{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:52:47Z","timestamp":1785909167032,"version":"3.56.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Oncol. Rev."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>While health technology assessment (HTA) acceptance of contextual real-world data (RWD) studies describing burden of disease, disease natural history, or treatment pathways is relatively common, HTA practices for RWD studies addressing real-world clinical efficacy, such as those using external control arms (ECAs), are still evolving and less standardized. The aim of this study was to use data from HTA submissions and reports to understand common analytical methods and data considerations for submissions using RWD-based ECA. This evaluation used ECA studies as a basis for investigating the use of RWD to evaluate clinical efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Secondary data were compiled from selected oncology submissions to HTA agencies between January 2016 and December 2022 that incorporated RWD-based ECA data, using natural language-processing text-mining to identify and select relevant cases. Submissions were reviewed in six countries across Asia Pacific (Australia), Europe (France, Germany, UK), and North America (Canada and US). Submissions that were rated both positive and negative by HTA agencies were included, with HTA feedback organized into generalizability, confounding, data quality, and data analysis categories.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 204 submissions identified, 100 cases were selected for the analysis of patterns highlighting sources of data for ECAs and RWD methodology best practices: Australia (n = 3), Canada (n = 34), France (n = 19), Germany (n = 15), UK (n = 26), and US (n = 3). A positive HTA recommendation was received by 69 of these 100 cases. Lung cancer was associated with the greatest number of cases\/submissions. Retrospective cohort studies were the most common source of RWD, with inverse probability of treatment weighting\/propensity score weight as the most common methodology used to generate real-world evidence. Most of the selected RWD-based ECA cases were from Canadian and UK HTA agencies. Positive comments focused on population adjustment, RWD viability, and alignment of data with standard of care (SoC) for that country\/indication; negative comments focused on missing\/limited data, lack of alignment with SoC, and potential risk of bias.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study captured challenges in considering RWD-based ECAs for HTA submission and presents criteria for creating viable RWD studies using ECAs. Data source selection, patient population comparison, and transparent presentation of potential biases were important factors in enhancing the credibility and utility of RWD-based ECAs in HTA decision-making processes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/or.2026.1605636","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:41:10Z","timestamp":1785908470000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessing real-world evidence utilization in oncology health technology assessments: insights from external control-arm studies"],"prefix":"10.3389","volume":"20","author":[{"given":"Gleicy","family":"Macedo Hair","sequence":"first","affiliation":[{"name":"Biostatistics and Research Decision Sciences (BARDS), Merck & Co., Inc.","place":["Rahway, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda E.","family":"Hanisch","sequence":"additional","affiliation":[{"name":"Science and Regulatory Policy, Merck & Co., Inc.","place":["Rahway, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahrul","family":"Mt-Isa","sequence":"additional","affiliation":[{"name":"Biostatistics and Research Decision Sciences (BARDS), MSD","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hozefa A.","family":"Divan","sequence":"additional","affiliation":[{"name":"Biostatistics and Research Decision Sciences (BARDS), Merck & Co., Inc.","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Ramus","sequence":"additional","affiliation":[{"name":"US Real World Solutions, IQVIA","place":["King of Prussia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Barrett","sequence":"additional","affiliation":[{"name":"Value and Access, IQVIA","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvinder S.","family":"Cheema","sequence":"additional","affiliation":[{"name":"Medical Affairs Consulting, IQVIA","place":["San Francisco, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YangYang","family":"Lu","sequence":"additional","affiliation":[{"name":"Value and Access, IQVIA","place":["New York City, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridevi","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"US Real World Solutions, IQVIA","place":["King of Prussia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Market Access Insights, IQVIA","place":["Frankfurt, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"B1","unstructured":"NICE real-world evidence framework. Corporate document [ECD9]\n          \n          \n          2022"},{"key":"B2","volume-title":"Guidance for Reporting Real-World Evidence","year":"2023"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S332","DOI":"10.1016\/j.jval.2023.09.1756","article-title":"HTA72 How is real-world evidence (RWE) being used in health technology assessment (HTA) decisions? Qualitative insights from comparisons of three RWE study types across multiple jurisdictions","volume":"26","author":"Hanisch","year":"2023","journal-title":"Value Health"},{"key":"B4","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1186\/s12874-021-01399-3","article-title":"Methods for the inclusion of real-world evidence in network meta-analysis","volume":"21","author":"Jenkins","year":"2021","journal-title":"BMC Med Res Methodol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.3390\/curroncol31040141","article-title":"Application of multi-criteria decision analysis (MCDA) to prioritize real-world evidence studies for health technology management: outcomes and lessons learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) collaboration","volume":"31","author":"Takhar","year":"2024","journal-title":"Curr Oncol"},{"key":"B6","article-title":"Real-world studies for the assessment of medicinal products and medical devices","year":"2021","journal-title":"Methodol Guide"},{"key":"B7","unstructured":"Background document: Guidance on the validity of clinical studies for joint clinical assessments\n          \n          \n          2024"},{"key":"B8","unstructured":"Overview of the development of the use of RWD including a review of international consensus methods currently developed\n          \n          \n          2020"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1016\/j.jval.2022.05.016","article-title":"A comparison of seven oncology external control arm case studies: Critiques from Regulatory and Health Technology Assessment Agencies","volume":"25","author":"Jaksa","year":"2022","journal-title":"Value Health"},{"key":"B10","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/j.jval.2025.02.012","article-title":"Use of real-world evidence in health technology reassessments across 6 Health Technology Assessment Agencies","volume":"28","author":"Jaksa","year":"2025","journal-title":"Value Health"},{"key":"B11","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.jval.2016.12.003","article-title":"Policies for use of real-world data in Health Technology Assessment (HTA): A comparative study of six HTA agencies","volume":"20","author":"Makady","year":"2017","journal-title":"Value Health"},{"key":"B12","unstructured":"Press release. Registry data \u2013 of sufficient quality \u2013 are suitable for the extended benefit assessment of drugs\n          \n          \n          2020"},{"key":"B13","unstructured":"Regulation (EU) 2021\/2282 of the European Parliament and of the Council of 15 December 2021 on health technology assessment and amending directive 2011\/24\/EU\n          \n          \n          2021"},{"key":"B14","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.jval.2023.01.010","article-title":"Using real-world data in the health technology assessment of pharmaceuticals: strengths, difficulties, and a pragmatic way forward","volume":"26","author":"Akehurst","year":"2023","journal-title":"Value Health"},{"key":"B15","unstructured":"Regulation (EU) 2021 of the European Parliament and of the Council on health technology assessment and amending directive 2011\/24\/EU: Position of the Council at first reading with a view to the adoption of a regulation of the European Parliament and of the Council on health technology assessment and amending directive 2011\/24\/EU\n          \n          \n          2021"},{"key":"B16","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.annonc.2021.12.015","article-title":"External control arms in oncology: current use and future directions","volume":"33","author":"Mishra-Kalyani","year":"2022","journal-title":"Ann Oncol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.2217\/cer-2021-0047","article-title":"Health technology assessment (HTA) in England, France and Germany: what do matched drug pairs tell us about recommendations by national HTA agencies?","volume":"10","author":"Schaefer","year":"2021","journal-title":"J Comp Eff Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"12302","DOI":"10.3389\/jpps.2024.12302","article-title":"Real-world data: a comprehensive literature review on the barriers, challenges, and opportunities associated with their inclusion in the health technology assessment process","volume":"27","author":"Zisis","year":"2024","journal-title":"J Pharm Pharm Sci"},{"key":"B19","unstructured":"[A19-43] Development of scientific concepts for the generation of routine practice data and their analysis for the benefit assessment of drugs according to \u00a735a social code book V \u2013 rapid report\n          \n          \n          2020"},{"key":"B20","unstructured":"Pharmaceutical Benefits Advisory Committee Guidelines. Guidelines for preparing a submission to the Pharmaceutical Benefits Advisory Committee (PBAC) version 5.0\n          \n          \n          2016"},{"key":"B21","doi-asserted-by":"publisher","first-page":"13345","DOI":"10.3390\/ijerph182413345","article-title":"Generating real-world evidence on the quality use, benefits and safety of medicines in Australia: history, challenges and a roadmap for the future","volume":"18","author":"Pearson","year":"2021","journal-title":"Int J Environ Res Public Health"},{"key":"B22","article-title":"Real-world data: assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products","year":"2024","journal-title":"Guidance for Industry"},{"key":"B23","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/s41698-022-00316-1","article-title":"A perspective on life-cycle health technology assessment and real-world evidence for precision oncology in Canada","volume":"6","author":"Regier","year":"2022","journal-title":"NPJ Precis Oncol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"105","DOI":"10.3390\/jmahp12020009","article-title":"Real-world evidence to reinforce clinical trial evidence in health technology assessment: a critical review of real-world evidence requirements from seven countries and recommendations to improve acceptance","volume":"12","author":"Thokagevistk","year":"2024","journal-title":"J Mark Access Health Pol"},{"key":"B25","volume-title":"Causal Inference: What If","author":"Hern\u00e1n","year":"2020"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.3390\/cancers16081489","article-title":"Availability and access to orphan drugs for rare cancers in Bulgaria: analysis of delays and public expenditures","volume":"16","author":"Kostadinov","year":"2024","journal-title":"Cancers (Basel)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"B28","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"}],"container-title":["Oncology Reviews"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/or.2026.1605636\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:41:14Z","timestamp":1785908474000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/or.2026.1605636\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":28,"alternative-id":["10.3389\/or.2026.1605636"],"URL":"https:\/\/doi.org\/10.3389\/or.2026.1605636","relation":{},"ISSN":["1970-5557"],"issn-type":[{"value":"1970-5557","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"article-number":"1605636"}}