The End of the “PRO Tax”: Top 10 Commercial PROs & their cost-effective alternatives

The End of the “PRO Tax”: Top 10 Commercial PROs & their cost-effective alternatives

A pragmatic blueprint for enterprise pharma to modernize eCOA strategies, selecting more cost-effective and modern instruments and leveraging regulatory shifts.

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Executive Summary: The 2025 Inflection Point

For decades, the clinical trial ecosystem has defaulted to high-fee, legacy Patient-Reported Outcomes (PROs). This reliance imposes a significant “PRO Tax”—not just in licensing costs, but in persistent operational delays, extended study startup timelines, and reduced R&D productivity. As we navigate the latter half of 2025, this model is no longer scientifically necessary or operationally sustainable.

The landscape has fundamentally shifted. ICH E6(R3) reached Step 4 in January 2025, mandating enhanced data governance, proportionate risk management, and Quality by Design (QbD).[1] Simultaneously, the FDA’s Patient-Focused Drug Development (PFDD) guidance has matured, emphasizing that regulators prioritize “fit-for-purpose” measurement over instrument brand names.[2] The regulatory risk is rapidly shifting from which instrument you use to how you implement, validate, and govern it within the specific Context of Use (COU).

Regulatory Modernization

ICH E6(R3) and FDA PFDD guidance prioritize fit-for-purpose validation (centered on Context of Use) and QbD over adherence to legacy commercial instruments.

Efficiency and Rigor

Modern instruments (e.g., PROMIS) offer strong psychometric properties, reduced patient burden, and efficient licensing structures, supported by mature migration methodologies.[3]

Agentic AI assistance

AI systems will support complex eCOA tasks —selection, licensing, migration— guided by the FDA’s 2025 AI risk-based credibility framework.[4]

Operational Imperative

Budget pressures and the need for faster time-to-site demand a re-evaluation of licensing friction and operational inertia.

This white paper provides a data-driven analysis of the most-used commercial PROs versus viable, operationally efficient alternatives, outlines a regulatory-aligned framework for migration (including bridging strategies).

The eCOA Landscape in 2025: Regulatory Modernization Meets Operational Inertia

The regulatory environment has evolved significantly, yet operational practices often lag, clinging to outdated risk perceptions.

ICH E6(R3) is Here: The New Demands on Data Governance

The adoption of ICH E6(R3) (Step 4, January 2025) marks a pivotal shift from retrospective documentation to proactive Quality by Design (QbD) and risk-based proportionality across the clinical trial lifecycle.[1] For eCOA stakeholders, the implications are profound. E6(R3) demands stringent data governance, emphasizing the integrity, traceability, and reliability of electronic records.

This elevates the importance of sponsor accountability for vendor technology and the quality of the data capture process. E6(R3) and FDA Part 11 Q&A require validated electronic systems with time-stamped audit trails, controlled access, and reliable certified copies. It is crucial to use unambiguous timestamps (date, time, and timezone/offset); harmonization to UTC is considered a best practice, not a mandate.

The Persistent Bottlenecks: Why Study Starts Are Still Delayed

Despite technological advancements, the industry continues to experience persistent delays in eCOA deployment. A primary driver of this stagnation is not the technology itself, but the friction inherent in the traditional eCOA management process:

  • Licensing Friction: Negotiating with decentralized copyright holders for commercial instruments remains a critical path item. Variability in response times and complex per-study agreements frequently delay trial starts. It is crucial to note that use of validated COAs for commercial trials virtually always involves licensing with the copyright holder and additional fees.
  • Translation and Linguistic Validation: The treadmill of translating and culturally validating legacy instruments adds significant time and cost.
  • Operational Inertia: Clinical teams often default to familiar instruments (e.g., SF-36, EQ-5D) due to historical precedent and a misperception of lower regulatory risk, despite the availability of scientifically rigorous alternatives.

The "Fit-for-Purpose" Doctrine (FDA)

It is critical to deconstruct the myth that the FDA prefers specific commercial instruments. The FDA’s PFDD series (e.g., Guidance 3: Selecting, Developing, or Modifying Fit-for-Purpose COAs) and the 2009 PRO Guidance consistently emphasize that regulators evaluate the validation of an instrument for the specific Concept of Interest (COI) and Context of Use (COU).[2] There is no universal validation; the evaluation is based on whether the instrument reliably measures what it claims to measure in the target population. This doctrine provides the foundation for justifying instrument replacement with strong rationale.

The Economic and Operational Case for Efficient Alternatives

A data-driven comparison reveals that modern alternatives often provide comparable measurement properties and significant operational advantages.

When evaluating alternatives to entrenched PROs, it is crucial to understand the total cost of ownership in an electronic Clinical Outcome Assessment (eCOA) context. While many modern instruments developed by academic consortia (e.g., PROMIS, RAND-36) may be low-cost or royalty-free for individual research/clinical use, electronic implementation for commercial trials often involves costs, such as platform fees or specific licensing requirements.[3]

The advantage of these modern alternatives lies in their operational efficiency: streamlined licensing processes, faster implementation times, and often lower overall cost compared to legacy instruments. Furthermore, many modern alternatives offer robust psychometric properties, CAT availability (where applicable), and reduced patient burden.

The Comparison Matrix: Top 10 Commercial PROs vs. Efficient Alternatives

The following analysis compares the most widely used commercial PRO instruments with viable, operationally efficient alternatives, assessing the regulatory risk of switching. A risk-based, COU-anchored migration and bridging plan (per ISPOR/C-Path) is assumed for all substitutions.[5]

Commercial
PRO (Domain)		Usage Band & EvidenceEfficient Alternative(s)eCOA Licensing Notes (Commercial Use)FDA/Regulatory Risk if Switching
EQ-5D-5L
(Generic Utility)		Very High. Foundational to HEOR; widely collected in RCTs.[6]PROMIS Global (HRQoL); PROMIS PROPr (Utility).EuroQol: Response target ~2 business days.[7] Fees apply. PROMIS: Streamlined licensing; platform/API fees may apply.Moderate. HTA bodies (e.g., NICE) often prefer EQ-5D. Keep EQ-5D or implement dual-capture with PROPr for pivotal programs; provide mapping justification.[8]
SF-36/SF-12
 (Generic HRQoL)		High. Among most used generic HRQoL instruments.RAND-36, PROMIS Global/Domain banks.SF-36v2 requires Optum licensing. RAND-36 is free.[9] PROMIS: Streamlined licensing.Low. RAND-36 content is equivalent. Map concepts; ensure faithful migration and mode equivalence.
EORTC
QLQ-C30
(Oncology HRQoL)		Very High (Oncology). Strong precedent; e.g., frequent use in ICI trials.[10]PROMIS Cancer domains (as add-ons).EORTC outlines permission/licensing processes; no official processing timeline is posted. PROMIS: Streamlined licensing.High for outright replacement. Keep QLQ-C30 as primary through bridging phase; add PROMIS for RWE continuity and analytic sensitivity.
FACIT-Fatigue / FACIT-G
(Fatigue & Cancer HRQoL)		High. Widely used across various conditions.PROMIS Fatigue, domain short forms.FACIT requires licensing for commercial trials.[11] PROMIS: Streamlined licensing.Low–Moderate. PROMIS Fatigue has strong validity; bridge for labeling continuity; defend via concept/score linkage and MID evidence.
WOMAC
(OA symptoms / function)		High. Commonly cited as the most used OA instrument.KOOS/HOOS and KOOS-JR/HOOS-JR.WOMAC licensing terms vary. KOOS/HOOS typically free or streamlined licensing.[12]Low-Moderate. KOOS/HOOS incorporate WOMAC content; show mapping and prespecify responder definitions.
SGRQ / SGRQ-C (COPD respiratory status)High. FDA has dedicated guidance on SGRQ for COPD trials.[13]CAT (COPD Assessment Test); E-RS: COPD.SGUL: Commercial per-patient, per-study fees for SGRQ.[14] CAT/E-RS licensing varies.Moderate–High for replacement. SGRQ preferred for HRQoL endpoints tied to precedent. CAT/E-RS (FDA-qualified COA) can be supportive or complementary.
BPI
(Pain intensity & interference)		High. MD Anderson short form used in trials.PROMIS Pain Interference (PI); PEG-3 (3-item).MD Anderson: License agreement; fees (incl. ~$200 processing fee).[15] PROMIS/PEG-3: Streamlined licensing.Low–Moderate. PEG-3 derived from BPI. If BPI used for labeling historically, co-administer for bridging; otherwise PROMIS PI/PEG-3 are fit-for-purpose.[16]
PedsQL
(Pediatric HRQoL)		High pediatric adoption.PROMIS Pediatric / Parent Proxy banks.PedsQL licensed for funded/commercial use via Mapi.[17] PROMIS Pediatric: Streamlined licensing.Moderate if switching mid-program; Low for new programs with COU fit. PROMIS covers core domains; PedsQL has extensive modules.
HADS (Anxiety / Depression)High cross-setting use.PHQ-9 (depression), GAD-7 (anxiety).HADS requires license (GL Assessment/Mapi).[18] PHQ-9/GAD-7 are widely endorsed/free to use.[19]Low (screening/monitoring contexts). Alternatives are well validated; ensure construct intent matches COU.
HAQ-DI
 (Rheumatology function)		High. Dominant instrument in RA trials.PROMIS Physical Function (PF).HAQ-DI licensing coordinated via Mapi Research Trust (ePROVIDE) for commercial/funded use.[20] PROMIS PF: Streamlined licensing.Low–Moderate. Cross-walks/linking between HAQ-DI and PROMIS PF exist. Use PROMIS PF with linkage or dual-collection during transition.

Exhibit: Licensing Cycle-Time Levers

The operational impact of the “PRO Tax” is evident in the licensing timelines and processes required by instrument owners.

  • EQ-5D (EuroQol): Incoming request response target ~2 business days (negotiation time separate).[7]
  • EORTC QLQ-C30: EORTC outlines permission/licensing processes; no official processing timeline is publicly posted.
  • SGRQ (SGUL): Timeline highly dependent on negotiation for per-patient, per-study fees.[14]
  • BPI (MD Anderson): License agreement required; processing fee (~$200) noted in addition to licensing fees.[15]
  • PROMIS (and similar): Streamlined electronic licensing agreements; implementation timeline primarily dependent on platform configuration rather than lengthy license negotiation.[3]

Managing these variable SLAs is a significant operational burden that delays study startup.

Addressing Adoption Hesitancy: The Comparability Challenge

The primary barrier to adopting efficient alternatives is the concern regarding comparability with historical data and established Health Economic and Outcomes Research (HEOR) models. This is particularly acute for utility values derived from EQ-5D, which are often preferred by Health Technology Assessment (HTA) bodies (e.g., NICE).[8]

However, the science of measurement linkage has matured significantly. Methodologies for cross-walks, linking (e.g., IRT), and bridging studies are now robust and well-documented (e.g., comparisons between EQ-5D and PROMIS PROPr). When replacing legacy PROs—especially those critical for HTA submissions—sponsors must implement dual-capture or a robust mapping strategy in pivotal programs to preserve trend interpretability and de-risk the transition.

Risk Mitigation: A Blueprint for Instrument Migration

A playbook for switching instruments without regulatory pushback, aligned with current best practices.

Switching from entrenched instruments to modernized alternatives is feasible when sponsors adhere to a structured, evidence-based approach. Regulators accept alternatives when COU, content validity, and measurement properties are demonstrated for that context; otherwise, the legacy measure should be maintained as primary or co-administered for bridging.

For substitutions, sponsors must follow ISPOR/C-Path best practices for faithful migration. When content or context changes are non-trivial, cognitive interviews/usability testing should be added, and targeted comparability testing conducted. It is strongly advised to co-administer legacy and candidate measures during at least one phase to bridge time series and ensure continuity.[5]

The 4 Pillars of Safe Migration

  1. Context-of-Use (COU) Justification: The foundation of any migration strategy is a robust “Evidence Dossier” aligned with FDA PFDD requirements (e.g., Guidance 3).[2] This must specify the concept of interest, target population, visit schedule, and endpoint construction. The justification must demonstrate that the new instrument is fit-for-purpose in the specific COU.
  2. Comparability and Bridging: To preserve trend interpretability, sponsors must determine the appropriate linkage strategy. This involves deciding between utilizing published cross-measure comparisons or implementing dual-collection (the “co-administer → bridge → replace if justified” pathway). If the legacy measure is a historical endpoint (e.g., QLQ-C30, SGRQ), co-administration is essential, with pre-specified linking (e.g., IRT or regression) if needed.
  3. eCOA Mode Equivalence (Faithful Migration): When migrating from paper or between electronic platforms, adherence to ISPOR 2023 Good Practices is essential.[5] The evidence required depends on the magnitude of the change:
    • Faithful Migration (Minimal Changes): If migration is faithful and content unchanged, extensive quantitative equivalence studies are often unnecessary; rigorous usability testing suffices.
    • Non-Trivial Changes: When content or context changes are non-trivial, cognitive interviews and usability testing must be added, and targeted comparability testing may be required.
  4. Endpoint Re-specification and Early Engagement: Sponsors must check the COA Compendium for precedents and engage early with the relevant FDA review division and HTA bodies. Proactive discussion regarding the migration strategy and any necessary re-specification of endpoints is crucial for alignment.

Case Vignettes: Successful Migration Strategies

  • Pain: Migrating from BPI to PROMIS Pain Interference (+ PEG-3 for burden minimization). Justification relies on strong MID and responsiveness evidence for PROMIS PI and the derivative nature of PEG-3.[16] Bridging recommended if BPI was used for prior labeling.
  • Osteoarthritis (OA): Switching from WOMAC to KOOS/HOOS. This is low-risk as KOOS/HOOS incorporate WOMAC items; the focus is on demonstrating content mapping and preserving responder thresholds.[12]
  • Oncology (The Hybrid Model): Recognizing the strong precedent, keeping EORTC QLQ-C30 for primary labeling claims while adding PROMIS domains (e.g., Fatigue, Physical Function) for deeper symptom analysis, reduced burden, and RWE continuity.[10] Outright replacement requires extensive bridging.

Conclusion: The Mandate for Intelligent Management

In October 2025, instrument selection is no longer just a scientific choice; it is an operational and economic imperative. The “PRO Tax” imposed by legacy instruments—in terms of licensing costs, delayed study starts, and operational friction—is unsustainable amid current R&D productivity pressures.

The regulatory landscape, defined by ICH E6(R3) and the FDA’s fit-for-purpose doctrine, actively supports the adoption of validated, modern alternatives, provided a robust bridging strategy is implemented where precedent matters. Adhering to legacy instruments due to outdated risk perceptions is increasingly viewed not as conservative, but as operationally negligent.

Achieving the agility required in modern clinical development demands a dual strategy: embracing scientifically rigorous, efficient alternatives and leveraging Agentic AI to manage complexity, reduce cycle times, and ensure compliance with new global standards. The era of intelligent instrument management is here.

The Castor Narrative: Accelerating eCOA Deployment

The strategies outlined in this white paper—intelligent instrument selection, managing licensing friction, and ensuring compliant migration—require a flexible, integrated infrastructure. Castor’s eCOA platform is designed to address the operational bottlenecks that create the “PRO Tax,” enabling faster deployment and the robust data governance required in the post-E6(R3) era.

How Castor Streamlines eCOA Execution

Rapid, Flexible Deployment

Castor addresses the persistent delays in eCOA implementation. By leveraging a comprehensive library of 120+ validated instruments (including EQ-5D-5L, EORTC, FACIT, PHQ9) and low/no-code tools, we enable rapid deployment, averaging 4-8 weeks. This flexibility allows sponsors to adapt questionnaires quickly as new requirements emerge.

Full-Service Instrument Management

Castor facilitates the adoption of efficient instrument strategies through full operational support. Our services include managing scale licensing (leveraging strong relationships with copyright holders), validated translations (80+ languages), and device provisioning if needed. This comprehensive approach minimizes the operational friction of the “PRO Tax.”

Unified Data Governance (E6(R3) Alignment)

Castor provides a unified platform natively integrating eCOA/ePRO with EDC and eConsent. This ensures a single source of truth (one login, one database, one audit trail), robust traceability, and the stringent data integrity required by ICH E6(R3). The platform is fully compliant with 21 CFR Part 11, GDPR, and HIPAA.

Optimized Patient and Site Experience

To maximize data quality (averaging >95% compliance), Castor prioritizes usability—ranked 1st for user friendliness (ISR eCOA/ePRO Benchmarking Report). Our patient-friendly BYOD (Bring Your Own Device) approach (web or app) reduces participant burden. We reduce site burden through simplified interfaces and a dedicated 24/7 multilingual global help desk.

By focusing on speed, integrated data governance, and comprehensive support, Castor empowers enterprise pharma to move beyond the “PRO Tax” and embrace a more efficient, compliant future for eCOA.

References

  1. ICH Harmonised Guideline E6(R3). Good Clinical Practice (GCP). Step 4 (January 2025). ICH.org.
  2. U.S. Food and Drug Administration. Patient-Focused Drug Development (PFDD) Guidance Series (e.g., Guidance 3: Selecting, Developing, or Modifying Fit-for-Purpose COAs, 2022); 2009 PRO Guidance. FDA.gov.
  3. Healthmeasures.net. PROMIS (Patient-Reported Outcomes Measurement Information System) Overview and Licensing. (Accessed Oct 2025). (Note: Licensing terms and platform fees may apply for commercial electronic implementation).
  4. FDA. (2025, January). Draft Guidance: Considerations for the Use of Artificial Intelligence To Support Regulatory Decision-Making for Drug and Biological Products. FDA.gov.
  5. ISPOR 2023 Good Practices for migration (faithful migration, cognitive interview, usability); C-Path migration guide. Value in Health / jscdm.org.
  6. Value in Health. Systematic review of RCTs using EQ-5D. (ISPOR.org).
  7. EuroQol. Posted licensing response target (2 business days). EuroQol.org.
  8. RTI Health Solutions. Considerations regarding HTA preferences for utility measures (e.g., NICE preference for EQ-5D). rtihs.org.
  9. RAND Corporation. RAND-36 vs SF-36v2 licensing (RAND-36 free vs SF-36v2 licensed by Optum).
  10. Annals of Oncology. Review of PRO instruments used in immune-checkpoint inhibitor clinical trials (frequent QLQ-C30 usage).
  11. FACIT Group. Licensing pages for commercial trials. FACIT.org.
  12. JOSPT/PubMed. KOOS/HOOS incorporate WOMAC items.
  13. U.S. Food and Drug Administration. Guidance on SGRQ use in COPD trials; E-RS qualification. FDA.gov.
  14. City St George’s, University of London. SGUL licensing pages (SGRQ).
  15. MD Anderson Cancer Center. Brief Pain Inventory (BPI) usage and licensing information (including processing fee note). MDAnderson.org.
  16. J Pain / PubMed / IU Indianapolis ScholarWorks. MIDs for PROMIS PI; PEG-3 development/validation (derived from BPI).
  17. PedsQL.org. Licensing for funded/commercial use via Mapi.
  18. ePROVIDE – Mapi Research Trust / GL Assessment. HADS licensing.
  19. Pfizer. PHQ-9/GAD-7 availability and validation.
  20. ePROVIDE – Mapi Research Trust. HAQ-DI licensing coordination.

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