Editing GSK plc (section)

====Rosiglitazone (Avandia)====
{{further|Rosiglitazone#Adverse effects|Rosiglitazone#Lawsuits}}
[[File:Avandia 2mg oral tablet.jpg|thumb|[[Rosiglitazone]]]]
The 2012 settlement included a criminal fine of US$242,612,800 for failing to report safety data to the FDA about Avandia ([[rosiglitazone]]), a [[Diabetes mellitus type 2|diabetes]] drug approved in 1999, and a civil settlement of US$657{{nbsp}}million for making false claims about it. The Justice Department said GSK had promoted rosiglitazone to physicians with misleading information, including that it conferred cardiovascular benefits despite an FDA-mandated label warning of cardiovascular risks.<ref name=USDOJJuly2012/>

In 1999, [[John Buse]], a diabetes specialist, told medical conferences that rosiglitazone might carry an increased risk of cardiovascular problems. GSK threatened to sue him, called his university head of department, and persuaded him to sign a retraction.<ref>{{Cite web |title=United States Senate Committee on Finance Report: The Intimidation of Dr. John Buse and the Diabetes Drug Avandia |url=https://www.finance.senate.gov/download/committee-staff-report-the-intimidation-of-dr-john-buse-and-the-diabetes-drug-avandia |url-status=live |archive-url=https://web.archive.org/web/20161111000154/https://www.finance.senate.gov/imo/media/doc/prb111507a.pdf |archive-date=11 November 2016 |access-date=11 September 2023 |website=www.finance.senate.gov |language=en}}</ref> GSK raised questions internally about the drug's safety in 2000, and in 2002, the company [[Medical ghostwriter|ghostwrote]] an article in ''[[Circulation (journal)|Circulation]]'' describing a GSK funded clinical trial that suggested rosiglitazone might have a beneficial effect on cardiovascular risk.<ref>[[Max Baucus]], [[Chuck Grassley]], [http://finance.senate.gov/newsroom/chairman/download/?id=a5c07780-6351-4905-8c63-52e4a7a7a66b "Finance Committee Letter to the FDA Regarding Avandia"] {{Webarchive|url=https://web.archive.org/web/20100805051726/http://finance.senate.gov/newsroom/chairman/download/?id=a5c07780-6351-4905-8c63-52e4a7a7a66b |date=5 August 2010 }}, United States Senate Finance Committee, 12 July 2010; for internal concerns, p. 2 and attachment E, pp.&nbsp;20–35; for ghostwriting, p. 3 and attachment H, pp. 58–109; for the ghostwriting, attachment I, p. 110ff; for cover letter to ''[[Circulation (journal)|Circulation]]'', attachment I, p.&nbsp;143; for the ghostwritten article, attachment I, pp.&nbsp;152–158.{{pb}}
{{cite journal |vauthors=Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI |display-authors=3 |date=August 2002 |title=Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus |journal=Circulation |volume=106 |issue=6 |pages=679–84 |doi=10.1161/01.CIR.0000025403.20953.23 |pmid=12163427 |doi-access=free}}</ref> From 2001, reports began to link the [[thiazolidinedione]]s (the class of drugs to which rosiglitazone belongs) to [[heart failure]].<ref name="pmid20154334"/> In April that year, GSK began a six-year, [[Open-label trial|open-label]], [[Randomized controlled trial|randomized trial]], known as RECORD, to examine rosiglitazone and cardiovascular events.<ref name="RECORDLancet">{{cite journal |vauthors=Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ |display-authors=3 |title=Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial |journal=Lancet |volume=373 |issue=9681 |pages=2125–35 |date=June 2009 |pmid=19501900 |doi=10.1016/S0140-6736(09)60953-3 |s2cid=25939495}}{{pb}}
{{cite journal |vauthors=Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Dargie H, Komajda M, Gubb J, Biswas N, Jones NP |display-authors=3 |title=Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol |journal=Diabetologia |volume=48 |issue=9 |pages=1726–35 |date=September 2005 |pmid=16025252 |doi=10.1007/s00125-005-1869-1 |doi-access=free}}{{pb}}
{{cite journal |title=RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes - Full Text View |website=ClinicalTrials.gov |date=21 March 2017 |url=https://clinicaltrials.gov/ct2/show/NCT00379769 |access-date=12 March 2020 |archive-date=17 June 2018 |archive-url=https://web.archive.org/web/20180617115741/https://clinicaltrials.gov/ct2/show/NCT00379769 |url-status=live }}</ref> Two GSK [[Meta-analysis|meta-analyses]] in 2005, and 2006, showed an increased risk of cardiovascular problems with rosiglitazone; the information was passed to the FDA and posted on the company website, but not otherwise published. By December 2006, rosiglitazone had become the top-selling diabetes drug, with annual sales of US$3.3{{nbsp}}billion.<ref name="pmid20154334">{{cite journal |vauthors=Nissen SE |date=April 2010 |title=The rise and fall of rosiglitazone |journal=European Heart Journal |volume=31 |issue=7 |pages=773–776 |doi=10.1093/eurheartj/ehq016 |pmid=20154334 |doi-access=free}} see table 1 for timeline.</ref>

In June 2007, ''[[The New England Journal of Medicine]]'' published a meta-analysis that associated the drug with an increased risk of [[Myocardial infarction|heart attack]].<ref>{{cite journal |vauthors=Nissen SE, Wolski K |year=2007 |title=Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes |journal=New England Journal of Medicine |volume=356 |issue=24 |pages=2457–71 |doi=10.1056/NEJMoa072761 |pmid=17517853 |doi-access=free |quote=Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance.}}</ref> GSK had reportedly tried to persuade one of the authors, [[Steven Nissen]], not to publish it, after receiving an advance copy from one of the journal's peer reviewers, a GSK consultant.<ref>{{cite news |last=Saul |first=Stephanie |date=30 January 2008 |title=Doctor Accused of Leak to Drug Maker |website=[[The New York Times]] |url=https://www.nytimes.com/2008/01/30/business/30cnd-censure.html |url-status=live |access-date=12 March 2020 |archive-url=https://web.archive.org/web/20230405075959/https://www.nytimes.com/2008/01/30/business/30cnd-censure.html |archive-date=5 April 2023}}</ref><ref>{{cite news |last=Harris |first=Gardiner |date=22 February 2010 |title=A Face-Off on the Safety of a Drug for Diabetes |website=[[The New York Times]] |url=https://www.nytimes.com/2010/02/23/health/23niss.html |url-status=live |access-date=12 March 2020 |archive-url=https://web.archive.org/web/20230605132307/https://www.nytimes.com/2010/02/23/health/23niss.html |archive-date=5 June 2023}}</ref> In July 2007, FDA scientists suggested that rosiglitazone had caused 83,000 excess heart attacks between 1999 and 2007.<ref name=Senatereport/>{{rp|4}}<ref name=Graham>[[David Graham (epidemiologist)|David Graham]], [https://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4308s1-08-fda-graham_files/frame.htm "Assessment of the cardiovascular risks and health benefits of rosiglitazone"] {{Webarchive|url=https://web.archive.org/web/20170517113056/https://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4308s1-08-fda-graham_files/frame.htm |date=17 May 2017 }}, Office of Surveillance and Epidemiology, Food and Drug Administration, 30 July 2007.</ref> The FDA placed restrictions on the drug, including adding a [[boxed warning]], but did not withdraw it.<ref>{{Cite web |date=14 November 2007 |title=FDA Adds Boxed Warning for Heart-related Risks to Anti-Diabetes Drug Avandia |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109026.htm |url-status=dead |archive-url=https://web.archive.org/web/20090618090859/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109026.htm |archive-date=18 June 2009 |website=U.S. Food and Drug Administration}}</ref> (In 2013, the FDA rejected that the drug had caused excess heart attacks.)<ref name=FDAheart/> A [[United States Senate Committee on Finance|Senate Finance Committee]] inquiry concluded in 2010, that GSK had sought to intimidate scientists who had concerns about rosiglitazone.<ref name="Senatereport">[http://www.finance.senate.gov/newsroom/chairman/download/?id=9e4b091f-de21-4df1-b65e-b227d74bec12 "Staff report on GlaxoSmithKline and the diabetes drug Avandia"] {{Webarchive|url=https://web.archive.org/web/20141206153734/http://www.finance.senate.gov/newsroom/chairman/download/?id=9e4b091f-de21-4df1-b65e-b227d74bec12 |date=6 December 2014 }}, Committee on Finance, United States Senate, January 2010.{{pb}}
[http://www.finance.senate.gov/newsroom/chairman/release/?id=bc56b552-efc5-4706-968d-f7032d5cd2e4 "Grassley, Baucus Release Committee Report on Avandia"] {{Webarchive|url=https://web.archive.org/web/20141206040504/http://www.finance.senate.gov/newsroom/chairman/release/?id=bc56b552-efc5-4706-968d-f7032d5cd2e4 |date=6 December 2014 }}, The United States Senate Committee on Finance, 20 February 2010.{{pb}}
Andrew Clark, [https://www.theguardian.com/business/2010/feb/22/glaxosmithkline-avandia-concerns-senate "Glaxo's handling of Avandia concerns damned by US Senate committee"], ''[[The Guardian]]'', 22 February 2010.</ref> In February that year the company tried to halt publication of an editorial about the controversy by Nissen in the ''European Heart Journal''.<ref>{{Cite journal |author1=Thomas F. Lüscher |author2=Ulf Landmesser |author3=Frank Ruschitzka |title=Standing firm—the European Heart Journal, scientific controversies and the industry |journal=European Heart Journal |volume=31 |issue=10 |pages=1157–1158 |date=23 April 2010 |doi=10.1093/eurheartj/ehq127 |doi-access=free}}{{pb}}
{{cite journal |pmid=20154334 |doi=10.1093/eurheartj/ehq016 |volume=31 |title=The rise and fall of rosiglitazone |date=April 2010 |journal=Eur. Heart J. |pages=773–6 |last1=Nissen |first1=SE |issue=7 |doi-access=free}}{{pb}}
{{cite journal |pmid=20499440 |volume=31 |title=The rise and fall of rosiglitazone: reply |year=2010 |journal=Eur. Heart J. |pages=1282–4 |last1=Slaoui |first1=M |issue=10 |doi=10.1093/eurheartj/ehq118 |doi-access=free}}{{pb}}
{{cite journal |pmid=20118174 |doi=10.1093/eurheartj/ehp604 |volume=31 |title=Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial |pmc=2848325 |year=2010 |journal=Eur. Heart J. |pages=824–31 |last1=Komajda |first1=M |last2=McMurray |first2=JJ |last3=Beck-Nielsen |first3=H |last4=Gomis |first4=R |last5=Hanefeld |first5=M |last6=Pocock |first6=SJ |last7=Curtis |first7=PS |last8=Jones |first8=NP |last9=Home |first9=PD |issue=7}}</ref>

The results of GSK's RECORD trial were published in June 2009. It confirmed an association between rosiglitazone and an increased risk of heart failure and fractures, but not of heart attack, and concluded that it "does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs."<ref name=RECORDLancet/> Steven Nissan and Kathy Wolkski argued that the study's low event rates reduced its statistical power.<ref>{{cite journal |last1=Nissen |first1=Steven E. |last2=Wolski |first2=Kathy |title=Rosiglitazone RevisitedAn Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality |journal=Archives of Internal Medicine |volume=170 |issue=14 |pages=1191–1202 |doi=10.1001/archinternmed.2010.207 |pmid=20656674 |date=July 2010 |quote=That study was limited by low event rates, which resulted in insufficient statistical power to confirm or refute evidence of an increased risk for ischemic myocardial events. |doi-access=free}}</ref> In September 2009, rosiglitazone was suspended in Europe.<ref>{{Cite web |date=17 September 2018 |title=European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim |url=https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-suspension-avandia-avandamet-avaglim |url-status=live |archive-url=https://web.archive.org/web/20190629145612/https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-suspension-avandia-avandamet-avaglim |archive-date=29 June 2019 |access-date=11 September 2023 |website=European Medicines Agency |language=en}}</ref> The results of the RECORD study were confirmed in 2013, by the Duke Clinical Research Institute, in an independent review required by the FDA.<ref>{{cite journal |last1=McHaffey |first1=Kenneth W. |display-authors=etal |year=2013 |title=Results of a reevaluation of cardiovascular outcomes in the RECORD trial |journal=American Heart Journal |volume=166 |issue=2 |pages=240–249 |doi=10.1016/j.ahj.2013.05.004 |pmid=23895806 |doi-access=free}}</ref> In November that year the FDA lifted the restrictions it had placed on the drug.<ref>[https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm "FDA requires removal of certain restrictions on the diabetes drug Avandia"] {{Webarchive|url=https://web.archive.org/web/20150504051733/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm |date=4 May 2015 }}, Food and Drug Administration, 25 November 2013.{{pb}}
[https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM354859.pdf "Readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes Trial (RECORD)"] {{Webarchive|url=https://web.archive.org/web/20170509191833/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM354859.pdf |date=9 May 2017 }}, Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, Food and Drug Administration, 5–6 June 2013.{{pb}}
Steven Nissen, [https://www.forbes.com/sites/matthewherper/2013/05/23/steven-nissen-the-hidden-agenda-behind-the-fdas-avandia-hearings/ "Steven Nissen: The Hidden Agenda Behind The FDA's New Avandia Hearings"] {{Webarchive|url=https://web.archive.org/web/20170508133620/https://www.forbes.com/sites/matthewherper/2013/05/23/steven-nissen-the-hidden-agenda-behind-the-fdas-avandia-hearings/ |date=8 May 2017 }}, ''[[Forbes]]'', 23 May 2013.{{pb}}
[https://www.forbes.com/sites/matthewherper/2013/05/23/the-fda-responds-to-steve-nissens-criticism-of-upcoming-avandia-meeting/ "The FDA Responds To Steve Nissen's Criticism Of Upcoming Avandia Meeting"], ''[[Forbes]]'', 23 May 2013.</ref> The boxed warning about heart attack was removed; the warning about heart failure remained in place.<ref name=FDAheart>{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/ucm376389.htm |title=FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines |publisher=Food and Drug Administration |date=25 November 2013 |access-date=16 December 2019 |archive-date=24 April 2019 |archive-url=https://web.archive.org/web/20190424011624/https://www.fda.gov/Drugs/DrugSafety/ucm376389.htm |url-status=dead }}<br />
[https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM143413.pdf Avandia. Prescribing information"] {{Webarchive|url=https://web.archive.org/web/20190327025224/https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM143413.pdf |date=27 March 2019 }}, Food and Drug Administration.</ref>