The newly published FDA guidance document, "Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development," is intended to help sponsors identify the optimal dosage for radiopharmaceutical therapies (RPTs) used in oncology. It describes the limitations of traditional dose-finding approaches, and recommends clinical trial design considerations for dosage optimization. RPTs have characteristics of both external beam radiation therapy (EBRT) and systemic drug therapy. Historically, RPT dosages were limited by absorbed dose limits derived from EBRT, but established normal organ absorbed dose limits derived from EBRT data may not be fully applicable to RPTs due to differences in physical properties and how the radiation is delivered. A major challenge for RPT dose escalation is that standard trial designs focus on acute and subacute toxicities and may not adequately capture the potential for delayed, cumulative, or irreversible toxicities associated with RPTs. The maximum tolerated dose (MTD) of many RPTs has not been established, and it has become apparent that an MTD-based strategy is suboptimal for determining recommended dose regimens. To remedy these issues, the Guidance recommends optimal design features to improve outcomes.
In general, it is best to evaluate a broad patient population to assess dosage performance in relevant subgroups. At the same time, patient specific factors and the characteristics of the target population should be considered when determining RPT dosages. Trials that explore dosages exceeding EBRT limits should be conducted in participants with limited life expectancy from cancer where the risk of delayed organ failure is acceptable. Sponsors should also consider baseline toxicities and prior radiation doses when determining eligibility for participants who have previously received EBRT or RPT.
Dosage optimization involves finding the administered activity and schedule (interval and number of administrations) that optimizes the overall benefit risk profile for patients. RPTs should generally be administered for a fixed number of cycles to manage the risk of cumulative toxicity. Protocols should set a maximum cumulative administered activity based on available data. While a dose-limiting toxicity (DLT) period of one cycle may be enough for initial dose-finding, longer-term safety data is needed to justify a recommended dosage for subsequent trials. Sponsors should compare multiple dosages before selecting a dosage for marketing application trials, as the optimized dosage may not be the highest one studied. Regarding the trial structure, the guidance encourages considering innovative clinical trial designs, such as adaptive designs or model-based approaches, with features such as fixed cycles, cumulative activity limits, and randomized dose-response trials.
Patient safety is a priority. The Guidance underlines the importance of incorporating appropriate safeguards into patient monitoring, especially when considering dosages that might exceed EBRT limits or previously established RPT dosages. This monitoring plan should be based on dosimetry results and a detailed critical radiation safety analysis. Due to the potential for delayed radiation toxicity, sponsors should monitor for a pre specified list of late radiation adverse events of special interest (rAESI) for at least five years after the last dose. For participants with prior radiotherapy, sponsors should correlate safety data with the cumulative radiation absorbed dose. In addition, pre-specified safety monitoring rules should be incorporated to respond to potential serious adverse reactions or dosage modifications. The informed consent process should communicate the potential risks of long-term, late-onset, and cumulative radiation toxicity.
Dosimetry studies are crucial for understanding radiation dose distribution and relating it to biological effects, both in tumors and normal tissues. Phase 1 studies of radioactive drugs must include studies to obtain sufficient data for dosimetry calculations. Dosimetry studies provide radiobiological context for safety and efficacy data and help support dosage optimization. Sponsors should provide radiation dosimetry protocols with detailed descriptions of their imaging acquisition methods, image processing, and calculations. Sponsors should also consider using both absorbed dose and biological effective dose (BED) calculations when reporting dosimetry results.
The guidance promotes an approach to dose selection that incorporates all available nonclinical and clinical data, including PK and PD characteristics, dose-response / exposure-response relationships, and safety/tolerability data.
This FDA's guidance calls for a more sophisticated and tailored approach to dosage optimization for oncology therapeutic radiopharmaceuticals, acknowledging their unique characteristics and the potential for delayed toxicities. This involves integrating dosimetry, long-term safety monitoring, and robust clinical trial design to determine the optimal dosage that maximizes benefit while minimizing risks for patients. Finally, the guidance emphasizes the importance of early engagement and ongoing communication between sponsors and the FDA regarding dosage optimization strategies throughout the development process.