Lauren Neighbours is a Research Scientist at Rho. She leads cross-functional project teams for clinical operations and regulatory submission programs and has over ten years of scientific writing and editing experience. Lauren has served as a project manager and lead author for multiple clinical studies across a range of therapeutic areas that use patient- and clinician-reported outcome assessments, and she worked with a company to develop a patient-reported outcome instrument evaluation package for a novel electronic clinical outcome assessment (eCOA).
Jeff Abolafia is a Chief Strategist for Data Standards at Rho and has been involved in clinical research for over thirty years. He is responsible for setting strategic direction and overseeing data management, data standards, data governance, and data exchange for Rho’s federal and commercial divisions. In this role, Jeff is responsible for data collection systems, data management personnel, developing corporate data standards and governance, and developing systems to ensure that data flows efficiently from study start-up to submission or publication. Jeff has also developed systems for managing, organizing, and integrating both data and metadata for submission to the FDA and other regulatory authorities.
With the industry-wide push towards patient-centricity, electronic clinical outcome assessments (eCOAs) have become a more widely used strategy to streamline patient data collection, provide real-time access to data (for review and monitoring), enhance patient engagement, and improve the integrity and accuracy of clinical studies. These eCOAs are comprised of a variety of electronically captured assessments, including patient reported outcomes (PROs), clinician-reported and health-care professional assessments (ClinROs), observer reported outcomes (ObsROs), and patient performance outcomes administered by health-care professionals (PerfOs). The main methods for collection of eCOA data include computers, smartphones, and tablets, as well as telephone systems. While many companies have chosen to partner with eCOA vendors to provide these electronic devices for use in a clinical study, other sponsors are exploring “bring your own device (BYOD)” strategies to save costs and start-up time. No matter what strategy is used to implement an eCOA for your clinical study, there are several factors to consider before embarking on this path.
Designing a Study with eCOAs
The decision to incorporate an eCOA into your clinical study design is multifaceted and includes considerations such as the therapeutic area, the type of data being collected, and study design, but the choice can first be boiled down to 2 distinct concepts: 1) the need for clinical outcome data from an individual, and 2) the need for this data to be collected electronically. Thus, the benefits and challenges to eCOAs can be aligned with either or both of these concepts.
Regarding the first concept, the need for clinical outcome data should be driven by your study objectives and a cost-benefit analysis on the optimal data collection technique. Using eCOAs to collect data is undoubtedly more patient-centric than an objective measure such as body mass index (BMI), as calculated by weight and height measurements. The BMI calculation does not tell you anything about how the patient feels about their body image, or whether the use of a particular product impacts their feelings of self-worth. If the study objective is to understand the subjective impact of a product on the patient or health-care community, a well designed eCOA can be a valuable tool to capture this information. These data can tell you specific information about your product and help inform the labeling language that will be included in the package insert of your marketed product. Additionally, FDA has encouraged the use of PROs to capture certain data endpoints, such as pain intensity, from a patient population who can respond themselves (see eCOA Regulatory Considerations below). Of course, it’s important to note that the inherent subjectivity of eCOAs does come with its own disadvantages. The data is subject to more bias than other objective measures, so it’s critical to take steps to reduce bias as much as possible. Examples of ways to reduce bias include single- or double-blind trial designs, wherein the patient or assessor is not aware of the assigned treatment, and building in a control arm (e.g., placebo or active comparator) to compare eCOA outcome data across treatment groups.
Another important concept is the process for identifying and implementing the electronic modality for eCOA data collection. Many studies still use paper methods to collect clinical outcome data, and there are cases when it may make more sense to achieve your study objectives through paper rather than electronic methods (e.g., Phase 1 studies with limited subjects). However, several types of clinical outcome data can be collected more efficiently, at lower cost, and at higher quality with electronic approaches (e.g., diary data or daily pain scores). From an efficiency standpoint, data can be entered directly into a device and integrated with the electronic data management system being used to maintain data collection for the duration of the study. This saves time (and cost) associated with site personnel printing, reviewing, interpreting, and/or transcribing data collected on paper into the electronic data management system, and it also requires less monitoring time to review and remediate data. Additionally, paper data is often “dirty” data, with missing or incorrectly recorded data in the paper version, followed by missing or incorrectly recorded data entered into the data management system. The eCOA allows for an almost instantaneous transfer of data that saves the upfront data entry time but also saves time and cost down the road as it reduces the effort required to address queries associated with the eCOA data. Aside from efficiencies, eCOA methods allow for more effective patient compliance measures to be implemented in the study. The eCOA device can be configured to require daily or weekly data entry and real-time review by site personnel prior to the next scheduled clinic visit. Additionally, the eCOA system can send out alerts and reminders to patients (to ensure data is entered in a timely manner) and to health-care personnel (to ensure timely review and verification of data and subsequent follow-up with patients as needed). The downsides to electronic data collection methods tend to be associated with the costs and time to implement the system at the beginning of the study. It’s therefore essential to select an appropriate eCOA vendor early who will work with you to design, validate, and implement the clinical assessment specifically for your study.
eCOA Regulatory Considerations
In line with the industry push for patient-focused clinical studies, recent regulatory agency guidance has encouraged the use of eCOAs to evaluate clinical outcome data. The fifth authorization of the Prescription Drug User Fee Act (PDUFA V), which was enacted in 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), included a commitment by the FDA to more systematically obtain patient input on certain diseases and their treatments. In so doing, PDUFA V supports the use of PRO endpoints to collect data directly from the patients who participate in clinical studies but also as a way to actively engage patients in their treatment. The 2009 FDA guidance for industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims , further underscores this idea by stating “[the use] of a PRO instrument is advised when measuring a concept best known by the patient or best measured from the patient perspective.” The 2013 Guidance for Industry on Electronic Source Data in Clinical Investigations provides the Agency’s recommendations on “the capture, review, and retention of electronic source data” and is to be used in conjunction with the 2007 guidance on Computerized Systems Used in Clinical Investigations for all electronic data and systems used in FDA-regulated clinical studies, including eCOAs. To support these efforts, the FDA has developed an extensive Clinical Outcome Assessment Qualification Program, which is designed to review and assess the design, validity, and reliability of a COA for a particular use in a clinical study. Furthermore, the newly formed Clinical Outcome Assessment Compendium is a collated list of COAs that have been identified for particular uses in clinical studies. The COA Compendium is further evidence of FDA’s commitment to patient-centric product development, and it provides a helpful starting point for companies looking to integrate these assessments into their clinical development programs.
Before choosing an eCOA for your clinical development program, the following regulatory factors should be considered:
- FDA holds COAs to the same regulatory and scientific standards as other measures used in clinical trials. Thus, it is advisable to refer to the Guidance for Industry on Patient-Reported Outcomes and the available information on the COA Assessment Qualification program and COA Compendium provided by the Agency when implementing eCOAs into your development program. If you plan to divert from currently available regulatory guidance, make sure to have a solid rationale and supporting documentation to substantiate your position.
- The qualification of an eCOA often requires input from patients and/or health-care professionals to evaluate the effectiveness of the assessment. This input is necessary for the regulatory agency to determine whether the eCOA can accurately measure what it’s supposed to measure (validity) and to demonstrate it can measure the outcome dependably (reliability).
- Data collected from qualified and validated eCOAs can be used to support product labeling claims. The key is to use an eCOA when it’s appropriate to do so and to make sure the eCOA supports your intended labeling claims because the instrument will be evaluated in relation to the intended use in the targeted patient population.
- For the cases where an instrument was developed for paper based collection or an instrument is collected using multiple modes, it may be necessary to test for equivalence. This regulatory expectation is often required (especially for primary and secondary endpoints) to ensure that the electronic version of the instrument is still valid and data collected with mixed modes are comparable.
A CRO Can Help with your eCOA Strategy
CROs partner with sponsor companies to develop and execute their product development strategies. In some cases, this involves implementing clinical outcome measures into a development program and then facilitating the interactions between the company and regulatory authorities to ensure adequate qualification of the COA prior to marketing application submission. Whether or not you choose to engage a CRO in your development plan, consider seeking outside consultation from the experts prior to establishing your eCOA strategy to give you and your company the best chance of success.
CROs Can Help:
- Determine endpoints where eCOA data is appropriate
- Determine the cost/benefit of electronic vs paper data capture
- Determine the best mode of electronic data capture
- Recommend eCOA vendors when appropriate
- Perform equivalence analysis
- Facilitate discussions with regulatory authorities
- Manage the entire process of eCOA implementation