ABSTRACT
Radiopharmaceuticals play a crucial role in medicine and are being highly utilized in diagnostic imaging and radiotherapy. Nuclear medicine is considered highly beneficial in diagnosing organs associated with any kind of pathological condition, particularly cancer.
Data Bridge Market Research analyses that the radiopharmaceuticals market is expected to undergo a CAGR of 10.40% during the forecast period. This indicates that the market value of USD 4.80 billion in 2021 would rocket up to USD 11.69 billion by 2029. “Diagnostic Applications” dominates the application segment of the radiopharmaceuticals market owing to rising incidences of medical ailments such as diabetes that are responsible for making the lower part of the body symptomatic and vulnerable.
- 95% of Radiopharmaceuticals are Used for Diagnostic Purposes
Radiopharmaceuticals are widely utilized in the diagnosis or therapeutic treatment of numerous human disease. Around 95% of radiopharmaceuticals are used for diagnostic purposes, while the remaining 5% is utilized for therapeutic applications. An increase in the demand for radiopharmaceuticals is being witnessed as they generally have no pharmacologic effects, and are utilized in tracer quantities. These pharmaceuticals differ significantly from conventional drugs due to the no dose-response relationship.
INTODUCTION
Radiopharmaceuticals refer to the pharmaceutical formulations that consist of radioactive substances, such as radioisotopes and molecules labeled with radioisotopes. These formulations intended to be used either in diagnosis or therapy. Radiopharmaceuticals are known to be one of the significant components of nuclear medicine practice. These pharmaceutical formulations are administered to patients for diagnostics, management, and treatment of numerous diseases.
These medicinal formulations contain radioisotopes which are considered safe for administration in humans for the purpose of diagnosis or for therapy. After the discovery of radioactivity, radiotracers were tried as a therapeutic medicine. However, the first significant applications came with the availability of cyclotrons for acceleration of particles for producing radioisotopes.
- Radiopharmaceuticals Possess one or More Radionuclides
Radiopharmaceuticals are pharmaceutical or medicinal products that possess one or more radionuclides when ready for use. Nuclide is defined as an elemental species characterized by its mass number ‘A’, its atomic number ‘Z’, and its nuclear energy state. The mass number ‘A’ is the sum of the number of protons and neutrons in its nucleus. Atomic number ‘Z’ is number of protons which is also same as number of electrons in a neutral atom. Isotopes of an element are basically nuclides with the same atomic number but different mass numbers. These elements hold the same place in the periodic table, and possess similar chemical properties.
- Nuclear Medicine are Being Recommended for Chronic Diseases
Approximately 30 million patients are diagnosed or treated with the use of molecular imaging techniques and nuclear medicine. Nuclear medicine consists of diagnostic and therapeutic techniques that deploy radiopharmaceuticals for cardiovascular disorders, neurologic disorders, and oncology. The technique offers cellular and molecular information for tracking tissue function, supporting treatment planning, assessing treatment responses, probing, evaluating disease progression, and guiding tissue sampling. The most powerful analytic tools available today are nuclear medicine and molecular imaging procedures, and offer physicians critical patient information that can be used to make important medical decisions. These therapies are categorized under the key component to personalized medicine. Patients may be required to undergo more invasive and more expensive tests if personalized medicine did not exist.
The molecular imaging market is expected to gain market growth in the forecast period of 2021 to 2028. Data Bridge Market Research analyses the market to account for USD 7.51 billion by 2028 and will grow at a CAGR of 6.39% in the forecast period. The rise in demand for detection and monitoring of diseases such as cancer and other rare genetic disorders further accelerate the market of radiopharmaceuticals.
ACCESS AND AVAIALIBILITY
- Nuclear Medicine Global Initiative (NMGI) Produced a Report on the Standardization of Administered Activities in Pediatric Patients
Over 140 countries across the globe can avail SPECT or SPECT/CT, with close to 27,000 systems installed. While around 109 have deployed PET/CT and over 5,200 systems. The usage of the nuclear medicine techniques varies among countries owing to the costs, training of workforce, availability of radiopharmaceuticals and regulatory issues. Nuclear Medicine Global Initiative (NMGI) produced a report on the standardization of administered activities in pediatric patients in 2014. It was decided that the second project of the NMGI would be to assess the availability of therapeutic and diagnostic radiopharmaceuticals by country and region after the success of this first project. It collates and analyzes the data and develops a report outlining the current availability and issues that prevents patient access to these resources.
OBJECTIVES:
The objective of this review article is to use secondary data from research publications, journals, case studies, published articles, and other sources to discover answers to specific queries. The following goals are intended to be met by this research:
- Collect information regarding the availability of radiopharmaceuticals
- Identification of issues impeding use of radiopharmaceuticals
- Finding actions that could be taken to mitigate the identified barriers
The review highlights information regarding the availability of radiopharmaceuticals across the globe, such as availability of generators, radionuclides and cold kits. It also focuses on use of central pharmacies along with listing of radiopharmaceuticals required but not available. The identification of issues impeding use of radiopharmaceuticals will also be seen, including shipping, facilities, access, regulatory requirements and training. The information could be beneficial for mitigating identified barriers, encourage commercial interest and research and development, and enhancing patient access.
MATERIALS AND METHODS
A detailed questionnaire on access, availability, and issues associated with the radiopharmaceutical sent to key contacts and the nuclear medicine societies of the countries that are listed in the IAEA database. NMGI project members (Table 1) developed this questionnaire and was made available by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) via direct correspondence with country nuclear medicine societies or secure online portal. The information that was obtained was confirmed as applicable for the entire country, and also was based on country internal information data compilation and gathering. The responses were correlated into continental regions. According to World Bank income classification, the review decides whether countries were of low, low-middle, high-middle, or high income. Data were compiled and summarized, with verification of information.
RESULTS
- 35 Countries Provided Complete Data for the Survey Listed in Table 2.
16 were from the Asia-Pacific region, Australia, 8 from Africa, 4 countries responded from Europe, 5 from Latin America, and the United States and Canada. Mexico was included in Latin America to facilitate the analysis. The cohort represents 76.4% of global SPECT camera sites and 71.1% of global PET camera sites (Table 3) based on data from the IMAGINE database on individual country activity.
- Europe Displayed Low Responses that Proved Challenges in Obtaining Accurate Country-Based Data
The data represent 91.3%–100.0% of nuclear medicine camera sites for North America, Latin America, and Australia. 73% of sites are represented are represented in Asia. More than 50% of nuclear medicine camera sites were spotted in African country. The responses came from both low-income and middle-income countries with nuclear medicine sites. Europe displayed low responses that proved challenges in obtaining accurate country-based data in this region.
The manufacturer and supplier of 99mTc generators were named by Responders (Table 4).
- 32 99mTc Generator Suppliers Globally were Reported
There were 32 99mTc generator suppliers globally. 18 supplying to a single country, resulting 10 manufacturers that supply to multiple countries or continents. 6 producers that supply to 4 or more countries. United States is known to be the major user of 99mTc, and accounts for 50% of the global market while it relies on only 3 suppliers of generators. Most countries reliant on a single generator supplier, the supply to Africa is the most limited. A large number of suppliers of generators are associated with the Asia-Pacific region, often imported from Europe, but also locally produced. Due to the limited number of respondents from European countries, the data for Europe are not representative of the actual situation.
53 companies selling cold kits for radiopharmaceutical preparation are enlisted in Tables 5 and 6. Over half of the 33 radiopharmaceutical kit manufacturers deliver to only a single country. 1 manufacturer supplies to 3 countries, 6 distribute to 5 or more countries, 8 provide cold kits to 2 countries, 5 manufacturers supply to 4 countries and 6 distribute to 5 or more countries. The data for the United States showed that only 8 suppliers for diagnostic kits and 5 suppliers of kits for therapeutics, along with 131I capsules and solutions being supplied by local pharmacies. Responders were further asked regarding the radiopharmaceuticals that they used by imaging category and their utility in each category. The responses were divided into 3 groups, including:
- SPECT Imaging
- PET Imaging
- Therapy
The Rising Cases of Cancer and the Increasing Healthcare Infrastructure Is Escalating the growth of Diagnostic Radiopharmaceuticals
Diagnostic radiopharmaceuticals and contrast media market is expected to gain market growth in the forecast period of 2022 to 2029. Data Bridge Market Research analyses the market to grow at a CAGR of 6.30% in the above-mentioned forecast period. Diagnostic radiopharmaceuticals are basically the molecules containing a drug attached with a radioisotope targeted toward a certain tissue/organ for diagnosis as well as treatment of diseases such as cancer, cardiovascular diseases, and hyperthyroidism. Radiopharmaceuticals are being extensively used in a technique called molecular imaging as biomarkers for specific molecular procedures that determine the onset and/or growth of a disease. The rising cases of cancer and the increasing healthcare infrastructure are the significant factors responsible for driving the diagnostic radiopharmaceuticals and contrast media market growth.
SPECT Radiopharmaceuticals
A total of 13 different radiopharmaceuticals were listed, for brain imaging. This came with highest country use—based on survey responses being 99mTc-diethylenetriaminepentaacetic acid and 99mTc-hexamethylpropyleneamine oxime at 74%. This was followed by 99mTc-ethylcysteinate dimer at 51%.
99mTc-pertechnetate at 89% followed by 131I at 86% was the most commonly used for thyroid imaging. Parathyroid imaging had 99mTc-sestamibi with the highest use at 97%. For subtraction scanning 99mTc-pertechnetate at 80% was used, and 201Tl at 23%. The highest use was seen for 99mTc-macroaggregated albumin at 86% for perfusion scans for pulmonary imaging, followed by 99mTc-diethylenetriaminepentaacetic acid aerosol at 63%, and 34% for ventilation scans of Technegas (Cyclomedica Asia Pacific). Cardiac myocardial perfusion imaging reported to have 99mTcsestamibi with the highest use at 94%, and 201Tl-chloride. 99mTc-tetrofosmin having similar use at 45% was also seen. The highest use is 99mTchepatoiminodiacetic acid at 51% of countries was witnessed for liver/biliary agent, followed by 99mTcmacroaggregated albumin at 43% (shunt studies). 99mTc-mebrofenin at 40%, and 99mTc-sulfur colloid at 34% was stated. The most highly used agents were 99mTc-denatured red blood cells at 43% (for spleen imaging). It was followed by 99mTc-sulfur colloid at 34% and 99mTc-tin colloid at 31% for bone and spleen imaging. The agent with the highest use for renal imaging includes 99mTc-diethylenetriaminepentaacetic acid at 94%. It is followed by 99mTc-mercaptoacetyltriglycine at 83% and 99mTc-dimercaptosuccinic acid at 89%. Adrenal imaging is performed predominantly with 131I-metaiodobenzylguanidine (MIBG) at 60%, followed by 131I-norcholesterol at 17%, 123I-MIBG at 37%, and 131I-aldosterol at 11%. 99mTc-methylene diphosphonate was the most common at 97% for bone scanning along with 99mTc-hydroxymethylene diphosphonate at 29%, and 99mTc-hydroxymethylene diphosphonate at 34%. The highest use was observed for 99mTc-pertechnetate at 71% for gastrointestinal imaging, with 99mTc-sulfur colloid and 99mTc-red blood cells at 57%.
The highest use by responders was 131I-MIBG at 60%, for SPECT tumor imaging along with 67Ga-citrate at 46%, 123I-MIBG at 34% and 201Tl-chloride at 43%. A total of 10 agents were supplied by responders for inflammation and infection imaging. The most highly used was 99mTc-radiolabeled WBC at 57%, LeukoScan (sulesomab; Immunomedics, Inc.) and ciprofloxacin at 11% and 67Ga-citrate at 49%.
Sentinel lymph node imaging is performed with 7 agents, 3 of which are restricted to use in a single country. 99mTc-nanocolloid with a use of 74%, 99mTc-antimony colloid at 11%, 99mTc-sulfur colloid with a use of 20%, and 99mTc-phytate at 9% are used in multiple countries. 131I-sunflower oil for confirmation and localization of a lymphatic leak were utilized in South Africa. 4 agents are used in vitro studies, including 51Cr-chromate at 17%, 125I-human serum albumin at 6%, 14C-urea at 26% use and 51Cr-ethylenediaminetetraacetic acid at 9%, and these agents see limited use due to restricted availability.
In vitro diagnostics (IVD) market is expected to gain market growth in the forecast period of 2021 to 2028. Data Bridge Market Research analyses the market to reach at an estimated value of 585.81 billion and grow at a CAGR of 5.95% in the above-mentioned forecast period. The rise in geriatric population and subsequent growth in the prevalence of chronic and infectious diseases drives the in vitro diagnostics (IVD) market.
PET Radiopharmaceuticals
- Only 28 Indicated they provided PET Services, Out of the 35 Countries that Provided Responses to the Survey.
The lowest numbers of PET sites was witnessed in the low- and low-middle income countries. Survey responders witnessed a total of 34 PET agents, along with 5 radiometal radionuclides (64Cu, 68Ga, 82Sr/82Rb, and 44Sc). 18F-FDG (Fig. 3A) shows the most highly used PET agent. Eleven other 18F-labeled PET agents are enlisted in (Fig. 3B). 68Ga has experienced significant growth because of the availability via a long-lived generator. 68Ga-prostate-specific membrane antigen, which is at 50% use is the most highly used 68Ga tracer, followed by 68Ga-DOTATATE at 46% and 68Ga-DOTATOC at 25% use (Fig. 3C). Several radiopharmaceutical agents have been developed with 11C. 11C-methionine and 11Ccholine at 32%, and 11C-Pittsburgh compound B, which isused at 25% are two most highly used (Fig. 3D).
Therapeutic Radiopharmaceuticals
Use of Radiopharmaceuticals for Therapeutic Applications
The limited use other than 131I owing to the limited access and high cost was indicated the responses. 131I was used for hyperthyroidism in 94% of countries. 91% of countries used it for thyroid cancer. 16 radiopharmaceuticals were provided by responders for therapy, along with the next most prevalently used i.e. 153Sm-ethylenediaminetetramethylene phosphonate. It is used for bone pain palliation at 51%, an d 131I-MIBG was used in 51% of countries. 177Lu-DOTATOC was reported to have 11% use, 177Lu-DOTATATE 29% and and 90Y-DOTATATE 11%. 177Lu-prostate-specific membrane antigen is under research use at the time of the survey. Restricted availability of 32P was noted, along with various countries showing they would use 32P if it was available.
Training and Education
All countries witnessed a lack of trained and qualified staff for performing certain tasks, such as radiopharmaceutical quality control and quality assurance, production, final dispensing and cell labeling. Low-income and low-middle-income countries identified the lack of educationand training of staff, including physicists, radiopharmacists, clinicians, and radiochemists, as a barrier to providing certain services. The results shows them being unable to provide complex procedures such as radionuclide therapy such as 177Lu-targeted therapies, cell labeling, and other new radiopharmaceutical tracers that are generally required in-house quality assurance and quality control. A lack of training in good manufacturing practices and quality control/quality assurance even in some high-income countries. Radiation safety personnel and drug release were noted as inhibiting patient access and growth.
DISCUSSION
The report highlights various important issues regarding radiopharmaceutical availability and access at a global level. There was variability in response among countries and regions as with the first NMGI project. However, approximately 75% of global nuclear medicine sites was covered in the survey obtained country-based responses. The data obtained spanned all geographical regions and country income statuses in (Table 3). Limited data was available from European countries, the results from comparable socioeconomic countries with similar nuclear medicine infrastructure (IMAGINE database). The data offers a valuable portrayal of the use of nuclear medicine, current availability and challenges that restrict its use and future growth.
- The Survey Displayed a Lack of Availability of Generators as an Ongoing Issue
Numerous efforts were made including the U.S. Department of Energy, IAEA, Nuclear Medicine Europe, and high-level working groups with the aim of ensuring a sustainable supply of 99Mo/99mTc generator equipment. The survey displayed a lack of availability of generators as an ongoing issue. Several countries possess only a single supplier, with limited to once a week or once a fortnight deliveries, and problems with reliability of supply.
Low- and Middle-Income Countries were Identified as Having these Issues Mainly.
The problem of supply chains has been highlighted in the recent outbreak of coronavirus disease COVID-19) pandemic. Generator supplies to numerous countries was greatly declined owing to the flight restrictions (13–16). The dependency of the nuclear medicine field and individual countries on distributers or single-source manufacturers of their radiopharmaceutical cold kits is highlighted in the survey data. There were several cold kits that are no longer available, especially in developing countries, such as sulfur colloid, 99mTc-macroaggregated albumin, brain perfusion agents, 99mTc-pyrophosphate, 99mTc-hepatoiminodiacetic acid, antimony colloid, 99mTc-mercaptoacetyltriglycine, and 99mTc-hydroxymethylene diphosphonate. This was seen because of the regulatory factors (preventing importation), only having a single sole supplier of cold kits with limited product availability, and high costs to import the products. Numerous countries do not have any access to ventilation agents for performing a ventilation– perfusion scan. These regions commonly perform perfusion-only imaging. Non-18F-FDG PET tracers had limited availability in most countries because of the barriers, including no access to a cyclotron, studies not being funded by healthcare providers, high cost, and lack of suppliers. 68Ga generator supply has been identified as restricted in many countries. This restriction increased demand in the future with more widespread clinical use of 68Ga-peptide studies.
Due to the high cost, lack of regulatory approval and no available supplier or distributor numerous therapeutic tracers were not available. In the past 10 years, significant changes have been made and increase in the burden regarding handling, production, and transportation of radiopharmaceuticals. Most countries did not use or have access to 123I-MIBG, 131I-MIBG and 123I, mainly due to cost. The information is true for low- and middle-income countries. Peptide radionuclide ligand and peptide receptor radionuclide therapeutics including 177Lu-Lutathera had limited use across all countries. It should be mentioned that this field is rapidly changing. Many more sites and countries are expected to have access to these therapeutic radiopharmaceuticals since the survey was completed.
All countries have issues of radiopharmaceutical access and availability is clearly shown in data obtained in this survey project. The capability to address these issues varies according to the funding, nuclear medicine infrastructure and country. The problems with limited suppliers of cold kits, and many diagnostic SPECT radiopharmaceuticals was witnessed in low-, middle- and high-income countries globally. Problem is not restricted just to countries with challenges in funding of nuclear medicine studies. The workforce issues could be addressed in part by coordinated efforts for improving the training of technologists, scientists in nuclear medicine and physicians. IAEA programs play a part in supporting direct training along with asdocumentation and position papers on infrastructure requirements and protocols. The ability of nuclear medicine societies to identify access issues and work with regional societies/associations may play a role in detecting sources of radioisotopes and kits, and facilitating local regulatory approvals. To be involved in stability of supply chains and provision of supplies is important for companies and professional organizations e.g., Nuclear Medicine Europe.
IAEA and the World Health Organization are supporting access programs
Especially in low- and middle-income countries, IAEA and the World Health Organization are supporting access programs through regional initiatives. Strategic initiatives aimed at promoting the funding and use of SPECT and PET radiopharmaceuticals are projected to align with approvals and drug development in countries, in the context of targeted therapies and personalized medicine. The initiatives benefit from sharing of health technology assessments and cooperation between countries. This will enhance time to approvals and economic justification of new studies. Global efforts to improve access and availability of radiopharmaceuticals will lead to major industry wide events such as 99Mo–99mTc shortages. The importance of nuclear medicine in routine patient care will be a key driver of any approach.
Nuclear medicine equipment market is expected to gain market growth in the forecast period of 2021 to 2028. Data Bridge Market Research analyses the market to account to grow at a CAGR of 6.7% in the above mentioned forecast period. The growing awareness regarding the importance of early diagnosis of diseases is escalating the growth of nuclear medicine equipment market.
CONCLUSION
This NMGI revealed an interesting portrayal of the issues that are associated with the availability, regulatory barriers, supply, cost, and other factors related to the use of radiopharmaceuticals internationally. Low and middle-income countries have limited availability of standard diagnostic radiopharmaceuticals. To address the varied causes of reduced supply, various strategic initiatives are required. Nuclear medicine is widely being deployed and rapidly expanding across the globe. One of the key strategy for ensuring patients can benefit from these vital therapeutic and imaging procedures is addressing the issues of access and availability of radiopharmaceuticals.
The Nuclear Medicine Global Initiative Project divulged in the concepts regarding the diagnostic or thereupatic applications of radipharmaceuticals. The study helps in understanding the specific challenges encountered during the design, in vitro and in vivo evaluation, (radio)synthesis, and clinical translation. Various other challenges were also highlighted in the survey, including delays in transport of radioactive materials, the denial of shipments by some carriers and need for compliance with transport regulations, among others. It shows some regions are still being driven by needs in meeting regulatory demands than by commercial regard. However, the consistent growth in the healthcare systems throughout the globe is expected to positively impact the radiopharmaceutical market in the coming years.
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