FDA Guidance Addresses Patient Outcomes in Cancer Clinical Trials

June 16, 2021 - FDA has released draft guidance that provides recommendations to sponsors about which patient-reported outcomes (PRO) concepts to measure in cancer clinical trials. 

The guidance, Core Patient-Reported Outcomes in Cancer Clinical Trials, addresses how to incorporate assessment of PROs in clinical trials of drugs and biological products that support product labeling describing anti-tumor activity in cancer patients. 

A core set of PROs including disease symptoms, symptomatic adverse events, and physical function may be significant contributors to a patient’s health-related quality of life.

“Patients would like to better understand symptoms they may experience and how a cancer therapy can affect their quality of life,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases at FDA’s Center for Drug Evaluation and Research, said in the guidance. 

“One way to accomplish this is to ask patients in clinical trials about the severity of their symptoms and ability to function using rigorously developed patient-reported outcomes, Pazdur continued. 

First, FDA recommended collecting and separately analyzing core PROs, including disease-related symptoms, symptomatic adverse events, overall side effect impact summary measure, physical function, and role function. 

Doing so will minimize patient burden and improve the quality of data collected by focusing on the most meaningful and measurable outcomes. 

Therefore, the second recommendation included five instrument considerations and examples for the core PROs, including:

• Disease-related symptoms
• Symptomatic adverse events
• Overall side effect impact summary measure
• Physical function
• Role function.

FDA recommended using disease-related symptoms when a group of common cardinal disease symptoms exists. 

And for symptomatic adverse events, the agency recommended selecting a concise set of the most important symptomatic adverse events expected to occur from an item library.

In trials with active controls, sponsors should assess symptomatic adverse events for all patients. Sponsors should also provide a rationale for selecting symptomatic adverse events that will be assessed, based on mechanism of action, early clinical data, and input from patients and healthcare providers. 

An overall side effect impact summary measure can inform the tolerability of treatment.

Clinical trial leavers may consider a single global impression of severity item, FDA stated. For example, PRO surveys might ask the patient to choose a response that best describes the severity of their side effects from treatment over the past week.

For physical function, sponsors should select scales that measure defined concepts and assess varying levels of ability to perform activities that require physical effort. 

Lastly, patients may want to know how treatment may impact working and carrying out daily activities. They might also want information about other functionable abilities, including cognitive function. 

The third section of the guidance focused on trial design considerations. 

FDA said that there should be four considerations when determining the frequency of PRO assessment for core PROs.

For example, baseline assessment should be a reference point for assessing change, while assessment frequency should be higher within the first few treatment cycles and may be less frequent in later cycles. 

Additionally, assessment frequency should consider administration schedule of the study drugs. Different assessment frequencies can be selected for each core concept depending on the outcome and research objective. 

Other trial design considerations include establishing procedures for mitigating missing data, methods to lessen patient burden, and providing a pre-specified plan for the analysis of PRO data. 

Section four centered on labeling considerations.

First, FDA said that a claim of non-inferiority should be supported by evidence that the measure of sensitivity is adequate. 

Second, sponsors should pre-specify the PRO hypothesis, test it within the clinical trial, control the type I error rate, define the statistical analysis methods, and justify the endpoint definition, if a claim of superiority in a certain PRO endpoint is sought.

Lastly, exploratory PRO findings, not included in statistical hierarchy, are considered descriptive. FDA stated that it will review these data and consider whether inclusion of descriptive PRO data in labeling is appropriate.