New FDA guidance on oncology therapeutic radiopharmaceuticals

Review of this new guidance for radiopharmaceuticals

At TRACER, a Contract Research Organisation (CRO) specialized in imaging, we collaborate with radiopharmaceutical developers. We are therefore excited about this long-awaited document. Let’s review this document in this blog and discuss how it may apply to your radiopharmaceutical therapy drug development.

With this new guidance, the FDA acknowledges that due to differences in delivery, dose rate, and biodistribution, EBRT-derived organ limits are not directly applicable to RPTs and may prevent finding the optimal dosing in clinical trials. This solves a much-discussed problem in the industry [2].

The challenge with RPTs vs. EBRT

Historically, dose escalation for Radiopharmaceutical Therapy (RPT) has often stopped before reaching the Maximum Tolerated Dose (MTD). Instead, absorbed dose limits for critical organs were based on thresholds derived from External Beam Radiation Therapy (EBRT). From this, there is also little knowledge on Dose Limiting Toxicity (DLT) for RPTs.

What does this document encompass?

In one sentence: Maximize the benefit/risk profile of therapeutic radiopharmaceuticals by optimizing their administered activity and schedule in clinical trials.

It applies to radiopharmaceuticals that:

• are systemically administered;
• emit alpha, beta, and/or gamma radiation;
• are used for the treatment of cancer or related symptoms.

For first-in-human (FiH) trials, the earlier published FDA guidance Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations (2019) still applies.

Before we continue, what could you be missing?

Let’s briefly address a few shortcomings right away. This document is explicitly limited to oncology. While oncology dominates current RPT development, radiopharmaceuticals are also advancing in neurodegenerative, cardiovascular, and inflammatory diseases[3].
Alpha, beta, and/or gamma radiation is included, but auger emitters are missing. While they are mostly being researched in a preclinical setting, some are entering clinical trials already[4]. And finally, as the document itself states, it does not address personalized dosimetry and theranostic co-development. These areas will likely need future regulatory guidance.

What are the key takeaways:

• EBRT and RPT dose limits should differ
• EBRT organ absorbed dose limits are not directly applicable to RPTs
• Dose selection must consider the unique properties of each RPT

Recommended RPT dosing strategy

For RPTs, emphasis should shift from acute/subacute toxicity to long-term, cumulative, delayed, or irreversible toxicities — with appropriate long-term follow-up

Have EBRT limits been discarded?

No, EBRT limits should be used as a starting point, and for FiH trials this limit should not be exceeded. Administration of dosages that would result in a higher dose than EBRT organ limits or previously identified RPT dose limits needs to be justified. When studying optimal dosing, there should be a risk-based approach in participant selection. To explain, let’s divide participants into 2 groups:

1. Population 1 (high risk): Higher dosages may only be tested in cancer patients with a limited life expectancy due to their disease.
2. Population 2 (lower risk): For earlier-stage patients, doses should not exceed those already established in higher-risk groups.

Dosage limits in clinical trials with radiopharmaceuticals

• FiH study: EBRT limits should not be exceeded.
• Use a fixed number of cycles.
• Multiple dosages should be compared, and this should include initial dose finding trial(s) and a randomized dose-response trial.
• Specify cumulative administered activity and dose absorbed by critical organs.
• Limits should be justified based on available RPT data.
• In case of uncertainties, lower limits are considered appropriate.
• Emerging data may alter the limits.
• Further dose escalation is possible when data suggest the optimal dose has not been reached, toxicity is at acceptable limits, and only after FDA consultation.
• Backfill cohorts may be used to obtain more data on the considered dosage for further clinical trials.

Inclusion and exclusion criteria for RPT trials

Earlier EBRT and/or RPT-treated patients cannot be generally excluded. Exclusion should be based on clinical concerns regarding cumulative radiation doses received, baseline toxicity, organ function, and other variables. However, patients who’ve received any kind of radiation therapy should form a cohort for which the organ-specific safety data and cumulative administered activity received from prior treatments are recorded and taken into account.

Additional RPT trial considerations

The new guidance emphasizes:

• Informed consent must address uncertainties about delayed toxicities.
• Safety monitoring for at least 5 years after the last dose.
• Use the radiation Adverse Events of Special Interest (rAESI) list.
• Special attention to drug-specific dosimetry in the safety analysis plan.
• Use exploratory early biomarkers for delayed toxicity.
• Special attention to the cohort with previous ERBT and/or RPT treatment.
• Phase 1 studies must include dosimetry calculations for efficacy and safety.
• Imaging and dosimetry calculations with the intended radioisotope are preferred; if not feasible, use a surrogate and combine with pharmacokinetic modeling.
• Due to the short range of alpha-emitting isotopes, micro-scale dosimetry is encouraged.

Why discuss your RPT development with TRACER?

TRACER is an imaging CRO, meaning we specialize in (nuclear) imaging in clinical trials, especially in early-phase clinical trials. We provide full support from isotope selection for surrogate imaging to study design, conduct, and reporting. This new FDA guidance strongly reinforces the importance of dosimetry and imaging — areas where TRACER has years of experience.

If you are developing an RPT, we would be glad to discuss how this guidance applies to your program.

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