Preparing clinical infrastructure for radiopharmaceutical trials

This article is part of Parexel's "Advancing radiopharmaceutical development" playbook series. This series offers insights across feasibility and site selection, patient-guided trail design, regulatory strategy, and supply chain and logistics management to support sponsors in this evolving market.  

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Charting the regulatory course for RPT breakthroughs

Most regulators have limited experience reviewing next-generation RPT product submissions, particularly theranostics, because comparatively fewer RPTs have been developed than “traditional” non-RPT oncology drugs. This difference in regulatory review experience can create uncertainty for RPT sponsors about how their data will be interpreted and decisions made, particularly if sponsors are considering global development programs. To mitigate regulatory risk, sponsors must have RPT trial experience and former regulators’ understanding of FDA and EMA processes on their team. At Parexel, we advise sponsors to devise an RPT regulatory strategy that incorporates the following approaches: 

• Engage with regulators to overcome gaps in written guidance.

The existing framework of formal regulatory guidelines is not in pace with scientific advancements in the field. Recently, we systematically analyzed guidance documents from the FDA, NRC, and EMA that cover the clinical development of anticancer RPTs.¹  We found several key gaps in regulatory guidance for developing theranostics. Current guidelines for in vivo companion diagnostics, especially targeted diagnostic RPTs codeveloped with their therapeutic counterparts, do not align with recent clinical advances. While the FDA provides guidance on the non-clinical aspects of therapeutic RPTs, and the EMA has acknowledged the need for specific clinical guidelines through a published concept paper, neither agency has yet issued formal written guidelines for the clinical development of these agents. The lack of comprehensive, technically relevant guidelines poses challenges and risks for sponsors.

To mitigate these risks, we recommend that sponsors engage with the FDA through early and frequent discussions and correspondence to confirm the acceptability of their clinical development plan, including dose optimization and the validation of novel endpoints specific to theranostic agents. Sponsors pursuing European market authorization can seek formal scientific advice from the EMA after completing dose determination and should ensure that they are well-prepared to discuss their Phase 3 trial design.  

As an enduring solution, sponsors might also advocate for the agency to issue new guidance on clinical development of RPTs, and/or update existing guidance to add RPT subsections.  

• Apply strong knowledge of radiation dosimetry.

Radiation dosimetry is crucial for developing RPTs, especially for safety monitoring and dose determination. Pharmacokinetic (PK) data are necessary in Phase 1 trials; however, acquiring such data for RPTs can be challenging due to short isotope half-lives. Additionally, relying solely on plasma PK profiles can be misleading, as they only serve as surrogates and do not directly reflect the radiation dose reaching tumors and healthy tissues. To understand this better, mass balance data proves valuable information, allowing researchers to monitor the RPT's absorption, distribution, metabolism, and elimination. This broader assessment aids in interpreting PK data more accurately, particularly concerning radiation exposure.

Determining the optimal dosage for RPTs is complex. Establishing the upper limit of dose range is challenging, and there are concerns about underdosing if relying solely on radiation dosimetry based on external beam radiation therapy (EBRT). EBRT-derived thresholds for normal organ absorbed radiation dose are generally lower than those of RPTs. Sponsors can propose exceeding these EBRT thresholds in protocol amendments if emerging safety and tolerability data in patients support higher RPT doses. However, it is vital to remember that high cumulative radiation doses may cause long-term, irreversible adverse effects, requiring an extended safety follow-up of 10 years. Ultimately, defining maximum efficacy and acceptable safety as the optimal dose depends on the specific cancer type and available alternative treatments.

• Adhere to Project Optimus guidelines for dose optimization.

The FDA's Project Optimus signifies a significant change in oncology drug development, prioritizing the identification of the "optimal dose"—the dose yielding maximal efficacy with an acceptable safety profile.²  This proactive strategy shifts from merely finding an "approvable" dose to the optimal dose. The FDA now asks two key questions about dosing: "Can the dose go higher?" and "Can the dose go lower?" Determining the optimal dose is mandatory under Project Optimus, and neglecting to demonstrate this can lead to the FDA imposing a clinical hold on the investigational drug.

Developing RPTs involves unique considerations aligned with Project Optimus principles, including challenges in obtaining and interpreting PK data, the dose-exposure relationship, and the importance of radiation dosimetry. To reduce uncertainties and facilitate agreement on study initiation and the determination of the recommended Phase 2 dose (RP2D), sponsors should gather data for integrated dose-exposure-response analyses and present these to the FDA before and after randomized dose-finding studies. Project Optimus encourages sponsors to investigate a broad range of doses (amount, frequency, duration) to characterize the dose-exposure-response relationship. After dose escalation, the FDA expects randomized dose-finding studies in a clearly defined disease testing no less than two dose levels with 20 to 40 patients in each dose level cohort.

Whereas Project Optimus is an FDA initiative, appropriate determination of the RPT dose(s) is expected by all regulatory agencies and should be well-justified in regulatory protocols and submissions.

• Prepare for reviews involving multiple divisions.

Dual regulatory pathways for drug and radiation safety complicate the review and approval of RPT submissions. For example, at the FDA, both the Office of Oncologic Diseases (OOD) and the Division of Imaging and Radiologic Medicine (DIRM) review new investigational new drug (IND) applications and new drug applications (NDAs). While the EMA handles quality and non-clinical and clinical reviews internally, the FDA involves the Nuclear Regulatory Commission (NRC) for packaging and manufacturing reviews.

Sponsors planning US IND submissions and early interactions with the FDA must factor in the fact that they will receive viewpoints from multiple FDA divisions and the NRC. For example, when planning pre-IND and end-of-phase 1 (EOP1) meetings, sponsors should know that both oncology and nuclear medicine regulators will review dose optimization and dosimetry plans, at least in the United States. We recommend that sponsors submit their Phase 1 data as soon as possible, including once topline results are available, because reviews by multiple divisions may take longer or include contrasting advice.

Sponsors must establish a plan for long-term safety monitoring in their clinical trials.  Regulatory agencies will expect sponsors to comprehensively understand and characterize any potential delayed or persistent adverse events (AEs) that may arise following the cessation of treatment. We recommend proposing a minimal follow-up period of 90 days, with adjustments based on emerging data and regulatory feedback. AE monitoring should be robust, especially regarding myelosuppression, and should account for the unique nature of RPTs.
 

Resources

1. Voids in regulatory guidance for development of theragnostic radiopharmaceuticals in oncology, 2025 ASCO Annual Meeting Abstract (May 22, 2025).
2. Project Optimus: Reforming the dose optimization and dose selection paradigm in oncology, FDA Oncology Center of Excellence webpage (Accessed May 25, 2025).

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