{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:28:03Z","timestamp":1792380483828,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The purpose was to evaluate retrieval\u2010augmented generative (RAG) artificial intelligence (AI) methods for assessing the regulatory compliance of drug information and adherence to best practices in clinical trial protocols. Integrated systems containing RAG and large language model (LLM) components were employed to evaluate drug information and clinical trial protocols. The drug information for adalimumab, insulin glargine, atorvastatin calcium, sertraline, and alprazolam was evaluated for compliance with Food and Drug Administration (FDA) clinical pharmacology guidance for indications, use in specific populations, and warnings and precautions. The reasons for the withdrawal of rofecoxib, valdecoxib, and troglitazone were elicited. The clinical trial protocol evaluation system was used to assess a Phase\u20102a clinical trial protocol of Rifafour in tuberculosis with the FDA E9 and E9 (R1) guidance documents. The RAG system correctly identified the indications, use in specific populations, and warnings and precautions for adalimumab, insulin glargine, atorvastatin calcium, sertraline, and alprazolam. The drug information was evaluated against the requirements in the guidance documents, confirming compliance when present and providing explanations for deficiencies. The causes underlying the withdrawal of rofecoxib, valdecoxib, and troglitazone were explained. The clinical protocol summary included study design, population definitions, treatments, dose levels, and route of administration. The summary of the statistical analysis plan included primary\/secondary endpoints, statistical tests, pharmacokinetic parameters, and handling of missing data and outliers. The findings aligned with manual protocol reviews. RAG\u2010based AI methods can improve the usefulness of LLMs in document\u2010restricted settings and are a promising approach for evaluating the compliance of clinical pharmacology documents.<\/jats:p>","DOI":"10.1002\/psp4.70201","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T08:02:35Z","timestamp":1771488155000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Retrieval Augmented Generation (\n                    <scp>RAG<\/scp>\n                    ) for Evaluating Regulatory Compliance of Drug Information and Clinical Trial Protocols"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3786-6025","authenticated-orcid":false,"given":"Shreyas","family":"Waikar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Artificial Intelligence and Clinical Pharmacology Laboratory University at Buffalo, The State University of New\u00a0York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5180-7790","authenticated-orcid":false,"given":"Amruta Gajanan","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Artificial Intelligence and Clinical Pharmacology Laboratory University at Buffalo, The State University of New\u00a0York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9943-150X","authenticated-orcid":false,"given":"Murali","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Artificial Intelligence and Clinical Pharmacology Laboratory University at Buffalo, The State University of New\u00a0York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"OpenAI \u201cChatGPT (June 26 Version) Large Language Model \u201d(2023) https:\/\/chat.openai.com\/chat."},{"key":"e_1_2_9_3_1","unstructured":"Google AI \u201cBard Large Language Model \u201d(2023) https:\/\/bard.google.com."},{"key":"e_1_2_9_4_1","unstructured":"Meta \u201cLlama 2: Open Source Free for Research and Commercial Use \u201d(2024) https:\/\/llama.meta.com\/llama2\/."},{"key":"e_1_2_9_5_1","unstructured":"Anthropic \u201cMeet Claude \u201d(2024) https:\/\/www.anthropic.com\/claude."},{"key":"e_1_2_9_6_1","unstructured":"xAI \u201cGrok 3 Beta\u2014The Age of Reasoning Agents \u201d(2025) https:\/\/x.ai\/news\/grok\u20103."},{"key":"e_1_2_9_7_1","unstructured":"DeepSeek\u2010AI \u201cDeepSeek\u2010V2: A Strong Economical and Efficient Mixture\u2010of\u2010Experts Language Model \u201d(2024) https:\/\/ui.adsabs.harvard.edu\/abs\/2024arXiv240504434D."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3279"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.16215"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-023-09892-6"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-024-09921-y"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70155"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70125"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70205"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70188"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.70127"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.70100"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.70039"},{"key":"e_1_2_9_19_1","unstructured":"P.Lewis \u201cRetrieval\u2010Augmented Generation for Knowledge\u2010Intensive NLP Tasks \u201d(2020) https:\/\/ui.adsabs.harvard.edu\/abs\/2020arXiv200511401L."},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-025-01520-1"},{"key":"e_1_2_9_21_1","volume-title":"Title 21\/Chapter I\/Subchapter D Food and Drugs","author":"Code of Federal Regulations","year":"2025"},{"key":"e_1_2_9_22_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2018"},{"key":"e_1_2_9_23_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2011"},{"key":"e_1_2_9_24_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2022"},{"key":"e_1_2_9_25_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2018"},{"key":"e_1_2_9_26_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2018"},{"key":"e_1_2_9_27_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2019"},{"key":"e_1_2_9_28_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2019"},{"key":"e_1_2_9_29_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2022"},{"key":"e_1_2_9_30_1","volume-title":"An Early Bactericidal Activity, Safety and Tolerability of GSK3036656 in Subjects With Drug\u2010Sensitive Pulmonary Tuberculosis","author":"Anonymous","year":"2021"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc-2022-0085"},{"key":"e_1_2_9_32_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"1998"},{"key":"e_1_2_9_33_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2021"},{"key":"e_1_2_9_34_1","unstructured":"J.Ip \u201cRAG Evaluation \u201d(2025) https:\/\/deepeval.com\/guides\/guides\u2010rag\u2010evaluation."},{"key":"e_1_2_9_35_1","unstructured":"J.Ip \u201cG\u2010Eval \u201d(2025) https:\/\/deepeval.com\/docs\/metrics\u2010llm\u2010evals."},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1991.03470170063023"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-9556(24)14959-8"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1993.03500120070028"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199708283370901"},{"key":"e_1_2_9_40_1","volume-title":"U.S. Department of Health and Human Services","author":"United States Food & Drug Administration (FDA)","year":"2025"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70201","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70201","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70201","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T04:21:36Z","timestamp":1773807696000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,19]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/psp4.70201"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70201","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,19]]},"assertion":[{"value":"2025-10-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70201"}}