country, and those concerns show no sign of going away. “It seems prudent, and experts in the antiterrorism world have recommended, that we decrease our reliance on highly enriched uranium, which could become fissile material for a dirty bomb,” said Norenberg, who also serves as executive director of the National Association of Nuclear Pharmacies. “In concept, this is absolutely worthwhile and most people are supportive. But in the short term, we have not yet shown the technical ability to completely eliminate highly enriched uranium from the medical isotope production arena.”

It may take 7 to 15 years to perfect the technology, and when it happens, it will likely have a cost impact of perhaps 5% to 10% or more. Such an increase will be nothing new to nuclear pharmacists who have seen double-digit price boosts over the past year and a half. Reasons for the increases include facility upgrades at generator manufacturers, and difficulties brought on by the Mo-99 shortages. “We’ve seen huge increases in the cost of the technetium-99 generators,” DePietro Bruce confirmed. “The cost of buying generators has gone up about 20% this year. Last year, they went up about 40% to 50%.”

Technetium-99m (Tc-99m), the isotope that breaks down from Mo-99, is used in more than 35,000 medical procedures a day in the United States. The drugs generated from nuclear substances are relatively low cost, about $100 per unit of use, but Norenberg points out that because they are radioactive and constantly decaying, they are impossible to stockpile in bulk. “They have to be produced the same day you are going to use them,” Norenberg said. “And this creates a difficult problem in an unreliable supply paradigm.”

The unreliability has inevitably filtered down to patients in the form of delays and alternative studies. Over at the Department of Radiology and Radiological Sciences at Vanderbilt University, Nashville, Tenn, alternatives such as thallium-201 are used, but there are drawbacks. “The images produced are not as good as with technetium, and the radiation dose to patients is larger with thallium,” said Dominique Delbeke, MD, PhD, director of nuclear medicine and positron emission tomography at Vanderbilt. “Other alternatives are PET radiotracers of perfusion such as rubidium-82 and N-13-ammonia that are used at some facilities, but are not widely available—and not reliably reimbursed.”

Other procedures, Norenberg said, do not work well with alternatives. Myocardial perfusion imaging, for example, uses Tc-99m along with other radiopharmaceuticals. By all accounts, Tc-99m provides an effective and sensitive diagnostic imaging tool for assessing myocardial perfusion injuries such as ischemia. “If these are unavailable, you could use a thallium-based radiopharmaceutical, and in some instances it can give you high-quality information,” Norenberg said. “However, in other instances it can’t answer those questions, and the patient may need to have more invasive procedures that increase morbidity and mortality—procedures such as cardiac catheterization and the use of intravenous contrast agents. It is not trivial to take someone from a relatively noninvasive imaging modality into a highly invasive cardiac angiography application.”

According to Delbeke, CT also could be used as an alternative to some nuclear medicine procedures, but it is more radiation dose to the patient, and it does not give quite the same information. Another alternative is a PET radioisotope, labeled with fluorine-18, that can be produced locally by cyclotron. “Fluorine-18 labeled to fluorodeoxyglucose (FDG) is the PET radioisotope used mainly for oncology,” said Delbeke, SNM’s vice president-elect. “Fluorine-18-fluoride can be used as an alternative to Tc-99m bone scintigraphy. But right now it is not reimbursed, and it is not available everywhere because not everybody has a cyclotron.”

Economically speaking, the 500 commercial nuclear pharmacies that operate in the United States represent more than a billion dollars in commerce, and Mo-99 comprises more than 90% of that business. “From a strictly commercial business perspective, unavailability of this isotope would have a dramatic impact on this industry,” Norenberg warned. “And it would mean not only patients getting delayed, or less optimal imaging procedures—but it would also impact jobs and support personnel, as well as the economic footprint that each of these nuclear pharmacies makes in their communities.”

In most major markets, shortages are still causing delays and brief periods of unavailability. As it stands now, these intermittent shortfalls have not caused widespread outages throughout the country—yet. If nothing is done, Delbeke and others say that less desirable studies will continue to be necessary, and more shortages will be inevitable. “This year, on several occasions, we have had these shortages,” Delbeke lamented. “And we have a radiopharmacy that supplies the isotope not only to our own nuclear medicine department, but also to the heart institute that we have here at Vanderbilt. The cardiologists are complaining heavily when they don’t get their supply. Certainly it is a crisis.”

Michael M. Graham, MD, PhD

Care and Consequences

Almost half (48%) of SNM survey respondents said that the August 2008 Netherlands reactor shutdown led to postponements of procedures. Almost 19% said procedures were canceled. For SNM president-elect Graham, shortages in rural Iowa were at their worst following the Canadian shutdown in December 2007. “In January 2008, we basically completely ran out of Tc-99m,” Graham said. “We had a generator that was 2 weeks old that we were limping along with, and we got to the point where we were able to do only one study on a particular Friday, down from our typical 20 to 30 studies per day. We almost had to shut down. Fortunately, we were finally able to get a new generator on Monday.”

Many sites—whether rural or urban—do not get generators, but instead receive tracers from central pharmacies. Graham in Iowa City, however, usually gets generators delivered twice a week. “For some time, we have been getting only one a week, and that is where we are at the moment,” Graham said. “Our generator is running down, so we are not able to get as much Tc-99m as we need. We are now doing most cardiac studies with thallium-201 instead of Tc-99m.”

Familiar problems in the supply chain are partly to blame. Industry watchers agree that reactor officials have not communicated adequately with generator producers, and generator producers have not communicated well to customers about impending shortages. “There is a role for an organization such as SNM to try to coordinate the maintenance schedules of the alternative reactors so that they are not all on the same schedule,” Delbeke said. “There is no coordination between these sites as far as their operation. Ultimately, a country like the United States and Europe should try to become independent and have their own source.”

While worst-case scenarios have so far been avoided, urgency increases with each passing year. “Shortages have not directly caused a patient death that I know of, but certainly there have been many cases where shortages have delayed critical medical imaging procedures,” Norenberg said. “There are options to go to second or third string choices, but we are not fielding our best resources when we do so.”

Greg Thompson is a contributing writer for Axis Imaging News.