{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T03:08:43Z","timestamp":1779073723799,"version":"3.51.4"},"reference-count":60,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Clinical trials for rare diseases face a fundamental mathematical challenge that conventional randomized controlled trial (RCT) designs cannot overcome. With approximately 95% of the estimated 10,000\u201316,000 rare diseases lacking approved therapies, and drug development programs failing at rates exceeding 75% in non\u2010oncology indications, the field confronts a stark reality: Traditional trial designs demand patient numbers that simply do not exist. This perspective article examines the critical mismatch between the statistical requirements of different trial designs (the \u201cdemand\u201d) and the actual patient populations available for study (the \u201csupply\u201d). We demonstrate mathematically that alternative trial designs\u2014particularly patient\u2010as\u2010own\u2010control and natural history comparator models\u2014can reduce required sample sizes by 5\u2010 to 20\u2010fold while maintaining statistical rigor. We further point out that a substantial proportion of rare disease trial failures stem not from therapeutic inefficacy but from recruitment and retention challenges inherent to underpowered RCT designs\u2014challenges that are directly addressable through appropriately matched trial design. Given that most rare disease development programs receive only one opportunity to demonstrate efficacy, the continued application of inappropriate statistical models represents both a scientific failure and an ethical and economic challenge to the rare disease community. We propose that regulatory agencies formalize acceptance of alternative trial designs for rare diseases, supported by explicit mathematical frameworks that transparently account for genetic heterogeneity, pediatric populations, and the statistical efficiency gains achieved through within\u2010subject correlation.<\/jats:p>","DOI":"10.1111\/cts.70551","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T03:10:31Z","timestamp":1778296231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Supply and Demand in the Mathematics of Rare Disease Drug Development: Why Choosing the Right Model Is Crucial"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8920-0110","authenticated-orcid":false,"given":"Marshall L.","family":"Summar","sequence":"first","affiliation":[{"name":"George Washington University, CEO, Uncommon Cures  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet","family":"Woodcock","sequence":"additional","affiliation":[{"name":"Center for Drug Evaluation and Research, U.S. Food and Drug Administration  Silver Spring, Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4582.769"},{"key":"e_1_2_12_3_1","unstructured":"J. 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