{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:52:57Z","timestamp":1793649177437,"version":"4.5.1"},"reference-count":19,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Intern Med"],"published-print":{"date-parts":[[2023,5,1]]},"abstract":"Importance<\/jats:title>Idelalisib is a first-in-class phosphatidylinositol 3-kinase inhibitor that received US Food and Drug Administration accelerated approval in July 2014 as a single-agent treatment for relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Serious adverse effects were reported in 2016 leading to termination of postmarketing registry trials. However, idelalisib remained on the market until 2022 when Gilead voluntarily withdrew the drug for the accelerated approval indication.<\/jats:p><\/jats:sec>Objective<\/jats:title>Evaluate the regulatory oversight of the accelerated approval pathway and evidence generation for idelalisib during premarketing (2008-2014), postmarketing (2014-2016), and premarketing withdrawal periods (2016-2022).<\/jats:p><\/jats:sec>Data Sources<\/jats:title>ClinicalTrials.gov, FDA.gov, PubMed database.<\/jats:p><\/jats:sec>Study Selection<\/jats:title>Clinical trials investigating the safety and effectiveness of idelalisib.<\/jats:p><\/jats:sec>Data Extraction and Synthesis<\/jats:title>Study characteristics and relative risk (RR) of safety outcomes were abstracted. Data were pooled using random effects meta-analysis. The analysis was performed in October of 2022.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Trial status, recruitment status, publication status, serious adverse events (SAEs), fatal adverse events (FAEs), and all-cause mortality.<\/jats:p><\/jats:sec>Results<\/jats:title>Overall, 31 idelalisib trials met selection criteria. In total, 20 of 30 (65%) included SLL and\/or FL; 13 (42%) trials were completed, 13 (42%) had published results, and 7 (23%) were randomized clinical trials (RCTs). Overall, 6 RCTs of idelalisib had publicly available data on safety outcomes. By the initial postmarketing period (2016), the cumulative RR for SAEs was 1.86 (95% CI, 1.63-2.11), for FAEs was 3.30 (95% CI, 1.56-7.00), and for death was 1.35 (95% CI, 0.85-2.12). In the premarketing withdrawal period, only a single phase 3 trial was enrolling patients for FL and was terminated. However, idelalisib was not withdrawn from the market until 2022. Gilead reported cumulative sales revenue of $842 million during market authorization (2014-2022) and annual sales had a steady decline from $168 million to $62 million during the premarketing withdrawal period (2016-2021).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>Findings of this systematic review and meta-analysis show that serious risks of SAE, FAE, and death with idelalisib treatment were evident by 2016. However, idelalisib remained on the market for another 6 years, with minimal evidence generation. It was voluntarily withdrawn for FL and SLL accelerated approval indications coinciding with decreasing revenue generation. Closer attention for safety and effectiveness of drugs reaching market by accelerated approval is needed.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamainternmed.2023.0190","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T15:01:58Z","timestamp":1679324518000},"page":"435","source":"Crossref","is-referenced-by-count":23,"title":["Clinical Trials Portfolio and Regulatory History of Idelalisib in Indolent Non-Hodgkin Lymphoma"],"prefix":"10.1001","volume":"183","author":[{"given":"Titas","family":"Banerjee","sequence":"first","affiliation":[{"name":"Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung Sun","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyson","family":"Haslam","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay","family":"Prasad","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"6","key":"ioi230007r1","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1001\/jamaoncol.2017.5618","article-title":"A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review.","volume":"4","author":"Beaver","year":"2018","journal-title":"JAMA Oncol"},{"issue":"7","key":"ioi230007r2","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1001\/jamainternmed.2019.0462","article-title":"Assessment of the clinical benefit of cancer drugs receiving accelerated approval.","volume":"179","author":"Gyawali","year":"2019","journal-title":"JAMA Intern Med"},{"issue":"3","key":"ioi230007r3","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1002\/med.v41.3","article-title":"Targeting phosphatidylinositol 3-kinase gamma (PI3K?): discovery and development of its selective inhibitors.","volume":"41","author":"Zhu","year":"2021","journal-title":"Med Res Rev"},{"key":"ioi230007r4","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105579","article-title":"Properties of FDA-approved small molecule phosphatidylinositol 3-kinase inhibitors prescribed for the treatment of malignancies.","volume":"168","author":"Roskoski","year":"2021","journal-title":"Pharmacol Res"},{"issue":"5","key":"ioi230007r5","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/S1470-2045(22)00200-5","article-title":"The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.","volume":"23","author":"Richardson","year":"2022","journal-title":"Lancet Oncol"},{"issue":"8","key":"ioi230007r6","doi-asserted-by":"publisher","first-page":"e362","DOI":"10.1016\/S1470-2045(22)00260-1","article-title":"PI3K inhibitors in haematological malignancies.","volume":"23","author":"Benjamin","year":"2022","journal-title":"Lancet Oncol"},{"issue":"3","key":"ioi230007r7","first-page":"e123","article-title":"Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.","volume":"3","author":"Moher","year":"2009","journal-title":"Open Med"},{"issue":"21","key":"ioi230007r9","doi-asserted-by":"publisher","first-page":"3357","DOI":"10.1182\/blood-2015-03-633156","article-title":"Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed\/refractory indolent lymphoma.","volume":"125","author":"Cheah","year":"2015","journal-title":"Blood"},{"issue":"12","key":"ioi230007r10","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1093\/jjco\/hyaa153","article-title":"Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed\/refractory follicular lymphoma and chronic lymphocytic leukemia.","volume":"50","author":"Fukuhara","year":"2020","journal-title":"Jpn J Clin Oncol"},{"issue":"11","key":"ioi230007r11","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1056\/NEJMoa1315226","article-title":"Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.","volume":"370","author":"Furman","year":"2014","journal-title":"N Engl J Med"},{"issue":"11","key":"ioi230007r12","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1056\/NEJMoa1314583","article-title":"PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma.","volume":"370","author":"Gopal","year":"2014","journal-title":"N Engl J Med"},{"issue":"1","key":"ioi230007r13","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1186\/s12955-019-1232-8","article-title":"Idelalisib addition has neutral to beneficial effects on quality of life in bendamustine\/rituximab-treated patients: results of a phase 3, randomized, controlled trial.","volume":"17","author":"Montillo","year":"2019","journal-title":"Health Qual Life Outcomes"},{"issue":"7","key":"ioi230007r14","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1038\/s41375-020-01108-x","article-title":"Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma.","volume":"35","author":"Morschhauser","year":"2021","journal-title":"Leukemia"},{"issue":"10","key":"ioi230007r15","doi-asserted-by":"publisher","first-page":"2779","DOI":"10.3109\/10428194.2015.1022770","article-title":"Management of adverse events associated with idelalisib treatment: expert panel opinion.","volume":"56","author":"Coutr\u00e9","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"ioi230007r16","doi-asserted-by":"publisher","first-page":"5489","DOI":"10.1182\/blood-2019-123179","article-title":"Risk of serious adverse events, infection and sepsis in patients with relapsed and refractory chronic lymphocytic leukemia\/ small lymphocytic lymphoma treated with idelalisib.","volume":"134","author":"Kopel","year":"2019","journal-title":"Blood"},{"key":"ioi230007r8","unstructured":"US FDA. Oncologic Drugs Advisory Committee Meeting (April 2022). Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Hematologic Malignancies. Accessed September 26, 2022. www.fda.gov\/media\/157762\/download"},{"key":"ioi230007r17","unstructured":"FDA Alerts Healthcare Professionals About Clinical Trials with Zydelig. (idelalisib) in Combination with other Cancer Medicines. US Food & Drug Administration; 2016. Accessed August 11, 2022. www.fda.gov\/drugs\/drug-safety-and-availability\/fda-alerts-healthcare-professionals-about-clinical-trials-zydelig-idelalisib-combination-other"},{"key":"ioi230007r18","unstructured":"Carroll? J. UPDATED: Gilead picks up blockbuster FDA blood cancer approvals for idelalisib. Fierce Biotech. 2014. Accessed August 11, 2022. www.fiercebiotech.com\/regulatory\/updated-gilead-picks-up-blockbuster-fda-blood-cancer-approvals-for-idelalisib"},{"key":"ioi230007r19","unstructured":"Kansteiner, F. FDA accelerated approvals targeted for revamp in House Energy and Commerce committee chair's new bill; March 8, 2022. Accessed February 14, 2022. www.fiercepharma.com\/pharma\/house-energy-and-commerce-committee-chair-pallone-takes-fdas-accelerated-approval-pathway"}],"container-title":["JAMA Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/articlepdf\/2802537\/jamainternal_banerjee_2023_oi_230007_1681506430.52455.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T15:03:21Z","timestamp":1682953401000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/fullarticle\/2802537"}},"subtitle":["A Systematic Review and Meta-analysis"],"short-title":[],"issued":{"date-parts":[[2023,5,1]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,5,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamainternmed.2023.0190","relation":{},"ISSN":["2168-6106"],"issn-type":[{"value":"2168-6106","type":"print"}],"subject":[],"published":{"date-parts":[[2023,5,1]]}}}