Isotopes for Medicine and the Life Sciences (1995)

Both radioisotopes and enriched stable isotopes are essential to a wide variety of applications in medicine, where they are used in the diagnosis and treatment of illnesses. This report focuses primarily on these medical uses and those in the allied life sciences, but isotopes also find wide parallel uses in research in chemistry, physics, and geosciences, with additional needs existing in the commercial sector.

The U.S. Department of Energy (DOE) and its predecessors, the Atomic Energy Commission and the Energy Research and Development Agency, have supported the development and application of isotopes in a stellar example of technology transfer that began before the term was popularized. These technologies have been transferred to the private sector and have allowed the development of both the radiopharmaceutical and nuclear medicine instrumentation industries. One of every three hospitalized patients in the United States undergoes a nuclear medicine procedure, with a total value estimated at $7 billion to $10 billion per year. More than 36,000 diagnostic medical procedures that employ radioactive isotopes are performed daily in the United States, and close to 100 million laboratory tests that use radioactive isotopes are performed each year. Radionuclides are also used to deliver radiation therapy to a growing number of patients each year (approximately 180,000 in 1990).

In recent years the very success of nuclear medicine and the increased use of stable and radioactive isotopes in a number of fields have combined with the end of the Cold War to bring DOE to an important crossroad. Since its inception isotope production at the various multimission DOE laboratories has been a secondary mission that has been started and stopped to meet the needs of the laboratories' primary missions of basic and applied research in nuclear and par-

ticle physics, nuclear weapons, and nuclear power production. Support for all three of these areas has declined precipitously in the past decade, even as the demand for isotopes has increased, and aggressive competition from Canada and the Republics of the former Soviet Union in the sale of stable isotopes and radioisotopes threatens to cut DOE out of the market altogether. The concerns of U.S. clinicians and researchers about the continuing availability of enriched stable isotopes and radionuclides have increased sharply since 1989. The nuclear medicine community in particular has been highly vocal in its concern that the needs of the various users in the United States will not be adequately met in a future market controlled by one or two foreign sources and have suggested that DOE fund a new accelerator facility with production of isotopes as its primary mission, a National Biomedical Tracer Facility (NBTF).

In response to this urging and with the realization that changing national and scientific priorities would reduce the funding for the accelerator-based facilities at Los Alamos National Laboratory (Los Alamos Meson Physics Facility [LAMPF]) and Brookhaven National Laboratory (Brookhaven Linac Isotope Production Facility [BLIP]), DOE turned to the Institute of Medicine to undertake an intensive examination of isotope production and availability, including the education and training of those who will be required to sustain the flow of radioactive and stable materials from their sources to laboratories and bedsides. This document is the report of the committee formed to examine these matters and provide recommendations for action.

From its earliest discussions it became clear to the committee that any consideration of a national isotope policy would have to deal with several distinct, but interrelated, parts: the continued supply of enriched stable isotopes, the production of radioactive isotopes by neutron bombardment of targets in nuclear reactors, and the production of radionuclides for nuclear medicine practice and research by charged-particle bombardment in accelerators. The report addresses these three classes of isotope production in turn, attempting in each case to sort out the issues of production of commercially viable products from research and development on future products. It also addresses related matters: research appropriate for a medical isotope facility, requirements for education and training in relation to isotope production facilities, and the possibilities for collaboration between industry and the national laboratories as a means of meeting future requirements and opportunities.

Enriched stable isotopes are critical starting materials in the production of many widely used radioisotopes. They are also important research and diagnostic tools in themselves and offer a number of unique applications to medicine, nutrition, and the life sciences. A dependable supply of enriched stable isotopes con-

trolled by the United States is crucial for research, therapy, diagnosis, and other applications.

An adequate supply of enriched stable isotopes currently exists for the production of most biomedically significant radionuclides, but DOE inventory of enriched stable isotopes is being depleted through sales without replacement. The pool of isotopes formerly available only on a lease basis for nondestructive uses no longer exists. A large portion of the heavy stable isotopes currently being used are supplied by Russian sources. The exact extent of these inventories is unknown, but Russian supplies of most enriched stable isotopes are estimated to greatly exceed U.S. supplies.

Since the electromagnetic isotope separators, the calutrons, at Oak Ridge National Laboratory are currently in the standby mode, U.S. production of the majority of enriched stable isotopes is at a standstill. Future separations are planned only to replace high retail volume isotopes or as distinct contracts are negotiated. Some research communities—for example, those in the biological, physical, and earth sciences—frequently require only small quantities, but a great variety, of enriched stable isotopes. These research isotopes are seldom commercially viable and as a result, are not readily available from either domestic or foreign sources. A national policy of providing a subsidy for enriched stable isotopes used in small quantities for research purposes should be adopted (Recommendation 4, Chapter 2). In the near term this means that the electromagnetic separation capabilities of the Oak Ridge National Laboratory calutrons should be maintained in standby mode until a more cost-effective source of enriched stable isotopes can be developed or external sources fail to meet demand. If a more cost-effective technology does not emerge within 5 years, subsidized operation of the calutrons should be resumed (Recommendation 1, Chapter 2).

New technologies that may provide more cost-effective separation methods within 3 to 5 years are being developed. The development of new separation technologies or improvements in existing ones, must be encouraged and supported, and the most promising of these must be evaluated for their commercial viability. This should include efforts for the efficient, cost-effective production of large amounts of enriched stable isotopes—including kilogram quantities of light isotopes (Recommendation 2, Chapter 2).

The expanded application of enriched stable isotopes into new research areas should be encouraged (Recommendation 3, Chapter 2). The use of enriched stable light isotopes—for example, carbon-13, oxygen-18, and the stable calcium isotopes—will likely increase if they can be produced more cheaply and in large quantities. Research opportunities and applications will be promoted by offering greater amounts of isotopes at reduced costs. A number of enriched stable light isotopes that are crucial for research and other applications are not available or are priced beyond the means of researchers.

The supply of technetium-99m, the workhorse of nuclear medical practice, depends on the production of its parent, molybdenum-99. In the short term the supply of reactor-produced radionuclides for commercial use, including molybdenum-99, is sufficient. Radiopharmaceutical companies state that the present domestic and foreign suppliers are reliable and that they have or soon will sign long-term supply contracts with existing producers. In view of the demonstrated reliability of the current sources of commercially valuable isotopes and their steps to secure adequate backup, the committee recommends that the Omega West reactor at Los Alamos National Laboratory or reactors at other facilities NOT be reopened as a dedicated source of molybdenum-99 and other reactor-produced isotopes (Recommendation 1, Chapter 3). A federally supported U.S. reactor for the production of research radioisotopes is definitely justified. At present, the University of Missouri Research Reactor (MURR) is playing a major role as the supplier of radionuclides for research facilities and radiopharmaceutical manufacturers. Federal support at present is limited to the provision of reactor fuel and peer-reviewed research grants. In order to assure the continued supply of radionuclides (other than molybdenum-99) for medical and research facilities, the committee recommends core support for reactor-based isotope production. The University of Missouri Research Reactor appears to be the best currently available facility that can meet this need (Recommendation 2, Chapter 3).

In the long term, if short-lived reactor-produced radionuclides become important for cancer therapy and other medical uses, the present number and condition of production reactors in North America will be inadequate. Because reactors have finite lifetimes and because future demands may exceed current capabilities, the committee recommends that DOE ensure that plans for the Advanced Neutron Source reflect the importance of isotope production, and in particular of molybdenum-99, by providing funding at an appropriate amount to insure availability (Recommendation 3, Chapter 3).

Certain radionuclides (gallium-67, indium-111, iodine-123, thallium-201) are produced by cyclotrons with an energy of about 30 million electron volts (MeV). In the short term, there does not appear to be any problem with the availability of the radionuclides produced on such commercially located accelerators.

There is, however, a clear need for a higher energy machine to provide researchers with radionuclides for new applications. Brookhaven National Laboratory (BLIP) and Los Alamos National Laboratory (LAMPF), as the primary domestic sources of these radionuclides, have been unreliable because of scheduling problems and costs. There is also concern about each of these facilities

because of their ages and the missions for which they were constructed have changed. The future outlook for LAMPF is not clear, and the expertise that has been assembled there over the years will be lost when the accelerator facility is shut down. The linear accelerator (linac) that BLIP uses is expected to be available in the future since it is one of the injectors that the Relativistic Heavy Ion Collider will employ when it is completed, although for only a few weeks per year. It could probably be available for radioisotope production during the remainder of the year, assuming that operating funds are also available. The present processing facilities at BLIP are inadequate, outdated, and poorly maintained, in part because of their age.

In the short term an upgraded BLIP facility, including an extended running time, and the cyclotrons of Canada's Tri-University Meson Facility (TRIUMF) in Vancouver, British Columbia, can meet many of the radiotracer needs of the research community. However, both facilities have a mandate to operate as basic physics accelerators and cannot meet the full demand for research radionuclides. DOE should create a dedicated, reliable source for research radionuclides that has stable core support for the production of radioisotopes that are not available from commercial suppliers (Recommendation 1, Chapter 4). An NBTF that can incorporate the production facilities with the necessary infrastructure for research and training in isotope production and related activities is essential for the United States to maintain continued leadership in biomedical research using radiotracers.

The choice between cyclotron and linac is beyond the scope and expertise of this committee report, but an accelerator with an energy of 80 MeV would be sufficient for preparation all of the radionuclides envisioned for current and future use. A high-beam current would be required to ensure the production of large quantities of a few commercially viable isotopes and also allow multiple-target irradiations that will produce small quantities of experimental radionuclides.

Until such a facility is established, the needs of the isotope user community should be met by an upgraded BLIP supplemented by additional operating funds to allow for an extended operating period and a processing and distribution section that is similar to that at the University of Missouri Research Reactor (Recommendation 2, Chapter 4). Implementation of this recommendation should alter the current basic research environment and attitude at the BLIP facility and put isotope production and distribution on equal footing with in-house medical research.

The cooperative arrangement between government and industry at Canada's Tri-University Meson Facility (TRIUMF) has lead to successful technology transfer to the private sector (Nordion International, Inc). DOE should explore the utility of such models for coupling commercial production and research in the United States (Recommendation 3, Chapter 4). This idea is discussed further in Chapter 5.

A national advisory board should be established to assist in the operation of and the setting of priorities for the radioisotope production facilities at both the upgraded BLIP and NBTF (Recommendation 4, Chapter 4). This idea is elaborated upon in Chapter 6.

The current DOE operations for isotope production (stable and radioactive) are not commercially self-sufficient because the leaders of these operations cannot:

1. negotiate prices freely with customers,

2. commit to long-term supply and pricing,

3. compete with the private sector, or

4. control their costs (e.g., they cannot avoid new DOE regulations with respect to waste management and remediation).

The revolving fund provision of the Energy and Water Development Appropriations Act of 1990 (Public Law 101-101), by reducing DOE flexibility still further, has hindered rather than helped the establishment of a reliable and affordable domestic isotope supply.

The TRIUMF-Nordion model in Canada is an example of a public-private partnership that has addressed this problem in a way which is beneficial to both the scientific and the commercial partners.

In the United States, a healthy set of partnerships exists between national laboratories and universities, primarily involving research. Successful partnerships between national laboratories and industries in research and development have also been established (the cooperative research and development agreement mechanism).

NBTF is not likely to be financially self-sufficient if sales from isotopes and related services are the sole sources of funding, but NBTF could be operated by a partnership of for-profit and not-for-profit organizations. Solicitations for a successful bidder from the private sector could be based partially on the proposed return of part of the profits as royalties to be used for the support of research and education programs. In this partnership scenario,

1. DOE would pay for the cost of construction of NBTF, which would be a dedicated facility (Recommendation 2, Chapter 5);

2. DOE would subsidize the production of research isotopes as well as fund the operation of the research and education programs, in whole or in part, via the not-for-profit institution;

3. the private-sector partner would be responsible for the production, packaging, marketing, pricing, and sales of radioactive isotopes (Recommendation 5, Chapter 5);

4. there would be an agreement distributing beam time of NBTF between production of commercial products and production of the radioisotopes necessary for approved research programs; and

5. there would be a management board that oversees and approves the distribution of the beam time and the return of royalties from the private-sector partner to the not-for-profit partner.

DOE should encourage such a partnership between one or more for-profit institutions and at least one not-for-profit institution (university, national laboratory, or some combination) to operate NBTF (Recommendation 3, Chapter 5). The Canadian model of TRIUMF-Nordion is one that could be emulated in the United States.

The commercial aspects of NBTF cannot be fully understood at this time. As discussed in this report, some radioisotopes produced by NBTF would be attractive to the commercial market. Others will become attractive in the future as new nuclear medicine techniques evolve. However, it is clear to the committee that the commercial potentials of these particular radioisotopes are limited for the foreseeable future, and are certainly not large enough to allow NBTF to be supported by commercial profits.

The requirement that NBTF be financially self-sufficient should be removed. Production of promising but as yet unprofitable isotopes as well as the in-house programs of research and education should be supported primarily by DOE funds and competitive research grant funds of users, with some contribution from royalties from the private-sector partner (Recommendation 4, Chapter 5).

NBTF should be operated as a user facility in the mold of current physical science operations at national laboratories (Recommendation 1, Chapter 5). Indeed, proposals for NBTF from national laboratories should be reviewed along with those from universities and the private-sector partner (Recommendation 6, Chapter 5). The national laboratories offer a tremendous technical infrastructure that would benefit the construction and operation of the NBTF. An evolving interest and expertise in new models of cooperation with the private sector could make this potential a reality.

On the basis of its congressional mandate, its historic role, and its technical resources and expertise, DOE has important roles to play in all aspects of isotope production, research, and education. Although the full cost recovery provision of the Energy and Water Development Appropriations Act of 1990 (Public Law 101-101) has hindered rather than helped DOE to promote isotope research and application, the concept of centralized management is not without merit. The important research, development, and educational activities associated with isotope production and distribution are, however, still spread throughout DOE.

A National Isotope Program, reporting directly to the director of the Office of Energy Research of DOE, should be created to consolidate the administration of all isotope-related activities: production and distribution, research and development, and education and training (Recommendation 1, Chapter 6).

A national advisory committee should be formed to assist the director of the National Isotope Program in prioritizing critical needs in technology development and in choosing among applicants wishing to use the reactor and accelerator isotope production facilities or obtain their products. This National Isotope Program Advisory Committee should also provide advice on the development and execution of the several educational programs associated with isotope production and use (Recommendation 2, Chapter 6).