Abstract
Since the late 1950s, radiopharmaceuticals have been used for diagnosis and treatment in clinical nuclear medicine in China. Over the decades, China has successfully established a relatively sophisticated system for radiopharmaceutical production and management, supported by state-of-the-art facilities. With the rapid growth of the national economy, the radiopharmaceutical market in China is expanding at a remarkable pace. This burgeoning market has led to an escalating demand for clinical-stage radiopharmaceuticals, either produced domestically or imported. Despite this positive trajectory, the development and application of radiopharmaceuticals in China have been hindered by several challenges that persist, such as inadequate research, insufficient investment, limited availability of radionuclides, shortage of trained personnel in related fields, and imperfections in policies and regulations. In an exciting development, the regulation reforms implemented since 2015 have positively affected China’s drug regulatory system. The introduction of the “Mid- and Long-Term Development Plan (2021–2035) for Medical Isotopes” created concurrently an opportune environment for the advancement of innovative radiopharmaceuticals. In this review, we aim to provide an overview of the approval process for novel radiopharmaceuticals by the National Medical Products Administration and the status of radiopharmaceuticals in research and development in China. Preclinical development and clinical translation of radiopharmaceuticals are undergoing rapid evolution in China. As practitioners in the field in China, we provide several practical suggestions to stimulate open discussions and thoughtful consideration.
Radiopharmaceuticals are compounds that contain radionuclides or their labeled ligands, and they are widely used in tumor diagnosis and treatment, myocardial imaging, early detection of neurodegenerative diseases, and imaging of inflammatory diseases, among other uses. In 2020, the global market size of radiopharmaceuticals was $5.9 billion, with radioactive diagnostic drugs accounting for 90% of the market. The corresponding market size in China was approximately ¥4.456 billion (∼$624 million), accounting for about 8% of the global radiopharmaceutical market (1). With the popularization of SPECT, PET, and PET/CT, research and development of diagnostic radiopharmaceuticals represented by 99mTc-, 18F-, or 68Ga-labeled agents have advanced rapidly, especially of positron-emitting radiopharmaceuticals. Almost 10 y after the discovery of [68Ga]Ga-PSMA-11, it was approved by the U.S. Food and Drug Administration as the first 68Ga-labeled radiopharmaceutical for PET imaging of prostate-specific membrane antigen (PSMA)–positive prostate cancer in the United States in 2020 (2). This means that the clinical potential of targeted radiopharmaceuticals is rapidly transforming into a clinical practicality. In recent years, with the rapid development of targeted ligands and the widespread application of new medical radionuclides, therapeutic radiopharmaceuticals have attracted more attention. 153Sm, 89Sr, 223Ra, 90Y, 131I, 177Lu, 225Ac, and other radionuclides are commonly used to treat cancer bone metastases, liver cancer, thyroid cancer, and other malignant conditions, and they have shown enormous therapeutic potential. In March 2022, [177Lu]Lu-PSMA-617 was approved for the treatment of metastatic castration-resistant prostate cancer (3), which demonstrated good clinical therapeutic efficacy and tolerance (4,5).
Radiopharmaceuticals were developed in China in the late 1950s, with industries mainly distributed in Beijing, Chengdu, and Shanghai. After more than 60 y of development, a relatively complete system for the research and development, production, supply, and clinical application of radiopharmaceuticals has been established. Nevertheless, the radiopharmaceutical industry in China started late and is still in a rapid development stage, with gaps remaining in several aspects in China compared with developed countries. In recent years, the development and supply of radionuclides and radiopharmaceuticals have progressed rapidly. China has successively formulated and introduced multiple policies to promote the healthy development of the radiopharmaceutical industry, with an overall tone of strict supervision. In China, most radiopharmaceuticals used in clinical practice are generic drugs, with diagnostic radiopharmaceuticals as the mainstays of clinical use and research. The number of innovative therapeutic radiopharmaceuticals is limited, and radiopharmaceuticals with global intellectual property rights are countable. Although the development of radiopharmaceuticals has similarities to drug discovery, significant differences allow a faster, safer, and more cost-effective route for progressing radiolabeled molecules into human studies (6–8). This review aims to provide an overview of the process for acquiring National Medical Products Administration (NMPA) approval for an innovative radiopharmaceutical in China and discuss the current status of research and development of radiopharmaceuticals in China.
INTRODUCTION TO RADIOPHARMACEUTICAL ADMINISTRATION IN CHINA
China’s nuclear medicine has undergone a development process of more than 60 y, completing the transformation of drugs and equipment heavily relying on importation to domestic substitution and, more recently, to the stage of independent innovation and translation (9). The 2020 edition of the Pharmacopoeia of the People’s Republic of China includes 24 types of radiopharmaceuticals labeled with 11 radionuclides: 99mTc, 18F, 131I, 153Sm, 89Sr, 125I, 32P, 67Ga, 201Tl, 51Cr, and 133Xe (10). For a long time, China’s radiopharmaceuticals, especially the medical radionuclides, heavily depended on importation. This dependence hindered the development of radiopharmaceuticals and nuclear medicine in China. In 2021, 8 state departments, including the China Atomic Energy Authority, the Ministry of Science and Technology, and the NMPA, jointly issued the “Mid- and Long-Term Development Plan (2021–2035) for Medical Isotopes” (11), aiming to establish a stable and independent medical isotope supply and security system, accelerate the research and development of innovative radiopharmaceuticals and medical equipment, and expand the popularity of nuclear medicine in China. The plan holds significant importance and presents a road map for promoting the development of China’s radiopharmaceutical industry (12).
Radiopharmaceuticals were included as pharmaceuticals by the Drug Administration of the Ministry of Health of China in 1974. The 1977 edition of the Pharmacopoeia of the People’s Republic of China accommodated radiopharmaceuticals for the first time (13). On January 13, 1989, the “Provisions for the Administration of Radioactive Pharmaceuticals” was officially implemented and the radiopharmaceutical administration entered the era of supervision (14). In 2006, the NMPA issued the “Regulations on the Administration of the Preparation of Positron Radiopharmaceuticals by Medical Institutions,” which stipulated the licensing conditions for the use and preparation of radiopharmaceuticals at medical institutions (15). This regulation has been in use to this day. The license is divided into 4 levels: to use radioimmunoassay kits for in vitro diagnosis, a class I or higher-level license should be held; to use radiopharmaceuticals, a class II or higher-level license should be granted; to prepare radiopharmaceuticals, a class III or higher-level license should be obtained; and for the development of and related clinical research into a new type of radiopharmaceutical, a class IV license should be obtained. The introduction and use of new radiopharmaceuticals without market authorization in medical institutions are mainly through clinical investigator–initiated trials. Investigators should submit complete preclinical study data to the Clinical Research Management Committee and the Ethics Committee for approval of clinical studies (recruiting a limited number of patients) that are not intended to seek marketing approval and are used for internal research purposes (12,16). Some examples of such radiopharmaceuticals include [18F]FES, 68Ga-labeled PSMA-targeting tracers, [68Ga]Ga-DOTATATE, and 68Ga-labeled fibroblast activation protein inhibitors (12). Investigator-initiated trials have accelerated preliminary clinical translation and evaluation of various radiopharmaceuticals in China. The bonus policy will continuously benefit the development of radiopharmaceuticals in China.
According to the old version of the Drug Administration Law and the Provisions for Drug Registration, the approval number of radiopharmaceuticals can be issued only to the enterprise holding the production license of radiopharmaceuticals, which restricts the rapid development of the industry to a certain extent. Enterprises have low enthusiasm for and a slow pace in the research and development of radiopharmaceuticals, and no innovative radiopharmaceutical has been approved for marketing for a long time in China. In 2019, the newly revised Drug Administration Law implemented the market permit holder system. This system separates the drug marketing license and production license, optimizes the resource allocation of the radiopharmaceutical industry, and greatly promotes the research and innovation of radiopharmaceuticals in China. With the promotion of the policy, some companies focusing on the research and development of radiopharmaceuticals have joined the field of radiopharmaceuticals to become market permit holders. This has improved the research and development capacity of radiopharmaceuticals and enabled them to meet more clinical needs. The market permit holder system promotes the transformation of the existing production model of radiopharmaceuticals, encourages the emergence of enterprises specializing in the entrusted production of radiopharmaceuticals, reduces production costs, and saves social resources. Subsequently, on March 29, 2022, the “Provisions for the Administration of Radioactive Pharmaceuticals” was revised for the third time (17). Provisions have been made for the establishment of enterprises engaged in the production or the operation of radiopharmaceuticals. Since then, the production and business licenses for radiopharmaceuticals have been officially separated, and a market-oriented radiopharmaceuticals business market is gradually taking shape.
Since August 2021, the NMPA has made adjustments and provisions in 3 aspects for the production license of radiopharmaceuticals and the filing of positron radiopharmaceuticals prepared by medical institutions (18,19). The approval of radiopharmaceutical production and operation enterprises will be delegated by the NMPA to the provincial drug supervision and management department. The testing of 3 consecutive batches of radiopharmaceuticals has been adjusted to be undertaken after a manufacturer has obtained the production license for radiopharmaceuticals, and it may be performed simultaneously with the dynamic production batch for inspection of conformity to good manufacturing practices. The samples should be tested by drug testing institutions that meet the requirements in the “Provisions for the Administration of Radioactive Pharmaceuticals.” For the filing of a medical institution for the preparation of positron radiopharmaceuticals, the 3 consecutive batches of samples of the variety to be manufactured should be tested and the quality standard should be reviewed by drug testing institutions that meet the requirements in the “Provisions for the Administration of Radioactive Pharmaceuticals.”
NMPA APPROVAL PROCEDURES FOR RADIOPHARMACEUTICALS
In China, the development, production, and sales of novel drugs, devices, and cosmetics, including radiopharmaceuticals, were overseen by the China Food and Drug Administration (the predecessor of the NMPA), which was administered by the State Administration for Market Regulation (20). The China drug regulatory system has undergone substantial changes in the past 10 y. On August 18, 2015, the State Council of China released a policy document titled “Opinions on the Reform Review and Approval Process for Drugs and Medical Devices,” (21) marking the beginning of regulatory reform (22–25), including establishment of an expedited program, streamlining of investigational new drug (IND) applications, and improvement of the drug priority review system (26,27). Joining the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use in 2017 was another important milestone (28). This indicates that the agency is prepared to adopt the technical requirements of the International Council for Harmonisation for drug registration and become an active participant in global drug approval and regulation (29). On January 22, 2020, the State Administration for Market Regulation published the Provisions for Drug Registration (30) and the Provisions for the Supervision and Administration of Drug Production (31), which are the core supporting regulations in the field of drug supervision. These regulations will lay the foundation for the rule of law to strengthen drug quality and safety risk control, standardize and strengthen drug supervision, and ensure drug safety, effectiveness, and quality control. All efforts are aimed at achieving a more scientific and efficient drug regulatory process (Fig. 1).
Overview of NMPA process for new drug approval. NDA = new drug application.
Drug research and development are divided into 3 stages: preclinical research, clinical research, and marketing registration. The preclinical phase is fundamental in the progression to clinical-stage trials and subsequent NMPA approval. After the completion of the preclinical study, the drug sponsor applies for a commercial IND application with the NMPA. The U.S. Food and Drug Administration has a time limit of 30 d from IND application to license (32), whereas the NMPA has a time limit of 60 d. IND applications for phase I clinical trials with the NMPA are similar to the U.S. Food and Drug Administration guidance in overall content (33–35). The NMPA guidance has chapters that cover biologics and overseas data, and it states that the format and content of INDs can be prepared by direct reference to the International Council for Harmonisation’s common technical document (36). Ethnic sensitivity analysis is a China-specific requirement that needs to be implemented early in drug development plans (37,38). The International Council for Harmonisation published Ethnic Factors in the Acceptability of Foreign Clinical Data in 1998 (39). It also described the factors that need to be considered when extrapolating and facilitating the acceptance of foreign clinical data in new regions. Sponsors are encouraged to conduct early clinical trials in China or include China early in multiregional clinical trials to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis (36). These are called phase 0 clinical trials to support clinical trial conduct and registration (40,41). On completion of the phase III trial, the new drug application may be submitted to the NMPA. The expedited pathways instituted in 2021, such as breakthrough therapy drug procedures, conditional approval procedures, priority review approval procedures, and special approval procedures, have significantly reduced the time needed for new drug application approval compared with standard review. The median approval time of new drug applications was 15.4 mo in 2017–2021, which was significantly shorter than the time during the prereform period (22.1 mo in 2011–2013 and 31.5 mo in 2014–2016) (25).
Because of the particularity of radiopharmaceuticals in development and use, the implementation process of nonclinical and clinical studies of radiopharmaceuticals cannot refer to the technical requirements of conventional drugs. To facilitate innovation in radiopharmaceuticals in enterprises, as well as to promote and standardize the research and development and clinical application of radiopharmaceuticals in China, the Center for Drug Evaluation of the NMPA issued the “Guidance on Clinical Studies of Diagnostic Radiopharmaceuticals” (42) in October 2020, the “Guidance on Non-clinical Studies of Diagnostic Radiopharmaceuticals” (43) in February 2021, and the “Guidance on Clinical Studies of Therapeutic Radiopharmaceuticals” (44) in February 2023. In addition, to strengthen the quality control of 99mTc and positron radiopharmaceuticals, the NMPA issued “Guidelines for Technetium [99mTc] Radiopharmaceutical Quality Control” (45) and “Guidelines for Positron Radiopharmaceutical Quality Control” (46) in 2004. Further improvement of the technical guidance principle system, as well as guidance of the development and research of innovative or generic radiopharmaceuticals that are urgently needed in clinical practice, is an important task of high industry concern.
COMMERCIAL AND CLINICAL USE OF RADIOPHARMACEUTICALS IN CHINA
To date, more than 40 radiopharmaceuticals have been approved for commercial use by the NMPA. The radiopharmaceuticals approved for marketing are similar to those in Western countries. In terms of diagnosis, [18F]FDG and [99mTc]Tc-methylene diphosphonate are the most widely used radiopharmaceuticals in China. However, there are relatively few clinically approved therapeutic radiopharmaceuticals in China. Clinically available therapeutic radiopharmaceuticals include [131I]NaI oral solution (or capsules), [89Sr]SrCl2 injection, 125I brachytherapy source, [153Sm]Sm-ethylenediaminetetramethylene phosphonate, and 32P (12). In recent years, many domestic and foreign radiopharmaceutical companies have intensified their application for radiopharmaceutical registration in China as a result of the technologic progress of radiopharmaceutical research and development, as well as the introduction of NMPA policies to encourage the innovation of new drugs. [99mTc]Tc-3PRGD2 is a SPECT imaging agent developed by Professor Fan Wang from Peking University (47,48). As the first independently developed class I diagnostic radiopharmaceutical to obtain clinical trial approval in China, it completed a phase III clinical trial at 11 hospitals in 2022 (http://www.cde.org.cn). There is no significant difference between [99mTc]Tc-3PRGD2 SPECT/CT and [18F]FDG PET/CT in the differentiation of benign and malignant lung lesions. However, in the diagnosis of lymph node metastasis of lung tumors, [99mTc]Tc-3PRGD2 SPECT/CT outperformed [18F]FDG PET/CT in specificity and accuracy, and the clinical trial reached both primary and secondary endpoints. Moreover, [99mTc]Tc-3PRGD2 can be prepared via kit formulation, making it easily available for routine clinical use. It has spent more than 20 y moving from chemical modification to radionuclide labeling and from preclinical research to clinical translation. The success of [99mTc]Tc-3PRGD2 indicates that we have experiences to learn from in developing diagnostic radiopharmaceuticals in China.
As stated previously, with the development of the national economy, the market for radiopharmaceuticals in China has expanded rapidly. More than 70 research pipelines in China involve multiple domestic pharmaceutical companies. Several new radiopharmaceuticals have entered the approval process, clinical trials, or the marketing approval stage, and some of them are expected to be approved and provide clinical services to patients soon (Supplemental Table 1 [supplemental materials are available at http://jnm.snmjournals.org]). Since the Center for Drug Evaluation of the NMPA began implementing the priority evaluation system in 2016, many innovative drugs from multinational pharmaceutical companies have entered the priority evaluation process, and the speed at which imported drugs reach market in China has been greatly improved. In August 2020, Xofigo (223Ra injection; Bayer Healthcare) was approved by the NMPA for treating patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. Subsequently, SIR-Spheres resin microsphere (Sirtex Medical) was approved for marketing for the treatment of unresectable colorectal cancer liver metastases that failed standard treatment. The “Opinions on Reforming and Improving the Review and Approval System for Radioactive Pharmaceuticals” (49), issued by the NMPA in April 2023, will further promote the innovation of radiopharmaceuticals and encourage the importation and registration in China of original radiopharmaceuticals that have been listed overseas. The release of this policy document clarified the clinical use value of radiopharmaceuticals, gave direction for the reform of regulations and policies, and encouraged the training of professionals in the field of radiopharmaceuticals. It will play an important guiding role in promoting the research, development, and application of radiopharmaceuticals in China.
REFLECTIONS ON THE DEVELOPMENT OF RADIOPHARMACEUTICALS IN CHINA
After a series of significant events and the introduction of pertinent regulations and policies, China’s radiopharmaceutical industry is embarking on a historic new stage. It is undeniable that China faces a challenge in developing independent and original radiopharmaceuticals, with a reliance on imported medical radionuclides so far. Concerted efforts are required to address this, including the continuous training of young professionals in related fields, such as radiochemistry, nuclear medicine, and molecular imaging. Further critical steps include fostering domestic and international collaboration for the cultivation of nuclear medicine practitioners, encouraging sustained investment in basic research and translational studies, optimizing sincere cooperation among disciplines and departments, increasing deployment of imaging equipment and cyclotrons (some capable of producing radiometals on a small scale), integrating contract research organizations for the production of radiopharmaceuticals, improving the logistics system for transporting radiopharmaceuticals, and refining the approval and supervision processes for radiopharmaceuticals. These steps will collectively expedite the healthy development, approval, and use of innovative radiopharmaceuticals in China. Ultimately, only radiopharmaceuticals that effectively tackle unmet clinical challenges will successfully integrate into routine clinical practices. Given the unique properties of radiopharmaceuticals, careful consideration and reassessment before their commercialization are imperative.
CONCLUSION
In the past decade, China has improved its drug regulatory landscape to accelerate the acquisition of new drugs that address unmet medical needs, leading to the rapid development of radiopharmaceuticals in China. With the joint efforts of radiopharmaceutical research and development institutions, enterprises, commercial investors, and the nuclear medicine community, the development and approval of radiopharmaceuticals in China will steadily increase under the guidance and supervision of national regulatory authorities. The development and use of radiopharmaceuticals in China will contribute to the growth of nuclear medicine worldwide and improve the management of human diseases in the era of precision medicine.
DISCLOSURE
This work was supported in part by the National Key Research and Development Program of China (grant 2020YFA0909000), the National Natural Science Foundation of China (grants 82372014 and 82302236), and the Shen Kang–United Imaging Joint Research and Development Plan (grant SKLY2022CRT301). Weijun Wei is a consultant of α-Nuclide (Ningbo) Medical Technology Co., Ltd. No other potential conflict of interest relevant to this article was reported.
- © 2024 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication November 27, 2023.
- Revision received January 29, 2024.
