he absence of labeling related to Patient-Reported Outcome Measures (PROM) has been striking: Between 2010 and 2020, out of the 108 oncology drugs approved by the US Food and Drug Administration (FDA), only nine (8.3%) included PROM-related labeling. In June 2021, the FDA released a draft guidance document titled “Core Patient-Reported Outcomes in Cancer Clinical Trials.” This guidance aims to enhance the quality and consistency of data collection related to PROMs in cancer trials. However, despite its potential benefits, pharmaceutical companies have been slow to fully embrace these recommendations.

This article examines the challenges pharmaceutical companies face in implementing patient-reported outcomes (PROs) in cancer clinical trials as outlined in the FDA’s draft guidance. It highlights the value of PROs, outlines the key points from the FDA’s guidance, and proposes ways forward through collaboration to overcome the challenges and fully embrace the use of PROs in cancer trials.

The Value of Patient-Reported Outcomes in Oncology

PROs are essential tools for understanding the impact of cancer treatments on patients’ lives. They allow patients to directly report their symptoms, functional status, and overall quality of life. By incorporating PRO assessments into clinical trials, researchers gain valuable insights beyond traditional clinical endpoints, and the incorporation of PROM endpoints within drug labeling is valuable to both the patient and the prescribing physician in informing risk/benefit discussions beyond tumor response and survival.

The FDA’s Intentions

In the draft guidance, the FDA acknowledges the potential added value of PROs measuring symptoms and functional impacts when making risk/benefit assessments. However, the FDA has been hesitant to consider this data previously because of diverging PRO assessment strategies that have lessened the regulatory utility of the data collected. In response, the FDA proposes the systematic assessment of a core set of fit-for-purpose PROMs which would facilitate the collection of high-quality data.

Key Points from the Draft Guidance

1. Concepts to Measure: The draft guidance outlines specific PRO concepts relevant to cancer trials. These include disease-related symptoms, symptomatic adverse events, physical function, role function, and an overall side effect impact summary measure assessed as a single item. By focusing on a core set of PROs, consistency and comparability across trials can be improved. Some PROs currently deployed in cancer trials may not have the domain specificity to satisfy the core measurement concepts, and modification of existing instruments, i.e., using subscales or the development of new instruments, may be required.
2. Frequency of Assessments: The draft guidance emphasizes that PRO assessments should align with the administration schedule of the studied products. Baseline assessments should be included as a reference point for assessing change, and the frequency of assessments should be higher during the first few treatment cycles or months and can be less frequent as the trial progresses. This will require a shift from the traditional site-based assessments at the start of a new treatment cycle to more frequent, likely remote, intervisit assessments.
3. Mitigation of Missing Data and Improvement of Interpretability: Collecting the reason for missing data as well as implementing an adherence monitoring strategy should be considered while being mindful of the impact on patient burden. Electronic PROs should be considered to facilitate the capture and monitoring of assessments completed outside of the clinic.

Challenges Faced by Pharmaceutical Companies

Despite the FDA’s efforts, several challenges hinder widespread adoption of the draft guidance:

1. Operational Complexity: Implementing PRO assessments requires additional resources, including validated questionnaires, data collection tools, and trained personnel. Pharmaceutical companies may hesitate due to the associated costs, logistical complexities, or lack of internal expertise.
2. Lack of Standardization: While the guidance provides a core set of PROs, variations exist across cancer types and treatments. Currently, there are numerous indication-specific PROMs with differing levels of specificity. Pharmaceutical companies have struggled to harmonize PRO assessments across diverse clinical trials.
3. Regulatory Uncertainty: Some pharmaceutical companies may fear “going first,” concerned that the FDA may not accept the data for submission despite companies following the recommendations. Balancing PRO data collection with other complex trial priorities remains a delicate task.

The Way Forward

To address these challenges, collaboration is essential. Pharmaceutical companies, researchers, patient advocacy groups, and regulatory agencies need to work together to:

1. Raise Awareness: Educate stakeholders about the value of PROs and the FDA’s guidance. Highlight success stories where PROs influenced treatment decisions.
2. Standardize Practices: Develop industry-wide standards for PRO assessment. Collect the necessary data to validate the FDA’s recommendations, including use of subscales, development of new instruments with improved specificity, and more frequent administration of assessments. Harmonized PRO measures across trials may facilitate crosstrial comparisons.
3. Incorporate PROs Early: Integrate PRO considerations into trial design from the outset. Oncology trials are complex, with many moving parts. PRO strategy and selection should not be an afterthought during protocol design, and early planning ensures seamless implementation. Consult with experts when necessary.
4. Collaborate and Innovate: Perform novel research on emerging technologies such as computerized adaptive testing and objective measures of patient function obtained through sensors and wearables, or at least incorporate these as exploratory endpoints so that the data required to validate these assessments can be used to further advance understanding. Partner with academic researchers and technology vendors when appropriate.
5. Embrace Technology: Leverage digital tools for PRO data collection. Mobile apps and electronic diaries can enhance patient engagement, improve adherence, and decrease missing data.

Call to Action

Over the past decade, inclusion of PRO data in labeling for oncology drugs has neither been a regulatory requirement nor a guidance. Nonetheless, a significant amount of collected PRO data has essentially gone to waste as the information gathered regarding the patient experience while on treatment ultimately has not made its way to future prescribers, payers, and others. This information is valuable to both the patient and the prescribing physician in informing risk/benefit discussions beyond tumor response and survival. Adopting the FDA guidance would provide a framework by which sponsors could collect submission-ready data that would be both acceptable to the FDA and more likely to be included in labeling.

The FDA’s draft guidance represents a significant step toward patient-centered cancer research. By adopting PROs, pharmaceutical companies can enhance their understanding of treatment effects and improve patient outcomes. It is time to bridge the gap between guidance and practice and begin the necessary work to validate these recommendations so that all future trials and patients may benefit.