5
Molybdenum-99/Technetium-99m Demand

The focus of this chapter is on the current and future demand for molybdenum-99 (Mo-99) in the United States. The committee’s objective is to address explicitly the first part of the second charge of its statement of task (Sidebar 1.2) to assess the “current and projected demand and availability of medical isotopes in regular current domestic use.” The second part of this charge on availability of medical isotopes was addressed in Chapter 3. The projected demand assessment focuses on potential changes in the demand for Mo-99/technetium-99m (Tc-99m) over the next 5 years in response to technical, medical, and demographic developments. The committee judged that the available data are insufficient to support projections over longer time periods.

CURRENT DEMAND FOR Mo-99

As discussed in Chapter 3, Mo-99 supply and demand are usually in balance when there are no production or other supply disruptions. The most recent and likely the most reliable estimates of current supply and demand for Mo-99 are 12,000 6-day curies per week globally and between about 5000 and 7000 6-day curies per week in the United States for the calendar year 2006 (NNSA and ANSTO, 2007).

As will be discussed elsewhere in this chapter, demand for Mo-99 in 2006 was below that for 2005 based on numbers of patient visits for nuclear medicine procedures. Patient visits were reported to be recovering in 2007 (AuntMinnie.com Staff Writers, 2008), so the current (2008) demand



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5 Molybdenum-99/Technetium-99m Demand T he focus of this chapter is on the current and future demand for molybdenum-99 (Mo-99) in the United States. The committee’s objective is to address explicitly the first part of the second charge of its statement of task (Sidebar 1.2) to assess the “current and projected demand and availability of medical isotopes in regular current domestic use.” The second part of this charge on availability of medical isotopes was addressed in Chapter 3. The projected demand assessment focuses on potential changes in the demand for Mo-99/technetium-99m (Tc-99m) over the next 5 years in response to technical, medical, and demographic developments. The committee judged that the available data are insufficient to support projections over longer time periods. CURRENT DEMAND FOR Mo-99 As discussed in Chapter 3, Mo-99 supply and demand are usually in balance when there are no production or other supply disruptions. The most recent and likely the most reliable estimates of current supply and demand for Mo-99 are 12,000 6-day curies per week globally and between about 5000 and 7000 6-day curies per week in the United States for the calendar year 2006 (NNSA and ANSTO, 2007). As will be discussed elsewhere in this chapter, demand for Mo-99 in 2006 was below that for 2005 based on numbers of patient visits for nuclear medicine procedures. Patient visits were reported to be recovering in 2007 (AuntMinnie.com Staff Writers, 2008), so the current (2008) demand 

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 MOLYBDENUM-/TECHNETIUM-m DEMAND for Mo-99 could be slightly higher than the 2006 estimates provided by the NNSA and ANSTO (2007) report. However, because of supply disruptions in 2007 and 2008 that were described in Chapter 4, it is not likely that all of the demand for Mo-99 in 2008 had been met. PROJECTED DEMAND FOR MOLYBDENUM-99 The projected demand for Mo-99 is of great interest to both current producers and to potential new producers. Future demand is unknowable in a strictly quantitative sense because it will be determined by events that have yet to occur and that cannot necessarily be predicted. Several factors that could affect projected demand growth are discussed in the following sections of this chapter. The committee used several sources of information to develop projected demand estimates for this report, including published estimates, estimates provided to the committee at its information-gathering sessions, and commercial market analyses. Some of the projected demand information gathered by the committee was provided under nondisclosure agreements. The committee has not disclosed any proprietary information in this report, but it has used proprietary information to “ground truth” its projected demand estimates. The information sources used to develop demand growth estimates are not strictly independent. The commercially available market analyses are based on information provided by Mo-99 producers, technetium generator manufacturers, pharmaceutical companies, and hospitals. Mo-99 producers and technetium generator manufacturers use these market analyses and other information to develop their own projected demand estimates for business planning purposes. Consequently, there is likely to be some circu- larity of information and reasoning reflected in these various estimates. A commercial market analysis prepared by Bio-Tech Systems, Inc. (Bio-Tech Systems, 2006)1 provides a detailed assessment of future demand for Tc-99m. These estimates are based on the analysis of the radiopharma- ceutical market, including the potential penetration of alternate imaging modalities that could substitute for Tc-99m in diagnostic imaging, as well as the impacts of demographic changes on the demand for imaging pro- cedures. Demand for Tc-99m is an accurate indicator of Mo-99 demand 1 The National Academies, at the committee’s request, purchased the global rights to this report. The committee was not able to evaluate the methods or data used by Bio-Tech Systems to develop the estimates contained in this report and therefore cannot vouch for their accu- racy. However, based on conversations with industry representatives, the committee judges that this report is generally viewed as an authoritative and valuable source of information on the diagnostic radiopharmaceutical market. The report is available in the public access file for this study.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM because (as noted in Chapter 2) Mo-99 is used exclusively for diagnostic medical imaging, and all of the Mo-99 produced for this purpose is incor- porated into technetium generators. Table 5.1 provides information on historical (2002–2005) and forecast (2006–2012) growth rates for nuclear medicine procedures. The table shows total nuclear medicine procedures in the United States, the subset of those procedures2 that utilize Tc-99m (Tc-99m procedures), and Tc-99m doses.3 Several important observations can be made from this information: • T c-99m was used in about two-thirds of all nuclear medicine pro- cedures performed in the United States in 2005; this ratio is expected to decline to slightly less than 60 percent by 2012 (although in absolute num- bers, there is a projected growth in procedures using Tc-99m). This relative decline is reflected by the slightly lower annual projected growth rates for T c-99m procedures (sixth column in Table 5.1) compared to the annual projected growth rates for all nuclear medicine procedures (third column in Table 5.1). According to Bio-Tech Systems, this decline will primarily be due to the increased use of fluorine-18 labeled fluorodeoxyglucose (FDG) for some imaging procedures. FDG is described elsewhere in this chapter. • Annual growth rates for Tc-99m dose utilization (last column in Table 5.1) are expected to increase at a slightly higher rate (about 1 per- cent) than the annual growth in Tc-99m procedures. This could reflect a change in the proportion of cardiology procedures (which are projected to decrease as a percentage of all Tc-99m procedures; in 2005 they comprised about 60 percent of such procedures) to other general nuclear medicine procedures. • Historical annual growth rates for Tc-99m doses were above 8 percent early in this decade but are projected to decrease to between about 4 and 6 percent between 2006 and 2012. This growth rate is below the projected rate of growth of Tc-99m generator sales (see Table 5.2), which are projected to increase between about 7.5 percent and 9.4 percent per year between 2006 and 2012. As noted in the tables, the growth in sales for Tc-99m dose utilization is not expected to keep pace with Tc-99m generator sales growth rates. The estimates for projected growth in Tc-99m from the Bio-Tech Systems report (4–6 percent) are slightly lower that the growth estimates 2 A nuclear medicine procedure is a medical procedure that utilizes medical isotopes such as Tc-99m. The terms “procedures” and “studies” are used interchangeably. A number of common Tc-99m procedures are listed in Table 2.1. 3 A T c-99m dose contains millicurie (mCi) quantities of Tc-99m. Typical Tc-99m doses for diagnostic imaging procedures range from about 15 to 30 mCi.

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TABLE 5.1 Historical (2002–2005) and Forecast (2006–2012) U.S. Demand for Nuclear Medicine Procedures, Tc-99m Procedures, and Tc-99m Doses Tc-99m Total nuclear Annual growth procedures as Annual growth medicine rate of nuclear Total Tc-99m % of nuclear Annual growth Total Tc-99m rate of Tc-99m procedures medicine procedures medicine rate of Tc-99m doses utilized dose utilization Year (millions) procedures (%) (millions) procedures procedures (%) (millions) (%) 2002 14.1 6.7 10.2 72.2 5.4 17.7 8.7 2003 15.3 8.3 10.7 70.0 5.0 19.1 8.0 2004 16.1 5.4 11.1 68.6 3.2 20.2 5.9 2005 16.9 4.7 11.3 66.8 2.0 21.1 4.6 2006 17.7 4.7 11.7 66.0 3.5 22.1 4.5 2007 18.7 5.8 12.1 64.5 3.4 23.0 4.0 2008 19.8 6.0 12.6 63.5 4.4 24.3 5.5 2009 21.1 6.4 13.2 62.7 5.0 25.7 6.1 2010 22.4 6.1 13.8 61.5 4.2 27.1 5.3 2011 23.8 6.3 14.3 60.2 3.9 28.5 5.1 2012 25.3 6.3 14.9 59.1 4.3 30.0 5.2 NOTES: Data on procedures and doses are rounded from the original source. The 2002–2005 data are historical estimates; 2006–2012 data are forecast estimates. SOURCE: Bio-Tech Systems (2006, Exhibit 1-10). 

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0 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM TABLE 5.2 Sales of Technetium in the United States, 2002–2012 Technetium generator sales % Growth Average price per % Growth Year ($ millions) (annual) dose Tc-99m ($) (annual) 2002 115.9 13.0 6.55 4.0 2003 129.9 12.1 6.80 3.8 2004 142.6 9.8 7.05 3.7 2005 154.3 8.3 7.30 3.5 2006 166.9 8.1 7.55 3.4 2007 179.3 7.5 7.80 3.3 2008 195.2 8.9 8.05 3.2 2009 213.6 9.4 8.30 3.1 2010 231.7 8.5 8.55 3.0 2011 250.6 8.2 8.80 2.9 2012 271.2 8.2 9.05 2.8 NOTES: Data on procedures and doses are rounded from the original source. The 2002–2005 data are historical estimates; 2006–2012 data are forecast estimates. SOURCE: Bio-Tech Systems (2006, Exhibit 1-11). that the committee received from the other sources, which range from about 5 to 8 percent per year. One respondent told the committee that it was using a growth rate that was roughly half that figure for prudent business planning purposes. The NNSA and ANSTO (2007) report cites an annual projected worldwide growth rate of between 5 and 10 percent. This is substantially higher than the other estimates obtained by the committee. However, the global potential for future growth is probably greater than that for the United States because of the large populations and relatively small market penetrations of nuclear medicine technologies. FACTORS THAT COULD AFFECT PROJECTED DEMAND There are several factors that could affect the projected demand growth for Mo-99/Tc-99m in the United States. For example: • Radiopharmaceutical market changes could affect supplies of (or prices4 for) Mo-99/Tc-99m. 4 Under ideal market conditions, as the price of an item increases, suppliers are willing to provide more units of that item because they can cover the increasing marginal costs of production. The Mo-99 production industry does not appear to follow this ideal condition, however. As price increases, companies can increase supply to a point at little or no additional marginal cost. However, once a company reaches its supply capacity, it cannot increase supply in the short run at any price.

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 MOLYBDENUM-/TECHNETIUM-m DEMAND • Changes in health care practices, such as insurance coverage for certain procedures, could affect the demand for diagnostic imaging. • Demographic changes, for example, the aging U.S. population, could affect the demand for medical care, including demand for diagnostic imaging procedures. • Some Mo-99/Tc-99m use could be displaced by other diagnostic imaging modalities. These factors are briefly described in the following sections. Changes in Radiopharmaceutical Markets There have been substantial changes in the technetium generator manufacturing market in the past decade as has already been described in this report: GE Healthcare dropped out of the technetium generator busi- ness in the United States in 1999, leaving the market to two companies: Mallinckrodt and Bristol-Myers Squibb (BMS). In 2008, BMS sold its medi- cal imaging business to a venture capitalist firm (Avista Capital Partners), and a reorganized company, Lantheus, was launched that same year. The departure of GE Healthcare from the technetium generator market in the United States has increased the pricing power of the remaining two companies. Indeed, the Bio-Tech Systems report notes that prices for Tc-99m have been advancing more rapidly since the exit of GE Healthcare from the market, and that BMS (now Lantheus) has been especially aggressive in raising its prices. Technetium generator price increases are being moderated to a certain extent by the long-term contracts that generator manufacturers have in place with many customers. Nevertheless, prices could increase substantially as these contracts expire and are renegotiated. Limits on Medicare and private insurance reimbursements for diag- nostic imaging procedures may help to moderate future price increases for technetium generators and Tc-99m. Reimbursements for diagnostic imag- ing procedures are made directly to hospitals and clinics; these organiza- tions, in turn, are responsible for allocating the costs of those procedures for materials, for example, Tc-99m, labor, and facility usage. Although T c-99m is generally a small part of the total cost of most diagnostic imag- ing procedures, the ability of technetium generating manufacturers (and Mo-99 producers) to increase prices will likely be limited by reimburse- ment rates for the diagnostic procedures themselves. Moreover, technetium generator companies and Mo-99 producers will have to compete with each other and with hospitals/clinics for a portion of any reimbursement increases. Vertically integrated producers such as Mallinckrodt may have more flexibility to set prices for Mo-99 because they also control pricing for technetium generators.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM Another recent and important market development is the early 2008 expiration of the patent owned by Lantheus for the diagnostic radiopharmaceutical Cardiolite (generic name sestamibi; see Table 2.1) that is used in cardiac perfusion5 procedures. Generic sestamibi radio- pharmaceuticals are now being introduced by several companies.6 The availability of generics is likely to have a substantial impact on prices for Cardiolite and other cardiac perfusion agents. Companies that produce and sell these agents might seek a higher return on Tc-99m sales to help maintain profits. However, Medicare and insurance company reimburse- ments may limit these efforts. Reimbursement for diagnostic imaging procedures covers the cost of Tc-99m, any associated radiopharmaceu- ticals, and the procedure. Any increase in the costs of producing or sell- ing Tc-99m might have to be absorbed by the producers or hospitals if reimbursement limits are not raised. Changes in Health Care Practices Changes in health care practices could have substantial positive or negative impacts on the demand for Mo-99/Tc-99m. There was a sub- stantial decline in patient visits for nuclear medicine procedures—from 17.2 million visits in 2005 to 15.2 million visits in 2006 (IMV Ltd.7; Forrest, 2007), presumably because of changes in health care delivery or administration practices. Although the committee is not able to evaluate the exact cause of this decrease, it was able to confirm that the reported reduction is real and also that recovery to date is incomplete. As the present report was in National Academies review, IMV reported8 that the number of patient visits for nuclear medicine procedures in the United States had increased by 3 percent to 15.7 million from 2006 to 2007. There are several other changes that are having a downside impact on nuclear medicine procedures, and especially cardiology procedures: • Reimbursement cuts mandated by the Deficit Reduction Act of 2005 (Public Law 109-171). Recently, Medicare announced that it had spent $1.8 billion less on imaging services in 2007 as a result of this act. 5 Bio-Tech Systems (2006) estimates that this myocardial imaging comprises almost 60 per- cent of all Tc-99m based diagnostic imaging procedures. 6 Bio-Tech Systems (2006) notes that Cardinal Health, Draximage, and Teva Pharmaceuticals are planning to introduce generic products for perfusion imaging. Cardinal Health received approval while the present report was in preparation. 7 The committee relied on a summary of this report published by IMV Ltd., IMV Medical Information Division, Des Plaines, Illinois and available at http://www.marketresearch.com. 8 The data were reported in an article published on AuntMinnie.com on November 11, 2008, entitled “IMV: Nuclear med procedures up in 2007.”

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 MOLYBDENUM-/TECHNETIUM-m DEMAND • Widespread acceptance of the updated and more restrictive 2007 Appropriateness Criteria of the American Society of Nuclear Cardiology (ASNC) and American College of Cardiology Foundation (ACCF) for per- forming cardiac nuclear stress tests.9 • Insurance company preapproval requirements for medical proce- dures, which are likely to spread. In this cost-constrained environment, there is limited support for the devel- opment of new nuclear medicine tracers or technology improvements in cameras, quantification, and reconstruction algorithms. Displacement by Other Diagnostic Imaging Modalities There are alternative imaging modalities that could potentially reduce the future demand for Tc-99m based radiopharmaceuticals. Some poten- tially important alternatives are discussed in this section. The committee has focused this discussion on current and potentially new imaging modalities for cardiac and bone scanning, because these procedures account for over 75 percent of Mo-99/Tc-99m use (Bio-Tech Systems, 2006). If there are substantial changes in Mo-99/Tc-99m demand over next 5 years they are most likely to occur because of changes in the numbers of these procedures. The remaining 25 percent of Mo-99/Tc-99m use is broadly spread among multiple clinical indications, such as kidney function, cerebral perfusion, lung perfusion, gastric function, bladder function, thyroid scanning, and joint imaging. The committee judges that, in aggregate, these studies are likely to remain numerically stable over the next 5–7 years. Of course, it is also possible that new Tc-99m kits (Table 2.1) could be developed over the next 5 years that would expand the use of this isotope for diagnostic imaging. The information in the following sections is based primarily on direct experience of the committee’s medical experts. Radioisotope Alternatives The most widely used radioisotopic alternative to Tc-99m for perfu- sion imaging is thalium-201 (Tl-201). Tl-201 has strong biologic features for use in cardiac imaging: when injected intravenously, it is perfused into cardiac muscle. This radionuclide has serious limitations, however. The energy of gamma emission (about 80 keV) is less than optimal for detec- tion with gamma cameras, so images are not as high quality as those for 9 ASNC/ACCF appropriateness criteria for Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging (SPECT MPI).

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM Tc-99m (which has a 140 keV emission). Tl-201 also provides relatively large radiation dose to the patient, especially to kidneys. Also, this isotope is normally produced in commercial cyclotrons and is relatively expensive to make compared to Tc-99m. Nevertheless, Tl-201 continues to enjoy a moderate but consistent application in cardiology, often in conjunction with T c-99m agents. However, there is no compelling reason for the current levels of Tl-201 use to markedly increase in nuclear cardiology applications except when there are prolonged shortages of Tc-99m generators. Positron Emission Tomography (PET) Imaging The use of positron emission tomography (PET) is expanding rapidly in the United States because it provides higher-resolution images than T c-99m scans, and because PET data provide more accurate quantitative information about underlying biologic processes (see, e.g., Kudo, 2007). At the present time there are between 1 million and 2 million PET proce- dures performed annually in the United States, and there are approximately 1600 U.S. sites registered as PET facilities with the Centers for Medicare & Medicaid Services (CMS).10 Although the pace of purchase of new machines has slowed markedly recently for economic reasons, the number of patients being imaged with PET is continuing to expand using current excess capacity, and the rate of growth of PET procedures is projected to continue to be in double digits through 2012. PET imaging could poten- tially compete with many of the common indications for which Tc-99m radiotracers are used. There are three PET radiotracers approved for use and reimbursable by CMS that could compete with Tc-99m in cardiovascular procedures. The most widely used is rubidium-82 (Rb-82), which is obtained from a strontium-82 (Sr-82)/Rb-82 generator (see Bateman et al., 2006).11 The primary advantage of Rb-82 over Tc-99m tracers is that perfusion reserve12 can be measured quantitatively. However, Sr-82 has a short half- life (25 days) and must be made in a commercial cyclotron of 70 MeV or more, and the Sr-82/Rb-82 generator system is expensive. Moreover, imag- ing is complex to perform and requires significant infrastructure. Most private cardiology practices do not have the infrastructure or capabilities to perform this procedure. 10 http://www.cms.hhs.gov/MedicareApprovedFacilitie/NOPR/list.asp 11 The short half-life of Rb-82 (75 seconds) requires that it be produced at the site of clini- cal use. It is obtained by elution from a generator loaded with the parent isotope Sr-82. This Sr-82/Rb-82 generator has the same general design concept as an Mo-99/Tc-99m generator. 12 Perfusion reserve is the capacity of flow through a blood vessel system in an organ under a stress or stimulus.

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 MOLYBDENUM-/TECHNETIUM-m DEMAND A second type of positron tracer that has been useful in measuring cor- onary perfusion is nitrogen-13 (N-13) ammonia. This radiotracer has about a 10 minute half-life and must be continuously produced on a hospital- based cyclotron. There are growing numbers of hospital-based cyclotrons that are being installed, and it is possible that N-13 ammonia will be more widely used in the future. However, this is unlikely to displace Tc-99m use in cardiology given the demographics of use and referral patterns. A third type of positron tracer that could have an impact on Tc-99m use in cardiology is fluorine-18-labeled FDG. FDG has been shown to have increased uptake in plaque, especially in the common carotid arteries but also in coronary arteries. FDG myocardial viability assessment has been performed for some time, but it is not used for perfusion assessment, which is the basis for Tc-99m use. A number of myocardial perfusion agents are also under development (Higuchi et al., 2008) that could potentially displace Tc-99m. F-18 labeled BMS-747158, for example, is a promising cardiac tracer because it is cleared largely in first pass in the myocardium in proportion to blood flow. This tracer will probably compete with Rb-82 myocardial imaging, but the committee judges that it is unlikely to have a major impact on nuclear cardiology practice and use of Tc-99m tracers over the next 5 years for the reasons described below. The bulk of nuclear cardiology procedures are performed in the offices of specially trained cardiologists, who have expertise in the use of the gamma camera and Tc-99m compounds, but have not extended their practice to PET. In addition, the economic cost of replacing the less expen- sive and clinically well-accepted gamma camera and technetium perfusion agents with PET is usually not cost-effective for the relatively low procedure volume that is common in many private cardiology practices. Also, PET requires additional training to interpret and the more complicated perfor- mance procedures require additional support personnel, such as medical physicists, in addition to the usual nuclear medicine technologists. According to the Bio-Tech Systems report (2006), about 50 percent of Tc-99m use is dedicated to cardiovascular applications. The major advantage of Tc-99m for routine cardiovascular procedures is that it can be performed readily in an outpatient setting as an adjunct to the cardiolo- gist office practice, the equipment is easy to maintain, and the images are generated by simple computer systems. There are a number of agents in preclinical development or are being evaluated in clinical trials under a Food and Drug Administration (FDA)- approved Investigational New Drug (IND) application. However, the com- mittee judges that these research radiopharmaceuticals will have little or no impact on the number of currently used Tc-99m labeled cardiology drugs during the next 5–7 years.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM Fluorine-18 (F-18) bone scanning is generally regarded by nuclear medicine experts as diagnostically superior to the use of Tc-99m methylene diphosphonate (MDP) with planar or even SPECT imaging (Apolo et al., 2008). The availability of more than 1,600 PET facilities in the United States has led to FDG production and distribution through a network of commercial cyclotrons. These facilities have excess capacity for the raw material of FDG production, namely F-18, and these manufacturers have a strong economic incentive to produce more F-18 labeled radiotracers. F-18 is easy and inexpensive to produce as a generic product and a United States Pharmacopeia monograph exists that describes well-accepted methodol- ogy as a clinical-grade product. This agent is attractive for bone scanning because it is a simple salt (NaF) with a simple chemistry. Moreover, before the introduction of Tc-99m MDP and like agents for bone scanning, F-18 was covered for bone scanning under an approved New Drug Application (NDA; see Sidebar 8.1) issued by the FDA. However, F-18 for bone scanning has been relatively slow to penetrate the oncology market for several related reasons: (1) The NDA lapsed and was withdrawn by the original manufacturer; (2) F-18 procedures are not reimbursed by CMS or most insurance companies because of a lack of clinical efficacy data that shows improved clinical benefit in comparison to Tc-99m MDP; and (3) despite having an approved NDA in the past, the FDA made a recent decision to require additional clinical data on effectiveness prior to reinstituting NDA approval. Recently, a consortium of radiopharmacy companies, instrumentation manufacturers, and profes- sional societies began development of a clinical trial comparing Tc-99m MDP and F-18 bone scanning for detection of metastases in patients with prostate, breast, and lung cancer. Data collection is projected to be com- pleted by 2010, and this information will be submitted to the FDA with the goal of obtaining an NDA as a basis for subsequent reimbursement requests through CMS. A likely timeframe for approval and the degree to which this will reduce Tc-99m MDP use for bone scanning is uncertain. As is the case with cardiovascular applications of Tc-99m compounds, the ease and simplicity of use and the ease of reimbursement of Tc-99m bone scanning agents in comparison to PET scanning has inhibited wide- scale implementation of PET bone scanning with F-18. The committee judges that before Tc-99m bone scanning will be replaced, the important technical, regulatory, and reimbursement hurdles described above will need to be addressed. Other Imaging Modalities Intra-arterial contrast coronary angiography has been considered the gold standard for detecting coronary artery disease. This is particularly use-

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 MOLYBDENUM-/TECHNETIUM-m DEMAND ful prior to surgery because the technique gives accurate information about coronary anatomy. The disadvantage of this technique is that it is invasive, requires relatively high doses of radiation as well as intra-arterial contrast, and is associated with both morbidity and mortality, albeit at relatively low rates. Because of its high negative predictive value, Tc-99m perfusion imag- ing is usually done prior to intra-arterial coronary angiography to reduce the number of patients who need this more complicated procedure. An advantage of Tc-99m perfusion imaging is the recent discovery that the site of blockage in acute coronary syndromes is often in arteries that are subcritical in terms of their stenosis,13 often a 30 to 40 percent reduc- tion in diameter of the involved vessel. This is related to the involvement of the wall of the artery and the destruction of the underlying endothelium to create an eccentric change in the vessel diameter. It is also thought that perfusion changes on Tc-99m stress imaging may reflect defects in the perfusion bed of these vessels even when their lumen, or lining, is not com- pletely compromised. Computed tomography (CT) imaging is becoming widely used for coronary angiography, in conjunction with calcium scoring that indicates where deposits of calcium are located in coronary arteries. Although many cardiology offices have purchased CT machines, their use for coronary angiography is still unproven, and there are technical problems, includ- ing interferences from calcium deposits in the coronary artery, that limit the sensitivity of this method. Moreover, CT angiography is likely to be complementary to Tc-99m radiotracer use, not a replacement technology because it provides no direct information about myocardial ischemia or left ventricular function. Other molecular imaging modalities that potentially could be used as replacements for Tc-99m include nanocarriers, magnetic resonance imaging (MRI), and ultrasound. MRI of the myocardium has been touted as being highly effective for exploring biochemistry and perfusion of the myocar- dium. MRI is ideally suited to the assessment of cardiac morphology, con- tractile function, myocardial perfusion, and infarction (Shah et al., 2005; Hudsmith and Neubauer, 2008).14 At the time of this writing, however, MRI per se has not made major inroads into clinical practice of evaluating cardiovascular patients in most parts of the United States. The reason for this probably reflects the lack of specialized expertise and equipment that would be required to replace what is current practice. In fact, in almost all instances, MRI, CT, and ultrasound are complementary to Tc-99m radio- tracer use, not competitors. 13 Stenosisis the abnormal narrowing of a blood vessel. 14 Fora recent review of this field, see also Nature Clinical Practice Cardiovascular Medicine (2008), Volume 5, Supplement 2: Cardiovascular Molecular Imaging for Clinicians.

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 MEDICAL ISOTOPE PRODUCTION WITHOUT HIGHLY ENRICHED URANIUM Demographic Changes Current estimates of the projected demand for Mo-99/Tc-99m are based primarily on demographic factors. The U.S. population is aging, and the front edge of the baby boomer generation is reaching retirement age. As this population continues to age, its needs for diagnostic imaging will likely increase. For example, with respect to cardiovascular use of T c-99m, as long as there are no major changes in the amounts of public and private insurance, it seems likely that patients will choose their indi- vidual cardiology providers, who will preferentially use the facilities that they are familiar with (such as Tc-99m radiotracers and gamma cameras) in the development of treatment plans. In part this is because of an inherent conservatism in regulatory patterns as well, which make it more difficult for new techniques, no matter how meritorious, to be widely accepted and reimbursed in less than about a 5-year timeframe. FINDINGS AND DISCUSSION With respect to the study charge to estimate current and future demand for Mo-99 in the United States, the committee finds that: • Demand for Mo-99 in the United States in 2006 fluctuated between 5000 and 7000 6-day curies (Sidebar 3.1) per week. • Estimates of future demand growth for Mo-99 evaluated by the committee range from about 3 percent to 10 percent. These estimates are for both U.S. and global demand. The committee judges that demand growth for Mo-99/Tc-99m in the United States could range from 0 percent to 5 percent per year for the next 5 years, with the most likely growth rate in the range of 3 percent to 5 percent per year. These estimates assume that there are no major disruptions in Mo-99/Tc-99m supplies and no major changes in health care policies or practices. • The demand growth for diagnostic imaging modalities will likely continue over the long term as the U.S. population ages. The extent that this will be reflected in demand for Mo-99/Tc-99m will depend strongly on whether other diagnostic imaging modalities take hold in the market. • During the next 5 years, imaging modalities (e.g., PET, CT, MR) that could potentially displace Tc-99m use for medical diagnostic imaging probably will not find widespread use in the United States. The current practice of favoring clinical use of Tc-99m radiopharmaceuticals will con- tinue for the foreseeable future. Note that global demand for Mo-99/Tc-99m could grow more rapidly than demand in the United States in the mid to long term as nuclear medi-

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 MOLYBDENUM-/TECHNETIUM-m DEMAND cine technologies find more widespread application, especially in develop- ing countries. At present, almost all of the Mo-99/Tc-99m produced in the world is consumed by developed countries. There is a huge potential market for these isotopes in those countries that hold most of the world’s peoples such as India and China. Their demand for Mo-99 will almost certainly increase substantially as the increasingly affluent segments of their popula- tions demand improved health care. The relative low cost and ease of use of Tc-99m installations that rely on conventional gamma cameras will give these modalities a competitive advantage over PET, CT, and MRI. What is not clear at this point is whether these developing countries will develop indigenous production of Mo-99 or will purchase this isotope on world markets. If countries choose to purchase Mo-99 there could be significant impacts on Mo-99 supplies, supply reliability (Chapter 4), and prices in the United States. Although these impacts are likely to occur on timescales that are beyond the 5-year focus of this report, they should be of intense interest to Mo-99 producers who are contemplating conversion from highly enriched uranium (HEU)- to low enriched uranium (LEU)- based production or the construction of new facilities. It seems likely that, absent the development of truly superior imaging technologies, there will continue to be a flourishing long-term global market for these isotopes. Finally, although it is beyond the scope of this report, decisions by devel- oping countries to produce Mo-99 domestically also have implications for HEU minimization. It will be important for the U.S. government, especially the Department of State and the Department of Energy-National Nuclear Security Administration, as well as the International Atomic Energy Agency to encourage these countries to take the LEU path for Mo-99 production.