{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T14:15:40Z","timestamp":1778336140595,"version":"3.51.4"},"reference-count":31,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"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"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>The U.S. Food and Drug Administration (FDA) used an Active Postmarket Risk Identification and Analysis (ARIA) system to address a safety issue (serious infection) identified during clinical review of an application to market ustekinumab as a treatment for Crohn's disease (CD). FDA used an active\u2010comparator new\u2010user cohort design, data from six Sentinel Data Partners, a method developed in Sentinel for identifying serious infection, and ARIA analytic tools to estimate serious infection incidence in adult CD patients during treatment with ustekinumab or an active comparator (infliximab, adalimumab, or vedolizumab). Inverse probability of treatment weighting (IPTW) was used to control for baseline differences between treatment groups. Analyses compared ustekinumab and comparator cohorts with 15,490 and 51,503 patients, respectively. The primary composite outcome of serious infection or COVID\u201019 occurred in 747 ustekinumab patients (4.82 %; 44.1 per 1000 patient\u2010years) during mean 400\u2010day follow\u2010up. IPTW proportional hazard (Cox) regression estimated risk in the ustekinumab cohort vs. active comparator with hazard ratio 0.88 (95% confidence interval 0.80\u20130.96). Findings were similar (a) according to line of therapy (use or non\u2010use of an advanced inflammatory bowel disease therapy during a 183\u2010day baseline period) and (b) before and after the start of the COVID\u201019 pandemic. Additional analyses excluded large magnitude risks from ustekinumab for major types of serious infection. In conclusion, IPTW analyses excluded large magnitude risks from ustekinumab for serious infection. This report describes the first ARIA study to use complex confounding adjustment to help resolve a safety issue identified during FDA review of a marketing application.<\/jats:p>","DOI":"10.1002\/cpt.70227","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T14:55:28Z","timestamp":1774364128000},"page":"1514-1521","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Serious Infection in Crohn's Disease Patients Treated With Ustekinumab:\n                    <scp>US<\/scp>\n                    Food and Drug Administration Active Postmarket Risk Identification and Analysis in the Sentinel Initiative"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8438-4456","authenticated-orcid":false,"given":"Joel L.","family":"Weissfeld","sequence":"first","affiliation":[{"name":"Office of Surveillance and Epidemiology (formerly) and Office of Medical Policy (Currently), Center for Drug Evaluation and Research, Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geetha S.","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Population Medicine Harvard Medical School and Harvard Pilgrim Health Care Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suna C.","family":"Seo","sequence":"additional","affiliation":[{"name":"Office of New Drugs, Center for Drug Evaluation and Research Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6487-7766","authenticated-orcid":false,"given":"Andrew","family":"Giffin","sequence":"additional","affiliation":[{"name":"Office of Biostatistics, Center for Drug Evaluation and Research Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5176-5555","authenticated-orcid":false,"given":"Andrew L.","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Population Medicine Harvard Pilgrim Health Care Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2846-7879","authenticated-orcid":false,"given":"Sheryl A.","family":"Kluberg","sequence":"additional","affiliation":[{"name":"Department of Population Medicine Harvard Medical School and Harvard Pilgrim Health Care Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma R.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Population Medicine Harvard Pilgrim Health Care Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2709-0806","authenticated-orcid":false,"given":"Jamal T.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah K.","family":"Dutcher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce A.","family":"Korvick","sequence":"additional","affiliation":[{"name":"Office of New Drugs, Center for Drug Evaluation and Research Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"e_1_2_12_1_1","unstructured":"Cross discipline team leader review for stelara (ustekinumab) BLA 761044<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2016\/761044Orig1s000CrossR.pdf>. (September 2016). Accessed April 9 2025."},{"key":"e_1_2_12_2_1","unstructured":"Clinical review for stelara (ustekinumab) BLA 761044<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2016\/761044Orig1s000MedR.pdf>. (September 2016). Accessed April 9 2025."},{"key":"e_1_2_12_3_1","unstructured":"Food and Drug Administration.Postmarketing studies and clinical trials\u2014implementation of section\u00a0505(o)(3) of the federal food drug and cosmetic act guidance for industry<https:\/\/www.fda.gov\/media\/131980\/download>. (April 2011). Accessed April 9 2025."},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/jamia\/ocaa028"},{"key":"e_1_2_12_5_1","unstructured":"U.S. Food and Drug Administration.Assessment in support of the sentinel system<https:\/\/www.fda.gov\/media\/161944\/download>. (September 2022). Accessed December 2 2024."},{"key":"e_1_2_12_6_1","unstructured":"Sentinel.Serious infection following ustekinumab use in patients with crohn's disease: an inverse probability of treatment weighting analysis<https:\/\/www.sentinelinitiative.org\/studies\/drugs\/individual\u2010drug\u2010analyses\/serious\u2010infection\u2010following\u2010ustekinumab\u2010use\u2010patients\u2010crohn\u20100>. (June 2024). Accessed December 2 2024."},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.5253"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280219869742"},{"key":"e_1_2_12_9_1","unstructured":"Sentinel.Ustekinumab dispensing patterns: a descriptive analysis<https:\/\/www.sentinelinitiative.org\/studies\/drugs\/individual\u2010drug\u2010analyses\/ustekinumab\u2010dispensing\u2010patterns\u2010descriptive\u2010analysis>. (November 2020). Accessed December 2 2024."},{"key":"e_1_2_12_10_1","unstructured":"Sentinel.Serious infection following ustekinumab use in patients with crohn's disease or ulcerative colitis: a descriptive analysis<https:\/\/www.sentinelinitiative.org\/studies\/drugs\/individual\u2010drug\u2010analyses\/serious\u2010infection\u2010following\u2010ustekinumab\u2010use\u2010patients\u2010crohn\u2010s>. (May 2022). Accessed December 2 2024."},{"key":"e_1_2_12_11_1","unstructured":"Sentinel.Ustekinumab and comparator treatment utilization and pneumonia outcomes in patients with crohn's disease or ulcerative colitis: an updated descriptive analysis<https:\/\/www.sentinelinitiative.org\/studies\/drugs\/individual\u2010drug\u2010analyses\/ustekinumab\u2010and\u2010comparator\u2010treatment\u2010utilization\u2010and>. (March 2024). Accessed December 2 2024."},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjae013"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00688-2"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15706"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15745"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000002166"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000002411"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-022-07770-8"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2022.01.013"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-023-07897-2"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000002068"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2022.10.029"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/03007995.2024.2326585"},{"key":"e_1_2_12_24_1","doi-asserted-by":"crossref","DOI":"10.1177\/17562848241265013","article-title":"Comparative risk of serious infections and tuberculosis in Korean patients with inflammatory bowel disease treated with non\u2010anti\u2010TNF biologics or anti\u2010TNF\u2010\u03b1 agents: a nationwide population\u2010based cohort study","volume":"17","author":"Kim M.J.","year":"2024","journal-title":"Therap. Adv. Gastroenterol."},{"key":"e_1_2_12_25_1","unstructured":"STELARA\u2010ustekinumab solution<https:\/\/dailymed.nlm.nih.gov\/dailymed\/>. Accessed December 2 2024."},{"key":"e_1_2_12_26_1","unstructured":"Sentinel.How sentinel gets its data<https:\/\/www.sentinelinitiative.org\/about\/how\u2010sentinel\u2010gets\u2010its\u2010data>. Accessed December 2 2024."},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2979"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.5820"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020040526"},{"key":"e_1_2_12_30_1","unstructured":"Sentinel.Key database statistics<https:\/\/www.sentinelinitiative.org\/about\/key\u2010database\u2010statistics>. Accessed December 2 2024."},{"key":"e_1_2_12_31_1","unstructured":"Duke Margolis Institute for Health Policy.Slide deck for sixteenth annual sentinel initiative public workshop<https:\/\/healthpolicy.duke.edu\/events\/sixteenth\u2010annual\u2010sentinel\u2010initiative\u2010public\u2010workshop>. (November 2024). Accessed December 2 2024."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70227","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70227","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70227","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T03:28:28Z","timestamp":1778297308000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/cpt.70227"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70227","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]},"assertion":[{"value":"2025-09-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}