FDA Issues New Guidance For Clinical Trial Dosage Of Oncology Therapeutic Radiopharmaceuticals

By Tim Sandle, Ph.D.

Radiopharmaceuticals, developed during the 1930s, are important medicines for both diagnosis and therapy.¹ While there are multiple nuclear medicine applications and designs, the drugs consist of a radioisotope (such as technetium-99m)² attached to a biological molecule that undergoes radioactive decay after administration. The function of the molecule is to target specific organs, cells, or tissues, either for therapeutic purposes (primarily oncology) or for imaging techniques that aid the visualization of specific bodily functions.

The safe administration of radiopharmaceuticals during clinical trials is an important component when establishing drug safety and efficacy.³ This has become a more complex assessment as more precision and personalized radiopharmaceuticals are developed to target specific molecular markers.⁴ To provide clinical guidance for dosing in general, in August 2024 the U.S. FDA issued the document Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.⁵ Since this did not describe radiopharmaceuticals in detail, additional guidance is being proposed. In August 2025, the agency issued a draft guidance titled Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development⁶ and is accepting public comments through October 20, 2025.

Administration Of Radiopharmaceuticals

The dosage of a radiopharmaceutical relates to both the recommended interval between administrations and the number of administrations/cycles, together with the administered activity, which refers to the radiation dose. A clinical trial will seek to optimize the dosage by assessing the appropriate administered activity and schedule to maximize the therapeutic effect while minimizing toxicity to the patient.

Maximum Tolerated Dose

Dose-finding trials (including the dose escalation and dose expansion portions of an oncology drug) have the primary objective of selecting the recommended Phase 2 dosage. Before the development of medicines that interact with a molecular pathway for a specific disease, oncology drugs were designed to determine the maximum tolerated dose (MTD). These drugs had steep dose-response relationships and carried risks of substantial toxicity for the recipient. The approach for MTD setting was stepwise, demonstrated by increasing doses in a small number of patients at each dose level for short periods of time until a prespecified rate of severe or life-threatening dose-limiting toxicities was reached.

It also was commonplace to draw on external beam radiation therapy data to calculate organ tolerance. Subsequent case studies have shown this to be an inadequate approach due to differences in dose rate and the distribution of radiation.

Is The MTD Still Relevant?

Newer medicines that interact with molecular pathways demonstrate different dose-response relationships with wider therapeutic indices.⁷ This often means that doses below the MTD can display similar activity to the MTD with fewer toxicities than the MTD. However, patients will often receive such therapies for longer periods, and these extended time frames can potentially lead to persistent symptomatic toxicities (including renal toxicity, xerostomia, xerophthalmia, and bone marrow failure), which need to be accounted for.

The FDA’s concern, which also relates to the intention behind the August 2024 guidance, is that too many newer drugs are labeled for administration at the maximum tolerated dose (or the maximum administered dose). Consequently, this results in recommended dosages that could be unnecessarily high. This means that the medicine can become poorly tolerated, with adverse impacts on the quality of life of the patient. In addition, the patient’s ability to remain on the drug can be reduced, resulting in the maximal clinical benefit not being achieved.

The legacy issue arising from the traditional dose setting approach and reliance upon external beam radiation therapy data has resulted in the MTD of many radiopharmaceuticals in relation to both acute and long-term toxicities not being established.

This leads the guidance document to express doubts about the continued appropriateness of relying upon an MTD-based dosing strategy. This is because such an approach is open to influence from multiple factors (including target expression, ligand specificity, physical properties of the isotope and stability, slopes of the dose-response and dose-toxicity relationships). Each of these is influenced by a particular patient population. This alternative direction is in keeping with the precision medicine paradigm.

The FDA guidance acknowledges that determination of the MTD can still yield information of value. Nonetheless, the FDA cautions that dosages selected for trials intended to support a future marketing application need to be based on a totality of available data from a range of dosages. Relying simply upon the MTD or normal organ tolerances is insufficient.

Implications For Clinical Trials

The existing regulatory framework permits administered activities per cycle that result in tissue absorbed doses that exceed established external beam radiation therapy organ tolerances or previously characterized radiopharmaceutical dosages to be studied in clinical trials, provided there is an adequate rationale. Such a rationale is ordinarily based on the optimized dose of a radiopharmaceutical being unidentifiable at lower dosages. From pre-trial discussions with the FDA, higher dosages can be permitted in trials. The important caveat is to include safeguards around:

• Appropriate participant selection.

The selection of clinical trial participants should be specific to the disease or treatment being studied. Trials that include an objective of defining the MTD of a radiopharmaceutical, beyond the dose previously established, can only be conducted in participants who have limited life expectancy due to cancer-related mortality.

In contrast, dosages in participants at lower risk of morbidity from their disease should not exceed dosages that have been characterized in participants at greater risk for cancer-specific mortality.

• Good trial design.

With trial design, protocols should be designed so that the radiopharmaceutical is administered for a fixed number of cycles. This is to mitigate the risk of delayed or cumulative toxicity. The guidance also stipulates that the first dosage of the drug should not exceed the external beam radiation therapy organ dose limits.

To make any increases from agreed doses, discussions need to be held with the FDA and safety, preliminary efficacy dosimetry, and pharmacokinetic data presented.

• Adequate safety monitoring.

Subject safety is paramount to any clinical trial. With radiopharmaceuticals, since the onset of radiation toxicity can be delayed by months or years, monitoring against a prespecified list of late radiation adverse events needs to continue for a minimum of five years after the last dose or until death. This should be assessed against pre-study biomarkers from blood and urine samples. If the subjects have received previous forms of radiotherapy, such assessments must account for previous doses so that the cumulative effect is accounted for.

• Effective radiation dosimetry evaluation.

The accuracy of measurement is important in assessing the dose and safety factors discussed above. Measurement is based on dosimetry calculations for each novel molecular entity. This enables any potential toxicity/efficacy associated with exposure to radiation to be calculated. For solid tumors, imaging techniques are available; however, specific biomarkers are required for hematological assessments.⁸

The assessments can be either isotope- or product-specific in nature, depending on the properties of the radiopharmaceutical, based on the physical and effective half-life, types of decay products, and associated energies relating to different medicines. The required information needs to be clearly set out within a study protocol.

Given that radiopharmaceutical clinical trials bring with them complex challenges, including logistical complexity due to short radioisotope half-lives, the need for specialized facilities, the importance of understanding cumulative dose, and the special risks for subject safety, the FDA guidance provides a strong framework for these evaluations.

References

1. Tucker WD, Greene MW, Weiss AJ, Murrenhoff A (1958) Methods of preparation of some carrier-free radioisotopes involving sorption on alumina. Transactions American Nuclear Society. 1: 160–161
2. Segrè E, Seaborg GT (1938) Nuclear Isomerism in Element 43. Physical Review. 54 (9): 772
3. Healy, A., Ho, E, Kuo, P., and Zukotynski, K. A brief overview of targeted radionuclide therapy trials in 2022. Front Nucl Med. 2023; 3:1169650
4. Zhang, S., Wang, X., Gao, X. et al. Radiopharmaceuticals and their applications in medicine. Sig Transduct Target Ther 2025; 10, 1: https://doi.org/10.1038/s41392-024-02041-6
5. FDA. Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases, August 2024: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases
6. FDA. Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development, August 2025: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oncology-therapeutic-radiopharmaceuticals-dosage-optimization-during-clinical-development?utm_source=substack&utm_medium=email
7. Lepareur, N, Ramée, B., Mougin-Degraef, M, and Bourgeois, M. Clinical advances and perspectives in targeted radionuclide therapy. Pharmaceutics. 2023; 15:1733
8. Garske-Román, U, Sandström, M, Fröss Baron, K. et al. Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity. Eur J Nucl Med Mol Imaging. 2018; 45:970–88

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.