Over the past 15 years, the clinical trials industry has undergone a notable transformation: Patient-reported outcomes (PROs), once dismissed due to their subjective nature, are now acknowledged as crucial clinical research data points. This shift is due, in part, to regulatory bodies and professional societies embracing patient-centric research and recognizing PROs as valuable sources of information about a treatment's effectiveness as well as indicators of patient quality of life.¹

This heightened attention to PROs underscores a concerted effort to ensure that patient experiences and outcomes are central considerations in the evaluation of healthcare treatments and interventions—and it paves the way for a more nuanced understanding of therapeutic effectiveness, extending beyond mere survival rates to encompass the overall well-being and day-to-day experiences of patients. This is a positive step forward for trial participants who have long felt ignored in drug development processes.  

In this article, we will expand on the idea of patient reported outcomes as essential components of every clinical trial, and we’ll discuss why these outcomes are stronger and more accurate when they are captured electronically.  
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Key Takeaways:

• PRO data comes directly from the patient, providing valuable insights into how they experience a treatment. They are especially important in instances where patient quality of life is a key factor in treatment success.  
• Technology, such as electronic PROs (ePROs), allows for more accurate and real-time data collection from patients.
• Not only do regulatory agencies support PRO collection in clinical trials, they also support the use of technology to capture them.  
• While the use of ePROs in clinical trials may seem straightforward, their implementation requires careful planning and consideration.  
• Innovations are emerging that have the potential to make ePRO more intuitive, engaging, and integrated into patients' lives, ultimately enhancing the accuracy and richness of the data collected.
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Patient-Reported Outcome Measures: Definitions

Let's begin by answering: What are patient-reported outcomes? The FDA defines a PRO as a measurement based on a report that comes directly from a patient without interpretation by a clinician or anyone else.² Typically, PROs are collected through questionnaires—often referred to as patient-reported outcome measures (PROMs)—that are given to, and completed by, the patients directly. Validated PRO measures are used to ensure the questions, response options, and the general assessment approach are standardized for all participants.¹ Examples include questionnaires about symptoms or how a disease or treatment affects everyday life.³

Historically, participants were given pen and paper to complete these measures. Today, technologies such as mobile phones or computers are more commonly used to capture what are called electronic patient-reported outcomes, or ePRO.  

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Clinical Research and the Benefits of Using PROs

PROs play an indispensable role in clinical trials, bridging the gap between clinical evaluations and tangible impacts on patients' lives. Here are some of the advantages of incorporating them in clinical trial endpoints.

Measure What Matters: Health-Related Quality of Life

By including patient-reported outcome measures in clinical trials, researchers amplify patient voices, putting an emphasis on measuring how they feel in the midst of an intervention. This is especially important in conditions where the goal is to improve symptoms rather than to cure a disease. For example, in the field of oncology, the conventional clinical endpoint—overall survival—must be weighed against the quality-of-life PRO measure. Numerous treatments may be able to prolong life, but accompanying side effects can render some therapeutics intolerable. In these cases, longevity may not be the most important consideration for the patient. The most accurate way to measure health-related quality of life is to ask patients themselves using a validated PRO.

Ensuring a Holistic View of Efficacy

Researchers have a tendency to focus on the statistical significance of objective outcomes; in these instances, PROs are often overlooked.⁴ When researchers focus exclusively on objective data, they’re missing half the story. This is not to diminish the importance of objective outcomes measurement, but instead to suggest that clinical trials can and should be designed more holistically, taking into consideration both subjective and objective data capture. A combination approach provides a more robust picture of a therapeutic's impact. It can also help to identify patterns and trends that may not have been captured otherwise, ultimately leading to a better understanding of treatment efficacy.

Supporting Regulatory Requirements

Regulatory agencies’ gradual appreciation of PROs has evolved into expectations that are clearly outlined in guidance documents. For example: The FDA's Patient-Focused Drug Development Initiative,⁵ which aims to gather and integrate patient perspectives into drug development, explicitly emphasizes the importance of incorporating PROs into clinical trials.

Improving Clinical Care

When PROs inform the research and development process, the continuum of care also benefits. Physicians use PRO data from clinical research to determine which therapeutic will have fewer side effects or contribute to better health outcomes and quality of life outcomes for their patients. During a recent study,⁶ researchers interviewed clinicians about the impact of PROs on their practice. They concluded that PROs inform "nuanced conversations with patients" and provide physicians with the "confidence [needed] to choose the best healthcare treatment while considering toxicity and side effects."^6(p4-5)

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ePRO: The Electronic Revolution

While the intent of PROs is to make drug development more patient-focused, the traditional method of capturing them has been anything but. For too long, paper-based PROs—laden with logistical and interpretative challenges—have stood as barriers to the dynamic flow of patient-centric data. Using technology to capture PROs can reduce or eliminate many of these barriers.

The Advantages of ePROs versus Paper-Based PROs

• Data capture anywhere, anytime: ePRO systems streamline the data collection process, providing a simple and efficient method for patients to report outcomes. Often, a participant can use their own smartphone or tablet to complete ePRO questionnaires. This allows patients to report symptoms as they occur and from anywhere, increasing accuracy and reducing recall bias, which is common with traditional PROMs data collection.  
• Enhanced patient compliance: The convenience of ePRO technology supports higher compliance rates among patients. Devices such as smartphones or tablets can facilitate regular and timely entries, integrating seamlessly into the daily lives of patients. In addition, notifications can be sent directly to participants’ devices, reminding them to complete ePRO tasks.
• Data accuracy and reliability: ePRO platforms ensure greater accuracy of data. With built-in validation checks and time-stamped entries, these systems minimize errors and inconsistencies that can occur with manual paper entries.
• Increased patient safety: The use of electronic platforms allows for informed intervention strategies through real-time data monitoring. ePRO gives researchers and practitioners visibility into patients’ experiences and health status between visits. This has immense implications for patient safety and outcome efficacy. For example, if a patient reports severe symptoms through ePROs, the clinical team can be automatically alerted and intervene promptly.
• Reduced administrative burden: ePROs eliminate the need for the manual data entry required with paper questionnaires, streamlining the workflows of research staff. For sites that do both research and clinical practice, this is particularly important: Less paperwork means more time and effort that can be dedicated to supporting patients.
• Cost-effectiveness: An obvious, but important, consequence of reduced administrative burden is increased cost efficiency. The costs associated with conducting a traditional clinical trial are exorbitant. ePROs are an attractive solution for managing those costs, especially for smaller research teams.

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ePRO and the FDA

We know regulatory agencies support PROs, but how do they feel about ePROs? Despite the many advantages of ePROs, some researchers still hesitate to incorporate them, concerned that regulatory agencies won’t accept the electronic format. In recent years, the FDA has distributed guidance that proves otherwise.  

Very little is mentioned about a preferred mode of PRO administration in the FDA’s most recent PFDD guidance.⁵ Yet, the language and themes of the documents strongly favor digital data capture when applicable. For example, the FDA encourages researchers take action to reduce respondent burden when it comes to capturing clinical outcome assessments (of which ePRO is a subset).⁷ Electronic formats are known to be more convenient for trial participants.  

In addition, the FDA has released guidance that supports the use of digital health technologies (DHTs) such as mobile apps to capture outcomes, including ePROs.⁸ With this guidance, the agency acknowledged that DHTs can improve the quality and efficiency of data collection, providing real-time, high-quality data directly from patients.  
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Considerations for Successful ePatient-Reported Outcome Measurement in a Clinical Trial

While ePROs offer advantages to patient-centric research, there are many considerations that must be taken into account when implementing this technology in a clinical trial.  

Digital literacy: Ensuring that patients from different backgrounds have the necessary skills to effectively use electronic patient-reported outcome systems can sometimes be a challenge. Providing support and training to improve digital literacy is crucial for successful implementation.

Technical issues: As with any electronic system, technical issues may arise that can disrupt data collection and cause delays in the trial. Proper testing and troubleshooting processes should be put in place to minimize these challenges. ePRO technologies should also have offline functionality—meaning participants can still capture data when there is no internet connectivity.  

Financial considerations: Computers, smartphones, and tablets have proliferated our society. However, it’s important for trial sponsors to consider those who may not own any of these devices and those who may have very outdated devices. A solution to this challenge could be to provide provisioned devices to participants, with the ePRO software downloaded onto the device.

Culture and language: It is imperative that ePROs be translated but also adapted, culturally and linguistically, for the populations who will use them. This ensures the ePROs are relevant, accessible, and genuinely reflective of diverse patient experiences and backgrounds.

Accessibility for all: We must ensure ePRO platforms are optimized for those with disabilities. Enabling universal access through adaptive technologies and user-friendly interfaces supports equitable healthcare.

Technological integration and interoperability: Integrating ePRO systems with existing healthcare technologies and ensuring the seamless transfer of data across the healthcare continuum are essential. With technology integrations, electronic health records and ePRO systems can work together. Finding interoperable systems is key to unlocking siloed patient insights and longitudinal health records for more better patient care.  

The benefits of ePRO far outweigh any of the above challenges. With a strong study design and plan, these roadblocks can be anticipated and mitigated.  

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The Latest ePRO Innovations in Measuring Patient and Public Involvement

A new wave of technological advancements is set to transform how patient data is collected, analyzed, and utilized in clinical trials—and healthcare at large. These innovations promise to make ePRO tools more intuitive, engaging, and integrated into patients' lives, enhancing the accuracy and richness of the data collected. Below, we delve into some of the most promising areas of innovation for ePRO technologies.

‍Artificial intelligence (AI): The integration of AI into ePRO systems will change the way patient data is processed and interpreted. By leveraging machine learning algorithms, ePRO platforms can automatically analyze patient responses for insights into treatment efficacy, symptom patterns, and quality of life. This technology enables real-time data analysis, facilitating quicker adjustments to treatment plans and more personalized patient care. Moreover, AI can identify subtleties and trends in the data that may be invisible to human analysts, offering a deeper understanding of patient experiences.

An application of AI, natural language processing (NLP) can help to interpret the nuances and complexities of language within an ePRO response. NLP technology is used to analyze free-text responses from patients, allowing for the extraction of meaningful insights from qualitative data. This can enrich the quantitative data collected through structured questionnaires, providing a more comprehensive view of the patient experience.

‍Voice recognition: “Hey, Siri. Add milk to my grocery list.” Speaking with virtual assistants has become commonplace for many, whether it’s Apple’s Siri, Amazon’s Alexa, or Google Assistant. This same voice recognition technology can be used to help make ePRO systems more accessible and user-friendly.

Patients can simply speak their responses into their devices, making it easier for individuals with visual impairments, physical disabilities, or limited tech-savviness to participate in reporting. This technology can also capture more nuanced patient feedback, as the tone and inflection of voice may convey additional information about the patient's condition and well-being. As voice recognition technology continues to advance, we anticipate even greater accuracy and ease of use, further improving patient engagement and data quality.

Virtual reality (VR): VR technology is beginning to make its mark on ePRO collection by creating immersive environments in which patients can report their experiences. This can be particularly useful in assessing and managing mental health conditions, chronic pain, or rehabilitation progress. VR can simulate real-world scenarios or therapeutic settings, providing researchers with a rich, contextual understanding of patient experiences. Additionally, VR's interactive nature can make the reporting process more engaging, potentially increasing compliance and the depth of information provided by participants.

Gamification: Incorporating game design elements into ePRO tools is a novel approach that boosts patient engagement and compliance. By transforming routine reporting tasks into challenges or competitions, patients are more likely to consistently participate and provide accurate data. Gamification strategies—including earning rewards, reaching levels, or social-sharing features—tap into human motivations, making the data collection process enjoyable and rewarding. This approach not only enhances the quality and quantity of data collected but also improves patient satisfaction with the research process.

Wearable devices: Wearable technology continues to advance rapidly, offering unprecedented opportunities for passive and continuous data collection. These devices can monitor a wide range of physiological and activity data, such as heart rate, sleep patterns, exercise, and more. When integrated with ePRO systems, wearable devices provide a comprehensive picture of a patient's health and lifestyle, enriching self-reported data with objective measures. This combination of qualitative and quantitative data offers a holistic view of patient well-being, enabling more nuanced analysis and personalized care.

Acoustic biomarkers: When you put some of these technologies together, the result is transformative. For example, the use of artificial intelligence and voice recognition can capture and analyze “acoustic biomarkers” such as cough and other respiratory sounds. An app on a smartphone can listen in and capture the sounds; then, artificial intelligence analyzes the data to determine what type of cough or sound it is. For example, researchers in Kenya analyzed about 33,000 spontaneous coughs and 1,200 forced coughs from 149 people with tuberculosis and 46 people with other respiratory conditions; the technology was able to identify tuberculosis coughs 70 percent of the time.⁹  

This approach could revolutionize ePRO by enabling non-invasive, real-time monitoring of patients' health conditions through acoustic biomarkers, making clinical trials more efficient and patient friendly. It showcases a future where patient experiences and symptoms are monitored continuously and accurately, enhancing the quality and reliability of clinical data.

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The Path Ahead: Embracing PROs for Patient-Centric Trials

The path ahead is clear. By harnessing the power of PROs, we prioritize each patient's voice, focusing not only on approving treatments for their clinical efficacy but also the quality of life they provide to patients.  

By using technology to capture patient-reported outcomes, we’re making PROs easier, more empathetic, and more accurate. This is not just a win for the patients; it's a win for clinical research, healthcare providers, and regulatory agencies alike—and an essential component of truly patient-centric clinical trials.  

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References

1. Mercieca-Bebber R, King MT, Calvert MJ, Stockler MR, Friedlander M. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. 2018;9:353-367. doi: 10.2147/prom.s156279

2. FDA. Focus Area: Patient-Reported Outcomes and other Clinical Outcome Assessments. FDA.gov. September 2022. Accessed March 7,2024. https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-patient-reported-outcomes-and-other-clinical-outcome-assessments

3. NCI. patient-reported outcome. Cancer.gov. 2023. Accessed March 7,2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/patient-reported-outcome  

4. Heneghan C, Goldacre B, Mahtani KR. Why clinical trial outcomes fail to translate into benefits for patients. Trials. 2017;18(1). doi: 10.1186/s13063-017-1870-2

5. FDA. FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making. FDA.gov. April 2023. Accessed March 8, 2023. https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical    

6. Cruz Rivera S, McMullan C, Jones L, Kyte D, Slade A, Calvert M. The impact of patient-reported outcome data from clinical trials: perspectives from international stakeholders. J Patient Rep Outcomes. 2020;4(1). doi: 10.1186/s41687-020-00219-4

https://jpro.springeropen.com/articles/10.1186/s41687-020-00219-4

7. CDER. Patient-Focused Drug Development: Methods to Identify What Is Important to Patients. FDA. June 2022. Accessed March 8, 2024. https://www.fda.gov/media/159500/download    

8. FDA. Digital Health Technologies (DHTs) for Drug Development. FDA.gov. December 2023. Accessed March 8, 2023. https://www.fda.gov/science-research/science-and-research-special-topics/digital-health-technologies-dhts-drug-development  

9. Sharma M, Videlis Nduba, Njagi LN, et al. TBscreen: A passive cough classifier for tuberculosis screening with a controlled dataset. Sci Adv. 2024;10(1). doi: 10.1126/sciadv.adi0282

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