On May 31, 2018, FDA issued draft guidance on nonclinical studies and labeling recommendations for products containing a radioactive compound (i.e., a radionuclide) that are used to treat patients with cancer--known as oncology therapeutic radiopharmaceuticals. The guidance is intended to help IND sponsors design an appropriate nonclinical program to support first-in-human (FIH) trials. The guidance also provides recommendations for certain aspects of product labeling.
The guidance describes methods for evaluating toxicities associated with the radionuclide and any ligand component, for use in determining appropriate dosing for FIH testing that minimizes risks to patients. These methods are recommended for development of new systemically-administered radiopharmaceutical products with no previous clinical experience. When there is prior clinical experience with the radionuclide or ligand components, the nonclinical program may be abbreviated accordingly, and the FIH dose may be based on existing clinical data.
To inform dose selection for FIH testing, FDA recommends that a single-dose biodistribution and dosimetry study be conducted on both males and females from at least one scientifically-justified species of animals. The animal biodistribution and dosimetry study (ABD) examines post-administration radioactivity in organs by generating time-integrated activity curves, which can then be used to estimate activity in human organs based on known methods for animal-to-human extrapolation. FDA provides suggestions regarding various aspects of study design, including (1) sampling duration and intervals, (2) organs for assessment, and (3) accounting for aspects of the planned clinical biodistribution and dosimetry study that might affect distribution of the product.
Typically, the data from the ABD study, together with general knowledge of organ-specific radiation-induced toxicities, are sufficient to address toxicities from radiation. However, to identify any ligand-related toxicities, FDA recommends that the sponsor conduct a general toxicology study on the cold pharmaceutical (i.e., product containing a ligand) in the same species used for the ABD study, prior to initiating a FIH study.
While not required to initiate FIH testing, or to move to phase 2, sponsors are also instructed to conduct long-term toxicity assessment studies to support marketing. FDA’s recommendations for study design and circumstances when studies may not be needed are described in the guidance.
FDA recommends basing FIH dose selection on two factors: (1) the radioactive administered dose and (2) the mass dose of the pharmaceutical. The appropriate radiation administered dose is determined based on the ABD data. As described above, the activity over time in each source organ is extrapolated from animals to humans to obtain the estimated absorbed doses in human organs. The radiation dose administered in patients is then adjusted based on tolerated absorbed radiation doses in human organs. There are currently no accepted criteria for determining organ tolerance for internal radiation from radiopharmaceuticals. Thus, sponsors are instructed to rely on published information regarding the tolerance of normal human organs to external beam radiation therapy. To estimate the equivalent dose of an alpha-emitting radiopharmaceutical, a relative biological effectiveness (RBE) of 5 (e.g., a 5:1 ratio of biological effectiveness) is recommended to account for the difference in toxicity as compared to external beam radiation. Unless the dose is sufficiently low, results from general toxicology studies or other nonclinical studies with the cold pharmaceutical should be considered to determine the appropriate FIH mass dose.
The guidance also discusses information for product labeling relating to reproductive toxicity, genotoxicity, carcinogenicity, contraception, and use in lactating women. While no nonclinical studies directed to these concepts are necessary during development (or for approval), the inherent risks related to each must be described in product labeling.