SPIRIT-PRO Extension

What it is

— The SPIRIT-PRO Extension (Standard Protocol Items: Recommendations for Interventional Trials — Patient-Reported Outcomes) is a consensus protocol guideline that sets out the minimum content a clinical trial protocol must include when one or more patient-reported outcomes (PROs) are designated as a primary or key secondary endpoint. Published in JAMA in 2018 (Calvert, Kyte, Mercieca-Bebber et al.) via a Delphi consensus of trialists, methodologists, PRO experts, regulators (FDA, EMA-adjacent), patients, and journal editors, it extends the parent SPIRIT 2013 Statement (Chan et al.) with 16 PRO-specific items — 11 new items plus 5 elaborations of existing SPIRIT items. It is maintained within the SPIRIT/CONSORT ecosystem and the PROTEUS Consortium (Patient-Reported Outcomes Tools: Engaging Users & Stakeholders), alongside its reporting-stage sibling CONSORT-PRO. SPIRIT-PRO governs the plan: what a trial commits to in advance about which PRO is measured, why, when, how, and how its data will be handled — so that PRO endpoints are pre-specified, defensible, and not retrofitted after unblinding. It is a reporting/protocol-content checklist, not a risk-of-bias instrument and not a quality score.

When to use

— Apply SPIRIT-PRO when you are writing or registering the protocol of an interventional trial in which a PRO is a primary or important secondary endpoint — health-related quality of life, symptom burden, functional status, treatment satisfaction, or other constructs reported directly by the patient. This is the correct guideline for a trial protocol manuscript, a registry record (ClinicalTrials.gov / EudraCT) PRO section, and the PRO methods underpinning a regulatory labeling claim or an HTA/payer submission that relies on trial-based PRO evidence. Decision rules for choosing the right family member: use SPIRIT-PRO for the interventional-trial protocol; use CONSORT-PRO to report the completed trial's PRO results; use the base SPIRIT 2013 when no PRO is a key endpoint; and use measurement-property standards such as COSMIN and ISOQOL to select and validate the instrument itself (SPIRIT-PRO assumes you cite, but does not adjudicate, the instrument's validation evidence). SPIRIT-PRO does not govern non-interventional or observational studies: a primary claims/EHR/registry PRO study is reported under STROBE/RECORD-PE, planned under HARPER or the ENCePP checklist, and (for a systematic review of PRO studies) registered under PRISMA-P.

What it requires

— The 16 items force pre-specification of the PRO design elements that otherwise drift: a clear PRO research hypothesis and the specific PRO concepts/domains measured (not just "quality of life" in the abstract); justification of the instrument chosen and its measurement properties in the target population; the PRO data-collection schedule (assessment time points, their rationale, and alignment with the clinical endpoints); the mode and setting of administration (paper, ePRO, interview) and steps to standardize it; who completes the PRO (patient vs proxy) and how proxy/assisted completion is handled; a pre-specified PRO-specific analysis plan including the handling of multiplicity across domains and time points, the estimand and how intercurrent events (death, treatment discontinuation, disease progression) are addressed for a self-reported outcome; an explicit plan for missing PRO data — expected mechanisms, minimization strategies, and the primary and sensitivity analytic approaches; and a plan for PRO data monitoring, management, and reporting (training, real-time completeness checks, dissemination to patients). For PRO endpoints the missing-data and intercurrent-event items carry unusual weight: PRO scores are not measured once the patient is too sick to respond or has died, so attrition is rarely missing-completely-at-random, and a credible protocol pre-commits to the estimand and to sensitivity analyses rather than defaulting to complete-case analysis.

When NOT to use — limitations and common misapplications

— SPIRIT-PRO is a reporting/protocol-content checklist; it is not a risk-of-bias instrument, not a quality score, and not a license to call a PRO endpoint valid. Concrete failure modes: (1) Wrong study type — applying SPIRIT-PRO to a non-interventional or observational PRO study (a claims-, EHR-, or registry-based PRO analysis); those use HARPER/ENCePP at the protocol stage and STROBE/RECORD-PE for reporting, never SPIRIT-PRO, because SPIRIT items assume randomized allocation, blinding, and trial assessment schedules that observational data lack. (2) Wrong family member — citing SPIRIT-PRO to report a completed trial (use CONSORT-PRO) or invoking it when no PRO is a key endpoint (use base SPIRIT). (3) Mistaking it for instrument validation — completing SPIRIT-PRO does not establish that the instrument is reliable, valid, or responsive in the population; that is the job of COSMIN/ISOQOL evidence the protocol must cite. (4) Checklist-as-theater — ticking 16 items while leaving the estimand, the multiplicity strategy, or the missing-PRO-data plan vague defeats the purpose; the value is the pre-specification, not the page count. (5) Treating completion as causal/unbiased proof — a fully SPIRIT-PRO-compliant protocol can still produce biased PRO estimates if attrition is informative and the analysis ignores it; transparency of the plan is necessary, not sufficient.

How it maps to this catalog

— In this repo, SPIRIT-PRO's substantive requirements are implemented by concepts a methodologist can pre-specify against: - The PRO endpoint itself, its development, and its measurement properties: pro-rwe, pro-development, and pro-validation supply the construct definition and the validity/reliability/responsiveness evidence the protocol must justify and cite. - The protocol-content discipline (SPIRIT-PRO's administrative and methods items): study-protocol-or-sap-elements provides the pre-specification and amendment-control habits the checklist demands. - The estimand and intercurrent-event items: estimands-ate-att-intercurrent-events-rwe and estimand-analysis-traceability-rwe operationalize the ICH E9(R1) estimand framing — including treatment-policy vs hypothetical vs while-alive strategies for death and discontinuation — that a PRO primary endpoint forces. - The missing-PRO-data items: missing-data-pattern-table-rwe, multiple-imputation-longitudinal-rwe, and mmrm-repeated-measures-rwe implement the mechanism characterization, primary analysis, and sensitivity analyses the protocol must pre-commit to; attrition-and-loss-to-follow-up-rwe characterizes the informative-dropout structure typical of PRO follow-up. - The multi-domain, multi-time-point structure: composite-endpoint-construction-rwe and longitudinal-outcomes-modeling-rwe inform how multiplicity and repeated measures are handled, and picots-framework-rwe anchors the PRO hypothesis to population/intervention/comparator/outcome/timing.

Applied note (PRO data in RWE — what transfers and what does not)

SPIRIT-PRO is written for interventional trials, so it does not directly govern a claims/EHR/registry RWE study. But its measurement and missing-data discipline transfers to real-world PRO collection in product/disease registries, pragmatic trials (often the bridge between SPIRIT-PRO and RWE), and PRO-enabled cohort studies: pre-specify the PRO concept and instrument with cited measurement evidence (COSMIN/ISOQOL), fix the assessment schedule and administration mode, define who reports (patient vs proxy), and — most critically for RWE, where follow-up is visit-driven and attrition is heavy and informative — pre-commit to the estimand, the handling of death and disenrollment as intercurrent events, and the primary and sensitivity analyses for missing PRO data rather than defaulting to complete-case scores. For a primary non-interventional PRO study, use SPIRIT-PRO only as a measurement reference and report under STROBE/RECORD-PE with a HARPER/ENCePP protocol.