Pamedic Spotlight｜Interpretation of the Technical Guidelines for Non-clinical Studies of Therapeutic Radiopharmaceuticals

Therapeutic radiopharmaceuticals, usually consisting of radionuclides and non-radioactive parts, selectively deliver radionuclides to the lesion site, making use of the decay characteristics of radionuclides while  releasing rays or particles to destruct the lesion cells.

The Guiding Principles apply to radiotherapeutic drugs administered by the systemic route, but not to radiotherapeutic drugs administered by the local route, such as intratumoural, intrathecal and inhalation.

Therapeutic radiopharmaceuticals boast unique characteristics, including radioactivity, targeting, and temporal changes in chemical composition. In non-clinical studies, factors such as information on the clinical intended use of the drug, the characteristics of the subject, the pharmacological activity and toxicological profile of the ligand or carrier fraction, and radiation safety should be considered. Non-clinical studies of radiotherapeutic drugs should include pharmacodynamics, pharmacokinetics, toxicology, internal exposure dose estimation and radiation safety assessment. If it is proposed not to conduct a particular study, a fully justified basis should be provided.

1. The purpose of non-clinical studies of therapeutic radiopharmaceuticals is to provide non-clinical safety and efficacy supportive data for proposed clinical trials and/or product laucnhing.

2. Carcinogenicity tests for radiotherapeutic drugs are generally not required, but the risk of carcinogenicity should be indicated in the instructions.

3. Radionuclides produce radiation and carry a risk of reproductive toxicity. Reproductive toxicity tests are generally not required.

4. Before the first human clinical trial of therapeutic radiopharmaceuticals is carried out, non-clinical pharmacokinetic data should be used to estimate the absorbed dose to human organs/tissues and the effective dose to the whole body, so as to provide data for radiation safety assessment. It is recommended that the methods recommended by the International Commission on Radiological Protection (ICRP) publication, Medical Internal Irradiation Dose Committee (MIRD) should be used to estimate the absorbed dose and effective dose of internal irradiation in human body.

5. The selection of animal species should be carried out by using animal species that have relevance to the human body in terms of pharmacological activity (e.g. target binding), pharmacokinetic characteristics, etc. The reasonableness of the selection of animal species needs to be elaborated.

6. For the safety study, the general toxicological test should be carried out in the organisations certified by the Good Laboratory Practice (GLP) for non-clinical studies of drugs and comply with the GLP. considering the special characteristics of radiopharmaceuticals, when it is not possible to comply with the GLP, the test should be carried out in accordance with the principles of the GLP, so as to ensure that the quality of the test and the data are true, complete, and traceable.