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The Evolution of PRO Collection: From Paper Diaries to ePRO Systems

Executive Summary

PROs are defined as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation by a clinician or anyone else.” These outcomes offer a unique and essential perspective on how patients experience their condition and treatment.PROs encompass:

  • Symptoms and side effects(e.g., pain, fatigue, nausea, or anxiety)
  • Functional outcomes including physical, emotional, social, sexual, role-based, and cognitive functioning
  • Multidimensional constructs such as health-related quality of life (HRQoL) and health utility (Mercieca-Bebber et al., 2018)

Unlike traditional clinical endpoints such as laboratory results or imaging, PROs capture the subjective impact of disease and treatment on a patient’s daily life.

Limitations of Paper-Based PROs

Historically, PRO data were collected using paper diaries and questionnaires. While simple, paper-based methods have significant drawbacks:

  • Recall bias: Patients often backfill entries, compromising accuracy.
  • Low compliance: Manual diaries lack reminders or time-stamps, with adherence rates as low as 30%.
  • Data integrity issues: Handwriting errors, skipped questions, and transcription mistakes reduce reliability.
  • Delayed insights and operational burden: Manual collection, entry, and verification slow decision-making and increase cost.
The Transition to ePRO

Electronic PRO (ePRO) systems have transformed data collection by enabling real-time, accurate, and scalable capture of patient-reported information. Key advantages include:

  • Improved data quality: Automated validation reduces errors, ensures completeness, and enforces protocol compliance.
  • Higher patient engagement: Mobile access, automated reminders, and intuitive interfaces increase adherence.
  • Faster access and decision-making: Real-time dashboards allow early detection of adverse events and efficient trial management.
  • Regulatory compliance: Systems meet global standards (21 CFR Part 11, GCP) with audit trails, electronic signatures, and standardized data formats.
  • Operational efficiency: Reduced manual tasks lower costs, and cloud-based platforms support global scalability.
  • Enhanced patient safety and sustainability: Real-time symptom monitoring enables timely clinical intervention, while eliminating paper supports eco-friendly trials.

The Era of Paper Diaries: A Starting Point with Limitations

Early clinical research relied on paper diaries and questionnaires to capture PROs. While simple and accessible, these methods struggled as trials became larger, more complex, and geographically diverse. Paper diaries could not meet the growing need for real-time, high-quality, and scalable data collection, highlighting the need for more efficient, reliable, and patient-friendly solutions.

Key Challenges of Paper-Based PRO Collection
  1. Recall Bias
    Patients frequently completed diary entries retrospectively, leading to significant recall bias. Stone et al. (BMJ 2002) found only 11% of entries were on-time despite 90% self-reported accuracy.This practice “backfilling,” compromises data reliability.
  2. Compliance Monitoring
    Lack of automated reminders or time-stamps made adherence hard to track. A notable issue, often referred to as “parking lot syndrome,” involved patients completing multiple diary entries just before a site visit (Bingham et al., 2019). Compliance rates with paper PROs have been reported as low as 30%, compared to 90-97% with ePROs (José and Langel, 2010).
  3. Data Integrity Issues
    Handwritten responses were susceptible to transcription errors, illegibility, incomplete entries, and logical inconsistencies. Complex assessments often led to skipped questions or misinterpreted branching logic. Lack of time-stamps permits falsification (Coons et al., 2015).
  4. Delayed Insights
    Manual processes such as distributing, collecting, and transcribing paper diaries delays data availability. These inefficiencies hindered timely decision-making and could potentially compromise patient safety or trial outcomes.
  5. Time-Consuming Processes
    Paper-based data collection is labor-intensive. Study staff had to prepare, distribute, and manually enter data, while also managing missing or inconsistent entries(Weber et al., 2005).
  6. High Setup and Storage Costs
    Maintaining both physical and digital records to meet audit and compliance requirements increase complexity and cost. Scanning, archiving and storage inflate budgets (Meirte et al., 2020; Mercieca-Bebber et al., 2018).
  7. Logistical Risks
    Paper diaries completed at home had to be mailed back to study sites, introducing risks such as loss, delays, or non-return of critical data (Mercieca-Bebber et al., 2018).
    These limitations drove adoption of electronic solutions that improve integrity, engagement and compliance.

Transition to Digital: The Emergence of ePRO Systems

The adoption of electronic patient-reported outcome (ePRO) systems transformed clinical trial data collection. Initially deployed on handheld devices, ePRO now spans smartphones, tablets, and web platforms, eliminating the limitations of paper while enhancing quality, compliance, and efficiency. As trials became more complex, global, and patient-centric, ePRO emerged as an essential tool for accurate, timely, and scalable data capture, accepted across all trial phases, including post-marketing.

Emergence of ePRO Systems
Why ePRO Outperforms Paper

A. Real-Time Data Capture and Reduced Recall Bias

ePRO enables patients to record symptoms at the moment they occur. This eliminates retrospective “back-filling” and significantly reduces recall bias. Automatic time-stamping ensures temporal accuracy, enhancing the reliability of patient-reported data.

B. Enhanced Data Quality and Accuracy

ePRO systems eliminate common errors associated with paper-based methods, such as:

  • Illegible handwriting
  • Missed fields
  • Transcription errors
  • Skip pattern inconsistencies

Built-in validation logic, edit checks, and data consistency rules ensure that entries are complete, accurate, and protocol-compliant(Coons et al., 2015).

C. Improved Patient Compliance and Engagement

ePRO boosts adherence via:

  • Automated reminders and alerts
  • Mobile compatibility for personal devices
  • Intuitive survey navigation

These tools reduce patient burden and improve engagement. Studies consistently report higher compliance rates with ePRO (Kiderlen et al., 2023). Push notifications, texts or calls remind patients automatically.

D. Faster Access to Data and Better Decision-Making

Real-time data access allows sponsors and CROs to:

  • Identify trends or adverse events promptly
  • Intervene clinically when needed
  • Adjust trial protocols efficiently

Automation accelerates database lock and interim analyses. Basch et al. (2016)demonstrated that real-time symptom monitoring via ePROs significantly improved overall survival and quality of life for cancer patients. The system triggered email alerts to nurses for severe symptoms, enabling timely clinical interventions.

E. Regulatory Compliance and Data Traceability

ePRO systems are designed to meet global regulatory standards, offering:

  • Audit trails
  • Automated timestamps
  • Electronic signatures
  • Standardized data formats

These features ensure traceability and compliance with Good Clinical Practice (GCP) (Zbrozek et al., 2013; Hudgens et al., 2023).

F. Operational Efficiency and Cost Reduction

While ePRO implementation involves upfront investment, it significantly reduces:

  • Manual data entry and cleaning
  • Source data verification
  • Printing, storage, and shipping costs

By automating workflows and minimizing manual tasks, ePRO systems enhance operational efficiency and deliver long-term cost savings.

G. Improved Patient Safety

Real-time symptom reporting enables early detection of safety signals. Investigators can respond promptly to adverse events or deteriorating health, enhancing patient monitoring and clinical intervention. A 2025 meta-analysis of lung-cancer trials found ePRO alerts improved HRQoL (Xia et al.).Clinicians can intervene during critical windows, extending survival.

Improved Patient Safety

Source: Mazza, G.L., Dueck, A.C., Ginos, B., Jansen, J., Deal, A.M., Carr, P., Blinder, V.S., Thanarajasingam, G., Jonsson, M., Lee, M.K. and Rogak, L.J., 2024. Optimization of alert notifications in electronic patient-reported outcome (ePRO) remote symptom monitoring systems (AFT-39). Quality of Life Research, 33(7), pp.1985-1995.

H. Completeness and Timeliness of Data Collection

ePRO platforms ensure that all required fields are completed before submission. Features like logic-based question flows, built-in instructions, and automated prompts improve:

  • Data completeness
  • Timeliness
  • Monitoring efficiency

I. Environmentally Sustainable

By replacing paper-based methods, ePRO systems support eco-friendly trial operations. Digital workflows eliminate the need for printing, shipping, and physical storage, reducing waste and carbon footprint aligning with sustainability goals and digital transformation initiatives in life sciences(Pawar et al., 2017).

Comparison between paper-based PROs and Electronic PROs

Paper-Based PROs (pPROs) Electronic PROs (ePROs)
Data Collection Handwritten on printed forms Entered via electronic devices (phone, tablet, web etc.)
Data Accuracy & Quality Prone to human errors (e.g., handwriting, transcription), backfilling, and recall bias Real-time entry, edit checks and forced fields cut errors
Timeliness & Availability Data access is delayed due to manual handling and entry Real-time data capture and instant availability for analysis
Patient Compliance Lower compliance; dependent on memory and motivation Higher compliance with automated reminders and easier access
Monitoring & Oversight Limited or delayed oversight; real-time issues often go unnoticed Enables real-time remote monitoring and early intervention
Patient Experience Less convenient; patients must carry forms and remember timing More user-friendly; can use personal devices at any time
Accessibility & Inclusion More accessible for non-digital users; no internet or device needed May exclude users with low digital literacy or no device/internet access
Administrative Effort High; includes distribution, collection, transcription, and storage Reduced; automation minimizes manual work and errors
Cost Lower initial cost; higher over time due to labor and storage Higher set-up cost, lower total cost
Multilingual Requires separate forms per language Supports multiple languages in one system
Data Management & Reporting Manual entry, storage, and analysis; time-consuming Automated capture, storage, and real-time analytics and reporting
Scalability Limited scalability; resource-intensive for multi-site studies Highly scalable across regions, sites, and geographies
Implementation Considerations Familiar workflow; minimal tech needs but resistant to change Needs training, devices, connectivity

Regulatory Endorsement and Industry Standards

FDA and EMA guidance now recommend validated ePRO systems. Key considerations include:

  • 21 CFR Part 11 Compliance:Ensures requirements for electronic records and electronic signatures. Compliant systems provide audit trails, user authentication and data-integrity controls.” (eCFR, USFDA, 2025).
  • FDA PRO Guidance (2009): Provides direction for selecting, developing, and interpreting PRO tools in support of labelling claims. It emphasizes the need for validated instruments and encourages electronic collection methods to enhance data quality and traceability (PRO guidance, USFDA, 2009).
  • ISPOR and CDISC Standards:
    • ISPOR (International Society for Pharmacoeconomics and Outcomes Research): Provides best practices for PRO instrument development and validation, ensuring equivalence between paper and electronic modes and regulatory compliance (Coons et al., 2009; Zbrozek et al., 2013).
    • CDISC (Clinical Data Interchange Standards Consortium): Defines standardized models for ePRO data collection, analysis, and submission, improving traceability, interoperability, and audit-readiness(Hudgens et al., 2023).

The Modern ePRO Landscape

As clinical trials evolve toward decentralized, patient-centric, and technology-enabled models, ePRO systems have matured from simple digital diaries into comprehensive electronic Clinical Outcome Assessment (eCOA) platforms.

Key Innovations Driving Modern ePRO Systems

  1. Bring Your Own Device (BYOD)

    BYOD lets participants use their own phones or tablets.This approach:
    • Enhances patient convenience and familiarity
    • Improves engagement and compliance
    • Reduces hardware provisioning costs for sponsors
    BYOD is particularly beneficial in large-scale, global, or long-duration studies, where device deployment can be logistically challenging and expensive(Coons et al., 2015; Thukral et al., 2022).

  2. Wearable and Sensor Integration

    ePRO systems now integrate with wearables and remote sensors, combining subjective patient-reported data with objective physiological metrics such as heart rate, activity levels, sleep quality, or oxygen saturation.

    This fusion of real-world data (RWD) with PROs enhances the depth and clinical relevance of trial insights. The WEAR study showed this fusion clarifies RA disease activity (Stradford 2024).

  3. Multilingual and Cross-Cultural Support

    With the globalization of clinical trials, modern ePRO systems helps to ensure:
    • Linguistic and contextual appropriateness
    • Regulatory compliance for global submissions
    • Inclusivity across diverse patient populations
    Features like language selection, right-to-left text support, and localized formatting are now standard (Soto-Rey 2018 and Storck 2018).

  4. Cloud-Based Dashboards and Real-Time Analytics

    Advanced ePRO platforms utilize cloud technologies to deliver:
    • Real-time access to patient-reported data
    • Interactive dashboards for sponsors and sites
    • Risk-based monitoring tools to flag compliance issues, protocol deviations, or safety concerns
    Teams can respond to safety or compliance signals within hours, improving outcomes in oncology and immuno-oncology studies(Generalova et al., 2021; Dickson et al., 2024).

Navigating ePRO Implementation: Challenges and Mitigation Strategies

While ePRO systems offer substantial benefits in terms of data quality, patient centricity, and operational efficiency, their implementation presents a range of challenges. These span technical, operational, human, and regulatory domains, each requiring thoughtful planning, risk mitigation, and cross-functional collaboration to ensure successful deployment.

A. Patient Access and Digital Literacy

Challenges:

  • Device gap: many patients lack a smartphone or tablet. This may require sponsors to provision devices, adding logistical and financial complexity.
  • Digital Literacy: Older adults or patients from underserved communities may lack familiarity with mobile technology. Without proper onboarding, this can lead to non-compliance and compromised data quality.

Mitigation Strategies:

  • Provide pre-configured devices with support to ensure access and data quality.
  • Design intuitive user interfaces with simple navigation.
  • Provide multi lingual training materials (e.g., videos, guides).
  • Offer caregiver or site-level support when needed.
B. Technical and Logistical Complexity

Challenges:

  • Device Management: Provisioned models require procurement, distribution, maintenance, and replacement of devices, placing strain on site and sponsor resources.
  • Connectivity Issues: Inconsistent cellular or Wi-Fi coverage, especially in rural or remote areas, can delay data transmission or interrupt assessments.
  • System Support: Technical failures or software bugs must be resolved quickly to prevent data loss or patient dropout.

Mitigation Strategies:

  • Use centralized device logistics to streamline handling and reduce site burden.
  • Conduct site-level feasibility assessments for connectivity.
  • Use offline-capable systems that sync when connectivity is restored
  • Establish 24/7 technical support for patients and sites.
C. Data Security, Privacy, and Compliance

ePRO systems must comply with stringent data protection regulations, including, GDPR (EU), HIPAA and 21 CFR Part 11 (US).

Challenges:

  • Data breaches can erode patient trust and lead to legal consequences.
  • Non-compliance may result in regulatory findings or trial delays.

Mitigation Strategies:

  • Implement encryption, user authentication, and audit trails.
  • Ensure vendors follow documented validation and compliance protocols.
  • Conduct privacy impact assessments during planning.
D. System Validation and Regulatory Readiness

Before deployment, ePRO systems must be validated to demonstrate reliability, accuracy, and audit-readiness, especially for trials intended for regulatory submission.

Challenges:

  • Validation requires time, expertise, and alignment with sponsor Quality Management Systems (QMS).
  • User Acceptance Testing (UAT) must simulate real-world use scenarios.

Mitigation Strategies:

  • Engage experienced QA and IT teams for validation.
  • Use standardized validation templates and protocols.
  • Select vendors that can supply prior 483s or inspection success letters.
E. Cost and Resource Allocation

Challenges:

  • Upfront Investment: Licensing, device procurement (if not BYOD), staff training, translations, and infrastructure.
  • Ongoing Costs: Maintenance, upgrades, patient support, and data monitoring must be factored into long-term budgets.

Mitigation Strategies:

  • Model 3-year ROI: fewer queries, faster database lock, less SDV
  • Explore cost-saving options like BYOD or reusable device inventories.
  • Align internal stakeholders on budget early in the study design phase.
F. End-User Engagement and Acceptance

Challenges:

  • Staff Buy-In: Investigators and coordinators may resist workflow changes introduced by ePRO systems.
  • Patient Fatigue: Frequent or lengthy assessments can lead to disengagement and missing data.

Mitigation Strategies:

  • Set clear expectations with sites and stakeholders early.
  • Communicate the clinical and operational benefits of ePRO.
  • Incorporate visual progress tracking or feedback tools to motivate patients.

Proactive mitigation turns these barriers into competitive advantages and protects the patient experience.

Conclusion

The evolution from paper diaries to ePRO systems represents a critical advancement in patient-centric clinical research. By combining high-quality data capture, regulatory compliance, and patient engagement, ePRO technology strengthens trial integrity, operational efficiency, and clinical decision-making. Organizations adopting validated, user-friendly, and scalable ePRO solutions are better positioned to conduct inclusive, efficient, and impactful trials that truly reflect patient needs.

The transition from paper diaries to ePRO systems represents a significant advancement in clinical research. By enabling real-time data capture, improving compliance, and enhancing data quality, ePRO technology has reshaped how patient experiences are measured and understood. As trials become decentralized and patient-centric, ePRO systems are essential for ensuring data integrity, regulatory compliance, and meaningful patient engagement. Their seamless integration with modern technologies and global scalability makes them indispensable in today’s research landscape.

Organizations that invest in scalable, validated, and user-friendly ePRO solutions are better positioned to conduct high-quality, efficient, and inclusive clinical trials, ultimately accelerating the development of therapies that truly reflect patient needs and outcomes.

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