As patient's health and quality of life became an increasingly important component of treatment response, clinical outcome assessments, or COAs, became an important part of evaluating the safety and efficacy of medical products. In January we covered COAs and their use in general. This post will focus on patient reported outcomes (PROs).
What patients report directly about their health condition and disease symptoms (i.e., without the interpretation of a clinician) is very important and could influence the course and outcome of their treatment. In clinical trials, PROs can be utilized to determine the safety and efficacy of medical products. Because they are subjective in nature and are influenced by the patient’s perception of their own disease, PRO measures must be well defined and collected in a consistent and robust manner. Instruments intended to capture health outcomes directly from patients can be developed and validated with appropriate sample sizes and rigorous study design. Once tested in the population of interest, or multiple populations in some cases, and adequately validated according to scientific rigor, they can then be used alone or in combination with biomarkers in research studies or clinical trials. PROs combined with biospecimens or digital biomarkers from connected devices can provide direct or indirect evidence not only for medical safety but also for efficacy in clinical trials in support of labeling claims.
The Road From Paper to Electronic Mode
The digital revolution wave extended how healthcare is captured and delivered. Clinical trial processes were no exception, and many remember the transition to EDC platforms to capture patient data in clinical trials. Naturally, paper-based health assessments rode the tide and electronic COA (eCOA) have become a mainstay in clinical trial operations.
The FDA encourages the use of electronic PROs (ePROs) whenever possible for the simple fact that paper PROs lack the timestamp and thus an inability to confirm when the data are entered by the patient. As we enable more remote clinical trial engagement, ePROs take on even greater significance. However, there is much more to the migration of a PRO to an ePRO than simply making a digital copy. The transition must ensure that the patient responses are equivalent between paper and electronic formats. This is not a straight line as the equivalency may need to be tested in multiple populations and the extent of changes impact the work needed to switch to the electronic road.
According to the ISPOR task force guidance, when a paper PRO is delivered in a new modality such as in a mobile app and only minor modifications are needed (things like spacing, font, etc.) small groups of 5-10 patients may undergo cognitive debriefing and usability testing interviews. However, when more significant modifications are made to PROs (when digitizing them), the process of migration necessitates robust clinical study designs and statistical analyses. This guidance was published by the ISPOR task force in response to the release of the FDA guidance “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims” and is likely key to follow if pharma is to adopt these electronic measures in clinical trials knowing the FDA will require a certain level of rigor. The ISPOR task force indicates when moderate changes are made to a PRO, equivalency testing is required which subsequently turns into a full-fledged psychometric testing protocol when substantial changes are implemented. In a nutshell, equivalency is measured by comparing the psychometric properties of the data collected from the device to that from the paper, and under the psychometric testing. It is assumed that the substantial changes may render the ePRO as a new measure and thus should be subjected to the same original process of development and validation before this new ePRO can be utilized in clinical trials.
In all modification levels usability testing is required, which is completed in the target patient population where it examines the ability of the participants to use the device and software and complete the digital assessment as intended.
Factors to consider when optimizing and implementing ePROs are covered in a paper by Fleming and colleagues in the journal Therapeutic Innovation & Regulatory Science (2015). Among them is the modality and device type on which the ePRO is presented, that includes audio, computer, tablet, smartphone, touchscreen, keyboard and mouse. Although a meta-analysis of over 40 ePRO studies found that device type did not impact equivalency, it is still important to keep in mind user experience as a factor in compliance, accuracy and longitudinal data capture.
While site-based ePRO compliance is ensured by the clinical research team, capturing remote ePRO compliance is more challenging as it depends on the patient's engagement and adherence to the ePRO study protocol reporting schedule and requires continuous monitoring by the site. This adds a burden to an already overwhelmed research and clinical staff.
Alternative mechanisms to monitor patient engagement are needed. One possible solution is real time analysis of data and utilization of notification applications embedded in the ePRO delivery platform to help nudge and encourage action by patients.
When designed and developed appropriately with thoughtful implementation for engagement, patient-centered and clinically meaningful ePROs can make a significant difference in the approval of a new medical product and treatment.
References and Resources
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. 2009. Value in Health 12(4):419-429
Doward LC and McKenna SP. Defining Patient Reported Outcomes. 2004. Value in Health 7(1):S4-S8
Fleming S, Barsdorf AI, Howry C, et al. Optimizing electronic capture of clinical outcome assessment data in clinical trials: the case of patient-reported endpoints. 2015. Therapeutic Innovation & Regulatory Science 49:797–804
Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009.
Powers JH, Patrick DL, Walton MK, et al. Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force. 2017. Value in Health 20(1):2-14
Walton MK, Powers JH, Hobart J, et al. Clinical Outcome Assessments: Conceptual Foundation—Report of the ISPOR Clinical Outcomes Assessment – Emerging Good Practices for Outcomes Research Task Force. 2015. Value in Health 18(6):741-752
Weldring T and Smith SMS. Patient-Reported Outcomes (pROs) and patient-Reported Outcome Measures (pROMs). 2013. Health Services Insights 6:61–68