FDA Issues Updated Guidance for PROs in Cancer Trials

New draft guidance for industry highlights core patient-reported outcomes (PROs) and considerations for instrument selection and trial design in cancer clinical trials. The non-binding recommendations were developed by the Oncology Center of Excellence (OCE), Center for Drug Evaluation and Research (CDER), and Center for Biologics Evaluation and Research (CBER) at the FDA.

Specifically, the guidance pertains to “trials for anti-cancer therapies intended to demonstrate an effect on survival, tumor response, or delay in the progression of a malignancy,” authors wrote. However, PRO measurement may not be feasible for all cancer trial populations and heterogeneity in PRO assessment strategies has lessened the regulatory utility of this data, they explained.

By conducting a systematic assessment of a core set of PROs, parties can facilitate high quality data on symptoms and functional impacts, overcoming this hurdle. Authors defined a core set of PROs as “including disease symptoms, symptomatic adverse events, and physical function, that may be important contributors to a patient’s health-related quality of life (HRQOL) and that may be sensitive to the effect of the disease and treatment under study has been described.”

Additional measures include an overall side effect impact summary measure, role function, and others important to patients based on the context of an individual trial, such as swallowing or cognitive function in advanced esophageal cancer or neuro-oncology, respectively. Selection of outcomes outside of the core set should also aim to minimize patient burden and improve the quality of data collected.

With regard to instruments, authors noted those used should be well-defined and reliable to ensure accurate results are presented. “Sponsors should provide support for the selection of PRO instrument(s) with available data and/or published peer-reviewed literature guided by the principles laid out in the PRO guidance,” they said.

The FDA is also developing an additional set of guidelines to address capture and analysis of clinical outcome assessment data.

If the PRO instruments or measurement systems used were developed prior to publication of PRO guidance, trial sponsors should provide reasoning as to why the endpoint measured is well-defined, relevant, and reliable. PRO measures should also include questions related to the concept of interest.

“For instance, a well-defined physical function scale should include questions on a range of activities requiring physical effort and should not contain specific questions tied to or dependent on other concepts such as side effects or symptoms,” researchers wrote.

Subscale or subsets of questions from existing PRO instruments can also be used to inform benefit/risk assessments or support labeling claims. However, in this case they ought to be prospectively defined and measurement properties should have been evaluated. When selecting instruments for a particular cancer trial context, authors recommend early consultation with the FDA.

While considering trial design, several factors ought to be included. These include assessment frequency, establishing procedures for missing data, exploring methods to lessen patient burden, documenting reasons for mission PRO data, providing a plan for PRO data analysis, noting deviation from the instrument’s scoring manual, and recording use of concomitant therapies among participants.

Furthermore, “inclusion of PRO data in the product label will depend on the adequacy of the design and conduct of the trial, the strengths and limitations of the instrument within the given context of use, and the quality of submitted data,” authors wrote.

Any claim of non-inferiority or equivalence should be supported by evidence that the sensitivity of the measure is adequate, while if a claim of PRO endpoint superiority is sought, the PRO hypothesis should be pre-specified and tested within the clinical trial.

In addition, the guidance notes exploratory PRO findings are considered descriptive and the FDA “will review these data and will evaluate and consider whether inclusion of descriptive PRO data in labeling is appropriate on a case-by-case basis, taking into consideration any factors that may affect the interpretability and reliability of the findings.”