adioligand therapy (RLT) is emerging as an important treatment modality in a wide range of cancer types by harnessing the power of radioisotopes to deliver radiation to the target. However, as an innovative technology, RLT presents several regulatory and logistical challenges. In this article, one global pharmaceutical company shares its experience in ensuring accessibility of RLT to patients in Singapore.

Radiopharmaceuticals refers to any radioactive material that is administered to a patient as a diagnostic or therapeutic agent. A diagnostic radiopharmaceutical emits γ (gamma) or β+ (beta-plus) radiation which can penetrate the body and be detected by devices such as gamma cameras, single-photon emission computed tomography (SPECT) scans, or positron emission tomography (PET) scans, for medical imaging purposes. Therapeutic radiopharmaceuticals release high-energy types of radiation such as alpha or beta particles within a short range of tissue to destroy or weaken unwanted cells or tissues, such as tumors or overactive thyroid cells.

RLT, a type of therapeutic radiopharmaceutical, uses a ligand that targets cancer cells expressing a specific biomarker combined with a therapeutic radionuclide to selectively deliver cytotoxic radiation to tumor cells or the tumor microenvironment while limiting impact on nearby healthy cells.

RLT follows a theranostic approach in which radioligand imaging (RLI), a type of diagnostic radiopharmaceuticals of a diagnostic biomarker, is used to select patients for RLT directed against the same biomarker. Lutetium (¹⁷⁷Lu) oxodotreotide was the first RLT to be approved by the US Food and Drug Administration (US FDA), European Union European Medicines Agency (EU EMA), and Singapore Health Sciences Authority (HSA) for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Many other RLT products are currently in development across different types of cancer.

Radioligand Therapy (RLT) Regulatory Framework in Singapore

RLT is regulated by multiple agencies in Singapore: The Ministry of Health (MOH), the HSA, and the National Environment Agency (NEA). Each agency has its own requirements and focuses on different aspects of the supply of and treatment with RLT (e.g., radiation safety, product quality, safety, efficacy, etc.).

The MOH regulates the provision of nuclear medicine services in Singapore under the Healthcare Services Act 2020 and its regulations, including the Healthcare Services (Nuclear Medicine Service) Regulations 2023. The regulations include requirements for personnel (e.g., license holder), processes (e.g., quality management system), equipment and fittings (e.g., radiation shielding), radiation safety, and provision of nuclear medicine service for imaging and therapy purposes (e.g., pre- and post-treatment protocols).

HSA regulates therapeutic products in Singapore under the Health Products Act 2007 and its regulations, including the Health Products (Therapeutic Products) Regulations 2016. The regulation of HSA governs the quality, safety, efficacy, and Good Distribution Practices of the therapeutic product.

The NEA regulates radioactive materials used in Singapore under the Radiation Protection Act 2007 and its regulations, including the Radiation Protection (Ionising Radiation) Regulations 2023. The scope of the regulations includes requirements for radioactive material licenses covering their importation, distribution, supply, and waste disposal, and radiation exposures (e.g., occupational, medical, public).

Unique Characteristics and Challenges of Radioactivity

The radioactive nature of RLT is a unique characteristic: Its radioactivity is lost quickly over time due to radioactive decay, leading to short shelf life. For example, lutetium (¹⁷⁷Lu) oxodotreotide has a shelf life of 72 hours. The shelf life is further reduced upon receipt because of the time it takes to receive international shipments from European manufacturing sites into Singapore.

Important steps that the company took to proactively address these unique challenges included:

• Due to the rapid decrease in potency of the RLT, an efficient logistical plan/supply chain that ensured timely delivery and administration to patients within its shelf life was established in advance.
• This plan/chain subsequently helped in managing and resolving unforeseen circumstances such as delayed or missed delivery and flight schedules.
• Advance collaboration with local regulators and agencies created better understanding of relevant local laws, regulations, requirements, and licenses; for example, companies involved must obtain licenses from HSA and NEA depending upon their role (e.g., dealer’s license to import, wholesale, and/or manufacture).

Recommendations and Conclusion

RLT is emerging as an essential pillar in cancer treatment, and scientific innovation in RLT is progressing rapidly. It is important for organizations that are considering developing or distributing RLTs to understand the regulations from different agencies and to manage the complex logistics for supplying RLT in Singapore. Engage early with relevant agencies to familiarize yourself with their requirements and ensure compliance, build strong coordination within your supply chain to guarantee precise and timely delivery of RLT to patients, and establish contingency plans in advance to prepare for unforeseen circumstances.

References available upon request.

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