China's New Radiopharmaceutical Policy Signals Strong Support for Therapeutic Nuclear Medicine Development

To better promote and guide clinical research and development in the field of radiopharmaceuticals for therapeutic use, and to clarify technical standards, the Center for Drug Evaluation (CDE) released the “Technical Guidelines for Clinical Evaluation of Radiopharmaceuticals for Internal Use (Draft for Comment)” (hereinafter referred to as the “Draft Guidelines”) over a month ago. The Draft Guidelines primarily provide guidance on aspects not covered by general drug development guidelines, such as dose exploration, dosimetry, and radiation protection, and are open for industry comment.

The “Draft for Comments” provides relatively clear guidance for the clinical development of radiopharmaceuticals for internal use. In conjunction with the previously issued “Technical Guidelines for Clinical Evaluation of Radiopharmaceuticals for Internal Diagnostic Use” and “Technical Guidelines for Non-clinical Studies of Radiopharmaceuticals for Internal Diagnostic Use,” it further streamlines the clinical development pathway for nuclear medicine drugs, while also attracting significant attention from numerous nuclear medicine companies, including Xiantong Medicine, New Radiomedicine, HTA, and Full-Life Technologies.

Xiantong MedicineFocusing on the research and development of radiopharmaceuticals in three major therapeutic areas: central nervous system, cardiovascular, and oncology. In the field of neurodegenerative diseases, Xiantong Medicine possesses Aβ imaging agents and tau protein imaging agents. In the cardiovascular sector, PET imaging agents for myocardial blood flow quantification and myocardial viability assessment are in Phase II clinical trials. In oncology, the company maintains seven to eight product pipelines. Among its current portfolio of over a dozen pipelines, two projects are at the New Drug Application (NDA) stage, four are in clinical development, and five to six are in the pre-IND stage.

New RadiomedicineIt primarily focuses on three major business areas: the supply of medical isotopes, the research and development of novel radiopharmaceuticals such as microspheres, and CDMO technical services. In July this year, its independently developed Yttrium [90Y] Carbon Microsphere Injection received approval from the Center for Drug Evaluation (CDE) to commence clinical trials.

HTAHTA Co., Ltd. is a holding company under China Isotope & Radiation Corporation, which itself is a subsidiary of China National Nuclear Corporation. Its products and business scope cover multiple fields, including radiopharmaceuticals, radiolabeled compounds, nuclear medicine services, radioactive sources, tracers, and medical devices. HTA operates the largest domestic network for the production, distribution, and technical services of radiopharmaceuticals. Currently, it holds 33 approval licenses for radiopharmaceuticals. Its pipeline of projects under development spans cardiovascular diseases, neurology, oncology, and theranostics. With comprehensive R&D, manufacturing, safe transportation, and nuclear technology service systems, HTA remains committed to the industrialization of nuclear technology applications.

Full-Life TechnologiesFocusing on the global R&D of innovative radiopharmaceuticals and the production and supply of radionuclides, the company was established one year ago, with two product pipelines approaching the Preclinical Candidate (PCC) stage.

To understand the impact of new policies on radiopharmaceuticals on industry development and to assess the progress of industrialization in this field, VBInsight held an event on July 28"Radiopharmaceuticals" Series Online Panel, invited an Associate Professor from the School of Radiation Medicine and Protection, Suzhou Medical College, Soochow UniversityWang Guanglin, Senior Vice President of Xiantong MedicineWang Peng, Deputy General Manager of New RadiomedicineGe Qiang, CFO of Full-Life TechnologiesWu Yixia, Registration Supervisor at HTAXu Xiaomin, engaging in multi-party discussions on the new policies for radiopharmaceuticals, with the aim of contributing to the development of the industry.

In recent years, the state has introduced numerous favorable policies to support the development of the radiopharmaceutical sector.

In the research and development of diagnostic radiopharmaceuticals, the Center for Drug Evaluation (CDE) issued the Technical Guidelines for Clinical Evaluation of Radioactive In Vivo Diagnostic Drugs in October 2020 and the Technical Guidelines for Non-clinical Research of Radioactive In Vivo Diagnostic Drugs in February 2021, respectively, to promote and standardize the R&D of radioactive in vivo diagnostic drugs in China.

As radiopharmaceuticals for in vivo diagnosis continue to advance, an increasing number of radiopharmaceuticals for in vivo therapy are entering clinical trials, with policy support for the nuclear medicine industry gradually expanding to promote clinical research on these therapeutic agents. The "Draft for Comment" is preciselyPromoting the development of the therapeutic radiopharmaceutical industry through technical guidelines, continuously sending positive signals to the radiopharmaceutical sector.

Wang Peng, Vice President of Xiantong Medicinestated, “In China, there is limited experience in the research and regulation of radiopharmaceuticals for internal radiotherapy among industry players, regulatory authorities, and clinical trial institutions. However, it is foreseeable that the number of clinical trials for radioactive therapeutic drugs in China will increase significantly in the coming years. Therefore, the release of this ‘Draft for Comments’ provides technical guidance for domestic radiopharmaceutical companies to conduct clinical research on radioactive therapeutic drugs. Meanwhile, the issuance of clinical research guidelines by regulatory authorities in the traditionally ‘niche’ field of radioactive therapeutic drugs reflects the growing attention at the national level to the research and development of nuclear medicines, particularly therapeutic radiopharmaceuticals, sending a positive signal for the development of China’s nuclear medicine industry.”

Clinical trials of radiopharmaceuticals may follow the general principles for clinical research; however, their unique aspects in dose exploration, dosimetry, and radiation protection are not addressed by the guidelines for conventional drug development.

Drug development must consider efficacy while not neglecting safety.The Draft for Comments places particular emphasis on clinical safety issues, devoting substantial space to providing “very clear guidelines,” primarily reflected in two aspects: dosage and radiation protection.

Wang Guanglin, Associate Professor at the School of Radiation Medicine and Protection, Suzhou Medical College of Soochow UniversityHe contributed to the writing of this section, explaining why safety concerns are particularly critical for therapeutic radiopharmaceuticals. “Typically, diagnostic radiopharmaceuticals may be administered at doses of 10–20 millicuries, whereas therapeutic radiopharmaceuticals can involve doses as high as 200–300 millicuries. Due to the significantly higher radiation dose, deterministic effects may occur.” Deterministic effects refer to radiation-induced biological effects that have a threshold dose; their severity increases with dose, becoming more pronounced at higher levels. Examples of deterministic effects include suppression of hematopoietic function and renal impairment.

“Dosimetry is a critical tool for safety assessment. Current technologies are unable to accurately measure the emissions of alpha-emitting radiopharmaceuticals and their decay daughter nuclides after administration in humans, nor can they precisely track the distribution and metabolism of these agents within the body. For instance, accurate dosimetric evaluation of Ac-225, which has three decay daughters, is highly challenging. However, the Draft for Comment clearly proposes that surrogate imaging agents can be used to assess biodistribution and tumor uptake, providing excellent guidance for clinical research,” further explained Wang Guanglin.

The “Draft for Comment” emphasizes clinical safety in its content and adopts a balanced regulatory approach.

“I believe the Draft for Comments demonstrates foresight and openness, providing both clear direction and ample room for the development of nuclear medicine.”Wang Peng, Vice President of Xiantong MedicineIt is believed that the "Draft for Comments" sets forth clear technical requirements in areas such as efficacy and safety assessment, while also providing ample room for exploration in aspects related to radioactive characteristics where the industry has not yet reached a clear consensus or where existing scientific methods remain inadequate, such as dosimetry for alpha-emitting radionuclides.

Ge Qiang, Deputy General Manager of New RadiomedicineHe added, “The new regulatory policies for radiopharmaceuticals are relatively lenient regarding requirements for alpha-emitting radionuclides, microdosing, and radioligands. For instance, non-clinical general toxicology studies may be conducted using non-radioactive ‘cold’ compounds, and the biodistribution of alpha-emitting radiopharmaceuticals can be assessed using alternative imaging agents. However, safety assessments are approached with great caution and strictness. This rigor extends beyond clinical aspects to include pharmacology and toxicology; specifically, safety data from external irradiation cannot be solely relied upon for internally administered radiopharmaceuticals.”

The drug development process is generally divided into preclinical research, clinical trial approval, clinical trials, and new drug marketing approval. However, the "Draft for Comments" was released prior to the issuance of technical guidelines for preclinical studies. What are the underlying reasons for this?

On the one hand, the growing pipeline of radiopharmaceuticals for systemic radiotherapy, with an increasing number of candidates entering clinical trials, has led to a rising demand from pharmaceutical companies to conduct clinical studies. On the other hand, it is more challenging to establish non-clinical technical guidelines for radiopharmaceuticals than to develop clinical technical guidelines.

Ge Qiang, Deputy General Manager of New RadiomedicineIt was stated that several therapeutic radiopharmaceuticals have already been marketed abroad, with abundant clinical trials and reference literature available; however, non-clinical evaluation data have not been fully disclosed. Furthermore, the development of radiopharmaceuticals in China has long been sluggish, with limited systematic preclinical studies conducted, and currently, few institutions in the country are capable of undertaking non-clinical research.

“If the ‘Draft for Comments’ is officially issued, the only remaining hurdle to clearing the development pathway for radiopharmaceuticals used in internal radiotherapy will be the technical guidelines for preclinical studies. ‘However, issuing technical guidelines for non-clinical studies of radiopharmaceuticals used in internal radiotherapy remains a significant challenge.’”Wang Peng, Vice President of Xiantong MedicineDue to characteristics such as radiation and decay associated with radionuclides, radiopharmaceuticals exhibit distinct features in nonclinical research compared to conventional drugs. These features are addressed and reflected in the *Technical Guidelines for Nonclinical Research of Radiopharmaceuticals for In Vivo Diagnosis*. However, controversies persist regarding certain aspects, such as whether nonclinical safety studies should be conducted using hot-labeled products and whether the concept of “microdosing” is accepted in China. Furthermore, the radioactive doses of radiopharmaceuticals for therapy are often tens to hundreds of times higher than those of diagnostic radiopharmaceuticals, and their dosing intervals are significantly longer than those of conventional drugs. These factors pose additional challenges for the nonclinical research of therapeutic radiopharmaceuticals in practical implementation. In addition, no specific guidelines for the nonclinical research of therapeutic radiopharmaceuticals have been officially released globally. The number of therapeutic radiopharmaceuticals for in vivo use approved in recent years is very limited, making it difficult to obtain evaluation information on the nonclinical research of these drugs from other regulatory agencies. Overall, it is not an easy task to issue technical guidelines for the nonclinical research of therapeutic radiopharmaceuticals for in vivo use at this stage.

Wang PengIt was also stated that the Center for Drug Evaluation (CDE) has established a specialized team for reviewing radiopharmaceuticals. However, as most reviewers lack backgrounds in radiopharmaceutical-related fields, additional time is required to gain an in-depth understanding of the specific characteristics of these drugs. Nevertheless, with an increasing number of radiopharmaceuticals entering preclinical and clinical research stages, the volume of products reviewed by the CDE has gradually risen, leading to continuous accumulation and enhancement of expertise. “The CDE may be discussing the issuance of guidelines on Chemistry, Manufacturing, and Controls (CMC) for radiopharmaceuticals.”

Based on the route of administration, radiopharmaceuticals for therapeutic use can be classified into those administered systemically and those administered locally. Due to differences in the routes of administration, there are significant disparities in the absorption, distribution, metabolism, and excretion (ADME) processes of systemically versus locally administered radiopharmaceuticals after they enter the body. Consequently, substantial differences exist in all aspects of clinical development between radiopharmaceuticals delivered via these two distinct routes. The “Draft for Comments” applies exclusively to the clinical development of new systemically administered radiopharmaceuticals. For locally administered therapies, such as iodine-125 ([125I]) sealed seed sources and yttrium-90 ([90Y]) microsphere radiopharmaceuticals, there are currently no corresponding guidelines, leaving a policy gap that urgently needs to be addressed.

Xu Xiaomin, Registration Director at HTAIn summary, both Europe and the United States have issued registration documents tailored to the unique characteristics of radiopharmaceuticals. However, China’s “Administrative Measures for Radiopharmaceuticals,” first promulgated in 1989, has undergone several revisions but has not seen substantial changes. “While technical standards introduced domestically in the past two years are gradually aligning with international norms, China’s regulatory framework for radiopharmaceuticals and the alignment of its guiding principles still require further strengthening.”

Since the implementation of China’s Drug Administration Law in 2019 and the Provisions for Drug Registration in 2020, China’s drug registration system has adopted the implied approval mechanism for clinical trials and the Marketing Authorization Holder (MAH) system, gradually aligning with international regulatory standards for radiopharmaceuticals.

However, the regulation of radiopharmaceuticals in China still has its unique characteristics.Xu Xiaomin“For example, certain interventional therapy products, such as microspheres and sealed seed sources, hold a certain market share. While these products are regulated as medical devices abroad, they are classified as drugs in China, posing challenges for domestic R&D and regulatory submissions.”

Ge Qiang, Deputy General Manager of New RadiomedicineTaking microspheres as an example, this matter is explained in detail. Currently, the Center for Drug Evaluation (CDE) has approved Investigational New Drug (IND) applications for three microsphere products (one of which has been marketed). The first is Fangen Medicine’s Yttrium-90 [⁹⁰Y] glass microsphere system, classified as a drug-device combination product with the drug as the primary component. “As I understand it, the microspheres should be considered the drug, while the infusion device included in the system should be considered the device.” The second is Grand Pharma’s Yttrium-90 [⁹⁰Y] resin microspheres. “Unlike the first marketed microsphere product, regulatory authorities classified the infusion device as a packaging component for submission purposes.” The third is New Radiomedicine’s Yttrium-90 [⁹⁰Y] carbon microspheres. “We also encountered regulatory uncertainties during the submission process, so we communicated with the CDE and consulted the Center for Medical Device Standardization Administration for product attribute classification, which resulted in its designation as a drug-device combination product.”

Ge Qiangstated, “Furthermore, in accordance with the relevant regulations issued by the state in 2011—which stipulate that radioactive microparticles are not regulated as medical devices—the National Medical Products Administration (NMPA) has provided four classifications for radioactive microspheres. The outcomes of these classifications have been largely consistent: microspheres are not considered medical devices but are instead regulated as pharmaceuticals, either as standalone drugs or as drug-device combination products where the drug component is primary.”

Although radiopharmaceutical companies have become increasingly active in the capital market in recent years, with a growing number of biotech firms emerging in the industry and traditional pharmaceutical giants such as Hengrui Medicine and Grand Pharma entering the radiopharmaceutical sector,Full-Life Technologies CFO Wu Yixiastated, “The threshold and barriers in the field of nuclear medicine are high, making it difficult for intense internal competition to arise.”

Regulatory oversight of radiopharmaceuticals involves multiple agencies, including the National Nuclear Safety Administration, the Ministry of Ecology and Environment, and the Ministry of Transport. Companies must obtain qualifications and certifications from various regulatory bodies before they can engage in radiopharmaceutical operations. For instance, due to their radioactive nature, radiopharmaceuticals are subject to supervision by ecological and environmental authorities, and a “Radiation Safety License” must be secured before conducting relevant hot-cell testing. This poses a significant challenge for startups. During its first three years, New Radiomedicine focused on infrastructure development and obtaining the Class A “Radiation Safety License” required for R&D and production activities.

At the same time, this is no easy feat for large foreign pharmaceutical companies either.Wang Peng, Vice President of Xiantong Medicine“Foreign pharmaceutical companies such as Novartis and Bayer are looking to introduce some of their radiopharmaceutical products into China, aiming to reduce production, transportation, and distribution costs through localized manufacturing. However, finding domestic CRO/CDMO/CMO providers that meet their requirements poses a significant challenge,” said Wang Peng. He noted that there is a particular shortage of CRO/CDMO resources in China’s radiopharmaceutical sector, as well as CMO resources compliant with EMA and FDA standards.

Ge Qiang, Deputy General Manager of New RadiomedicineHe stated that the currently marketed radiopharmaceuticals for systemic radiotherapy abroad are relatively limited. The industry must develop novel agents, including new ligands (small molecules, peptides, antibodies), target selection, and strategies for discovering new drugs, which represent a crucial direction for the future.

He further added that large-scale, stable supply of radionuclides is essential for the industrialization of radiopharmaceuticals. New Radiomedicine plans to achieve commercial supply of Yttrium-90 (Y-90) in China in the second half of this year, and may subsequently export Y-90 to the Asia-Pacific region. “We expect to begin supplies by around October or November this year.”

“A stable supply of radionuclides is a critical direction for industrialization.”Wang Guanglin, Associate Professor at the School of Radiation Medicine and Protection, Suzhou Medical College, Soochow UniversityHe introduced, “Currently, the main focus is on the two radionuclides Lu-177 and Ac-225. In addition, I believe that Pb-212, being developed by Researcher Dai Xiongxin at the China Institute for Radiation Protection (CIRP), and At-211, being developed by Professor Liu Ning at Sichuan University, represent new directions. Other alpha-emitting radionuclides and Yttrium-90 are also areas of significant interest.”

Meanwhile, he emphasized that resolving the supply issues of radionuclides cannot rely solely on increased corporate investment; relevant government departments must also contribute to addressing the supply challenges for radionuclides such as Lu-177 and Ac-225 produced via reactors and large-scale accelerators.

Xu Xiaomin, Registration Director at HTAIt was stated that the development of theranostic paired drugs may become a future trend, with Lu-177-labeled therapeutic agents potentially serving as a breakthrough point. Radiopharmaceutical Drug Conjugates (RDCs) remain a critical pathway, requiring the identification of suitable targeting vectors to achieve precise diagnosis and treatment. Intracavitary intervention continues to be an effective approach for the treatment of solid tumors.

Full-Life Technologies CFO Wu Yixiastated that radiopharmaceuticals are not an entirely new field, but rather a resurgent one. In less than a decade, from Bayer’s Xofigo (radium [223Ra] dichloride injection) and Novartis’s Lutathera (177Lu-DOTATATE) to the approval of Pluvicto (177Lu-PSMA-617) this year, the substantial investments by major pharmaceutical companies in the radiopharmaceutical sector, along with their achievements in clinical development and commercialization, have demonstrated the significant promise of therapeutic radiopharmaceuticals. “However, the radiopharmaceutical field cannot rely solely on the individual success of one or two drugs. If more compelling clinical data can be disclosed within the next two years, the value of radiopharmaceuticals will be further validated, facilitating the launch and promotion of additional products.”

Wang Peng, Vice President of Xiantong MedicineIn summary, “over the next 2–5 years, all radiopharmaceutical companies, both domestic and international, must continue to explore, particularly the intrinsic principles of radiopharmaceutical therapies themselves, so as to extend the success seen in individual cases such as Lutathera and Pluvicto to a broader range of drugs.”