Drugmakers seek greater leeway in radiopharmaceutical dosing guidance

Stakeholders are asking the US Food and Drug Administration (FDA) for further clarification on a draft guidance on optimizing doses for radiopharmaceutical therapies (RPT) to treat cancer. Some also took issue with the agency’s focus on cumulative toxicities and asked it to align the guidance with international guidelines.

In August, FDA issued a draft guidance on determining the optimal dosage for RPT used in oncology. A key aspect of the guidance is that it attempts to address the two different methods of cancer radiation treatment by laying out different dosing recommendations between RPT products and external beam radiation therapy (EBRT). (RELATED: Radiopharmaceuticals: FDA draft guidance offers tailored approach for optimizing dose, Regulatory Focus 19 August 2025)

Friends of Cancer Research (FoCR) agreed with FDA on the importance of incremental dose escalation and tracking cumulative radiation exposure. However, it asked for clarifications in certain areas to help sponsors better justify their approaches. For instance, the group asked the agency to clarify that organ-specific dose limits based on EBRT may be directly applicable for RPTs because there are differences in radiation distribution, biological effects, and retention times. It also asked for more details on establishing cumulative dosage limits based on patient characteristics such as comorbidities and radiosensitivity.

FoCR asked FDA to encourage sponsors to use structured, incremental dose-escalation frameworks that use per-cycle activity, total cumulative activity, and inter-cycle timing. It also asked the agency to encourage sponsors to reach out to regulators early to justify proposed dose-escalation strategies using integrated preclinical, clinical, and modeling data.

Regarding safety monitoring, FoCR said FDA should note that incorporating early biomarkers and longitudinal data in study designs could improve consistency of safety data. It also made several recommendations on how to improve safety monitoring.

"Encourage the use of early biomarkers to predict delayed toxicities and guide adaptive dosing decisions," said FoCR. "These biomarkers should be prospectively defined, with clear thresholds that prompt dose modification, temporary holds, or closer monitoring.

"Provide guidance on integrating acute toxicity data with cumulative or delayed toxicity signals to inform dose decisions across multiple treatment cycles," the group added. "This integration should account for patient heterogeneity and prior therapies."

FoCR also asked FDA to emphasize to sponsors that long-term follow-up can help detect delayed organ-specific toxicities and may consider recommending minimum follow-up durations or intervals. The group also asked for clarification on how safe adaptive trials may be conducted with prospectively defined early biomarkers used as exploratory safety endpoints in early-phase studies.

The European Federation of Organizations for Medical Physics (EFOMP) wrote to FDA to state that while it acknowledges that the guidance does not address other aspects of the clinical development of RPTs, the field faces significant challenges. It noted that the terms dose and dosing mean different things in radiotherapy and medical oncology and asked the agency to avoid using them without further specification. It also asked the agency to be more specific with its terminology and noted several EU directives that may be useful.

"As a potential positive development, EFOMP sees an opening for harmonizing procedures between the US and Europe, of interest for industrial, scientific and clinical development," said EFOMP.

Eli Lilly also commented on the draft guidance and said it was pleased that FDA was open to allowing dose escalation for RPTs beyond EBRT limits as long as the sponsor can justify.

"Adherence to EBRT limits has restricted the exploration of maximum tolerated doses (MTDs) for RPTs and limited our understanding of the true benefit-risk profile of these therapies," said Lilly. "We support the approach outlined in the draft guidance of using EBRT limits to inform the initial dose in dose finding studies, and the totality of existing preclinical and clinical data (e.g., PK/PD, toxicities, organ function, lab values, etc.) to establish steps for dose escalation.

"FDA’s suggested approach reflects a welcome shift away from overly restrictive EBRT-based dosage constraints, paving the way for innovation and more effective RPT dosing strategies that better balance safety with therapeutic potential," the company added. "This evolution is critical to ensuring that patients are not denied access to therapies that could offer meaningful clinical benefit."

Lilly took issue with FDA's repeated mention of cumulative toxicities in the draft guidance and pointed out that cumulative toxicities are not unique to RPTs. The company also noted that confounding factors make it hard to determine what may be responsible for the toxicity. It further said that it was concerned about a risk of surveillance bias during follow-ups if comparable monitoring requirements are not shared across therapies.

Lilly also asked the FDA to consider whether the priority for dosage optimization should be based on patient safety or benefit. The company added that while the agency stresses the need to minimize patient risks, it's up to the oncology community to determine whether the greater risk is from the disease or the treatment.

"Long-term or delayed toxicities are only a threat if the patient survives long enough to experience them," said Lilly. "Many times, patients with early-stage and/or potentially curable disease are both better able to withstand and more willing to risk downstream effects from more aggressive treatment, if the treatment will lead to increased survival.

"The guidance, once finalized, should not preclude or restrict RPT trial participation or dosage limits based on disease stage," the company added.

AstraZeneca shared similar concerns about FDA's focus on cumulative toxicities. "We encourage the FDA to consider a reduced emphasis on cumulative radiation dose limits in RPT dose escalation studies and emphasize the totality of clinical and pre-clinical evidence to permit dose escalation designs with clinical safeguards agreed upon at the IND stage.

"We propose that clinical data be considered the primary foundation for decisions in dose escalation, with dosimetry data serving a supplementary and exploratory role," the company added.

AstraZeneca said that while it agrees with FDA that optimal doses for RPTs may be different than the dosages limited by EBRT tolerances, it recommended using early clinical surrogates of late radiation toxicity as safety endpoints in dose escalation studies to close the knowledge gap while allowing treatments to advance. The company also asked the agency to discuss dose escalation beyond EBRT limits during the pre-IND phase.

"Moreover, we emphasize that optimal dose determination for RPTs must consider both efficacy and toxicity and the totality of the risk/benefit profile," said AstraZeneca. "Clinical benefit, including improvement in overall survival, can justify acceptance of certain toxicities, as has long been the case for chemotherapy and other cancer therapies.

"Dosimetry is a valuable exploratory tool; however, its limitations should be recognized," the company added. "Biologically, fundamental differences in dose rate, pattern of dose distribution, and radiobiologic effects complicate assumptions about tissue tolerance."

Additionally, AstraZeneca encouraged FDA to harmonize its guidance to include guidelines such as those from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

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Drugmakers seek greater leeway in radiopharmaceutical dosing guidance

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