Shortage of FDG raw material threatens expanded use of PET

Clinical development of positron emission tomography could behampered by an ongoing shortage of oxygen-18, the raw materialfor a widely used PET tracer. The shortage is forcing PET researchersto ration isotope supplies and cut back on studies just as third-partyreimbursement is opening the floodgates of clinical PET use.

"It's going to be a disaster if there's not another sourceavailable to supply (oxygen-18) in the U.S. in the near future,"said Dr. R. Edward Coleman, director of nuclear medicine at DukeUniversity Medical Center in Durham, NC. "The number of PETcenters is increasing rapidly and so is the amount of oxygen-18needed by those PET centers."

Few PET researchers would disagree with Coleman about the seriousnessof the oxygen-18 shortage. Centers that need the isotope are beingput on a waiting list up to a year long, and often must cut backon the amount they order.

The reasons for the shortage are more complex, however, andtouch on the larger issue of the federal government's role inmeeting the nation's demand for stable and radioactive isotopes.That issue has sparked an ongoing feud between the U.S. Departmentof Energy (DOE) and Isotec, a Miamisburg, OH-based firm that isthe only U.S. supplier of oxygen-18.

Oxygen-18 is a stable isotope that is the cyclotron targetmaterial for fluorine-18, which in turn is the raw material for18-fluorodeoxyglucose. FDG-18 is used in over 90% of clinicalPET studies.

Problems with oxygen-18 supplies began several years ago, afterthe DOE closed down its Isotopes of Carbon, Oxygen and Nitrogen(ICON) facility at Los Alamos National Laboratory in New Mexicoin 1989.

The ICON plant consisted of a distillation column sunk 500feet deep into the ground. The column cryogenically distillednitrous oxide into oxygen-18-enriched water, which was then sentto PET facilities around the country for refinement into fluorine-18and FDG-18.

The DOE cited insufficient demand as the reason for its pullout,which left Isotec and an Israeli company as the world's principaloxygen-18 producers. Russia and China also have oxygen-18 facilities,but until very recently did not export isotopes.

The oxygen-18 market did not become severely squeezed untilAugust 1990, when Iraq's invasion of Kuwait threw the Middle Eastinto turmoil and forced the Israelis to shut down their oxygen-18plant, according to Vincent L. Avona, president of Isotec.

"You weren't getting any commercial freight planes flyingin that area of the world. Insurance rates were astronomical,nobody was going to freight stuff in and out of the country,"Avona told SCAN. "Nothing could move at all."

Isotec's share of the world's commercial oxygen-18 market surgedfrom one-third in 1989, when the DOE was still in the market,to over 90% after the Israelis shut down. Given the increasedclinical interest in PET, the company simply did not have thecapacity to meet demand, Avona said.

The Israeli facility is now operating again, but has yet tocatch up with a daunting backlog of orders.

PET industry agitation for another source of oxygen-18 hasprompted the DOE to consider reentering the business, this timeby finding a private company to restart and operate the closedICON facility. But in another twist to the story, Isotec petitionedto block the DOE from producing a number of isotopes, among themoxygen-18. The company based its petition on federal Atomic EnergyCommission guidelines that discourage the government from competingwith private isotope suppliers.

The petition led to a running battle between the DOE and Isotec,fought mostly in the pages of the Federal Register, where Isotec'spetition was published last year. Public comments solicited onthe issue reflected the anger of many clinicians upset at Isotec'sattempt to maintain a monopoly on a market it could not adequatelyserve.

The DOE issued a final notice in June 1992 denying Isotec'spetition. The agency cited Isotec's difficulty in meeting demandas the primary reason for its decision.

"The (public) comments note the past and current inabilityand question the future ability of (Isotec)...to meet future demandsover time," the DOE stated. "DOE believes that its removalfrom the actual or potential production and distribution of (isotopes)could aggravate market instability."

For its part, Isotec maintains that it filed the petition inan attempt to prevent the DOE from undercutting the substantialinvestment the company has made in building new isotope productionplants. In addition, the company filed its petition almost a yearbefore the oxygen-18 shortage became critical. Because of bureaucraticdelays, the petition was published in the Federal Register duringthe height of the shortage, according to Avona.

With Isotec's petition out of the way, the DOE's effort tofind a company to run the ICON plant has moved forward. Representativesfrom several firms toured the facility this summer, and the DOEis negotiating with one company that has expressed interest inthe operation.

It would take about a year from the time a contract is signedto get the ICON plant up and running, according to a DOE official.The plant could double the supply of oxygen-18, the official said.

Isotec is also working to expand its capacity, according toAvona. The company's third distillation column was completed thissummer and is now producing oxygen-18. Two more columns are beingbuilt and will come on-line in late 1994.

The increased production capacity made possible by Isotec'sthird distillation column is enabling the company to fill muchof the backlog of orders for oxygen-18. The shortage should beginto ease by spring of 1993, according to Avona.

"We've been working very hard to eliminate the backlog,"Avona said. "The wait should be reduced to just three orfour months, instead of a year."

Another company, Siemens' joint venture CTI PET Systems (CPS)of Knoxville, TN, is developing a cyclotron add-on module thatwill enable owners of Siemens cyclotrons to recycle oxygen-18-enrichedwater. The module can recover between half and three-quartersof the water used. It will be available on new Siemens cyclotronsand as a retrofit to existing systems in January, according toa company spokesperson.

A sister company of CPS, CTI Services, is working with foreignisotope producers to import oxygen-18, the spokesperson said.

The oxygen-18 shortage is just one in a series of difficultiesnuclear medicine has experienced in maintaining a steady supplyof stable and radioactive isotopes. In many cases, those difficultiesare related to the DOE's gradual withdrawal from isotope productionover the past several decades as commercial suppliers enter themarket. As problems arise with conventional isotope stocks, theDOE must scramble to find ways to meet demand.

In July, the world's supply of technetium-99m was nearly cutoff by a labor dispute at a Canadian nuclear reactor (SCAN 8/12/92).The reactor produces the vast majority of molybdenum-99, the rawmaterial for technetium-99m.

The DOE is planning to restart a research reactor, also atLos Alamos, to create a domestic source for molybdenum-99. DOEofficials expect to have the reactor producing molybdenum by April1993.

The DOE has also been ordered by Congress to conduct a projectdefinition study for a National Biomedical Tracer Facility (seestory, page 3). The NBTF, which is being strongly promoted bynuclear medicine specialists, would be dedicated to the productionof radiopharmaceuticals used in nuclear medicine.

Decisions by several third-party payers to reimburse for PETscans have contributed to the increase in clinical usage of themodality (SCAN 10/7/92). In addition, the Health Care FinancingAdministration could approve Medicare reimbursement for PET earlynext year, according to Michael McGehee of the Institute for ClinicalPET in Washington, DC. HCFA's action will most likely come aftera Food and Drug Administration ruling on FDG-18.

The FDA is in the final stages of its review of FDG-18, themanufacture of which had first been regulated as part of the practiceof pharmacy. In May an FDA advisory panel found FDG-18 safe andeffective for evaluating suspected epilepsy, establishing myocardialviability and localizing brain tumors (SCAN 7/1/92). Final FDAaction is expected by the end of the year.

The FDA and HCFA decisions will set off a surge in PET usagethat could strain production capacity even further.

"Next summer is going to be the most difficult time,"McGehee said. "Medicare reimbursement will come in the spring,and then we're looking not only at the purchase of machines, butat the same time existing facilities will certainly increase theirvolume as reimbursement is granted. That is going to stress thewhole system."