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Across regulatory authorities, the use of RWD\/RWE is consistently framed by the fit-for-purpose principle, centered on two foundational concepts: relevance and reliability. However, the absence of operational guidance has created uncertainty regarding how academic registries and healthcare databases can be designed or upgraded to meet regulatory expectations. Drawing on practical experience with disease registries in Japan and their regulatory applications, this review proposes a purpose-oriented framework clarifying the levels of relevance and reliability required according to specific regulatory objectives. We categorize considerations into three use cases: (1) drug development for rare diseases and rare molecular subtypes; (2) Pharmacovigilance; and (3) evidence generation for clinical questions that cannot be sufficiently evaluated through randomized controlled trials (RCTs). For each category, we outline essential requirements related to study design, data elements, quality management, governance, statistical planning, and operational feasibility. We further compare regulatory expectations across the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency (PMDA), and the International Council for Harmonisation (ICH). While international convergence is evident at the level of principles, operational thresholds and implementation frameworks differ. By articulating relevance and reliability as a shared regulatory language and emphasizing purpose-driven design and early regulatory engagement, this review provides practical recommendations for generating regulatory-grade RWE that meaningfully informs regulatory decision-making while complementing conventional clinical trials.<\/jats:p>","DOI":"10.1007\/s10147-026-03160-6","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:38:09Z","timestamp":1787225889000},"page":"2075-2086","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recommendations for generating real-world evidence with regulatory-grade relevance and reliability"],"prefix":"10.1007","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6824-1586","authenticated-orcid":false,"given":"Yasutoshi","family":"Sakamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Bando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Aoyagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Sokuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Misumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Oba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Okui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Miyazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunari","family":"Sadatsuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuma","family":"Koizumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Otake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinori","family":"Yuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Tajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Yoshihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Itoya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Annaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harumasa","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuko","family":"Okita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Kuroda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Yoshino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Ohtsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"3160_CR1","unstructured":"U.S. 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(2021) Basic principles on utilization of registry for applications. https:\/\/www.pmda.go.jp\/files\/000240810.pdf"},{"key":"3160_CR6","unstructured":"Pharmaceuticals and Medical Devices Agency (2021) Points to consider for ensuring the reliability in utilization of registry data for applications. https:\/\/www.pmda.go.jp\/files\/000240811.pdf"},{"key":"3160_CR7","unstructured":"U.S. FOOD &DRUG (2023) Real-world data: assessing registries to support regulatory decision-making for drug and biological products. https:\/\/www.fda.gov\/media\/154449\/download."},{"key":"3160_CR8","unstructured":"U.S. FOOD &DRUG (2024) Real-world data: assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/real-world-data-assessing-electronic-health-records-and-medical-claims-data-support-regulatory"},{"key":"3160_CR9","unstructured":"U.S. FOOD &DRUG (2023) Considerations for the design and conduct of externally controlled trials for drug and biological products. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/considerations-design-and-conduct-externally-controlled-trials-drug-and-biological-products"},{"key":"3160_CR10","unstructured":"U.S. FOOD &DRUG (2022) Submitting documents using real-world data and real-world evidence to FDA for drug and biological products. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/submitting-documents-using-real-world-data-and-real-world-evidence-fda-drug-and-biological-products"},{"key":"3160_CR11","unstructured":"U.S. FOOD &DRUG (2018) Use of electronic health record data in clinical investigations guidance for industry. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/use-electronic-health-record-data-clinical-investigations-guidance-industry"},{"key":"3160_CR12","unstructured":"European Medicines Agency 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Can Med Assoc J 180:23\u201324","journal-title":"Can Med Assoc J"}],"container-title":["International Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10147-026-03160-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10147-026-03160-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10147-026-03160-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:50:09Z","timestamp":1790355009000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10147-026-03160-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":16,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["3160"],"URL":"https:\/\/doi.org\/10.1007\/s10147-026-03160-6","relation":{},"ISSN":["1341-9625","1437-7772"],"issn-type":[{"value":"1341-9625","type":"print"},{"value":"1437-7772","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"assertion":[{"value":"9 June 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Employment\/Leadership postion\/Advisory role: Toshihiro\u202fMisumi (Takeda Pharmaceutical Co., Ltd., Boston Medical Sciences, and Anaut Inc.), Kenichi\u202fNakamura (EPS Holdings, Inc.), Yasunari\u202fSadatsuki (Bayer Yakuhin, Ltd.), Makoto\u202fMiyazaki (AstraZeneca K.K.), Kazuma\u202fKoizumi (MSD K.K.), Rie\u202fOtake (Takeda Pharmaceutical Co., Ltd.), Akinori\u202fYuri (Chugai Pharmaceutical Co., Ltd.), and Atsushi\u202fOhtsu (spouse employment at AstraZeneca K.K.). Stock ownership: Eri\u202fTajima (Roche). Honoraia: Bando Hideaki (Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd. and Guardant Health, Inc), Toshihiro\u202fMisumi (Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K. and Miyarisan Pharmaceutical Co., Ltd.), Koji\u202fOba (StatCom Co., Ltd. and DOTworld K.K.), and Takayuki\u202fYoshino (Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck & Co., Inc., Ono Pharma, Sumitomo Corp and Indivumed Japan G.K.).","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}