Not a glowing outlook

When the medical isotope shortage hit its peak earlier this year, Manuel Brown, chairman of the radiology department at Henry Ford Hospital and Health Network in Detroit, remembers months when his staff didn't know from one day to the next whether they would be able to perform nuclear imaging studies.

“There were nights when we couldn't respond to demands from the emergency rooms for things like lung scans, which are used to diagnose pulmonary embolisms,” says Brown, who also chairs the American College of Radiology's Commission on Nuclear Medicine. “There were some nights when we only had enough isotopes for one study, or weekends when we couldn't do any. It was very difficult, and it became a real problem in terms of providing good care to patients.”

The worldwide isotope shortage—well documented by now—was caused by an unexpected shutdown of Canada's Chalk River (Ontario) nuclear reactor in May 2009 due to leakage of radioactive water. The facility, which remained closed for repairs until this past August, produces roughly half of the U.S.' supply of molybdenum-99, a uranium-processing byproduct used to produce the medical isotope technetium-99.

More than 80% of the 18 million nuclear imaging studies performed annually in the U.S. use technetium-99 as a contrast agent.

The shortage became even more urgent when a nuclear reactor in Petten, the Netherlands, shut down for months of maintenance work between February and September 2010. With two of the five medical-isotope-producing reactors in the world simultaneously offline, radiology providers were unable to access a sufficient supply of technetium.

As a result, hospitals and imaging centers had to postpone PET and other types of nuclear scans used to diagnose certain cancers and heart and brain conditions. In some cases, doctors and their patients had to opt for less effective imaging techniques, says Steven Larson, chief of nuclear medicine at New York's Memorial Sloan-Kettering Cancer Center.

“We reduced by 15% to 20% the amount of technetium we used in certain procedures, but that reduces optimal imaging,” he explains. “We also used some alternative isotopes, which had been replaced by technetium because it has advantages.”

The isotope shortage has eased in recent months with the reactivation of the Chalk River and Petten facilities, but nuclear-medicine experts say unless the U.S. pushes forward with developing a domestic supply of medical isotopes, the sort of problems experienced over the past couple of years are likely to revisit in a much more pressing fashion. They note that four of the reactors producing molybdenum-99 are aging and expected to be in operation for only a few more years. The Chalk River reactor, for example, is scheduled for permanent closure by 2016.

“I think the events of the past two years have really woken us up to what the future will be if we don't make a concerted effort to solve the problem,” says Andrew Einstein, assistant professor of clinical medicine at Columbia University Medical Center's cardiology division.

Efforts to create a domestic supply of molybdenum-99 are under way, but they face a variety of challenges, including a medical isotopes innovation bill that is stalled in the Senate, uncertain research and development outcomes and competitive-cost concerns.

The severity of the recent medical isotope shortage may have been tough to navigate, but it could hardly be characterized as surprising, nuclear-medicine experts say.

Domestically, an isotope shortage had been looming since 1990, when the Cintichem nuclear reactor in Tuxedo, N.Y., was closed because of leaks in the facility's concrete walls. That reactor was the only U.S. facility producing molybdenum-99. As a result, the U.S.—which performs more nuclear imaging procedures annually than any other country—must import nearly 100% of the molybdenum-99 used by radiopharmacists to produce the medical isotope technetium-99.

While the world's aging nuclear-reactor infrastructure puts providers and patients around the global in straits during a shortage, the U.S. is particularly hard hit because of geography. That's because molybdenum-99 has a half-life of just 66 hours and technetium of less than seven hours. As a result, medical isotopes can't be stockpiled. Neither can they weather significant transportation delays such as the ones experienced this past April when a volcano in Iceland cut off travel throughout Europe, preventing crucial deliveries of molybdenum-99 from reactors in Belgium and France.

“As far as the North American market goes, we know Canada will be offline in 2016 at the latest, and it's the only reactor in this area” that produces molybdenum-99, says Robert Atcher, chairman of the Society of Nuclear Medicine's Medical Isotope Task Force. “Relying on Africa and Europe only for a supply of isotopes is a nonstarter, because the transportation issues are too crucial.”

There are other issues highlighting the need for a domestic isotope supply, as well, not the least of which is concern over national security. Currently, four of the five reactors manufacturing molybdenum-99 process bomb-grade uranium—also called highly enriched uranium, or HEU—to create the byproduct. Only the reactor in South Africa is equipped to create molybdenum through the processing of low-enriched uranium, or LEU, which can't be used to manufacture nuclear weapons. As a result, the U.S. runs the risk of bomb-grade uranium getting into the wrong hands because it has to ship HEU overseas for processing.

“This is one scenario where we'd likely have a major interruption of supplies if there was terrorist activity,” Larson says. “I'm very concerned about bomb-grade uranium getting into the wrong hands. There's no reason we can't have production of medical isotopes within our borders.”

A bill passed by House of Representatives in November 2009 would address domestic-supply and nuclear-weapon proliferation concerns, advocates of the legislation say. But the bill has been stalled in the Senate for more than a year, and its fate is unknown.

Sponsored by Rep. Edward Markey (D-Mass.), the American Medical Isotopes Production Act of 2009 would allocate $163 million of the Energy Department's budget to go toward funding of medical-isotopes technology. The five-year appropriation would provide a 50% match of research, development and construction funds to U.S.-based companies that have developed promising technology for producing medical isotopes without the use of HEU. The bill also would fund the retrofitting of an existing U.S.-based nuclear reactor—still undesignated—transforming it from a HEU-processing facility to one that processes low-enriched uranium for the purposes of creating molybdenum-99.

The bill, which has had major bipartisan support, passed the House on a vote of 400-17 in November 2009. But it stalled in the Senate last January when Sen. Kit Bond (R-Mo.) blocked its movement to the floor for a vote.

A spokesman for Bond declined Modern Healthcare's request for an interview, saying the senator would respond to questions about his objection to the bill only via e-mail. But in an April 13, 2010 letter sent to Reps. Markey and Fred Upton (R-Mich.), ranking member of the House Subcommittee on Energy and Environment, Bond said he objected to a provision of the bill that would phase out the use of HEU in the production of medical isotopes over a period of seven to 13 years.

Under the law, the Energy Department would discontinue the issuance of licenses allowing HEU to be shipped overseas for production of molybdenum-99. The ban would begin seven years after the law takes effect, but department officials would have the discretion to postpone the ban for six additional years should they determine that domestic production doesn't meet the demand for medical isotopes. The bill also has a provision that would allow the ban to be lifted for up to a year should a critical shortage occur at any point in time.

Bond questioned, however, whether technologies funded now—some new and some proven—would be capable of meeting the domestic demand for medical isotopes within the seven- to 13-year window.

“I remain concerned that your bill's main strategy, a cutoff of the current nuclear medical supply chain, will deprive millions of American patients of the medicine they need to fight cancer, heart disease and other ailments when the bill's ban goes into effect,” Bond wrote in his letter.

The National Nuclear Security Administration “confirmed that a domestic supply of nuclear medicine necessary to meet future U.S. patient needs does not currently exist,” he continued. “They also confirmed that currently announced or shortly expected plans to construct new nuclear medicine production facilities would still fall 25% short of meeting U.S. patient needs when (the bill's) supply cutoff went into effect.”

But many supporters of the bill, including representatives of the NNSA, dispute Bond's assertion, and add that they are puzzled by his objection.

“We've refuted statements made by Bond in that letter, and the National Nuclear Security Administration supports the bill,” says a spokesman for Markey's office who agreed to speak only on condition of anonymity. “This doesn't seem to be a reality-based objection.”

A spokesman for the NNSA said the agency was unable to comment on the debate over the bill as its leading medical isotope expert, Parrish Staples, director of the Office of European and African Threat Reduction, was traveling and unreachable. But during a Sept. 9, 2009 hearing on the isotopes bill at the House Energy and Commerce Committee's Energy and Environment Subcommittee, Staples voiced the NNSA's support of the bill.

He noted, for example, that the National Academies had determined that there are “no technical reasons that adequate quantities (of medical isotopes) cannot be produced” without HEU. “We agree with the language of the proposed legislation, which makes clear that the U.S. should accelerate its efforts to convert HEU research reactors worldwide from the use of HEU,” Staples told lawmakers.

Some proponents of the isotopes bill suggest that Bond's reasons for stalling the legislation may have another motivation: That he could be hoping to provide officials at the University of Missouri's research reactor time to pull together resources to compete for a portion of the bill's funding.

When the isotope production bill was unveiled in 2009, many expected that the University of Missouri research reactor would compete for the funds allocated to transform an existing nuclear facility into a LEU processing center. But according to Atcher, who says he has had conversations with officials at the reactor, the university's leadership determined that the bill's matching-funds requirement made the venture too expensive and financially risky.

“In my discussion with the leadership there, they said they couldn't justify in the current economic atmosphere putting up $8 million for the first phase of the project when there's no guarantee they'd make it to the second phase,” says Atcher, who adds that university officials thus far have been unsuccessful in finding an investment partner willing to put up early-stage funding, let alone someone willing to pony up $50 million of the estimated $100 million it would cost to complete construction and technology changes on the reactor.

“They don't know if they'd make a transition from the first level of design and regulatory activity,” Atcher says, “and they aren't going to put university funds at risk.”

A spokesman for the Missouri research reactor says the university's policy is not to comment on pending legislation, but Atcher and others close to the issue say University of Missouri officials have expressed their support of the legislation both publicly and directly to Bond.

“My understanding is that they have spoken with Bond and reinforced that they are supportive of this regardless of whether” they can compete for the funding.

Passage of the isotopes production legislation is the most expedient way of spurring innovation and creating a U.S.-based medical isotopes industry, experts say. But the Energy Department has been able to fund a few new technology projects even without support of the bill. They include projects by GE Hitachi and a joint venture between medical-products manufacturer Covidien Healthcare and the energy-technology company Babcock & Wilcox Co.

The department provided GE Hitachi with 50% of a $4.5 million investment covering conceptual development and testing of a new technology that would use existing U.S.-based nuclear reactors to irradiate metal with naturally occurring forms of molybdenum instead of uranium to create molybdenum-99. The molybdenum-99 would then be placed into a generator that processes it into technetium-99.

Chris Monetta, senior vice president of GE Hitachi Nuclear Energy's advanced fuel cycle program, says one advantage of the new manufacturing technology is that it would create less hazardous chemical waste than current medical isotope manufacturing methods.

Covidien and Babcock & Wilcox have received Energy Department funding for an alternative isotope processing technology that would use a liquid solution to extract molybdenum-99 from LEU. The process would generate only about 1% of the radioactive waste currently created by processing HEU to create medical isotopes, according to Covidien officials. The technology also has the potential to supply roughly 50% of the medical isotopes used annually in the U.S., says Covidien spokesman Stephen Littlejohn.

While both of the developing technologies are promising, they each have their challenges, including whether they ultimately will pass muster with regulators and providers. The GE Hitachi approach, for example, would require newly designed generators in order to convert the molybdenum-99 into the contrast agent technetium-99. That could mean additional costs that are passed down the supply chain, but not necessarily covered by an increase in reimbursement from payers. But Monetta says that he expects GE Hitachi's technology to be cost-competitive.

“The fact is, we know the price is going to go up, and that's the price we have to pay to have a supply chain that is up-to-date and reliable,” Atcher says. “But there has to be recognition that, given the value of scans that we do using technetium-99, there should be some provision by insurers to make sure we can cover costs,” he adds. “The danger is, people will say, ‘I'm not going to do an imaging procedure that will cost me money.' They'll use CT or fluoroscopy or something else that is less beneficial to patient care.”

Covidien and Babcock & Wilcox's technology also has its drawbacks. According to a June 11, 2010 article, “The options for the future production of the medical isotope 99Mo,” appearing in the European Journal of Nuclear Medicine and Molecular Imaging, liquid molybdenum-processing is still an immature technology, and scientists are uncertain how reliable it is. They also are uncertain what level of resources would be required to meet supply-chain needs. As a result, the overall cost associated with liquid-processing technology also is uncertain, Littlejohn acknowledges.

But proponents for development of new medical isotope technology argue that cost concerns shouldn't be a barrier to creating domestic production. They note that the price of molybdenum-99 rose exponentially during the worldwide shortage and that there has been no decrease in those costs since the Canadian and the Netherlands reactors went back online. That's partly because nuclear medicine experts worldwide have acknowledged that government support of reactor facilities has kept the costs of molybdenum-99 artificially low, Atcher says.

As a result, there has been little incentive to create a U.S.-based isotope industry as companies here would not be able to be price-competitive without similar government support. “The Canadians are now saying, ‘We've basically subsidized the U.S. to the tune of $20 million annually,” Atcher says. “The other four production facilities are subsidized to some extent by their countries as well.”

As a result, Atcher says, worldwide authorities are discussing what type of price adjustments need to be made to create a more competitive medical isotopes market and, ultimately, spur technology development.

“The Nuclear Energy Agency is basically saying we need to raise the price of moly so that it more accurately reflects the expense of moly production.”

But Brown, of the Nuclear Medicine Commission, says, given the technology challenges and unsettled legislative questions, he is concerned the U.S. may be no closer to having a reliable domestic source for isotopes come the Canadian reactor shutdown in 2016.

“I'm not at all confident,” he says. “Maybe there will be some fast-tracking of this issue in the new Congress. I don't think we'll see progress during the current lame duck period because there are so many other crucial things that need to be addressed. Hopefully, the next Congress will make this a priority issue.”