Using electronic patient-reported outcome (ePRO) technology to address key challenges in CNS trials
There is significant unmet need for both symptomatic and disease-modifying treatments for central nervous system (CNS) diseases. However, Phase 2 and 3 CNS trials have a trial failure rate of approximately 85%, second only to oncology.1 This high failure rate is due, in part, to the fact that endpoints are usually subjective and rely on self-reporting of symptoms by the study participants and observational reporting by the clinical investigator and, sometimes, caregivers. Inconsistent application of subjective rating scales and strong placebo response can also adversely affect results.
ePRO technology is designed to optimize the objectivity of inherently subjective data. By allowing for more frequent and timely data collection, ePRO can help to reduce the influence of placebo response, improve patient engagement and adherence, and identify true treatment effects. To maximize data quality and value, ePROs must be carefully designed and implemented.
ePROs offer several potential advantages in CNS trials:
Automated input validation, which helps ensure that entries are valid and complete. Studies have shown that ePRO is typically associated with less missing data.2
Greater data integrity, due to electronic time stamps that may encourage more timely entries and the greater sense of privacy that comes with self-recording symptoms and other sensitive feedback outside of the clinical trial setting. The use of ePROs also helps avoid secondary data entry errors associated with transcription of paper PROs into the study database.
Higher compliance, compared to paper PROs due to ease of use and ability to send alerts when assessments are scheduled.
Improved recruitment and retention, because of decreased patient burden. The use of ePROs may reduce the number of site visits and assessments required, which helps to limit travel and may make the study available to a wider, more diverse patient pool.
Decreased site burden, since ePRO technology allows for remote data collection, which can automate the process of collecting and storing PRO data and reduce the need for in-person visits. ePRO can also be used to send automated reminders and instructions about study-related tasks.
Enhanced safety, with ePROs that have real-time data monitoring features that allow messages to be sent to patients if their responses meet pre-determined thresholds.
5 best practices for designing, developing, and deploying ePRO in CNS trials
1. Define study objectives and identify potential PROMs
Developing clear study goals helps clarify what patient-reported outcome measure (PROM) data needs to be collected and how these data will be used to evaluate treatment effectiveness. In November 2022, the National Quality Forum issued technical guidance on how to select high quality PROMs for use in performance measures and how to develop digital patient-reported outcome performance measures (PRO-PM, or ePRO). This guidance defines 12 attributes of PROMs that are appropriate for use in digital PRO-PM and outlines a four-stage roadmap for developing a digital PRO-PM. Beyond reliability and validity, key attributes of an appropriate PROM include3:
Meaningfulness and relevance from the patient and/or caregiver perspective
Interpretable scores and defined and actionable cut points or targets
Low patient burden in terms of the length of the assessment and the time or effort needed to complete it
Fit with the standard of care and related workflow to minimize site burden
Cultural appropriateness for each setting of use
Creating and seeking feedback from a stakeholder advisory group that includes patients, caregivers, patient advocacy groups, clinicians, and payers ensures that the PROM reflects the perspectives of all those who will be affected by the measure or its completion and collection process.
2. Design a fit-for-purpose ePRO
When designing an ePRO, it is essential to consider the overall complexity of the study and the associated patient and site burden. The design and timing of questions and alarms is integral to successful implementation and execution of ePRO. Engaging subject matter experts (SMEs) from the ePRO vendor to work on the design and build is especially important in complex studies. An important consideration for ePRO design is whether to provision devices or to use a bring-your-own-device (BYOD) model. This decision may be informed, in part, by the nature of the assessment. Participant preference should also be factored into this decision.
While some participants may prefer the convenience and privacy of using their own device, others may be hesitant about downloading an app or paying for cellular data use. In addition to regulatory compliance and device security, accessibility may also be an issue for the BYOD model if the target population has low rates of smartphone use. Another important consideration is how the ePRO system will integrate with other study technologies. Bringing together all technology vendors prior to building the ePRO system enables better coordination of services to optimize both efficiency and sponsor, site, and patient experience
3. Test the ePRO System
The ePRO should be tested for reliability, validity, and user acceptance both in the settings and with the populations where it will be used. User acceptance testing (UAT) should include a 24-hour test to ensure that diary reminders and alarms trigger as expected. Working with an ePRO vendor that offers robust site and patient support services is critical for ensuring adoption and acceptance.
4. Developing ePRO training materials
Creating and implementing online training programs that educate patients, caregivers, and sites on the proper use of the software and devices used to complete ePROs can help to maximize adherence and data quality and minimize placebo response rate. The training should include information on the purpose and use of the ePRO system, the importance of accurate and complete data, and detailed guidance on entering data. It may be useful for this training to include instructions on how to confirm that internet connectivity is strong and stable enough to send and receive ePRO data and who to call for troubleshooting assistance
5. Creating a backup plan
Having a contingency plan in case there are issues with ePRO data collection or submission can help minimize the risk of missing data. This contingency may be a paper PRO that has been validated to be equivalent to the ePRO.
With proper planning and intelligent deployment, ePRO technology can help address some of the key challenges of CNS trials. To minimize site burden and ensure compliance with regulations for electronic record-keeping, sponsors must ensure that all study-related technology solutions work together as seamlessly as possible. Thus, early coordination among CRO partners and vendors prior to ePRO system development is critical. At Precision for Medicine, we have deep expertise in managing CNS trials that leverage ePROs and extensive experience in working with ePRO vendors to integrate their systems with other study technologies.
2. Coons SJ, Gwaltney CJ, Hays RD, 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 Health. 2009;12(4):419-429.
3. National Quality Forum. Building a Roadmap from Patient-Reported Outcome Measures to Patient-Reported Outcome Performance Measures, Technical Guidance – Final Draft, November 30, 2020.
Tracey Owens is a Director of Project and Clinical Trial Management at Precision, having 28 years of experience in managing Phase I-IV clinical trials. Tracey is highly experienced in providing directional oversight on rare disease, CNS, psychiatric and oncology clinical trials. Her experience notably includes: ALS, bipolar disorder, epilepsy, major depressive disorder, schizophrenia, idiopathic hypersomnia, CIDP, traumatic brain injury, multiple myeloma and dementia (including Alzheimer’s and Parkinson’s Disease.)
Vincent Shortino is a Sr. Clinical Trial Manager, bringing more than 20 years of experience to Precision. His experience spans all major therapeutic areas with a heavy emphasis on Cardiovascular and Rare Indications, across Phases I–IV. He brings solid perspectives inclusive of sites, pharma and CROs from his previous roles of Study Coordinator, Site Director, CRA, and Clinical Trial Manager.
Precision for Medicine is part of the Precision Medicine Group, an integrated team of experts that extends Precision for Medicine’s therapeutic development capabilities beyond approval and into launch strategies, marketing communication, and payer insights. As one company, the Precision Medicine Group helps pharmaceutical and life-sciences clients conquer product development and commercialization challenges in a rapidly evolving environment.