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Nuclear medicine

Radiopharmaceuticals under threat

Specialists propose measures to prevent stoppages in radioactive drug production, as happened earlier this year, from becoming recurrent in Brazil

Lab where the radiopharmaceutical iodine-131 is produced at IPEN

Léo Ramos Chaves

At the end of September, Brazil had to temporarily shut down production of radiopharmaceuticals—drugs containing radioactive elements used to diagnose and treat various diseases in oncology, cardiology, hematology, and neurology. Production of these substances by the Institute for Energy and Nuclear Research (IPEN) in São Paulo was stopped between September 20 and October 1, putting 9,000 daily medical procedures at risk, according to estimates by the Brazilian Society of Nuclear Medicine (SBMN). The situation resulted from IPEN lacking the funds needed to import raw materials and produce the chemical compounds, used mainly in human health care, demonstrating how fragile the service can be for the 2 million Brazilians who depend on these drugs. Funding shortages also jeopardize the research and development of new nuclear medicines in the country.

The federal government has a monopoly on the production of radiopharmaceuticals with a half-life of more than two hours in Brazil (see sidebar on page 69). IPEN is managed by Brazil’s National Nuclear Energy Commission (CNEN) and supplies 85% of the country’s demand for nuclear medicine. Its production chain depends largely on imported radioisotopes—radioactive substances manufactured in nuclear reactors that serve as the raw material for radiopharmaceuticals. The country mostly imports these raw materials from South Africa, Russia, and the Netherlands, some of the few nations with an exportable surplus. According to IPEN, it spends roughly US$15 million (approximately R$82.6 million) on radioisotope imports per year.

In 2021, IPEN’s budget for importing raw materials and all other production expenses was R$91 million, 46% lower than the previous year. On September 27, Marcos Pontes, the Minister of Science, Technology, and Innovation (MCTI) told the Brazilian House of Representatives that when the 2021 budget was released, it was immediately clear that it would not cover the demand for radiopharmaceuticals. The Ministry of Economy was alerted of the issue, but it made no response, resulting in production being shut down in September. Emergency funding was granted, with R$19 million reallocated to IPEN from other CNEN projects. The crisis was only temporarily resolved by the arrival of the budgeted R$82.6 million in October.

Two complementary solutions have been proposed by CNEN and IPEN to give the institute greater production autonomy and prevent the risks of drug shortages. The first is designed to address the budget problem and requires approval from Brazil’s national congress. The idea is for IPEN to keep the funds generated from radiopharmaceutical sales—somewhere around US$30 million per year—to use to produce more. Income from these sales is currently collected by the national treasury and redistributed in accordance with the federal budget.

“We would create a closed funding cycle, which would put an end to the recurring budget problems,” explained Pontes, who backed the proposal during a visit to congress. The measure would also provide financial support for IPEN to invest in research and innovation—today the institution only receives enough funds to cover costs.

Léo Ramos Chaves Iodine-131 processingLéo Ramos Chaves

Brazilian reactor
The other solution proposed by specialist is the construction of a Brazilian multipurpose reactor (RMB), which would afford the country greater autonomy and allow it to progress from radioisotope importer to exporter. The RMB would also help Brazil to become a center for the development of new radiopharmaceuticals of national interest. The reactor project was first floated by CNEN in 2008 and has been included in the list of national priorities in the federal government’s multiannual plan since 2012. Physical work on the structure, however, has not yet begun.

According to José Augusto Perrotta, technical coordinator of the RMB project, Brazil currently has four nuclear reactors in operation, dedicated to activities as diverse as fuel testing, development of new materials, and industrial and agricultural inputs. Domestic production of radioisotopes occurs mainly at IPEN’s IEA-R1 reactor, which has a maximum power of 5 megawatts (MW) and is located at the University of São Paulo (USP). One of the reactor’s limitations is that it does not have the capacity to mass produce molybdenum-99, the raw material of radiopharmaceutical technetium-99m, used in 80% of nuclear medical procedures performed in the country.

The RMB would be six times more powerful, at 30 MW, and in addition to producing radioisotopes for use in medicine, industry, and agriculture, would also be used to test nuclear materials and fuels and to generate neutron beams for research in various fields of science. The plan is for the reactor to have associated laboratories for each activity (see Pesquisa FAPESP issue nº 221). “It is this country’s great structuring project for nuclear science and technology,” says Madison Coelho de Almeida, director of research and development at CNEN.

For Almeida, construction of the RMB would complement the existing production chain. “We have large deposits of uranium, which is the basic input, and we have all the technology needed for the production cycle. With the RMB, we could become major global suppliers of radioisotopes,” he says. CNEN plans to build the reactor on an area of 1.2 million square meters (m2) in Iperó, São Paulo, provided by the São Paulo Navy Technological Center (CTMSP), and a further 800,000 m2 allocated by the São Paulo state government. It already has the required environmental and nuclear safety licenses.

The project is expected to cost US$500 million, which would be invested over a period of five years. “Economic studies indicate that with the income generated by its production, the RMB will be able to remain operational and self-fund research,” explains Perrotta. The Ministry of Economy’s proposed 2022 budget once again does not include any funding for the RMB. Pontes mentioned in his testimony in congress that the project could receive funds via the National Scientific and Technological Development Fund (FNDCT), managed by the Brazilian Funding Authority for Studies and Projects (FINEP), which should have a budget of R$8.46 billion in 2022. The problem is that the fund is constrained by the federal government.

Pontes also backed Proposed Amendment to the Constitution (PEC) No. 517/2010, drafted by senator Álvaro Dias (Podemos, Paraná), which would put an end to the state monopoly on radiopharmaceuticals. The PEC has already been approved in the senate and is now in the house of representatives. “It is not about replacing state production with private, it is about combining both,” said the minister. According to Almeida, data from the International Atomic Energy Agency (IAEA) show that most radiopharmaceuticals are produced privately on a global level.

Celso Cunha, president of the Brazilian Association for the Development of Nuclear Activities (ABDAN), says that there are companies willing to invest in both radiopharmaceutical production and the RMB. “Private initiatives could supplement IPEN and resolve the country’s radiopharmaceutical supply crisis,” he says. “But that will only happen if they are able to compete on equal terms.” According to Cunha, the institute’s prices do not reflect the impact of exchange rates on import costs, resulting in subsidies for the consumer. Products made by IPEN are also not taxed. “There is no way for a private company to compete against government subsidies,” he says.

Léo Ramos Chaves Labeling of the vials to hold the radiopharmaceuticalLéo Ramos Chaves

The subsidies currently in place are advantageous to users of the public and private health systems who require treatment with radiopharmaceuticals, but represent a cost for the federal government, which is ultimately paid by taxpayers. If there was no state monopoly, one potential consequence would be an increase in product prices and treatment costs.

Wilson Aparecido Calvo, head of IPEN, believes state involvement in the production of radioisotopes and radiopharmaceuticals is essential to improving care for patients in the Brazilian public health system (SUS) and ensuring universal access to nuclear medicine nationwide. He sees inspiration in Argentina’s approach, where the state monopoly was partly dismantled. “Argentina’s National Atomic Energy Commission [CNEA] produces radioisotopes with its own reactors and uses them to manufacture radiopharmaceuticals. The products are sold by Dioxitek, a company created by former CNEA employees. Previously, CNEA itself was in responsible for sales,” says Calvo.

“This is the model we are proposing for Brazil. The important thing is that the income from the sale of radiopharmaceuticals and radioisotopes is returned to the institutions that produce them,” says Calvo. According to him, South Africa and Australia also use hybrid systems, in which the states are responsible for manufacturing the products and the private sector sells them. Chile, according to the IPEN director, took a different approach that did not work. “They completely broke apart the monopoly. The policy adopted by the Chilean Nuclear Energy Commission was to privatize radiopharmaceuticals, which left the population highly vulnerable.”

An end to the monopoly, defended by some experts as a solution to the problem, is cause for apprehension at IPEN. “It could be the perfect excuse for the government to cut radiopharmaceutical funding even further and abandon the RMB project altogether,” says chemical engineer and former director of research and development at the institute Marcelo Linardi, who wrote a book entitled Ipen e a saúde (“IPEN and health”).

Linardi believes research into new products in Brazil and worldwide could also be seriously compromised, such as the development—with funding from FAPESP—of a new radiopharmaceutical specifically for diagnosing HER2-positive breast cancer, one of the most aggressive forms of the disease. “This type of cancer is currently diagnosed by a biopsy followed by immunohistochemistry, a method that is not 100% conclusive. This often leads to inadequate treatment. Our project is based on the development of a radiopharmaceutical that can identify the HER2 marker in metastatic cancer, to allow physicians to monitor the evolution of the disease and help choose the best therapy for each case,” says Emerson Bernardes, head of IPEN’s Radiopharmacy Center.

The most innovative prospect IPEN is currently working on is the result of a partnership with FAPESP through the Institutional Research Development Plan (PDIP), an initiative aimed at modernizing state research institutes. The institute’s laboratory infrastructure is being updated to allow it to develop new radiopharmaceuticals, including with nanotechnology. It will be the third in the world to be equipped with a near-field scanning optical microscope (NSOM), capable of subnanometric resolutions. The noninvasive instrument is used to map the interior of a molecule, observe ultrastructural changes, and study biological samples.

“Nanotechnology is the future of radiopharmaceuticals,” says Linardi, who was responsible for developing the project. The NSOM is scheduled to be installed in December and begin operating in mid-2022. One of IPEN’s research lines is studying radioisotopes from gold and palladium nanoparticles for use in brachytherapy, a procedure that directly exposes tumors to a high concentration of radiation without impacting healthy cells, reducing side effects in cancer treatment.

Substance types
Radiopharmaceuticals are grouped according to their radioactive decay period

Radiopharmaceuticals are divided into two distinct groups based on the time it takes their atoms to reduce their radioactive emissions. One group comprises radiopharmaceuticals with a half-life equal to or less than two hours. The products do not expire within this period, but their radioactivity falls by half every two hours, meaning their production and use need to be calibrated to make best use of their characteristics.

This group includes the radiopharmaceuticals used in positron emission tomography (PET), which is used to assess the structure of organs such as lungs, the liver, and the brain, in addition to bones. These substances account for 15% of the demand for nuclear medicine. Private production has been permitted in the country since 2006, to allow for greater physical proximity between laboratories and medical centers. The recent crisis did not affect the supply of these products.

According to the Brazilian Society of Nuclear Medicine (SBMN), roughly 450 clinics and hospitals provide nuclear medicine services nationwide, most located in large cities, primarily in the Southeast. Radiopharmaceuticals for PET are provided by three or four main suppliers, many of which have regional subsidiaries, but there are other small companies in the market—neither the SBMN nor the Brazilian Association for the Development of Nuclear Activities (ABDAN) know exactly how many companies operate in this sector, in which technological knowledge of the substances involved is fully established, with few major innovations.

The other group is composed of products with a half-life greater than two hours. Monopolized by the government and produced exclusively by IPEN, these were the products affected by the agency’s budget difficulties. The group contains 37 radiopharmaceuticals, each with its own distinct half-life. Technetium-99m, for example, loses half of its radioactivity every six hours.

According to George Coura Filho, a radiologist and president of SBMN, radiopharmaceutical shortages directly affect patient diagnosis and treatment and could potentially lead to irreversible health impacts. Then there are the even greater expenses for the health system.

Coura Filho cites myocardial perfusion scintigraphy as an example—the exam allows physicians to accurately stratify the risks of coronary insufficiency and determine the best treatment, whether that be medication, catheterization, or heart surgery. “An imprecise diagnosis due to a shortage of the resources needed to perform the procedure could lead to mistakes, causing a greater expense than the cost of the exam that was not carried out,” he explains.

1. Scientific, technological, and infrastructure training in radiopharmaceuticals, radiation, and entrepreneurship in the service of health, PDIP (nº 17/50332-0); Grant Mechanism State Research Institutes Modernization Program; Principal Investigator Marcelo Linardi (IPEN); Investment R$13,223,638.80.
2. Validation of the use of a HER2-specific DNA aptamer as a radiopharmaceutical for tumor imaging (nº 18/18112-3); Grant Mechanism Research for Innovation in Small Businesses (RISB/PIPE); Principal Investigator Sofia Nascimento dos Santos; Investment R$928,409.54.