Introduction
Patient-reported outcomes (PROs) refer to information about a patient’s health that is shared directly by the patient and not influenced by the interpretation of any other. Utilizing PROs enables the active participation of patients in their care outcomes – both in a clinical setting and in clinical research. PROs in clinical trials are important as they capture the patient’s perspective and ensure that the impact of an intervention is comprehensively evaluated. From a regulatory standpoint, agencies like the U.S. Food and Drug Administration (FDA) increasingly look to patients to understand how they describe their health status.
What are PROs in clinical trials?
The National Cancer Institute (NCI) defines patient-reported outcomes as a patient’s description of their symptoms and satisfaction with care or how a condition or intervention affects their physical, mental, emotional, spiritual, and social well-being. In clinical trials, PROs may assess disease progression, consequence(s) of the intervention being studied, functional status, and social, mental, and emotional limitations. These aspects influence a patient’s perceived health-related quality of life (QoL). PROs, included in clinical trials as primary or secondary endpoints, are increasingly recognized by regulators, clinicians, and patients as valuable tools.
While PROs may not have unconditional acceptance and wide use in clinical research across all therapeutic areas, they have been in use for over a decade in some. PROs are gaining a more prominent role in clinical research for cancer and conditions like multiple myeloma, but the use of PROs is in its exploratory phase. Tech advancements and digital health tools make clinical research more accessible with electronic PRO (ePRO) options.
How and What to measure?
PROs can be disease-specific, condition-specific, or generic. As the names imply, disease-specific PROs measure features specific to a disease or syndrome, while condition-specific PROs describe aspects of a particular condition, intervention, or treatment not uniquely associated with one disease. A recent study found that approximately 20 disease-specific PROs have been used in heart failure (HF) patients for research and clinical purposes. However, they have been used inconsistently. Generic PROs are used for any disease or population.
For HF, Savarese et al. found substantial disagreement between patient-reported information using the Kansas City Cardiomyopathy Questionnaire (KCCQ), which the FDA qualified as a clinical outcomes assessment, and physician-assigned clinical status defined by the New York Heart Association functional class, indicating an information gap that needs to be addressed.
Why have PROs been more common recently?
PROs in clinical trials are important as they capture the patient’s perspective and ensure that the impact of an intervention is comprehensively evaluated. Further, PROs have demonstrated precision in evaluating disease status and a good association with prognosis in randomized controlled trials (RCTs) for conditions like HF.
Including PROs in clinical research has been more common as PROs measured with high-quality PRO measures (PROMs) help evaluate treatment effects, identify unmet needs, and define meaningful outcomes for patients. In addition, regulatory agencies like the FDA published PRO guidelines for industry as early as 2006 and increasingly encourage using PROs in trials. Additionally, PROs bring value to clinical research in several ways including:
Assessing complex conditions
Complex conditions like HF and multiple myeloma impact mortality, morbidity, and different levels of a patient’s life, impairing various aspects of daily living. Moving away from the situation where physicians assessed disease status and symptom severity solely, PROs provide valuable insights into a patient’s disease experience. As medical staff assessment of patient symptom severity is often lower than PRO for multiple myeloma, Wang et al. suggest enriching the content of PROs and developing more high-quality PRO scales for multiple myeloma.
Converting disease-specific PROs to support cost-effectiveness analyses
When direct calculation of health utility is not possible, mapping algorithms are available to convert disease-specific PROs to EuroQol 5 Dimension (EQ-5D) to estimate QoL and then conduct cost-effectiveness analyses.
Non-disease-specific PROs provide more complete info
Especially for patients with multiple chronic diseases, non-disease-specific PROs might be useful for assessing interventions that might improve a symptom but simultaneously cause major complications. Such complications may otherwise be missed if only disease-specific PROs are used.
Mismatch between outcome definitions and patient experience
In cases where there is effective treatment, such as for tuberculosis (TB), but there exists a mismatch between conventional outcome definitions and a patient’s lived experience, PROs offer valuable insights into non-observable elements like health literacy and overall well-being, which contribute to the comprehensive evaluation of research end-points.
Facilitating the Inclusion of PROs in clinical trials
Standardization
As PROMs on health-related QoL are often designated secondary outcomes in trials, data collection and reporting may not be standardized, resulting in difficulty making comparisons and interpretations. In a study on cancer clinical trials, Pe et al. cautioned that having multiple ways of analyzing and interpreting PRO data could lead to flawed and inconsistent decisions by patients and medical staff alike and negatively affect patient outcomes. The authors present international stakeholder views on the need for standardization by building on existing PRO guidelines to establish recommendations on the design, analysis, presentation, and interpretation of PRO data in clinical trials.
Adherence to guidelines
A study by Newman et al. evaluated the quality of PRO reporting for RCTs studying pregnant women with diabetes. Evaluated against the internationally accepted guidelines Consolidated Standards of Reporting Trials (CONSORT-PRO), the researchers found that only 17% of RCTs included a PRO as a primary or secondary outcome. The median score was 46 (out of 100), indicating gaps in reporting. They emphasize the importance of including reliable PROs in trials. A study investigating the use of PROs in clinical trials of palliative radiotherapy found poor to moderate adherence to CONSORT-PRO. Further, studies on cystic fibrosis (CF), carpal tunnel syndrome (CTS), and multiple sclerosis (MS), conditions that can affect QoL substantially, found inadequate PRO reporting, prompting authors of all three studies to recommend greater adherence to CONSORT-PRO.
Change vs. baseline
As indicated by Di Maio, many cancer drugs have recently received regulatory approval based on single-arm studies. In these studies, QoL and PROs simply describe changes vs. baseline and trends over time, which can ultimately introduce bias. The authors recommend avoiding methodologically weak evidence and involving PRO experts in the planning, executing, and interpreting of findings.
Electronic PRO (ePRO)
Early research suggests that racial and ethnic minority groups, older patients, and patients with lower levels of education attainment may benefit even more from ePRO options. Contract research organizations (CROs) like Vial provide digital health tools such as ePRO, which are compliant and customizable for the convenience of trial participants.
How does the FDA weigh the benefits of positive PROs?
The FDA’s first publication of the draft guidance for PROs for industry came out almost 20 years ago. The FDA increasingly looks to patients to understand how they describe their health status. Clinical outcome assessments (COAs) may capture outcomes important to patients, and PROs, as defined by the FDA, are one form of COA. By researching, developing, and refining COA measures, the FDA actively strengthens its ability to use patient-focused methodology to inform decision-making. To improve how it assesses the benefit of positive PROs in HF, for example, the FDA works with academia to explore how previously developed PRO instruments may be modified to capture outcomes of diverse patient groups adequately.
Use of PRO assessments
Specifically for oncology drugs, Moore et al. evaluated all new drug applications (NDAs) submitted to the FDA from 2013 – 2022 that were approved through the accelerated approval process to assess whether those trials included PROs. They found that 59% of such trials included PRO assessments; however, PRO measurements were inconsistently utilized.
Role of PROs in drug approvals
A recent review sought to comprehensively characterize the inclusion of PROs and regulatory considerations in FDA-approved novel oncology drugs. The researchers analyzed FDA review documents and labels for novel oncology drugs from 2017 to 2022, including types of endpoints for PROs, PRO measures, designs of trials including PROs, and regulatory comments on PRO-related contents. They found that PROs currently do not play a significant role in oncology drug approvals and concluded that the use of PROs to support oncology drug approval is still in the exploratory stage. These findings are related to the deficiencies in the design and execution of PRO-related content in cancer clinical trial.
Vial – Reimagining Clinical Trials
Vial is a tech-first CRO that delivers faster, better, and more affordable clinical trial results for biotech sponsors. Vial CRO’s modern, intuitive technology platform integrates trial onboarding, patient enrollment, site communication, and data collection into one connected system for efficiency.
The Vial ePRO offers a seamless, user-friendly interface that is accessible by mobile or desktop. Interactive functions, built-in data validation, and skip logic provide quick, intuitive, compliant data capture. A connected data flow between Vial ePRO and Vial EDC enables effortless, accurate, and real-time data recording and storage. Connect with a team member today!
