Oncology drug developers should gather patient-reported outcomes (PROs) as part of their efforts to optimize dosing in early development, a Friends of Cancer Research white paper recommends.

FOCR released the white paper in conjunction with its annual meeting this month. It was developed by a group of industry, academic, patient and regulatory participants as part of the organization’s work to support the US Food & Drug Administration’s “Project Optimus” initiative to encourage better dose selection for new cancer therapies. (Also see “Premarket Dose Optimization Precedent In Oncology Likely Not Available Yet” – Pink Sheet, 20 Nov, 2023.)

One key message from the Friends paper is the potential for PROs to help define the “tolerability” of different doses – with the working group stressing the concept as not just quantifying adverse events (“safety”), but rather identifying adverse events that might impact adherence to therapy.

“It is increasingly recognized that any assessment of tolerability in a clinical trial without systematically collecting data about the patient’s experience is incomplete,” the white paper declares. However, the working group continued, there is not yet a clear path towards using those measures in dose optimization.

“A challenge to using PROs in dose-finding studies is that this is a novel approach, and as a result there are not standard methods for how to use and interpret PROs to assist in making decisions about dose,” the paper states. “Despite this, there are a variety of proposals for collecting PROs in early phase trials.”

“Overall, how PRO data are considered in the totality of evidence and how they can contribute to decisions about dosing is not yet fully established and would benefit from additional standards or guidelines,” the paper adds.

“PROs can complement investigator-derived safety information to determine the benefit-risk of different doses, particularly for treatment-related toxicities that are poorly captured by investigator assessment (e.g., low-grade diarrhea, blurry vision that is transient but recurs daily, etc.). While standards and guidelines are being developed, including PROs in dose-finding studies to optimize dose is encouraged to capture a comprehensive assessment of tolerability.”

The white paper offers three important “considerations” about incorporating PROs into dose finding, including:

• The role for ePROs to capture events outside of clinic visits;

• Using PROs to manage patients during the trial, rather than simply assessing them at the end; and

• There is growing guidance (including from FDA and prior FOCR work) on which PRO items to collect.

During the FOCR meeting, FDA’s Mirat Shah, who serves as the lead on Project Optimus in FDA’s Oncology Center of Excellence, supported use of PROs in dose optimization. “We believe that PRO information collected in early phase clinical trials can be extremely beneficial to both patients and drug makers.”

“Some of the situations where PRO information might be particularly valuable is if a product is associated with chronic symptomatic low-grade toxicities, so things like diarrhea or blurry vision, where it is very difficult to capture the full extent and the impact on a patient’s life in the context of clinic visits,” Shah noted.

Shah also suggested that sponsors can consider collecting PROs at different frequencies as they gain knowledge. “Just like other things like pharmacokinetics may be captured more frequently early on and then spaced out, that is also something that can be done with PROs: to collect them more frequently to understand the onset and trajectory of symptomatic toxicity and then space out that frequency.”

“I do want to add that at the FDA we don’t view PRO information as a replacement for standard safety measures, but rather something that can complement standard safety measurements and enhance our understanding of a patient’s experience on taking that drug,” Shah said.