{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:21:05Z","timestamp":1788394865292,"version":"build-2803163510"},"reference-count":40,"publisher":"American Medical Association (AMA)","issue":"14","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2022,10,11]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L\/min; mean difference [MD], \u22124.9 L\/min [1-sided 97.5% CI, \u2212\u221e to \u22120.6]; <jats:italic>P<\/jats:italic>\u2009=\u2009.01) and day 5 (25.1 vs 35.3 L\/min; MD, \u221210.2 L\/min [1-sided 97.5% CI, \u2013\u221e to \u20136.3]; <jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L\/min; MD, \u22121.2 L\/min [1-sided 97.5% CI, \u2212\u221e to 2.8]; <jats:italic>P<\/jats:italic>\u2009=\u2009.28) or on day 5 (34.7 vs 35.3 L\/min; MD, \u22120.6 L\/min [1-sided 97.5% CI, \u2212\u221e to 3.2]; <jats:italic>P<\/jats:italic>\u2009=\u2009.37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L\/min; MD, \u22129.3 L\/min [1-sided 97.5% CI, \u2212\u221e to \u22123.9]; <jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L\/min; MD, 1.1 L\/min [1-sided 97.5% CI, \u2212\u221e to 6.4]; <jats:italic>P<\/jats:italic>\u2009=\u2009.67). No drug-related serious adverse events were reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04310579\">NCT04310579<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jama.2022.17735","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T15:03:35Z","timestamp":1665500615000},"page":"1405","source":"Crossref","is-referenced-by-count":21,"title":["Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia"],"prefix":"10.1001","volume":"328","author":[{"given":"Jeffry","family":"Florian","sequence":"first","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rutger","family":"van der Schrier","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Gershuny","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Davis","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Office of Neuroscience, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Burkhart","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Prentice","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"},{"name":"Booz Allen Hamilton Inc, McLean, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aanchal","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"},{"name":"Booz Allen Hamilton Inc, McLean, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Racz","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murali","family":"Matta","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omnia A.","family":"Ismaiel","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Weaver","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney","family":"Boughner","sequence":"additional","affiliation":[{"name":"KCAS Bioanalytical Services. Shawnee, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Ford","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney","family":"Rouse","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Stone","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Office of Neuroscience, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Sanabria","sequence":"additional","affiliation":[{"name":"Spaulding Clinical Research. West Bend, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Dahan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Strauss","sequence":"additional","affiliation":[{"name":"Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"2","key":"jpc220005r1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.resp.2011.04.009","article-title":"Measuring the respiratory chemoreflexes in humans.","volume":"177","author":"Duffin","year":"2011","journal-title":"Respir Physiol Neurobiol"},{"issue":"6","key":"jpc220005r2","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1093\/bja\/aen094","article-title":"Opioids and the control of respiration.","volume":"100","author":"Pattinson","year":"2008","journal-title":"Br J Anaesth"},{"issue":"5","key":"jpc220005r3","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1111\/bcp.2005.59.issue-5","article-title":"Ventilatory responses of healthy subjects to intravenous combinations of morphine and oxycodone under imposed hypercapnic and hypoxaemic conditions.","volume":"59","author":"Ladd","year":"2005","journal-title":"Br J Clin Pharmacol"},{"issue":"6","key":"jpc220005r4","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1093\/bja\/aex295","article-title":"An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers.","volume":"119","author":"van der Schrier","year":"2017","journal-title":"Br J Anaesth"},{"issue":"3","key":"jpc220005r5","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1097\/ALN.0000000000001505","article-title":"Influence of ethanol on oxycodone-induced respiratory depression.","volume":"126","author":"van der Schrier","year":"2017","journal-title":"Anesthesiology"},{"issue":"4","key":"jpc220005r6","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1097\/00000542-200310000-00002","article-title":"When you breathe IN you inspire, when you DON\u2019T breathe, you...expire.","volume":"99","author":"Gross","year":"2003","journal-title":"Anesthesiology"},{"issue":"6","key":"jpc220005r8","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1111\/cts.v14.6","article-title":"Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat.","volume":"14","author":"Xu","year":"2021","journal-title":"Clin Transl Sci"},{"issue":"1","key":"jpc220005r10","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/imj.1967.16.issue-1","article-title":"A clinical method for assessing the ventilatory response to carbon dioxide.","volume":"16","author":"Read","year":"1967","journal-title":"Australas Ann Med"},{"issue":"1","key":"jpc220005r11","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1378\/chest.70.1_Supplement.118","article-title":"Measurement of ventilatory response to CO2 by rebreathing.","volume":"70","author":"Rebuck","year":"1976","journal-title":"Chest"},{"issue":"6","key":"jpc220005r12","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1152\/japplphysiol.00640.2005","article-title":"Role of acid-base balance in the chemoreflex control of breathing.","volume":"99","author":"Duffin","year":"2005","journal-title":"J Appl Physiol (1985)"},{"issue":"3","key":"jpc220005r13","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.clinthera.2009.03.002","article-title":"Self-reported sedation profile of immediate-release quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation.","volume":"31","author":"Datto","year":"2009","journal-title":"Clin Ther"},{"issue":"1","key":"jpc220005r15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1152\/physrev.1995.75.1.1","article-title":"Central control of breathing in mammals.","volume":"75","author":"Bianchi","year":"1995","journal-title":"Physiol Rev"},{"issue":"3","key":"jpc220005r16","first-page":"255","article-title":"The neuropharmacology of respiratory control.","volume":"34","author":"Mueller","year":"1982","journal-title":"Pharmacol Rev"},{"issue":"10-11","key":"jpc220005r17","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/0028-3908(74)90089-6","article-title":"The influence of increased brain 5-hydroxytryptamine upon the respiratory activity of cats.","volume":"13","author":"Armijo","year":"1974","journal-title":"Neuropharmacology"},{"issue":"2","key":"jpc220005r18","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1007\/BF00403646","article-title":"Adrenergic and serotonergic mechanisms in morphine-induced respiratory depression.","volume":"24","author":"Fl\u00f3rez","year":"1972","journal-title":"Psychopharmacologia"},{"issue":"2","key":"jpc220005r19","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/0028-3908(81)90200-8","article-title":"Role of monoaminergic systems in morphine-induced respiratory depression.","volume":"20","author":"Meldrum","year":"1981","journal-title":"Neuropharmacology"},{"issue":"2","key":"jpc220005r20","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0091-3057(80)90081-7","article-title":"Evidence that respiratory depression by serotonin agonists may be exerted in the central nervous system.","volume":"13","author":"Mueller","year":"1980","journal-title":"Pharmacol Biochem Behav"},{"issue":"12","key":"jpc220005r21","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1177\/0269881109106908","article-title":"Acute and chronic treatment with serotonin reuptake inhibitors exert opposite effects on respiration in rats.","volume":"24","author":"Annerbrink","year":"2010","journal-title":"J Psychopharmacol"},{"issue":"1","key":"jpc220005r22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0034-5687(98)00103-0","article-title":"Effects of serotonin re-uptake inhibition on ventilatory control in goats.","volume":"115","author":"Henderson","year":"1999","journal-title":"Respir Physiol"},{"issue":"4","key":"jpc220005r23","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1203\/00006450-200204000-00007","article-title":"Effect of maternal fluoxetine administration on uterine blood flow, fetal blood gas status, and growth.","volume":"51","author":"Morrison","year":"2002","journal-title":"Pediatr Res"},{"issue":"1","key":"jpc220005r24","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S0924-977X(03)00044-0","article-title":"Paroxetine influences respiration in rats.","volume":"14","author":"Olsson","year":"2004","journal-title":"Eur Neuropsychopharmacol"},{"issue":"1-2","key":"jpc220005r25","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.resp.2009.04.014","article-title":"Medullary serotonin neurons and central CO2 chemoreception.","volume":"168","author":"Corcoran","year":"2009","journal-title":"Respir Physiol Neurobiol"},{"issue":"1","key":"jpc220005r26","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/cns.2001.7.issue-1","article-title":"Paroxetine: a review.","volume":"7","author":"Bourin","year":"2001","journal-title":"CNS Drug Rev"},{"issue":"3","key":"jpc220005r27","doi-asserted-by":"publisher","first-page":"505","DOI":"10.5664\/jcsm.8942","article-title":"Selective serotonin reuptake inhibitor use is associated with worse sleep-related breathing disturbances in individuals with depressive disorders and sleep complaints.","volume":"17","author":"Robillard","year":"2021","journal-title":"J Clin Sleep Med"},{"issue":"2","key":"jpc220005r28","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1097\/00004714-199704000-00006","article-title":"Pharmacologic effect of imipramine, paroxetine, and sertraline on 35% carbon dioxide hypersensitivity in panic patients.","volume":"17","author":"Bertani","year":"1997","journal-title":"J Clin Psychopharmacol"},{"issue":"3","key":"jpc220005r29","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1097\/00004714-199706000-00006","article-title":"Modification of 35% carbon dioxide hypersensitivity across one week of treatment with clomipramine and fluvoxamine.","volume":"17","author":"Perna","year":"1997","journal-title":"J Clin Psychopharmacol"},{"issue":"3","key":"jpc220005r30","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1097\/00004714-200106000-00003","article-title":"The 35% CO2 hyperreactivity and clinical symptomatology in patients with panic disorder after 1 week of treatment with citalopram.","volume":"21","author":"Bertani","year":"2001","journal-title":"J Clin Psychopharmacol"},{"issue":"3","key":"jpc220005r31","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1097\/01.jcp.0000125682.97466.3c","article-title":"Modulation of hyperreactivity to 35% CO2 after one week of treatment with paroxetine and reboxetine.","volume":"24","author":"Perna","year":"2004","journal-title":"J Clin Psychopharmacol"},{"issue":"11","key":"jpc220005r32","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/S0006-3223(97)00160-1","article-title":"Effect of antipanic treatment on response to carbon dioxide.","volume":"42","author":"Gorman","year":"1997","journal-title":"Biol Psychiatry"},{"issue":"8","key":"jpc220005r33","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1016\/S0006-3223(97)00221-7","article-title":"Antipanic effect of fluoxetine measured by CO2 challenge test.","volume":"43","author":"Bocola","year":"1998","journal-title":"Biol Psychiatry"},{"issue":"12","key":"jpc220005r34","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1080\/15563650.2021.1989785","article-title":"2020 annual report of the American Association of Poison Control Centers\u2019 National Poison Data System (NPDS).","volume":"59","author":"Gummin","year":"2021","journal-title":"Clin Toxicol (Phila)"},{"issue":"9","key":"jpc220005r35","first-page":"1","article-title":"Drugs most frequently involved in drug overdose deaths: United States, 2011-2016.","volume":"67","author":"Hedegaard","year":"2018","journal-title":"Natl Vital Stat Rep"},{"issue":"8","key":"jpc220005r36","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1111\/pme.12777","article-title":"Development of a risk index for serious prescription opioid-induced respiratory depression or overdose in Veterans\u2019 Health Administration patients.","volume":"16","author":"Zedler","year":"2015","journal-title":"Pain Med"},{"issue":"1","key":"jpc220005r37","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1093\/pm\/pnx009","article-title":"Validation of a screening risk index for serious prescription opioid-induced respiratory depression or overdose in a US commercial health plan claims database.","volume":"19","author":"Zedler","year":"2018","journal-title":"Pain Med"},{"issue":"2","key":"jpc220005r38","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.0194","article-title":"Risk of opioid overdose associated with concomitant use of oxycodone and selective serotonin reuptake inhibitors.","volume":"5","author":"Yunusa","year":"2022","journal-title":"JAMA Netw Open"},{"key":"jpc220005r39","doi-asserted-by":"publisher","first-page":"S81","DOI":"10.1016\/S0924-977X(99)00030-9","article-title":"Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders.","volume":"9","author":"Nutt","year":"1999","journal-title":"Eur Neuropsychopharmacol"},{"issue":"3","key":"jpc220005r40","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1007\/s002100000290","article-title":"Effects of acute and chronic administration of fluoxetine on the activity of serotonergic neurons in the dorsal raphe nucleus of the rat.","volume":"362","author":"Czachura","year":"2000","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"jpc220005r7","unstructured":"Woodcock J to Wen L and Alexander-Scott L. August 31, 2016. Re: Docket No. FDA-2016-P-0689. US Food and Drug Administration, Silver Spring, MD. Accessed February 23, 2022. https:\/\/www.regulations.gov\/document\/fda-2016-P-0689-0003?"},{"key":"jpc220005r9","unstructured":"Collection of Race and Ethnicity Data in Clinical Trials Guidance for Industry and Food and Drug Administration Staff. Published October 26, 2016. Accessed February 23, 2022. https:\/\/www.fda.gov\/media\/75453\/download?"},{"key":"jpc220005r14","unstructured":"Bioavailability studies submitted in NDAs or INDs\u2014general considerations. US Food and Drug Administration.  Published 2019. Accessed April 9, 2019. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/bioavailability-studies-submitted-ndas-or-inds-general-considerations"}],"container-title":["JAMA"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/articlepdf\/2797225\/jama_florian_2022_pc_220005_1664819883.50896.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T15:03:39Z","timestamp":1665500619000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/fullarticle\/2797225"}},"subtitle":["A Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2022,10,11]]},"references-count":40,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2022,10,11]]}},"URL":"https:\/\/doi.org\/10.1001\/jama.2022.17735","relation":{},"ISSN":["0098-7484"],"issn-type":[{"value":"0098-7484","type":"print"}],"subject":[],"published":{"date-parts":[[2022,10,11]]}}}