{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:03:09Z","timestamp":1790222589582,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"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":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>In June 2026, the FDA issued a revised draft guidance describing the circumstances in which one adequate and well\u2010controlled clinical investigation plus confirmatory evidence may satisfy the statutory substantial evidence standard for establishing efficacy and safety. Confirmatory evidence includes real\u2010world evidence (RWE). The evolution of the regulatory use of RWE builds on more than two decades of FDA experience with real\u2010world data (RWD), first for pharmacovigilance and later in effectiveness and risk\/benefit determination. RWD\/RWE guidances have been released since the 21st Century Cures Act was passed in 2016, but implementation remains operationally and methodologically challenging. This article provides practical guidance for teams considering RWE as part of a registrational program. Key topics include selection of fit\u2010for\u2010purpose data, study design, protocol development, study execution and governance, data transformation, analysis and assessment of residual bias, and submission. Recommendations emphasize early FDA alignment, filling gaps in procedural documentation and systems, multidisciplinary collaboration, and anticipating technological demands associated with large real\u2010world datasets.<\/jats:p>","DOI":"10.1002\/cpt.70487","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:54:47Z","timestamp":1790222087000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Practical Guide to Implementing Real\u2010World Evidence as Primary Basis for Approval and Label Expansion"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8179-7223","authenticated-orcid":false,"given":"Tracy J.","family":"Mayne","sequence":"first","affiliation":[{"name":"Slipstream Life Sciences  Blue Bell Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1572-0564","authenticated-orcid":false,"given":"Maurice A.","family":"Brookhart","sequence":"additional","affiliation":[{"name":"Headwater Science  Durham North Carolina USA"},{"name":"Department of Population Health Sciences Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0153-8286","authenticated-orcid":false,"given":"Nancy A.","family":"Dreyer","sequence":"additional","affiliation":[{"name":"Dreyer Strategies, LLC  Boston Massachusetts USA"},{"name":"Department of Epidemiology University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_13_1_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1056\/NEJMsb2517623","article-title":"One pivotal trial, the new default option for FDA approval \u2013 ending the two\u2010trial dogma","volume":"394","author":"Prasad V.","year":"2026","journal-title":"N. 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Sci."},{"key":"e_1_2_13_7_1","volume-title":"H.R.34 \u2013 21st Century Cures Act, 114th Congress (2015\u20132016): Summary. Congress.gov, Library of Congress.Congress.gov, Library of Congress","author":"US Congress","year":"2016"},{"key":"e_1_2_13_8_1","unstructured":"U. S. Food and Drug Administration.Considerations for the use of real world data and real world evidence to support regulatory decision making for drug and biological products: Guidance for Industry<https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/considerations\u2010use\u2010real\u2010world\u2010data\u2010and\u2010real\u2010world\u2010evidence\u2010support\u2010regulatory\u2010decision\u2010making\u2010drug> (2023). Accessed August 05 2026."},{"key":"e_1_2_13_9_1","unstructured":"U. S. Food and Drug Administration.Real\u2010World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision\u2010Making for Drug and Biological Products: Guidance for Industry<https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/real\u2010world\u2010data\u2010assessing\u2010electronic\u2010health\u2010records\u2010and\u2010medical\u2010claims\u2010data\u2010support\u2010regulatory> (2024). Accessed June 9 2026."},{"key":"e_1_2_13_10_1","unstructured":"U. S. Food and Drug Administration.Data standards for drug and biological product submissions containing real world data: Guidance for Industry<https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/data\u2010standards\u2010drug\u2010and\u2010biological\u2010product\u2010submissions\u2010containing\u2010real\u2010world\u2010data> (2023). Accessed June 9 2026."},{"key":"e_1_2_13_11_1","unstructured":"U. S. Food and Drug Administration.Real World Data: Assessing registries to support regulatory decision making for drug and biological products: Guidance for Industry<https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/real\u2010world\u2010data\u2010assessing\u2010registries\u2010support\u2010regulatory\u2010decision\u2010making\u2010drug\u2010and\u2010biological\u2010products> (2023). Accessed August 05 2026."},{"key":"e_1_2_13_12_1","unstructured":"U. S. Food and Drug Administration.Submitting Documents Using Real\u2010World Data and Real\u2010World Evidence to FDA for Drug and Biological Products: Guidance for Industry<https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/submitting\u2010documents\u2010using\u2010real\u2010world\u2010data\u2010and\u2010real\u2010world\u2010evidence\u2010fda\u2010drug\u2010and\u2010biological\u2010products> (2022). 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