{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T16:14:49Z","timestamp":1781885689419,"version":"3.54.5"},"reference-count":16,"publisher":"Wiley","issue":"18-19","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["T32ES007018"],"award-info":[{"award-number":["T32ES007018"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Statistics in Medicine"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Many rare disease clinical trials are underpowered to detect a moderate treatment effect of an investigational product due to the limited number of participants available for the trials. In addition, given the complex, multisystemic nature of many rare diseases, it is challenging to confidently prespecify a single primary efficacy endpoint that is applicable to all trial participants with a heterogeneous clinical manifestation of their disease. Traditional trial designs and analysis methods often used in more common diseases to analyze the same endpoint(s) for all patients may be inefficient or impractical for a rare disease with heterogeneous clinical manifestations. To address these issues, we propose a novel trial design and analytic approach that allows for an evaluation of stratum\u2010specific efficacy endpoints in a broader population of participants. We develop several nonparametric global test methods that can accommodate the novel design and provide global evaluation of treatment effects. Using a case example in patients with Fabry disease, our simulation studies illustrate that the novel design evaluated using the global test methods may be more sensitive to detect a treatment effect compared to the traditional design that uses the same endpoint(s) for all patients.<\/jats:p>","DOI":"10.1002\/sim.70206","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T13:18:26Z","timestamp":1754572706000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Clinical Trial Design With Stratum\u2010Specific Endpoints and Global Test Methods for Rare Diseases With Heterogeneous Clinical Manifestations"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7164-5920","authenticated-orcid":false,"given":"Emily","family":"Shives","sequence":"first","affiliation":[{"name":"Office of Biostatistics U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yared","family":"Gurmu","sequence":"additional","affiliation":[{"name":"Office of Biostatistics U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonyul","family":"Lee","sequence":"additional","affiliation":[{"name":"Office of Biostatistics U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Morris","sequence":"additional","affiliation":[{"name":"Office of Biostatistics U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Office of Biostatistics U.S. Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543406.2018.1489402"},{"key":"e_1_2_9_3_1","unstructured":"FDA Center for Drug Evaluation and Research \u201cApplication Number 761278Orig1s000 Integrated Review \u201d(2023) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/761278Orig1s000IntegratedR.pdf."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010021\u201001805\u20105"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2307\/2531158"},{"key":"e_1_2_9_6_1","unstructured":"FDA Center for Drug Evaluation and Research \u201cMultiple Endpoints in Clinical Trials \u201d(2022) https:\/\/www.fda.gov\/media\/162416\/download."},{"key":"e_1_2_9_7_1","unstructured":"ClinicalTrials.gov \u201cPhase 3 Study to Evaluate Intravenous Trappsol(R) Cyclo(TM) in Pediatric and Adult Patients With Niemann\u2010Pick Disease Type C1 (TransportNPC) \u201d(2023) https:\/\/clinicaltrials.gov\/study\/NCT04860960."},{"key":"e_1_2_9_8_1","unstructured":"ClinicalTrials.gov \u201cArimoclomol Prospective Study in Participants Diagnosed With Niemann\u2010Pick Disease Type C \u201d(2023) https:\/\/clinicaltrials.gov\/study\/NCT02612129."},{"key":"e_1_2_9_9_1","unstructured":"Y.Wang \u201cGlobal Tests for Multiple Endpoints in Rare Disease Clinical Trials \u201d(2021) https:\/\/archive.nestat.org\/raredisease2021\/html\/schedule.html. New England Rare Disease Statistics Workshop presentation slides."},{"key":"e_1_2_9_10_1","series-title":"Lecture Notes\u2010Monograph Series","volume-title":"On O'Brien's OLS and GLS Tests for Multiple Endpoints","author":"Logan B.","year":"2004"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.21306"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1993"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/75.4.800"},{"key":"e_1_2_9_14_1","volume-title":"Statistical Power Analysis for the Behavioral Sciences","author":"Cohen J.","year":"1988"},{"key":"e_1_2_9_15_1","unstructured":"Y.Wang \u201cStatistical Considerations in Rare Disease Clinical Trials \u201d(2022) https:\/\/www.fda.gov\/media\/162732\/download."},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.8086"},{"key":"e_1_2_9_17_1","unstructured":"FDA Center for Drug Evaluation and Research \u201cE9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials \u201d(2021) https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/e9r1\u2010statistical\u2010principles\u2010clinical\u2010trials\u2010addendum\u2010estimands\u2010and\u2010sensitivity\u2010analysis\u2010clinical."}],"container-title":["Statistics in Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sim.70206","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T16:07:23Z","timestamp":1764173243000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/sim.70206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":16,"journal-issue":{"issue":"18-19","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/sim.70206"],"URL":"https:\/\/doi.org\/10.1002\/sim.70206","archive":["Portico"],"relation":{},"ISSN":["0277-6715","1097-0258"],"issn-type":[{"value":"0277-6715","type":"print"},{"value":"1097-0258","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2024-01-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70206"}}