{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:04:15Z","timestamp":1789617855420,"version":"build-2803163510"},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceutical Statistics"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Limited research has been conducted to assess the sensitivity of responder effects (i.e., the difference in proportion of response between treatment and control groups) between interventions to different dichotomous threshold scores created from a continuous patient\u2010reported outcome (PRO) (e.g., within\u2010patient improvement of 10 or more points in PRO scores). We investigated the subject in several complementary ways: (1) local sensitivity in magnitude to measure the impact on responder effect to small changes in the threshold value; (2) sensitivity in direction to capture changes in the direction of responder effects with changes in the threshold; (3) average sensitivity in magnitude to measure the impact on responder effect to uncertainty in the threshold; and (4) the standard deviation (width) of Holland's hill (distribution of responder effects across threshold scores) to gauge the robustness of responder effects to different thresholds. We focused on normally distributed outcomes where within\u2010group standard deviations may differ between intervention groups. Our findings indicate that, relative to equal group standard deviation, unequal group standard deviations give consistently higher levels of sensitivity for very small increases in the threshold value. For the case of no mean continuous treatment effect, responder analyses will generally misrepresent the direction of mean treatment effect when there is unequal group variability in the continuous PRO measure. By quantifying and elucidating subtle points on the sensitivity of responder effects\u2014and the additional challenges on interpretation imposed by unequal group standard deviations\u2014this article could be useful in the careful design, analysis, and interpretation of PRO studies.<\/jats:p>","DOI":"10.1002\/pst.70121","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:31:01Z","timestamp":1789615861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sensitivity of Responder Effects to Different Thresholds and Control Group Means on Patient\u2010Reported Outcomes: Varying Group Standard Deviations"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9586-0748","authenticated-orcid":false,"given":"Joseph C.","family":"Cappelleri","sequence":"first","affiliation":[{"name":"Statistical Research and Data Science Center, Pfizer Inc  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Ma","sequence":"additional","affiliation":[{"name":"Statistical Research and Data Science Center, Pfizer Inc  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Di Fusco","sequence":"additional","affiliation":[{"name":"Health Technology Assessment, Value &amp; Evidence, Pfizer Inc  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowu","family":"Sun","sequence":"additional","affiliation":[{"name":"CVS Health  Woonsocket Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1002\/pst.2273","article-title":"Should Responder Analyses Be Conducted on Continuous Outcomes?","volume":"22","author":"Abugov R.","year":"2023","journal-title":"Pharmaceutical Statistics"},{"key":"e_1_2_14_3_1","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1007\/s43441-021-00298-5","article-title":"Addressing Bias in Responder Analysis of Patient\u2010Reported Outcomes","volume":"55","author":"Cappelleri J. C.","year":"2021","journal-title":"Therapeutic Innovation & Regulatory Science"},{"key":"e_1_2_14_4_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/pst.331","article-title":"Consequences of Dichotomization","volume":"8","author":"Fedorov V.","year":"2009","journal-title":"Pharmaceutical Statistics"},{"key":"e_1_2_14_5_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1745-6215-8-31","article-title":"Responder Analyses and the Assessment of Clinically Relevant Treatment Effect","volume":"8","author":"Snapinn S.","year":"2007","journal-title":"Trials"},{"key":"e_1_2_14_6_1","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1198\/sbr.2011.10070","article-title":"Responder Analyses\u2014A PhRMA Position Paper","volume":"3","author":"Uryniak T.","year":"2011","journal-title":"Statistics in Biopharmaceutical Research"},{"key":"e_1_2_14_7_1","volume-title":"Patient\u2010Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision\u2010Making: Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders. Draft Guidance","author":"FDA (Food and Drug Administration)","year":"2023"},{"key":"e_1_2_14_8_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jclinepi.2021.01.026","article-title":"Patient Reported Outcome Measures in Clinical Trials Should Be Initially Analyzed as Continuous Outcomes for Statistical Significance and Responder Analyses Should Be Reserved as Secondary Analyses","volume":"134","author":"Collister D.","year":"2021","journal-title":"Journal of Clinical Epidemiology"},{"key":"e_1_2_14_9_1","doi-asserted-by":"crossref","first-page":"652","DOI":"10.2519\/jospt.2023.11853","article-title":"Responder Analyses: A Methodological Mess","volume":"53","author":"Cook C. 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G.","year":"2022"},{"issue":"235","key":"e_1_2_14_12_1","first-page":"65132","article-title":"Guidance for Industry on Patient\u2010Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims","volume":"74","author":"Food and Drug Administration (FDA)","year":"2009","journal-title":"Federal Register"},{"key":"e_1_2_14_13_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1177\/2168479015622667","article-title":"Interpreting Change in Scores on Patient\u2010Reported Outcome Instruments","volume":"50","author":"Coon C. D.","year":"2016","journal-title":"Therapeutic Innovation & Regulatory Science"},{"key":"e_1_2_14_14_1","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.jval.2022.07.010","article-title":"Is Iqwig's 15% Threshold Universally Applicable in Assessing the Clinical Relevance of Patient\u2010Reported Outcomes Changes? An ISPOR Special Interest Group Report","volume":"25","author":"Schlichting M.","year":"2022","journal-title":"Value in Health"},{"key":"e_1_2_14_15_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1586\/erp.11.12","article-title":"Interpreting Patient\u2010Reported Outcome Results: US FDA Guidance and Emerging Methods","volume":"11","author":"McLeod L. D.","year":"2011","journal-title":"Expert Review of Pharmacoeconomics & Outcomes Research"},{"key":"e_1_2_14_16_1","doi-asserted-by":"crossref","first-page":"e683","DOI":"10.1016\/S1470-2045(25)00520-0","article-title":"SISAQOL\u2010IMI Consensus\u2010Based Guidelines to Design, Analyse, Interpret and Present Patient\u2010Reported Outcomes in Cancer Clinical Trials","volume":"26","author":"Amdal C. 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F.","year":"2025","journal-title":"Lancet Oncology"}],"container-title":["Pharmaceutical Statistics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pst.70121","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pst.70121","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pst.70121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:31:06Z","timestamp":1789615866000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pst.70121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":22,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/pst.70121"],"URL":"https:\/\/doi.org\/10.1002\/pst.70121","archive":["Portico"],"relation":{},"ISSN":["1539-1604","1539-1612"],"issn-type":[{"value":"1539-1604","type":"print"},{"value":"1539-1612","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]},"assertion":[{"value":"2026-02-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70121"}}