Within the context of pragmatic clinical trials embedded within health care systems (ePCTs), PRO measures that are already being collected as part of routine clinical care and/or for quality assurance purposes could easily be integrated into the trial. However, in some cases, PROs are not collected routinely, necessitating a separate data collection protocol (although this seems to be rapidly changing).

To use PRO data most effectively in pragmatic research, it is useful to understand the different roles played by PROs in clinical research, clinical care, and quality assurance.

Clinical Research

PRO Measures as Study Endpoints

PROs play a significant role as study endpoints in the development and evaluation of new therapies (Willke et al. 2004; Gnanasakthy et al. 2016; Gnanasakthy et al. 2017). PROs have not been used as frequently as study endpoints in ePCTs, in large part because PROs are often not included as part of routine clinical care and thus the electronic health record (EHR), which is typically the main source of data for many ePCTs. Still, several trials within the NIH Pragmatic Trials Collaboratory have or are assessing PROs as trial endpoints (see Table).

Table. NIH Pragmatic NIH Collaboratory Trials With PROs

Abbreviations: NRS = numeric rating scale; PROMIS = Patient-Reported Outcomes Measurement Information System; CAT = computer adaptive testing; PEG = pain, enjoyment of life, and general activity; SF = short form

For NOHARM, all outcomes are collected via the EHR. For all other trials, separate mechanisms were needed to collect the measures.

As with all trial endpoints, researchers should specify in the research protocol whether a PRO endpoint will serve as a primary, secondary, or exploratory endpoint (FDA Guidance for Industry 2009). Often times there will be interest in the effect of an intervention on more than one aspect of the patient’s experience—for example, on pain severity, pain frequency, and interference in daily activities due to pain. With multiple PRO endpoints, care must be taken to create a strong a priori rationale for how the multiple endpoints will be handled at the analysis phase, because of the risk of Type I error inflation and/or challenges in interpreting patterns of results across endpoints. FDA has published guidance entitled Multiple Endpoints in Clinical Trials Guidance for Industry, which describe strategies managing multiple endpoints in a study.

It should be noted that ethical issues arise when collecting sensitive data that could signal distress, such as suicidal ideation, opioid use disorder, or depression. According to an article by Ali et al, investigators have an ethical obligation to monitor these signals and identify in advance if, when, and how such signals will trigger a response (Ali et al. 2022). Using examples from the NIH Collaboratory Trials, the authors offered preliminary recommendations and identified opportunities for future work, which include:

• Understanding and aligning stakeholder expectations
• Considering characteristics of the trial and study population to inform a response
• Defining triggers, thresholds, and responsibilities for action
• Identifying appropriate response mechanisms and capabilities
• Integrating with clinical practices and systems
• Addressing patient-subject privacy

PRO Measures as Monitoring Tools (Adverse Events and Symptoms)

PRO measures can also be used to capture or monitor the adverse effects of an intervention separately from its effectiveness. For example, clinical trial investigators collect adverse event (AE) data to ensure patient safety and inform sponsors, regulators, patients, caregivers, and clinicians about adverse effects of treatment. Clinicians typically grade AEs using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) (National Cancer Institute 2018). In order to better capture negative, uncomfortable, and impactful symptoms from the patient’s perspective, such as nausea and anxiety, the National Cancer Institute developed the PRO-CTCAE, which was designed for adults participating in oncology trials (Basch et al. 2014; Dueck et al. 2015).

PRO Measures as the Intervention

In some cases, the PRO measure can be the intervention. A study by Basch et al. demonstrated that clinical benefits were associated with self-report of symptoms in patients receiving care for cancer, such as improved health-related quality of life, fewer emergency department visits, fewer hospitalizations, longer duration of palliative therapy, and superior survival rates (Basch et al. 2016). In the study, patients recorded symptoms on a tablet, and an automated alert was sent to clinicians when patient-reported symptoms were severe or worsening. The authors postulate that the benefits were due to increased rates of discussion between patients and clinicians resulting in intensified symptom management and improved symptom control.

Clinical Care

Ideally, a PRO instrument will not only be a valid and reliable way to collect data, but it will also make a positive contribution to clinical care (Farnik and Pierzchała 2012). Data collected from a PRO instrument can be used in longitudinal reporting at the point of care and as part of clinical decision-making and review of systems. In addition, PRO data can be used to trigger patient education and interventions and as a means to triage patients to receive other services, helping the patient understand that the information they are reporting is meaningful to their care.

One of the NIH Collaboratory Trials within the NIH Collaboratory provides a good example of how a PRO-based intervention for research can be incorporated into clinical care. The Collaborative Care for Chronic Pain in Primary Care project was a mixed-methods, cluster-randomized pragmatic clinical trial designed evaluate the integration of psychosocial services into the primary care of patients with chronic pain. The intervention, the Pain Program for Active Coping and Training (PPACT), involves behavioral skills training designed to engage patients in their own care and help them manage their pain.

The study compared the effects of the intervention versus usual care on a number of measures, including patients’ pain symptoms, functional ability, satisfaction with healthcare services, and receipt of opioids and benzodiazepine medication. As part of the project, the patient completed a brief pain inventory (online using the EHR patient portal, using interactive voice response technology, or via a call with a medical assistant). For patients randomized to the active intervention, a more extensive intake evaluation was completed and compiled into an electronic summary outside the firewall of the EHR and sent to participant’s primary care physician through the EHR. The report incorporated real-time analysis and scoring of the data and presented the information in clinical context; as a result, it provided the physician with easily interpretable, actionable information derived from PRO data in order to promote discussion with the patient, trigger educational interventions, and aid in clinical decision-making (Debar et al. 2022).

Patient Satisfaction and Quality Assurance

A systematic review of 27 studies in the cancer setting suggests that PROs improved patient-provider communication and patient satisfaction, in part, because clinicians talked to patients about their feelings and health status and were able to develop a shared view of treatment goals, health status, or reason for the visit (Chen et al. 2013). Online patient self-reporting of toxicity symptoms during chemotherapy has been shown to be feasible, even among patients with advanced cancer and high symptom burdens (National Quality Forum 2013). PROs can also be used as reliable measures of healthcare performance; for example, the National Quality Forum endorses the use of PRO-based performance measures for the purposes of performance improvement and accountability (National Quality Forum 2013).