With the need to incorporate remote ways of working and interacting with study participants, sponsors and contract research organizations (CROs) have turned to technology for critical study activities ranging from patient consent and consultation to site monitoring. A particular instance of increased technology uptake has been in the area of patient-reported outcome (PRO) data collected by electronic methods, known as electronic PRO (ePRO) data.
Background
The U.S. Food and Drug Administration (FDA) defines a PRO as “any report of the status of patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.”1 Historically, PRO data has been used as an adjunct to primary data in the context of clinical trials. However, due in part to the emergence of the COVID-19 pandemic, sponsors have increased their reliance on PRO data in order to maintain trial continuity. In particular, the need to gather data remotely has catapulted ePRO data to the forefront.
Benefits of ePROs
Using ePRO data can help maintain clinical trial integrity and, even outside the context of COVID-19, will continue to be a valuable adjunct data collection tool for studies that aim to capture information about the patient experience.
ePROs are designed to optimize the objectivity of inherently subjective data. Compared to paper-based PROs, ePROs offer a number of potential advantages, such as:
- Input Validation: ePROs enable input validation, which helps ensure that patients make valid and complete entries. The use of ePROs also helps avoid the secondary data entry errors that may occur with paper-based assessments.
- Patient Safety: Some ePRO systems have a data monitoring feature, which allows messages to be sent directly to patients if their responses meet pre-determined levels.
- Data Integrity: ePRO systems have electronic time stamps that indicate when entries are made, which may encourage more timely entries and help limit “parking lot syndrome,” where patients fill out the PRO right before their office visit. Patients may also be more forthcoming when they can record symptoms and other sensitive feedback outside of the conventional clinical trial setting. In addition, ePROs are typically less time-consuming for patients than their paper counterparts.
- Data Security: ePRO data is stored on a server, with a backup, reducing the risk of data loss.
- Compliance: ePROs have a better compliance rate than paper PROs, where compliance is measured by the actual ePRO responses as a percentage of expected ePRO responses. Studies on satisfaction and ease of use have demonstrated that respondents prefer ePRO over paper and that ePRO measures typically produce less missing data.2 Certain ePRO systems can also be used to send automated reminders to patients, which help with both diary compliance and other study-related tasks.
- Speed of Assessment: Assessment calculations are made in real time, so investigators do not have to spend time manually tallying up responses and applying scores.
Transitioning from Paper PROs to ePROs
For sponsors who are considering a transition from paper-based PROs to ePROs, it is important to consider the type of PRO measure being adapted, the target population, the complexity of data capture requirements or scoring calculations, and the time frame required for patient reporting. Where possible, ePRO instruments should avoid free text responses, as these data may not be usable for analysis.
It is also critical to keep in mind that the adoption of electronic formats requires sponsors to either ensure that the data collected via paper and electronic methods are equivalent or to account for any identified differences between the two versions. The level of evidence needed to validate ePRO measures when migrating from paper-based PRO measures may vary depending on the amount of content and the format modifications required. According to an International Society for Pharmacoeconomics and Outcomes Research (ISPOR) ePRO Good Research Practices Task Force report, the magnitude of a particular modification is related to its potential impact on the content, meaning, and interpretations of the measure’s items or scales. Evidence for measurement equivalence can be generated through one or more of the following tests:2
- Cognitive testing to explore how participants understand, process, and respond to questionnaire items.
- Usability testing to determine whether respondents can use the ePRO software or device appropriately.
- Equivalence testing to evaluate the comparability between PRO scores from paper-based and electronic version.
- Full psychometric testing, including documentation of content and construct validity, as well as evidence of internal consistency and test-retest reliability.
Of note, the National Institutes of Health has an initiative called Patient-Reported Outcomes Measurement Information System (PROMIS®), which aims to develop, validate, and standardize data points across common medical conditions. This standardization will make it easier for sponsors to incorporate paper PROs and ePROs into their studies without having to perform independent validation.
Regulatory Perspective on ePROs
The FDA supports direct patient reporting, as some treatment effects are only known to patients and may not otherwise be captured as outcomes. Further, the FDA has indicated a preference for ePROs over paper-based PROs. In its 2009 final guidance on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, the agency addresses specific concerns sponsors may have when using ePRO instruments. For example, during the conduct of a clinical trial, investigators are deemed to be responsible for controlling, maintaining, and providing access to all source documentation in the event of an FDA inspection. The use of ePRO instruments may interfere with this responsibility if the sponsor or CRO maintains direct control over ePRO source data. Consequently, the FDA recommends that the clinical trial protocol, or a separate document, specify how ePRO source data will be handled and how investigators will meet the regulatory requirements.1
From Clinical Research to Clinical Practice
In addition to increasingly being relied on to restore or maintain patient participation, ePROs also play a key role in the broader efforts of the FDA to increase adoption of digitization initiatives across the clinical trial process. As conventional data collection methods give way to technologies that enable remote data collection and site monitoring, sponsors and CROs have an opportunity to introduce other methodologies that further the goal of accelerating the clinical trial process, while still prioritizing patient safety, optimizing efficiency and cost, and preserving—or even enhancing—data integrity.
Recent healthcare delivery challenges may have also opened the door for increased adoption of ePROs in clinical practice. For example, several studies have demonstrated the feasibility of ePRO reporting of the side effects of cancer treatment, with high patient acceptability and satisfaction.3,4 In clinical practice, ePROs could allow for more frequent evaluation, proactive identification of worsening symptoms or toxicities, and more effective remote management,5 both in times of public health emergency and in the post-COVID era.
References:
1. U.S. Food and Drug Administration. “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, December 2009.” Available at https://www.fda.gov/media/77832/download.
2. Coons SJ, et al. “Recommendations on Evidence Needed to Support Measurement Equivalence Between Electronic and Paper-based Patient-reported Outcome (PRO) Measures: ISPOR ePRO Good Research Practices Task Force Report.” Value in Health 2009;12(4):419-429.
3. Basch E, Iasonos A, Barz A, et al. “Long-term Toxicity Monitoring Via Electronic Patient-Reported Outcomes in Patients Receiving Chemotherapy.” J Clin Oncol 2007;25:5374-5380.
4. Basch E, Deal AM, Kris MG, et al. “Symptom Monitoring with Patient-reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial.” J Clin Oncol 2016;34:557-565.
5. Marandino L, Necchi A, Aglietta M, Di Maio M. “COVID-19 Emergency and the Need to Speed Up the Adoption of Electronic Patient-Reported Outcomes in Cancer Clinical Practice.” JCO Oncol Pract 2020;OP2000237.
