4

Medicine

 

INTRODUCTION

Nuclear medicine is a specialty that involves the use of radiopharmaceuticals (a radionuclide either by itself or attached to a molecule) in conjunction with highly specialized imaging instrumentation to detect the radionuclide emissions in the body after oral, inhalation, or intravenous administration. Radiopharmaceuticals may be used to assess normal physiologic processes, diagnose and treat diseases, measure the distribution of drugs, and monitor treatment effectiveness.

Fostered by unique partnerships between national laboratories, academia, and industry, the field of nuclear medicine has evolved over the past 55 years through advances in imaging instrumentation, radionuclide production, and radiopharmaceutical development. Nuclear reactors and particle accelerators have been developed to produce a wide array of radionuclides for diagnostic and therapeutic applications; innovative chemistry and automated synthesis devices have been designed to produce a multitude of new radiopharmaceuticals for imaging and treatment; and high-resolution and high-sensitivity instrumentation has been advanced for detection of radiopharmaceutical distributions in living systems, from small animal models to humans.

Radiochemistry is used in nuclear medicine to combine elemental radionuclides with biologically active chemical compounds to form radiopharmaceuticals. These agents are designed to trace specific metabolic or biologic pathways and localize to specific organs or sites of disease. Instruments with external detectors—such as gamma cameras, single photon emission computed tomography (SPECT), or positron emission tomography (PET) scanners—then produce an image of the distribution of radioactivity in the living system. Radiopharmaceuticals have been developed to study a wide range of normal processes and disease states, including normal brain function, aging, neurodegenerative diseases, cardiovascular disease, and cancer.



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4 Medicine INTRODUCTION Nuclear medicine is a specialty that involves the use of radiophar- maceuticals (a radionuclide either by itself or attached to a molecule) in conjunction with highly specialized imaging instrumentation to detect the radionuclide emissions in the body after oral, inhalation, or intravenous administration. Radiopharmaceuticals may be used to assess normal physi- ologic processes, diagnose and treat diseases, measure the distribution of drugs, and monitor treatment effectiveness. Fostered by unique partnerships between national laboratories, aca- demia, and industry, the field of nuclear medicine has evolved over the past 55 years through advances in imaging instrumentation, radionuclide produc- tion, and radiopharmaceutical development. Nuclear reactors and particle accelerators have been developed to produce a wide array of radionuclides for diagnostic and therapeutic applications; innovative chemistry and auto- mated synthesis devices have been designed to produce a multitude of new radiopharmaceuticals for imaging and treatment; and high-resolution and high-sensitivity instrumentation has been advanced for detection of radio- pharmaceutical distributions in living systems, from small animal models to humans. Radiochemistry is used in nuclear medicine to combine elemental radionuclides with biologically active chemical compounds to form radio- pharmaceuticals. These agents are designed to trace specific metabolic or biologic pathways and localize to specific organs or sites of disease. Instru- ments with external detectors—such as gamma cameras, single photon emis- sion computed tomography (SPECT), or positron emission tomography (PET) scanners—then produce an image of the distribution of radioactivity in the living system. Radiopharmaceuticals have been developed to study a wide range of normal processes and disease states, including normal brain func- tion, aging, neurodegenerative diseases, cardiovascular disease, and cancer. 49

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50 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE The field of nuclear medicine is highly diverse and multidisciplinary, but nuclear and radiochemistry are the core disciplines because radiophar- maceuticals are integral to every nuclear medicine study. The workforce for the field of nuclear medicine consists of personnel at all levels of education (B.S., M.S., Ph.D., Phar.M.D., and M.D.) in academia, industry, and gov- ernment laboratories. In academia, nuclear and radiochemistry expertise involving nuclear medicine is mainly found in radiology departments, not in chemistry departments. Those performing nuclear and radiochemistry in the field of nuclear medicine are trained in a wide variety of disciplines and may receive on-the- job training. The field of nuclear medicine is growing rapidly, and properly trained workers will be essential for continued success in this important area of modern health care. A BRIEF HISTORY OF RADIOPHARMACEUTICAL DEVELOPMENT1 The use of radioactivity in medicine started with Wilhelm Röntgen, who discovered x-rays in 1895. A week after his discovery, Röntgen took an x-ray of his wife’s hand, clearly revealing her wedding ring and bones. In 1901 he was awarded the Nobel Prize in Physics for his innovation. In 1934, building on the work of the Pierre and Marie Curie, their daughter Irène and her husband, Frédéric Joliot, created radioactive elements by irradiating stable isotopes with alpha particles. At the time there was significant interest in the use of radioactive materials in medicine and this discovery allowed for the quick, economic creation of radioactive materials in larger quantities. Based on these discoveries, Irène and Frédéric Joliot- Curie won the Nobel Prize in Chemistry in 1935. The important research of the Joliot-Curies is in many ways the foundation of modern nuclear medicine and radiopharmaceutical research, as the production of radionuclides by bombarding stable isotopes with various types of particles is the key method of production of many of the most widely used radionuclides for nuclear medicine imaging and therapy. George de Hevesy followed up on the work by the Joliot-Curies with his Nobel Prize–winning research on the use of radionuclides as tracers in the study of chemical processes, which paved the way for the development of radiopharmaceuticals that trace biochemical and physiological processes in vivo but do not produce any pharmacological effects. The invention of the cyclotron in the early 1930s by Ernest Lawrence paved the way for the discovery of many biologically relevant artificially For more information, see www.accessexcellence.org/AE/AEC/CC/historical_background. 1 php [accessed July 5, 2012].

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51 MEDICINE produced isotopes (e.g., iron-59, iodine-131, and technetium-99m) that have become invaluable nuclides for nuclear molecular imaging and therapy. John H. Lawrence, a physician, used his brother Ernest’s radioisotopes in humans, treating a leukemia patient in 1937. John was also one of the early presidents of the Society of Nuclear Medicine (1966-1967). A colleague of the Lawrence brothers, Joseph G. Hamilton, coined the term “nuclear medicine” after observing John’s treatments of people with radionuclides. In the late 1930s, Hamilton asked Nobel Laureate Glenn Seaborg if he could create a radioactive isotope of iodine with a half-life of about a week for studying thyroid metabolism, and Seaborg promptly produced radioiodine (iodine-133 or 131I), which is still used for imaging and therapy of thyroid diseases. After World War II there was enormous growth in the field of nuclear medicine. In 1946, a New York internist, Dr. Samuel M. Seidlin, together with colleagues Leo Marinelli and Eleanor Oshry at Montefiore Medical Center in New York City, treated and cured a patient with thyroid cancer using 131I obtained from Oak Ridge National Laboratory. This work was published in the Journal of the American Medical Association (Seidlin et al. 1946) and produced a flurry of publicity. After this, there were almost yearly discoveries in the new field of nuclear medicine, in both chemistry and phys- ics. The development of instruments to detect the various decays of radio- nuclides went hand in hand with new discoveries in radiopharmaceuticals. No one could have predicted how valuable the cyclotron would be- come to modern molecular imaging for the production of a variety of ra- dionuclides, especially the short-lived positron-emitting isotopes of carbon, nitrogen, oxygen, and fluorine. The availability of both small academic- and hospital-based cyclotrons spurred growth of the field and now regional cyclotron facilities have increased the availability of PET tracers, mostly through the production and distribution of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]fluorodeoxyglucose, FDG), the most widely produced and indispens- able molecular imaging agent. Figure 4-1A shows the international growth in publications about FDG since 1990. Figures 4-1B and 4-1C show the growth in publications for newer areas of nuclear medicine involving Fluorine-18 and Gallium-68. While the growth for both of these new areas is dominated by German- and U.S.-authored papers, more recently many other countries mostly in Europe and Asia are now contributing to the steep growth in num- bers of publications in these areas. RADIONUCLIDE PRODUCTION There are three major sources for the production of radionuclides for nuclear medicine applications—particle accelerators (linear and cyclotrons),

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52 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE A 900 China 800 England Germany 700 Japan Numuber of FDG Articles 600 United States All Countries 500 400 300 200 100 0 2000 2006 2004 2005 2008 2009 2003 2002 2007 2001 1990 1996 1998 1999 1994 1995 1992 1993 1997 1991 2010 Publication Year 4-1A.eps 1600 B China 1400 France Number of of Fluorine-18 or (18)F Papers England 1200 Japan Germany 1000 United States All countries 800 600 400 200 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Publication Year 4-1B.eps

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53 MEDICINE C 160 China 140 Number of of Gallium-68 or (68)Ga Papers England 120 Italy United States 100 Germany 80 All Countries 60 40 20 0 2000 2006 2004 2005 2008 2009 2003 2002 2007 2001 1990 1996 1998 1999 1994 1995 1992 1993 1997 1991 2010 Publication Year FIGURE 4-1 Keyword search of journal articles by country for nuclear medicine re- 4-1C.eps lated keyword, 1978-2010. (A) fluorodeoxyglucose (FDG), (B) Fluorine-18 or (18)F, (C) Gallium-68 or (68)Gallium. SOURCE: Web of Science keyword search, 2011. nuclear reactors, and radioisotope generators. Most radioisotopes used for radiodiagnostics and radiotherapeutics are produced by cyclotrons. Figure 4-2 shows the distribution of cyclotron facilities across the United States. As of October 2011, there are over 150 cyclotrons in the United States that are operated by commercial entities, universities, or hospitals producing radio- pharmaceuticals for PET centers (B. Clarke, SNM, personal communication, 2011). In addition to cyclotron-produced radioisotopes, nuclear reactors produce medical radioisotopes by either separation of isotopes from the fission materials (for example, 125/131I and 99Mo) or through neutron activa- tion of stable isotopes (for example, 64Cu from 64Zn, or natural Zn targets). A listing of the common PET, SPECT, and radiotherapeutic isotopes used in nuclear medicine is provided in Table 4-1. RADIOPHARMACEUTICAL CHEMISTRY There are many aspects of the field of radiopharmaceutical chemistry, including radionuclide production, organic chemistry, inorganic chemistry,

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54 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE FIGURE 4-2 Map of U.S. commercial PET radiopharmacies using small, self-shielded cyclotrons that supply PET imaging probes for molecular imaging diagnostics used in patient care and research (does not include 4-2.eps cyclotrons at medical schools). bitmap SOURCE: B. Clarke, Society of Nuclear Medicine, personal communication, 2011. biological chemistry, radiochemistry, automation (engineering), and regula- tory science. The evaluation of novel radiopharmaceuticals in biological assays and animal models is vital to the successful translation of new agents into human studies. Prior to human studies, one must have knowledge of the production of radiopharmaceuticals for human use, which includes un- derstanding federal regulations regarding production of the cold substrate, radionuclide, and radiopharmaceutical under good manufacturing practice guidelines. One must also have knowledge and proficiency in the safe han- dling of radioactivity—that is, radiation safety. Box 4-1 describes the various steps in the preparation of a radiopharmaceutical. Radiopharmaceutical Research and Development The development of radionuclide production requires extensive knowl- edge of nuclear reactions by bombardment of particles onto targets on a biomedical cyclotron or bombardment of neutrons on targets in a nuclear reactor. It is essential to apply nuclear and radiochemistry principles to maxi- mize yields and to set the energies of the bombarding particles to optimize yields of the desired radionuclide and minimize production of longer-lived

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55 MEDICINE TABLE 4-1 Widely Used Positron Emission Tomography, Single Photon Emission Computed Tomography, and Therapeutic Radionuclides for Imaging and Radiopharmaceutical Preparation Production Method Isotope Parent/Stable Isotope Half-life Positron Emission Tomography Radionuclides Fluorine-18 cyclotron (oxygen-18) 110 min Carbon-11 cyclotron (nitrogen-14) 20 min Nitrogen-13 cyclotron (oxygen-16) 10 min Oxygen-15 cyclotron (nitrogen-14/15) 122 s Copper-64 reactor (zinc-64) 12.7 h cyclotron (nickel-64) Gallium-68 generator (germanium-68) 68 min Rubidium-82 generator (strontium-82) 75 s Zirconium-89 cyclotron (yttrium-89) 3.3 d Iodine-124 cyclotron (tellurium-124) 4.2 d Single Photon Emission Computed Tomography Radionuclides Gallium-67 cyclotron (zinc-68) 78 h Technetium-99m generator (molybdenum-99) 6h Indium-111 cyclotron (cadmium-111) 2.8 d Iodine-123 cyclotron (xenon-124) 13.2 h Iodine-131 reactor (tellurium-130) 8d Thallium-201 cyclotron (thallium-203) 3.1 d Therapeutic Radionuclides Yttrium-90 reactor (strontium-90) 2.7 d Iodine-131 reactor (tellurium-130) 8d Lutetium-177 reactor (ytterbium-176) 6.7 d Rhenium-186 reactor (rhenium-185) 3.7 d Strontium-89 reactor (strontium-88) 50.5 d Samarium-153 reactor (samarium-152) 46.3 h SOURCES: Cyclotron (2010); IAEA (2003, 2009); Unterweger et al. (2010). byproduct radionuclides. A strong knowledge of targetry and separation chemistry is essential in order to produce high purity products. A solid working knowledge of organic chemistry combined with radio- chemistry is required for the design of radiopharmaceuticals labeled with radiohalogens (for example, 18F and radioiodines) and 11C. In the past 40 or more years, there have been a large number of 18F- and 11C-labeled small molecules designed for imaging of cancer, cardiovascular disease, and neurological diseases. While there are a substantial and growing number of PET radiopharmaceuticals that are FDA approved under an Investigational New Drug (IND), only FDG has been approved by FDA for use in patient care under a New Drug Application (NDA). Examples of PET radiopharma- ceuticals under FDA INDs include probes for imaging Alzheimer’s plaques (Nelissen et al. 2009; Rowe et al. 2008; Wong et al. 2010), cellular prolif-

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56 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE BOX 4-1 PREPARATION OF A RADIOPHARMACEUTICAL There are a number of components that comprise the preparation of radiopharmaceuticals for clinical and research applications. Using fluorine-18 (18F)-labeled fluorodeoxyglucose (FDG) as an example, the production process is highlighted below along with the radiochemistry emphasis areas that are associated with each part of the process. Radionuclide Production •  Areas of expertise involved in this stage: cyclotron engineer and targetry chemist Particles are accelerated by an accelerator (cyclotron, linear accelerator) or nuclear reactor react Box4-2A.eps with the stable isotope nucleus to give an excited compound nucleus that emits a particle yield- bitmap ing the radioactive isotope. Source: Image credits: The Crump Institute for Biological Imaging, Department of Pharmacology, University of California at Los Angeles. Brain & Mind. 2008. The cyclotron and PET [online]. Avail- able: http://www.cerebromente.org.br/n01/pet/petcyclo.htm [accessed March 7, 2012]. Radiopharmaceutical Chemistry •  Areas of expertise involved in this stage: radiochemist and nuclear pharmacist. OAc OH OTf O O AcO HO AcO HO 18F 18F- OAc OH FDG SOURCE: Henry VanBrocklin.

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57 MEDICINE Fluorine-18 fluoride ion from the cyclotron is reacted with the 2-deoxymannosetriflate precursor. The 18F-fluorodeoxyglucose tetraacetate intermediate is deprotected to give FDG. Automated chemistry synthesis units have been developed to provide reliable and reproducible batches of the radiopharmaceuticals and enhance chemist radiation protection. SOURCE: Henry VanBrocklin. Box4-2C.eps Quality Control bitmap •  Areas of expertise involved in this stage: radiochemist and nuclear pharmacist. SOURCE: Henry VanBrocklin. Box4-2D.eps The quality of every dose preparation must be assessed prior to injection into the patient. A series bitmap of tests are conducted to assure that the product is sterile and free of contaminants that might be harmful to the patient. (continued)

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58 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE BOX 4-1 Continued Patient Injection and PET Imaging •    reas  of  expertise  involved  in  this  stage:  nuclear  medicine  technologist,  nuclear  medicine  A physician, and medical physicist. SOURCE: A.D.A.M.,Box4-2E.eps Inc. bitmap Ten to twenty millicuries (mCi; 370-740 MBq) of FDG are injected intravenously 30 minutes prior to PET imaging SOURCE: Henry VanBrocklin Box4-2F.eps PET and CT scans following the injection ofbitmap FDG. Prominent FDG uptake is seen in the heart and brain because these are areas of high glucose metabolism. The fused PET/CT image combines the functional and anatomical scans in one image.

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59 MEDICINE eration (Bading and Shields 2008) and hypoxia in cancer (Chitneni et al. 2011), and blood flow for cardiovascular disease (Maddahi et al. 2011) (see the Clinical Applications section later in this chapter). Expertise in inorganic chemistry and radiochemistry has produced a burgeoning development of radiopharmaceuticals labeled with metal radio- nuclides, such as 68Ga, 64Cu, and 89Zr. A critical component of developing these radiometal-labeled agents is the design of chelators that form stable complexes of the radiometals in vivo. This occurs as the release of radiomet- als causes a high uptake in radiation-sensitive tissues such as bone marrow, and results in poor target-tissue contrast due to high accumulation of the radiometals in blood and liver (Wadas et al. 2010). Many of the current clinical SPECT radiopharmaceuticals are 99mTc chelates. Altering the chelate backbone structure has led to a variety of imaging probes for bone, tumor, and heart and for brain blood flow. Throughout the field of radiopharmaceutical chemistry is the theme of interweaving nuclear and radiochemistry with an understanding and practi- cal knowledge of biochemistry, cell and molecular biology, and medicine. When modifying a known biological targeting molecule with either a radio- halogen (for example, 18F or 123I) or a radiometal (for example, 68Ga, 64Cu, Zr, or 99mTc) chelate, one must first determine that the biological activity 89 of the new compound is not significantly altered from that of the parent molecule. The biodistribution in normal rodents is performed to demonstrate that the agents do not accumulate in non-target tissues. This is followed by evaluation of the radiopharmaceutical uptake in target or diseased tissues. Validation that the radiopharmaceutical is specifically accumulating in its target tissue often requires use of microscopic techniques such as immu- nohistochemistry. Many iterations of optimizing the overall chemistry and specific radiochemistry followed by a biological evaluation is often required prior to choosing an agent for initial testing in humans. Moving agents into the clinic often requires collaborations of nuclear and radiochemists with cancer biologists, neuroscientists, and clinicians of various specialties. How- ever, while it is important that nuclear and radiochemists embrace the many disciplines within the field of radiopharmaceutical sciences, the primary expertise of nuclear and radiochemistry is critical for success of this field. Clinical Applications For nuclear medicine imaging, a radiopharmaceutical is administered to the patient (typically intravenously) and a scanner that detects radioactivity in the patient is used to show the uptake of the tracer. Nuclear medicine images provide quantitative data on the biochemistry of normal tissues and disease conditions in living subjects in contrast to the anatomical imaging

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62 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE BOX 4-2 Continued primary goals of Ph.D. radiochemists in academia are in the areas of research and education. Many of these positions are as tenure track faculty members and involve having a research group that includes undergraduate students, gradu- ate students, postdoctoral trainees, and technicians. These faculty members may also teach courses in the area of imaging and nuclear medicine. Faculty members who are engaged in nuclear medicine research also either work at or direct cyclotron/PET facilities that produce radiopharmaceuticals for routine clinical studies and pre-clinical and clinical research. Aside from being a faculty member of a university, other career opportunities are as support staff that supervise or work in the PET/cyclotron facilities and also perform research in the labs of the faculty members. Nuclear pharmacists are also employed by academic universities and medical centers. Government careers. The DOE national labs and the National Institutes of Health (NIH) employ nuclear and radiochemists involved in nuclear medicine research. NIH currently has at least six groups that are located in the National Institute of Biomedical Imaging and Bioengineering, the National Cancer In- stitute, the National Institute of Mental Health, the National Heart Lung and Blood Institute, and the NIH Clinical Center. These groups employ nuclear and radiochemists for developing radiopharmaceuticals for various diseases. These positions are typically either technical support or Ph.D.-level jobs that are re- search oriented. The focus of the national labs has shifted in the past several years away from biomedical research into the area of using radiotracers for energy-related research. To determine the number of nuclear and radiochemists involved in nuclear medicine, the committee initially looked at a report on the nuclear medicine scientist workforce completed in 2006 by the SNM (Center for Health Workforce Studies, 2007). The report included survey data on physi- cians, nuclear pharmacists, physicists, and chemists. Out of the 898 survey respondents who indicated they were active in nuclear medicine science, 122 participants identified themselves as chemists. Those participants were asked to provide further information about their sub-specialization in chem- istry, and, 36.9 percent selected radiochemistry as their major area of inter- est while an additional 21.3 percent indicated organic chemistry as their subspecialty. To follow up on the 2006 survey and obtain more recent data, this com- mittee received input (Table 4-2) from the radiochemist and nuclear pharma- cist members of the SNM Radiopharmaceutical Sciences Council (RPSC) and

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63 MEDICINE TABLE 4-2 Results of a Questionnaire Sent to Nuclear Medicine Radiochemists by the Society of Radiopharmaceutical Sciences/ Radiopharmaceutical Sciences Council of the Society of Nuclear Medicine No. of Yes % Yes Responses Responses U.S. Respondents (110) Use radiotracers as part of job 107 97% Highest degree Ph.D. 78 72% Primary discipline (nuclear, chemistry, radiochemistry, 36 34% or radiopharmacy) Employed in academia 58 55% industry 22 21% medical facilities 9 9% Hold faculty appointment 73 69% in a radiology dept 39 58% in a chemistry dept 4 5% SOURCE: See Appendix D for questionnaire. the members of the Society of Radiopharmaceutical Sciences (SRS).2 There were a total of 110 responses received from U.S. members (110/425 or 25.9 percent response rate). The average age of the respondents was 52 (range: 26-83; median: 52). It was found that 34 percent of the respondents received their degrees in nuclear chemistry, radiochemistry, or radiopharmacy, which corresponds well with the 37 percent found in the earlier 2006 SNM survey (Center for Health Workforce Studies 2007). Positions at the Bachelor’s and Master’s Degree Level There are many positions requiring entry level B.S. and M.S. radiochem- ists in industry. For example, input to the committee from a sampling of industries that employ radiochemists in the nuclear medicine field (Table 4-3) show that 44 percent of the chemists employed have B.S. degrees, 30 percent have Ph.D.s, 20 percent have MS degrees, and 4 percent have A.A.S. degrees. Over the next 5 years, a 38 percent increase in the number of positions at the B.S./M.S. level at these companies is expected. This in- dicates the need for increasing training opportunities at the undergraduate level. Many, if not most, of the employees entering the nuclear medicine industrial workforce do not have any training in nuclear and radiochemistry As of July 28, 2011, there were 760 unique members (425 from the United States) of the 2 RPSC and SRS (Jennifer Mills, Society of Nuclear Medicine, personal Communication, July 28, 2011). See Appendix D for questionnaire.

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64 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE TABLE 4-3 Estimated Number of Employees Currently Employed in Industry and a 5-year Projection of the Number of Employees Needed in Industry, Stratified by Highest Degree of Employee Current Number of 5-year Projection of Employees Required Employees Associate’s degree 7 27 Bachelor’s degree 84 110 Master’s degree 38 58 Doctorate degree 60 106 Total employees 189 301 SOURCE: Data kindly provided by the following companies: Abbott, ABT, Covidien, Eckert Ziegler, GE, Genentech, IBA, Immunomedics, Merck, NorthstarTM, Siemens, Sofie Biosciences, Pfizer, and UPPI. and companies must rely on on-the-job training to educate their employees. A knowledgeable workforce will better serve this community. Academic Sector Demand Responses to the SRS/RPSC questionnaire also provided information on the ages of nuclear and radiochemists currently working in the academic sector of nuclear medicine. The average age of the academic survey respon- dents was 55 years, and 24 percent of the respondents were over the age of 60, suggesting that approximately 24 percent of the respondents will be of retirement age by 2016. This data suggests that a large component of the academic workforce will need to be replaced in the next 5-10 years. Much of the demand in academia is dependent on the federal funding climate. As of this writing, future federal funding from NIH and DOE for nuclear medicine based research is uncertain (see Figures 4-3 and 4-4 below for recent funding data). If federal funding dollars increase, the demand in academia will likely increase beyond that of replacing retired faculty and staff at universities. Industrial Sector Demand In order to determine the demand in the industrial sector, representa- tives from companies that are involved in the nuclear medicine industry that employ nuclear and radiochemists were contacted and asked for numbers of current employees and estimated demand over the coming 5 years. These companies were selected based upon their known activities in the area of nuclear and radiochemistry for the field of nuclear medicine. Table 4-5 summarizes the data obtained from 14 companies, with a response rate of

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65 MEDICINE FIGURE 4-3 US Department of Energy funding for Radiochemistry and Imaging 4-3.eps Instrumentation. bitmap NOTE: Since 2010, the program name has been Radiochemistry and Imaging Instrumen- tation. Previously, other names were used: Radiopharmaceutical Design and Synthesis in FY 2005, Medical Applications in FY 2006 and FY 2007, Radiopharmaceuticals and Imaging in FY 2008, and Radiochemistry and Instrumentation in FY 2009. SOURCE: DOE 2011. FIGURE 4-4 NIH Extramural funding for nuclear medicine research, 2004-2006. NCI, Na- tional Cancer Institute; NIBIB, National Institute of Biomedical Imaging and Bioengineering. 4-4.eps SOURCE: NRC/IOM 2007. Data originally provided by NCI and NIBIB. bitmap

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66 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE 88 percent. These data are not entirely representative, and there may be ad- ditional companies from which the committee neglected to obtain data. The data from the 14 companies suggest that there will likely be a large demand for trained nuclear and radiochemists in the next 5 years, with the projection being an approximately 60 percent increase in the nuclear medicine indus- trial workforce. In addition to nuclear and radiochemists being employed directly by the companies listed in the footnote of Table 4-3, many major companies outsource positions to academia, and an additional 40 full-time employees were reported from companies who responded to this question. Government Sector Demand U.S. national laboratories, NIH, and other agencies, including FDA and the National Institute of Standards and Technology, employ radiochemists and nuclear pharmacists involved in nuclear medicine research and regula- tory activities. At the FDA, there are about a dozen employees who work in the Radioactive Drug Research Committee program in the Division of Medical Imaging Products. There are at least six groups at NIH that employ radiochemists involved in nuclear medicine-related projects. A breakdown of the NIH radiochem- ists by degree is given in Table 4-4. The groups that employ radiochemists include the Laboratory of Molecular Imaging and Nanomedicine in the National Institute of Biomedical Imaging and Bioengineering, the Radioim- mune Inorganic Chemistry Section of the Radiation Oncology branch at the National Cancer Institute, the NIH Clinical Center,the Imaging Probe Development Center at the National Heart Lung and Blood Institute, and two groups at the National Institute of Mental Health. Although there are projected budget cuts in the intramural program at NIH, most of these laboratories are projecting stable numbers of staff and trainees over the next 5 years. TABLE 4-4 Estimated Number of Radiochemists Currently Employed at the National Institutes of Health, Stratified by Highest Degree Current Number of Employees Pharmacy degree 4 Bachelor’s degree 5 Master’s degree 5 Doctorate degree 30 Total employees 44 SOURCE: Data were kindly provided by the following individuals: Martin Brechbiel (NCI); Gary Griffiths (NHLBI); Peter Herscovitch (NIH Clinical Center); Robert Innis (NIMH); Dale Kieswetter (NIBIB); and Victor Pike (NIMH).

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67 MEDICINE ECONOMIC DRIVERS The PET, SPECT, and Therapeutic Radiopharmaceutical Market in the United States Recent market analyses indicate continued growth for nuclear medicine in both imaging and radiopharmaceutical development, which indicates the demand for nuclear and radiochemistry expertise will also continue. One report by Global Industry Analysts, Inc. (PR Web News Wire 2010), states that “nuclear medicine is one of the most promising and rapidly growing seg- ments of the medical imaging industry.” It says the global market for nuclear medicine is predicted to reach the US$1.69 billion by 2015, and attributes the growth to improvements in the development of molecular imaging-based diagnostics and treatments, along with an increased demand from the aging U.S. population. Another market report by Bio-tech Systems, Inc. (BTSI), states that the U.S. sales of SPECT and PET radiopharmaceuticals reached $1.16 billion in 2009, $1.20 billion in 2010, and are expected to rise to $6 billion by 2018 (BTSI 2006, 2010, 2011; PR Web News Wire 2009). BTSI’s reports also detail how PET procedures grew 9 percent in 2009 to about 2 million, and grew to 2.1 million in 2010. In addition, sales of 18F-labeled 2-FDG were increased from $276 million in 2009 to $299 million in 2010, consistent with the increased numbers of procedures. As new agents are developed and approved by FDA and new products are introduced to consumers, total PET radiopharmaceutical sales are pre- dicted to rise to $4.3 billion by 2018 (BTSI 2011), of which the majority of the increase will be from sales of new products other than FDG. For example, an FDA review panel unanimously recommended approval of a new PET agent (florbetapir) for imaging amyloid plaque associated with Alzheimer’s disease, while two other similar agents (florbetabane and flu- metamol) and an 18F-labeled cardiac blood flow agent (flurpiridaz) are in phase 3 clinical trials. SPECT sales were down 9 percent in 2010, primarily due to reductions in pricing of perfusion agents, increased use of generic Sestamibi,3 and the shortage of 99Mo for 99mTc radiopharmaceuticals (BTSI 2011). The 99Mo shortage was stabilized by the end of 2010 with two reac- tors back on line. The outlook for SPECT agents is improving, with a new agent, DaTscan (Ioflupane), recently approved for assisting in the evaluation of Parkinsonian syndromes. In addition to the market for diagnostics, therapeutic radiopharmaceuti- cals include both current and emerging products for lymphoma, myeloma, Sestamibi is a generic kit for the preparation of Technetium (Tc-99m). 3

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68 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE and cancers of the breast, prostate, brain, liver, pancreas, and other types of cancer that are resistant to traditional therapies. The U.S. sales of thera- peutic radiopharmaceuticals were $71 million in 2005, with rapid growth anticipated (BTSI 2006). There has been increased research activity in the area of therapeutic radiopharmaceuticals with a variety of molecular target- ing strategies and therapeutic radionuclides for a wide range of tumor types. Although there are currently no approved alpha-emitting products, there is a strong push in research and development of agents labeled with 212Bi, 213Bi, At, 223Ra, and 210Po. One agent, Alpharadin (223Radium Chloride), recently 211 closed successful phase III clinical trials and a 2012 filing for FDA approval is anticipated. This one agent alone may bring annual U.S. therapeutic ra- diopharmaceutical sales close to $1 billion by 2015 (PMLiVE 2012). Research Funding One of the underlying factors in creating the supply of expertise to meet the future demand is funding for basic research and education in nuclear medicine. Two of the key sources of funding over the years for basic and applied radiochemistry research with relevance to nuclear medicine have been the U.S. Department of Energy (DOE) Office of Science and Office of Biological and Environmental Research and NIH (Figures 4-3 and 4-4). Drastic funding cuts, nearly eliminating the DOE Medical Applications program in FY2006, and the desire to focus research activities on DOE mission-driven programs, including biofuels production and climate change research and the DOE Office of Biological and Environmental Research, funding for the Radiochemistry and Imaging Instrumentation (RII; formerly called Medical Applications and Measurement Science Research subpro- gram) significantly altered the DOE nuclear medicine research landscape. The cuts included funding for “molecular nuclear medicine research, re- search and technology development activities in imaging gene expression, magnetoencephalography, biosensors, PET instrumentation for human clini- cal applications, MRI and neuroscience research, radiation dosimetry for therapeutic dose estimation, and targeted molecular radionuclide therapy” (DOE 2005, p. 258). In 2008, Congress restored funding for the RII program, albeit at a re- duced level from the FY 2005 allocation. The RII had funding opportunity announcements in FY2008 and FY2010 to support basic radiochemistry and imaging instrumentation research. In FY2009 the RII funded the DOE Inte- grated Radiochemistry Research Programs of Excellence, a training program that was recommended in the 2007 report Advancing Nuclear Medicine Through Innovation (NRC/IOM 2007).

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69 MEDICINE These changes have been a significant programmatic shift for the RII program away from specific nuclear medicine applications to DOE mission centric applications of radiochemistry. While there are still opportunities for radiochemistry and imaging instrumentation, it is difficult for scientists in radiology departments and medical institutions to apply for these funds, given that they and their collaborators are not studying plant physiology and biofuel production. Overall, the reduction in congressional funding al- locations to this program and the shift in research emphasis resulted in the loss of this valuable source of funding, which has had a negative impact on the nuclear medicine training pipeline for the future workforce and on valuable technology development resources that represented a significant return for the DOE investment. NIH funding has supported many radiochemistry and imaging technol- ogy developments related to nuclear medicine (Figure 4-4).4 The focus, however, has been largely on the applications of the radiotracers and transla- tion into the clinic rather than on the underlying radiochemistry technology and new radiochemistry reactions. Since more recent NIH funding data for nuclear medicine were not available to the committee, it is not clear if NIH has been able to make up the difference created by the reduction in DOE funding, especially for nuclear medicine projects that are more basic sci- ence in nature. Funding increases from both DOE and NIH as well as other sources will likely be necessary to support the projected need for trained scientists and sustained future growth. Health Care Regulations Utilization of the technology in medical procedures also drives the supply and demand of the nuclear medicine workforce. The cost associated with a complete scan, including the radiotracer, professional fees, and scan- ner costs, all factor into the utilization of the technology. There is ongoing research in the area of cost effectiveness to determine the extent of health care savings offered by early diagnosis and staging, as well as the ability to determine patients’ response to therapy prior to treatment or sooner after treatment. The magnitude of the importance of this is clear from the fact that across all diseases and all drugs, on average, only ~20% of patients treated have a measurable positive response, while ~80% take the risk with no benefit and enormous resources are lost to healthcare. Research demon- strating that the benefits of nuclear medicine outweigh the costs will have a Note: The committee requested, but did not obtain more recent NIH nuclear medicine 4 funding data.

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70 ASSURING A FUTURE U.S.-BASED NUCLEAR AND RADIOCHEMISTRY EXPERTISE positive impact on the demand for more nuclear and radiochemists in this field. Cost reimbursement by insurance and Centers for Medicare and Med- icaid Services (CMS) will also dictate the utilization and growth of imaging technology, and thus employment of radiochemists. Flat or declining reim- bursement will reduce growth. On the other hand, as the U.S. population ages, the number of imaging studies based on molecular diagnostics of the biology of disease is likely to increase. Since the leading molecular imaging technique is PET, the need for radiochemists will also increase. The extent of the regulatory requirements, such as Medicare reimburse- ment and FDA oversight of radiopharmaceutical approval, on the industry may factor into the demand for radiochemists. Reimbursement for clinical nuclear medicine procedures dictated by CMS will determine the direction of growth or shrinkage in the field. Increased reimbursement equals growth in the number of procedures. Likewise, FDA regulations of radiopharma- ceutical approval will determine the demand for radiochemists. Since 1995, while there are a substantial and growing number of radiopharmaceuticals that are FDA approved under an IND, there have only been seven radiophar- maceuticals or radiotherapeutics approved by the FDA with NDA for patient care (see Appendix G). Current regulations treat radiopharmaceuticals like therapeutics, not accounting for the major administered mass differences between tracer molecules and therapeutic drugs. Establishment of a new regulatory paradigm or regulatory discretion may lead to an increase of new tracers, supporting the need for more radiochemists Finally, isotope availability is an important factor for the field. The lack of an adequate national supply of medical radioisotopes, especially 99Mo, creates a reliance on foreign sources. Fluctuation in foreign supply streams creates an uncertain future for 99mTc radiopharmaceuticals. Development of a national facility for long-lived isotope production would reduce the foreign dependence and create more demand for radiochemists. FINDING The nuclear and radiochemistry workforce within the field of nuclear medicine is a vital and important component. Radiochemists and related disciplines support the infrastructure that is needed to prepare the imaging agents and radiotherapeutics for research and patient care. According to market reports and predictions from several company representatives, the field is growing and a significant increase in the number of trained person- nel will be needed at every level of education (including B.S., M.S., Ph.D., and Phar.M.D.).

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