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=<div><a href="https://en.wikipedia.org/wiki/Rosiglitazone">https://en.wikipedia.org/wiki/Rosiglitazone</a></div><div>Rosiglitazone (trade name Avandia) is an <a href="https://en.wikipedia.org/wiki/Antidiabetic_drug" class="mw-redirect" title="Antidiabetic drug" style="text-decoration-line: none; background: none;">antidiabetic drug</a> in the <a href="https://en.wikipedia.org/wiki/Thiazolidinedione" title="Thiazolidinedione" style="text-decoration-line: none; background: none;">thiazolidinedione</a> class. It works as an <a href="https://en.wikipedia.org/wiki/Insulin" title="Insulin" style="text-decoration-line: none; background: none;">insulin</a> sensitizer, by binding to the <a href="https://en.wikipedia.org/wiki/PPAR" class="mw-redirect" title="PPAR" style="text-decoration-line: none; background: none;">PPAR</a> in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with <a href="https://en.wikipedia.org/wiki/Metformin" title="Metformin" style="text-decoration-line: none; background: none;">metformin</a> or with <a href="https://en.wikipedia.org/wiki/Glimepiride" title="Glimepiride" style="text-decoration-line: none; background: none;">glimepiride</a>. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a <a href="https://en.wikipedia.org/wiki/Meta-analysis" title="Meta-analysis" style="text-decoration-line: none; background: none;">meta-analysis</a> in 2007 that linked the drug's use to an increased risk of <a href="https://en.wikipedia.org/wiki/Myocardial_infarction" title="Myocardial infarction" style="text-decoration-line: none; background: none;">heart attack</a>,<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid17517853-1" style="text-decoration-line: none; background: none;">[1]</a> sales plummeted to just $9.5-million in 2012. The drug's patent expired in 2012.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-2" style="text-decoration-line: none; background: none;">[2]</a>It was patented in 1987 and approved for medical use in 1999.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-3" style="text-decoration-line: none; background: none;">[3]</a> Despite rosiglitazone's effectiveness at decreasing blood sugar in <a href="https://en.wikipedia.org/wiki/Type_2_diabetes_mellitus" class="mw-redirect" title="Type 2 diabetes mellitus" style="text-decoration-line: none; background: none;">type 2 diabetes mellitus</a>, its use decreased dramatically as studies showed apparent associations with increased risks of heart attacks and death.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Chen2012-4" style="text-decoration-line: none; background: none;">[4]</a> Adverse effects alleged to be caused by rosiglitazone were the subject of over 13,000 lawsuits against GSK;<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-bloomberg.com-5" style="text-decoration-line: none; background: none;">[5]</a> as of July 2010, GSK had agreed to settlements on more than 11,500 of these suits.Some reviewers recommended rosiglitazone be taken off the market, but an <a href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration" style="text-decoration-line: none; background: none;">FDA</a> panel disagreed, and it remains available in the U.S.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-6" style="text-decoration-line: none; background: none;">[6]</a> From November 2011 until November 2013, the federal government did not allow Avandia to be sold without a prescription from a certified doctor; moreover, patients were required to be informed of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-7" style="text-decoration-line: none; background: none;">[7]</a> In 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of a 2009 trial which failed to show increased heart attack risk.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlGlaxo%E2%80%99s_Avandia_Cleared_From_Sales_Restrictions_by_FDA-Bloomberg-8" style="text-decoration-line: none; background: none;">[8]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-9" style="text-decoration-line: none; background: none;">[9]</a>In Europe, the <a href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency" style="text-decoration-line: none; background: none;">European Medicines Agency</a> (EMA) recommended in September 2010 that the drug be suspended because the benefits no longer outweighed the risks.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-ema_recommend_suspend-10" style="text-decoration-line: none; background: none;">[10]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-bbc_ema_suspension-11" style="text-decoration-line: none; background: none;">[11]</a> It was withdrawn from the market in the UK, Spain and India in 2010,<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-ban-12" style="text-decoration-line: none; background: none;">[12]</a> and in New Zealand and South Africa in 2011.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Stuff.co.nz_4669573-13" style="text-decoration-line: none; background: none;">[13]</a><div class="toclimit-3" style="background-color: rgb(255, 255, 255);"><div id="toc" class="toc" role="navigation" aria-labelledby="mw-toc-heading" style="border: 1px solid rgb(162, 169, 177); background-color: rgb(248, 249, 250); padding: 7px; display: table;"><input type="checkbox" role="button" id="toctogglecheckbox" class="toctogglecheckbox" style="margin: 0px; position: absolute; opacity: 0; z-index: -1; display: none;" /><div class="toctitle" lang="en" dir="ltr" style="text-align: center; direction: ltr;"><h2 id="mw-toc-heading" style="margin: 1em 0px 0.25em; padding: 0px; overflow: hidden; border: 0px; line-height: 1.3; display: inline;">Contents</h2><label class="toctogglelabel" for="toctogglecheckbox" style="cursor: pointer;" /></div><ul style="list-style: none; margin: 0.3em 0px; padding: 0px;"><li class="toclevel-1 tocsection-1" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Medical_uses" style="text-decoration-line: none; background: none;">1Medical uses</a></li><li class="toclevel-1 tocsection-2" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Adverse_effects" style="text-decoration-line: none; background: none;">2Adverse effects</a><ul style="list-style: none; margin: 0px 0px 0px 2em; padding: 0px;"><li class="toclevel-2 tocsection-3" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Heart_failure" style="text-decoration-line: none; background: none;">2.1Heart failure</a></li><li class="toclevel-2 tocsection-4" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Heart_attacks" style="text-decoration-line: none; background: none;">2.2Heart attacks</a></li><li class="toclevel-2 tocsection-5" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Death" style="text-decoration-line: none; background: none;">2.3Death</a></li><li class="toclevel-2 tocsection-6" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Stroke" style="text-decoration-line: none; background: none;">2.4Stroke</a></li><li class="toclevel-2 tocsection-7" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Bone_fractures" style="text-decoration-line: none; background: none;">2.5Bone fractures</a></li><li class="toclevel-2 tocsection-8" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Hypoglycaemia" style="text-decoration-line: none; background: none;">2.6Hypoglycaemia</a></li><li class="toclevel-2 tocsection-9" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Weight_gain" style="text-decoration-line: none; background: none;">2.7Weight gain</a></li><li class="toclevel-2 tocsection-10" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Eye_damage" style="text-decoration-line: none; background: none;">2.8Eye damage</a></li><li class="toclevel-2 tocsection-11" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Hepatotoxicity" style="text-decoration-line: none; background: none;">2.9Hepatotoxicity</a></li><li class="toclevel-2 tocsection-12" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Contraindications" style="text-decoration-line: none; background: none;">2.10Contraindications</a></li></ul></li><li class="toclevel-1 tocsection-13" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Pharmacology" style="text-decoration-line: none; background: none;">3Pharmacology</a></li><li class="toclevel-1 tocsection-14" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#History" style="text-decoration-line: none; background: none;">4History</a></li><li class="toclevel-1 tocsection-15" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Society_and_culture" style="text-decoration-line: none; background: none;">5Society and culture</a><ul style="list-style: none; margin: 0px 0px 0px 2em; padding: 0px;"><li class="toclevel-2 tocsection-16" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Sales" style="text-decoration-line: none; background: none;">5.1Sales</a></li><li class="toclevel-2 tocsection-17" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Lawsuits" style="text-decoration-line: none; background: none;">5.2Lawsuits</a></li><li class="toclevel-2 tocsection-22" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Controversy_and_response" style="text-decoration-line: none; background: none;">5.3Controversy and response</a></li></ul></li><li class="toclevel-1 tocsection-23" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Research" style="text-decoration-line: none; background: none;">6Research</a></li><li class="toclevel-1 tocsection-24" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#Synthesis" style="text-decoration-line: none; background: none;">7Synthesis</a></li><li class="toclevel-1 tocsection-25" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#References" style="text-decoration-line: none; background: none;">8References</a></li><li class="toclevel-1 tocsection-26" style="margin-bottom: 0.1em;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#External_links" style="text-decoration-line: none; background: none;">9External links</a></li></ul></div></div><h2 style="margin: 1em 0px 0.25em; padding: 0px; overflow: hidden; border-bottom: 1px solid rgb(162, 169, 177); font-weight: normal; line-height: 1.3; background-color: rgb(255, 255, 255);">Medical uses[<a href="https://en.wikipedia.org/w/index.php?title=Rosiglitazone&action=edit&section=1" title="Edit section: Medical uses" style="text-decoration-line: none; background: none; white-space: nowrap;">edit</a>]</h2>Rosiglitazone was approved for glycemic control in people with <a href="https://en.wikipedia.org/wiki/Type_2_diabetes" title="Type 2 diabetes" style="text-decoration-line: none; background: none;">type 2 diabetes</a>, as measured by <a href="https://en.wikipedia.org/wiki/Glycated_haemoglobin" class="mw-redirect" title="Glycated haemoglobin" style="text-decoration-line: none; background: none;">glycated haemoglobin</a> A1c (HbA1c) as a surrogate endpoint, similar to that of other oral antidiabetic drugs.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid17636824-14" style="text-decoration-line: none; background: none;">[14]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid18955635-15" style="text-decoration-line: none; background: none;">[15]</a> The controversy over adverse effects has dramatically reduced the use of rosiglitazone.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Ajjan-16" style="text-decoration-line: none; background: none;">[16]</a>Published studies did not provide evidence that outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by rosiglitazone.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid17636824-14" style="text-decoration-line: none; background: none;">[14]</a><h2 style="margin: 1em 0px 0.25em; padding: 0px; overflow: hidden; border-bottom: 1px solid rgb(162, 169, 177); font-weight: normal; line-height: 1.3; background-color: rgb(255, 255, 255);">Adverse effects[<a href="https://en.wikipedia.org/w/index.php?title=Rosiglitazone&action=edit&section=2" title="Edit section: Adverse effects" style="text-decoration-line: none; background: none; white-space: nowrap;">edit</a>]</h2><h3 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">Heart failure[<a href="https://en.wikipedia.org/w/index.php?title=Rosiglitazone&action=edit&section=3" title="Edit section: Heart failure" style="text-decoration-line: none; background: none; white-space: nowrap;">edit</a>]</h3>One of the safety concerns identified before approval was fluid retention. Moreover, the combination of rosiglitazone with insulin resulted in a higher rate of congestive heart failure. In Europe there were contraindications for use in heart failure and combination with insulin.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid21153629-17" style="text-decoration-line: none; background: none;">[17]</a>A meta analysis of all trials from 2010 and 2019 confirmed a higher risk of heart failure and a double risk when rosiglitazone was administered as add-on therapy to insulin.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid19328563-18" style="text-decoration-line: none; background: none;">[18]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-19" style="text-decoration-line: none; background: none;">[19]</a> Two meta-analyses of real life cohort studies found a higher risk of heart failure compared to pioglitazone.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Chen2012-4" style="text-decoration-line: none; background: none;">[4]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid21415101-20" style="text-decoration-line: none; background: none;">[20]</a> There were 649 excess cases of heart failure every 100,000 patients who received rosiglitazone rather than pioglitazone.<h3 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">Heart attacks[<a href="https://en.wikipedia.org/w/index.php?title=Rosiglitazone&action=edit&section=4" title="Edit section: Heart attacks" style="text-decoration-line: none; background: none; white-space: nowrap;">edit</a>]</h3>The relative risk of ischemic cardiac events seen in pre-approval trials of rosiglitazone was similar to that of comparable drugs, but there was increased LDL cholesterol, LDL/HDL cholesterol ratio, triglycerides and weight.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-21" style="text-decoration-line: none; background: none;">[21]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-22" style="text-decoration-line: none; background: none;">[22]</a>In 2005, at the insistence of the World Health Organization, GSK performed a meta-analysis of all 37 trials involving use of rosiglitazone, finding a hazard ratio of 1.29 (0.99 to 1.89). In 2006 the GSK updated the analysis, now including 42 trials and showing a hazard ratio of 1.31 (1.01 to 1.70). A large observational study comparing patients treated with rosiglitizone with patients treated with other diabetes therapies was performed at the same time and found a relative risk of 0.93 (95% C.I. 0.8 to 1.1) for those treated with rosiglitazone. The information was passed to the FDA and posted on the company website, but not otherwise published. GSK provided these analyses to the FDA, but neither the company nor the FDA warned prescribers or patients of the hazard.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Nissen-23" style="text-decoration-line: none; background: none;">[23]</a> According to the FDA, the Agency did not issue a safety bulletin because the results of the meta analysis conflicted with those of the observational study and with the results of the ADOPT trial.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-24" style="text-decoration-line: none; background: none;">[24]</a>A <a href="https://en.wikipedia.org/wiki/Meta-analysis" title="Meta-analysis" style="text-decoration-line: none; background: none;">meta-analysis</a> in May 2007 reported the use of rosiglitazone was associated with a 1.4 fold increased risk of <a href="https://en.wikipedia.org/wiki/Myocardial_infarction" title="Myocardial infarction" style="text-decoration-line: none; background: none;">heart attack</a> and a numerically higher (but non-significant) increase in risk of death from all cardiovascular diseases against control. It contained 42 trials of which 27 were unpublished.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid17517853-1" style="text-decoration-line: none; background: none;">[1]</a> Another meta analysis of 4 trials with follow-up longer than 1 year found similar results.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Singh_1189%E2%80%9395-25" style="text-decoration-line: none; background: none;">[25]</a> Nissen's meta analysis was criticized in a 2007 article by George Diamond et al. in the <a href="https://en.wikipedia.org/wiki/Annals_of_Internal_Medicine" title="Annals of Internal Medicine" style="text-decoration-line: none; background: none;">Annals of Internal Medicine</a>. The authors concluded that Nissens' analysis had excluded trials with important data on the cardiovascular profile of rosiglitazone, had inappropriately combined trials of greatly differing design, and had inappropriately excluded trials with no cardiovascular events. The authors concluded that no firm conclusion could be drawn regarding whether rosiglitazone increased or decreased cardiovascular risk.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-26" style="text-decoration-line: none; background: none;">[26]</a> Investigators from the <a href="https://en.wikipedia.org/wiki/Cochrane_Collaboration" class="mw-redirect" title="Cochrane Collaboration" style="text-decoration-line: none; background: none;">Cochrane Collaboration</a> published a meta-analysis of their own on the use of rosiglitazone in Type II diabetes, concluding there was not sufficient evidence to show any health benefit for rosiglitazone. Noting the recent publication by Nissen, they repeated their meta analysis including only the trials included in the Nissen study that dealt with Type II diabetics. (The Nissen study included some trials in people with other disorders.) They did not find a statistically significant increase in cardiovascular events, but noted that all of the cardiovascular endpoints they analyzed showed a non-significant trend toward worse outcomes in the rosiglitazone arms.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-27" style="text-decoration-line: none; background: none;">[27]</a>In July 2007 the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. FDA scientist Joy Mele presented a meta analysis examining the cardiovascular risk of rosiglitazone in completed clinical trials. The study found an overall 1.4x increase in risk of cardiovascular ischemic events relative to the control arms. The results were heterogenous, with clear evidence of increased risk relative to placebo but not relative to other diabetes treatments and higher risk associated with combinations of rosiglitazone with insulin or metformin.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-28" style="text-decoration-line: none; background: none;">[28]</a> Based on the 1.4x increased risk relative to control groups, FDA scientist David Graham presented an analysis suggesting that rosiglitazone had caused 83,000 excess heart attacks between 1999 and 2007.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Senatereport-29" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none; background-color: rgb(255, 255, 102);">[</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Senatereport-29" style="background: none; text-decoration-line: none;">29]</a>: 4 <a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Graham-30" style="text-decoration-line: none; background: none;">[30]</a> The advisory panel voted 20 : 3 that the evidence available indicated that rosiglitazone increased the risk of cardiovascular events and 22 : 1 that the overall risk:benefit ratio of rosiglitazone justified its continued marketing in the United States. The FDA placed restrictions on the drug, including adding a [black?] <a href="https://en.wikipedia.org/wiki/Boxed_warning" title="Boxed warning" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none;">boxed warning</a> about heart attacks, but did not withdraw it.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-31" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none;">[31]</a>In 2000 a study to address the concerns regarding cardiovascular safety was requested by the <a href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency" style="text-decoration-line: none; background: none;">European Medicines Agency</a> (EMA). GSK agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed that rosiglitazone was non-inferior to treatment with metformin or a sulfonylurea with respect to the rate of cardiovascular events and cardiovascular death. European regulators concluded that due in part to design limitations, the results neither proved nor eliminated concerns of excess cardiovascular risk.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid21153629-17" style="text-decoration-line: none; background: none;">[17]</a>In February 2010, the FDA's associate director of drug safety, recommended rosiglitazone be taken off the market. In June 2010, they published a retrospective study comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States and concluded rosiglitazone was associated with "an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older".<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid20584880-32" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[32]</a> The <a href="https://en.wikipedia.org/wiki/Number_needed_to_harm" title="Number needed to harm" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none;">number needed to harm</a> with roziglitazone was sixty. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.Two meta analyses released in 2010, one incorporating 56 trials and a second incorporating 164 trials reached conflicting conclusions. Nissen et al. found again an increased risk for heart infarction against control, but no increased risk for cardiovascular death.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid20656674-33" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[33]</a> Mannucci et al. found no statistically significant increase in cardiac events but a significant increase in heart failure.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-34" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[34]</a> A 2011 drug class review found an increased risk of cardiovascular adverse events.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-drug_class_review-35" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none; background-color: rgb(255, 255, 0);">[</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-drug_class_review-35" style="background: none; text-decoration-line: none;">35]</a>A meta-analysis of 16 observational studies released in March, 2011, compared rosiglitazone to pioglitazone, finding support for greater cardiovascular safety for pioglitazone. The meta-analysis involved 810 000 patients taking rosiglitazone or <a href="https://en.wikipedia.org/wiki/Pioglitazone" title="Pioglitazone" style="background: none; text-decoration-line: none;">pioglitazone</a>. The study suggests 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid21415101-20" style="text-decoration-line: none; background: none;">[20]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-36" style="text-decoration-line: none; background: none;">[36]</a> This was confirmed by another meta-analysis involving 945 286 patients in 8 retrospective cohort studies, most in the US.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Chen2012-4" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[4]</a>In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-nytimes.com-37" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none;">[37]</a><h3 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">Death[</h3>There was no difference in all cause and vascular death in a meta-analysis of 4 trials against controls.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-drug_class_review-35" style="text-decoration-line: none; background: none;">[35]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Singh_1189%E2%80%9395-25" style="text-decoration-line: none; background: none;">[25]</a> Two meta-analyses of cohort studies found excess deaths against pioglitazone.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-Chen2012-4" style="text-decoration-line: none; background: none;">[4]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid21415101-20" style="text-decoration-line: none; background: none;">[20]</a><h3 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">Stroke.</h3></div><div>
</div><div>..</div><div><h2 style="margin: 1em 0px 0.25em; padding: 0px; overflow: hidden; border-bottom: 1px solid rgb(162, 169, 177); font-weight: normal; line-height: 1.3; background-color: rgb(255, 255, 255);">History[</h2>Rosiglitazone was approved by the US FDA in 1999 and by the EMA in 2000; the EMA however required two postmarketing studies on longterm adverse effects, one for chronic heart failure and the other for cardiovascular effects.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-ema_recommend_suspend-10" style="text-decoration-line: none; background: none;">[10]</a><h2 style="margin: 1em 0px 0.25em; padding: 0px; overflow: hidden; border-bottom: 1px solid rgb(162, 169, 177); font-weight: normal; line-height: 1.3; background-color: rgb(255, 255, 255);">Society and culture[</h2><h3 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">Sales[</h3>US sales of the drug were of $2.2 billion in 2006.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-47" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[47]</a> Sales in 2Q 2007 down 22% compared to 2006.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-48" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[48]</a> 4Q 2007 sales down to $252 million.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-49" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[49]</a>Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-fallout-50" style="text-decoration-line: none; background: none;">[50]</a><h3 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">Lawsuits[</h3>According to analysts from UBS, 13,000 suits had been filed by March 2010.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-51" style="text-decoration-line: none; background: none;">[51]</a> Included among those suing: <a href="https://en.wikipedia.org/wiki/Santa_Clara_County,California" title="Santa Clara County, California" style="text-decoration-line: none; background: none;">Santa Clara County, California</a>, which claims to have spent $2 million on rosiglitazone between 1999 and 2007 at its public hospital and is asking for "triple damages".<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-52" style="text-decoration-line: none; background: none;">[52]</a> In May 2010, GlaxoSmithKline (GSK) reached settlement agreements for some of the cases against the company, agreeing to pay $60 million to resolve 700 suits.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-53" style="text-decoration-line: none; background: none;">[53]</a> In July 2010, GSK reached settlement agreements to close another 10,000 of the lawsuits against it, agreeing to pay about $460 million to settle these suits.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-54" style="text-decoration-line: none; background: none;">[54]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-55" style="text-decoration-line: none; background: none;">[55]</a> <a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlGSK_settles_bulk_of_Avandia_suits_for$460M-FiercePharma-56" style="text-decoration-line: none; background: none;">[56]</a>In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007. The settlement stems from claims made by four employees of GlaxoSmithKline, including a former senior marketing development manager for the company and a regional vice president, who tipped off the government about a range of improper practices from the late 1990s to the mid-2000s.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-nytimes.com-37" style="text-decoration-line: none; background: none;">[37]</a><h4 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">United States investigations[</h4>GlaxoSmithKline was being investigated by the FDA and the US Congress regarding Avandia.Senators Democrat <a href="https://en.wikipedia.org/wiki/Max_Baucus" title="Max Baucus" style="text-decoration-line: none; background: none;">Max Baucus</a> and Republican <a href="https://en.wikipedia.org/wiki/Charles_Grassley" class="mw-redirect" title="Charles Grassley" style="text-decoration-line: none; background: none;">Charles Grassley</a> filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report noted the drug caused 500 avoidable heart attacks a month, and Glaxo officials sought to intimidate doctors who criticized the drug. It also said GSK continued to sell and promote the drug despite knowing the increased risk of heart attacks and stroke.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlInteractive:Timeline:The_story_of_Avandia|Need_to_Know|PBS-57" style="text-decoration-line: none; background: none;">[57]</a>The <a href="https://en.wikipedia.org/wiki/Senate_Finance_Committee" class="mw-redirect" title="Senate Finance Committee" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none;">Senate Finance Committee</a>, in a panel investigation, revealed emails from GSK company officials that suggest the company downplayed scientific findings about safety risks dating back to 2000. It was also alleged by the committee that the company initiated a "ghostwriting campaign", whereby GSK sought outside companies to write positive articles about Avandia to submit to medical journals.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlAvandias_Fate_May_be_Sealed_Today-58" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[58]</a> GSK defended itself by presenting data that its own tests found Avandia to be safe, although an FDA staff report showed the conclusions were flawed.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlAvandia_Safety_Questioned_Again-59" style="text-decoration-line: none; background: none;">[59]</a>On July 14, 2010, after two days of extensive deliberations, the FDA panel investigating Avandia came to a mixed vote. Twelve members of the panel voted to take the drug off the market, 17 recommended to leave it on but with a more revised warning label, and three voted to keep it on the market with the current warning label.<sup id="cite_ref-url12_panel_members_recommend_Avandia_withdrawal-FiercePharma_60-0" class="reference" style="background-color: rgb(255, 255, 255); line-height: 1; unicode-bidi: isolate; white-space: nowrap;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-url12_panel_members_recommend_Avandia_withdrawal-FiercePharma-60" style="text-decoration-line: none; background: none;">[60]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlWhat_is_the_meaning_of_the_Avandia_vote?-FiercePharma-61" style="text-decoration-line: none; background: none;">[61]</a> The panel has come to some controversy, however; on July 20, 2010, one of the panelists was discovered to have been a paid speaker for GlaxoSmithKline, arousing questions of a conflict of interest. This panel member was one of the three who voted to keep Avandia on the market with no additional warning labels.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-62" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[62]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-63" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none;">[63]</a>In 2011 the FDA has decided on revising its prescribing information and medication guides for all rosilitazone containing medicines. The US label for rosiglitazone (<a href="https://en.wikipedia.org/wiki/Avandia" class="mw-redirect" title="Avandia" style="text-decoration-line: none; background: none;">Avandia</a>, <a href="https://en.wikipedia.org/wiki/GlaxoSmithKline" title="GlaxoSmithKline" style="text-decoration-line: none; background: none;">GlaxoSmithKline</a>) and all rosiglitazone-containing medications (<a href="https://en.wikipedia.org/wiki/Avandamet" class="mw-redirect" title="Avandamet" style="text-decoration-line: none; background: none;">Avandamet</a> and <a href="https://en.wikipedia.org/w/index.php?title=Avandaryl&action=edit&redlink=1" class="new" title="Avandaryl (page does not exist)" style="text-decoration-line: none; background: none;">Avandaryl</a>) now include the additional safety information and restrictions.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid22232110-64" style="text-decoration-line: none; background: none;">[64]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-65" style="text-decoration-line: none; background: none;">[65]</a> The revised labels restrict use to patients already taking a rosiglitazone-containing medicine or to new patients who are unable to achieve adequate glycemic control on other diabetes medications and to those, who in consultation with their healthcare provider, have decided not to take Actos (<a href="https://en.wikipedia.org/wiki/Pioglitazone" title="Pioglitazone" style="text-decoration-line: none; background: none;">pioglitazone</a>) or other pioglitazone-containing medicines for medical reasons.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-66" style="text-decoration-line: none; background: none;">[66]</a>In June 2013 an FDA Advisory Committee reviewed all available data, including a re-adjudicated RECORD trial, found no evidence of increased cardiovascular risk with Avandia, and voted to remove the restrictions on Avandia marketing in the United States. In November 2013, the US FDA removed these marketing restrictions on the product.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-67" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[67]</a> Under the FDA’s instruction, Avandia’s maker, GlaxoSmithKline, had funded the Duke Clinical Research Institute to re-analyze the raw data from the study. At the 2010 panel, three panelists voted that the existing warnings were good enough; two were back in 2013. Seven voted to make those warnings more onerous, and five of them returned. But of the 10 who voted to restrict Avandia’s use, only four returned. And of the 12 who voted in 2010 to withdraw Avandia from the market, only three came back.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-68" style="text-decoration-line: none; background: none;">[68]</a><h4 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">European investigations[</h4>In 2000 a study to address the concerns regarding cardiovascular safety was requested by the EMA, and the makers agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed non-inferiority with regard to cardiovascular events and cardiovascular death when the treatment with rosiglitazone was compared with metformin or a sulfonylurea. For myocardial infarction, there was a non-statistically significant increase in risk. In their assessment, the European regulators acknowledged weaknesses of the study, such as an unexpectedly low rate of cardiovascular events and the <a href="https://en.wikipedia.org/wiki/Open-label_trial" title="Open-label trial" style="text-decoration-line: none; background: none;">open-label</a> design, which may lead to reporting bias. They found that the results were inconclusive.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid21153629-17" style="text-decoration-line: none; background: none;">[17]</a> The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-ema_recommend_suspend-10" style="text-decoration-line: none; background: none;">[10]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-bbc_ema_suspension-11" style="text-decoration-line: none; background: none;">[11]</a>According to a probe by the <a href="https://en.wikipedia.org/wiki/British_Medical_Journal" class="mw-redirect" title="British Medical Journal" style="text-decoration-line: none; background: none;">British Medical Journal</a> in September 2010, the United Kingdom's Commission on Human Medicines recommended to the Medicines and Healthcare Products Regulatory Agency (MHRA) back in July 2010, to withdraw Avandia sale because its "risks outweigh its benefits". Additionally, the probe revealed that in 2000, members of the European panel in charge of reviewing Avandia prior to its approval had concerns about the long-term risks of the drug.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-69" style="text-decoration-line: none; background: none;">[69]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlU.K.watchdogs_vote_for_Avandia_withdrawal%E2%80%93_FiercePharma-70" style="text-decoration-line: none; background: none;">[70]</a><h4 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">New Zealand[</h4>Rosiglitazone was withdrawn from the New Zealand market April 2011 because <a href="https://en.wikipedia.org/wiki/Medsafe" title="Medsafe" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none;">Medsafe</a> concluded the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-71" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[71]</a><h4 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6;">South Africa[</h4>A notice issued by the Medicines Control Council of South Africa on July 5, 2011 stated that it had resolved on July 3, 2011 to withdraw all rosiglitazone-containing medicines from the South African market due to safety risks. It disallowed all new prescriptions of Avandia.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-MCC-72" style="background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; text-decoration-line: none; background-color: rgb(255, 255, 102);">[7</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-MCC-72" style="background: none; text-decoration-line: none;">2]</a><h3 style="margin: 0.3em 0px 0px; padding-top: 0.5em; padding-bottom: 0px; overflow: hidden; line-height: 1.6; background-color: rgb(255, 255, 255);">Controversy and response[</h3>Following the reports in 2007 that Avandia can significantly increase the risk of heart attacks, the drug has been controversial. A 2010 article in Time uses the Avandia case as evidence of a broken FDA regulatory system that "may prove criminal as well as fatal". It details the disclosure failures, adding, "Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug, and that the FDA knew of the dangers months before it informed the public." It reports, "the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandia's heart risks", according to deputy FDA commissioner Dr. Joshua Sharfstein. GSK threatened academics who reported adverse research results, and received multiple warning letters from the FDA for deceptive marketing and failure to report clinical data.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlTIME-73" style="text-decoration-line: none; background: none;">[73]</a> The maker of the drug, GlaxoSmithKline, has dealt with serious backlash against the company for the drug's controversy.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlWill_Avandia_Be_Yanked_Off_the_Market?-US_News-74" style="text-decoration-line: none; background-image: none; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial;">[74]</a> Sales on the drug dropped significantly after the story first broke in 2007, dropping from $2.5 billion in 2006 to less than $408 million in 2009 in the US.<sup id="cite_ref-urlExclusive:Takeda_launches_Actos_DTC_campaign_today–Medical_Marketing_and_Media_75-0" class="reference" style="background-color: rgb(255, 255, 255); line-height: 1; unicode-bidi: isolate; white-space: nowrap;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlExclusive:Takeda_launches_Actos_DTC_campaign_today%E2%80%93_Medical_Marketing_and_Media-75" style="text-decoration-line: none; background: none;">[75]</a>In response to the rise in risk of heart attacks, the Indian government ordered GSK to suspend its research study, called TIDE, in 2010.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlwww.pharmalot.com-76" style="text-decoration-line: none; background: none;">[76]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlAvandia_Drug_Trials_Shut_Down_In_India%C2%AB_CBS_Detroit-77" style="text-decoration-line: none; background: none;">[77]</a> The FDA also halted the TIDE study in the United States.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-foodconsumer.org-78" style="text-decoration-line: none; background: none;">[78]</a>Three doctors' groups, the <a href="https://en.wikipedia.org/wiki/Endocrine_Society" title="Endocrine Society" style="text-decoration-line: none; background: none;">Endocrine Society</a>, the <a href="https://en.wikipedia.org/wiki/American_Diabetes_Association" title="American Diabetes Association" style="text-decoration-line: none; background: none;">American Diabetes Association</a> and the <a href="https://en.wikipedia.org/wiki/American_Association_of_Clinical_Endocrinologists" title="American Association of Clinical Endocrinologists" style="text-decoration-line: none; background: none;">American Association of Clinical Endocrinologists</a>, urged patients to continue to take the drug as it would be much worse to stop all treatment, despite any associated risk, but that patients could consult their doctors and begin a switch to a different drug if they or their doctors find concern.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-79" style="text-decoration-line: none; background: none;">[79]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-80" style="text-decoration-line: none; background: none;">[80]</a><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-81" style="text-decoration-line: none; background: none;">[81]</a> The <a href="https://en.wikipedia.org/wiki/American_Heart_Association" title="American Heart Association" style="text-decoration-line: none; background: none;">American Heart Association</a> said in a statement in June 2010: " ...the reports deserves serious consideration, and patients with diabetes who are 65 years of age or older and being treated with rosiglitazone should discuss the findings with their prescribing physician....". "For patients with diabetes, the most serious consequences are heart disease and stroke, and the risk of suffering from them is significantly increased when diabetes is present. As in most situations, patients should not change or stop medications without consulting their healthcare provider."<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-82" style="text-decoration-line: none; background: none;">[82]</a><sup id="cite_ref-urlAmerican_Heart_Association_Comment:Advisory_Committee_Recommends_that_U.S.Food_and_Drug_Administration_Keep_Rosiglitazone(Avandia)on_the_Market,Continue_Clinical_Trial_of_Safety_and_Efficacy–Health_News–redOrbit_83-0" class="reference" style="line-height: 1; unicode-bidi: isolate; white-space: nowrap;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-urlAmerican_Heart_Association_Comment:Advisory_Committee_Recommends_that_U.S.Food_and_Drug_Administration_Keep_Rosiglitazone(Avandia)on_the_Market,Continue_Clinical_Trial_of_Safety_and_Efficacy%E2%80%93_Health_News%E2%80%93_redOrbit-83" style="text-decoration-line: none; background: none;">[83]</a>As a result of the Avandia Affair, FDA required that cardiac safety be demonstrated for new drugs to treat type 2 diabetes. This process is described by Dr Robert Misbin in INSULIN-History from an FDA Insider, published June 1, 2020 on Amazon. Dr Misbin was the first FDA reviewer for rosiglitazone (Avandia) and cautioned about its potential to increase the risk of cardiovascular disease.<h2 style="margin: 1em 0px 0.25em; padding: 0px; overflow: hidden; border-bottom: 1px solid rgb(162, 169, 177); font-weight: normal; line-height: 1.3; background-color: rgb(255, 255, 255);">Research[</h2>Rosiglitazone was thought to be able to benefit patients with <a href="https://en.wikipedia.org/wiki/Alzheimer%27s_disease" title="Alzheimer's disease" style="text-decoration-line: none; background: none;">Alzheimer's disease</a> who do not express the <a href="https://en.wikipedia.org/wiki/Apolipoprotein_E" title="Apolipoprotein E" style="text-decoration-line: none; background: none;">ApoE4</a> <a href="https://en.wikipedia.org/wiki/Allele" title="Allele" style="text-decoration-line: none; background: none;">allele</a>,<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid16446752-84" style="text-decoration-line: none; background: none;">[84]</a> but the phase III trial designed to test this showed that rosiglitazone was ineffective in all patients, including <a href="https://en.wikipedia.org/wiki/Apolipoprotein_E" title="Apolipoprotein E" style="text-decoration-line: none; background: none;">ApoE4</a>-negative patients.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid20733306-85" style="text-decoration-line: none; background: none;">[85]</a>Rosiglitazone may also treat mild to moderate <a href="https://en.wikipedia.org/wiki/Ulcerative_colitis" title="Ulcerative colitis" style="text-decoration-line: none; background: none;">ulcerative colitis</a>, due to its anti-inflammatory properties as a PPAR ligand.<a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_note-pmid18471502-86" style="text-decoration-line: none; background: none;">[86]</a>...<ol class="references" style="margin: 0px 0px 0px 3.2em; padding: 0px; list-style-image: none; counter-reset: mw-ref-extends-parent 0 list-item 0; list-style-type: inherit; background-color: rgb(255, 255, 255);"><li id="cite_note-62" style="margin-bottom: 0.1em; counter-increment: mw-ref-extends-parent 1; counter-reset: mw-ref-extends-child 0; break-inside: avoid-column; background-color: rgb(234, 243, 255);"> <cite id="CITEREFMundy_A2010" class="citation news cs1" style="font-style: inherit; overflow-wrap: break-word;">Mundy A (2010-07-20). <a rel="nofollow" class="external text" href="https://www.wsj.com/articles/SB10001424052748704720004575377552600421936" style="text-decoration-line: none; background: url("");" w="w" resources="resources" src="src" mediawiki.skinning="mediawiki.skinning" images="images" external-ltr.svg="external-ltr.svg" right="right" center="center" no-repeat="no-repeat" padding-right="padding-right" px="px">"Panelist Who Backed Avandia Gets Fees From Glaxo"</a>. The Wall Street Journal.</cite><span title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=The+Wall+Street+Journal&rft.atitle=Panelist+Who+Backed+Avandia+Gets+Fees+From+Glaxo&rft.date=2010-07-20&rft.au=Mundy+A&rft_id=https%3A%2F%2Fwww.wsj.com%2Farticles%2FSB10001424052748704720004575377552600421936&rfr_id=info%3Asid%2Fen.wikipedia.org%3ARosiglitazone" class="Z3988" /></li></ol><div>
</div><div><div style="">Panelist Who Backed Avandia Gets Fees From Glaxo</div><div style="">By Alicia Mundy</div><div style="">Updated July 20, 2010 2:29 am ET</div><div style="">WASHINGTON—One of the panelists who voted in favor of the diabetes drug Avandia at a Food and Drug Administration advisory meeting last week is a paid speaker for the drug's maker, GlaxoSmithKline PLC, according to the company and its records.</div><div style="">
</div><div style="">The panel voted 20-12 to keep Avandia on the market, though most of the members wanted stronger warnings.</div></div><ol class="references" style="margin: 0px 0px 0px 3.2em; padding: 0px; list-style-image: none; counter-reset: mw-ref-extends-parent 0 list-item 0; list-style-type: inherit; background-color: rgb(255, 255, 255);"><li id="cite_note-63" style="margin-bottom: 0.1em; counter-increment: mw-ref-extends-parent 1; counter-reset: mw-ref-extends-child 0; break-inside: avoid-column;"><a href="https://en.wikipedia.org/wiki/Rosiglitazone#cite_ref-63" aria-label="Jump up" title="Jump up" style="text-decoration-line: none; background: none;">^{</a> }<cite id="CITEREFGallagher2010" class="citation news cs1" style="font-style: inherit; overflow-wrap: break-word;">Gallagher, James (2010-07-20). <a rel="nofollow" class="external text" href="http://triangle.bizjournals.com/triangle/stories/2010/07/19/daily18.html" style="text-decoration-line: none; background: url("");" w="w" resources="resources" src="src" mediawiki.skinning="mediawiki.skinning" images="images" external-ltr.svg="external-ltr.svg" right="right" center="center" no-repeat="no-repeat" padding-right="padding-right" px="px">"Report: Avandia panelist paid by GSK"</a>.</cite></li></ol><div>
</div></div><div>of the three panelists who recommended that the U.S. Food and Drug Administration allow GlaxoSmithKline to continue marketing Avandia with no further restrictions is a paid speaker for the drug company, reports The Wall Street Journal.The newspaper is reporting that endocrinologist David Capuzzi of Philadelphia was paid $14,750 to promote London-based GSK’s (NYSE: GSK) Lovaza. The Journal reports that Capuzzi said he informed the FDA of that arrangement and that he has given no talks regarding Avandia.Capuzzi was one of 33 experts convened by the FDA last week to make a recommendation on whether the regulatory agency should pull the diabetes drug from the market. Avandia has been linked to a 43 percent increase in heart attacks, and GSK, which has its North American headquarters in Research Triangle Park and employs about 5,000 across the Triangle, reportedly paid $460 million to settle 10,000 lawsuits related to the drug.The panel voted 20-12, with one abstention, to allow GSK to continue selling the drug, albeit with stricter regulation and warning labels. Capuzzi was one of three individuals on the panel who saw no need for stricter regulations.The revelations about Capuzzi’s speaking deal come as the National Institutes of Health, the primary backer for medical research in the U.S., works to strengthen its ethics and conflict of interest policies to prevent medical researchers who are paid to speak by drug companies from lending their expertise in research studies. The NIH and FDA operate under different guidelines.</div><div>=
<div><a href="https://www.jstor.org/stable/26950193">https://www.jstor.org/stable/26950193</a></div><div>
<div><div>Big data’s big bias</div><div>Jeanne Lenzer</div><div>BMJ: British Medical Journal</div><div>(4 pages)</div><div>Published By: BMJ</div><div>BMJ: British Medical Journal</div><div>https://www.jstor.org/stable/26950193</div><div>
</div><div>...Gottlieb has long supported deregulation of the FDA and ... intimidation of Dr John Buse and the diabetes drug Avandia....</div></div><div>=</div><div><p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">WASHINGTON, Nov 20 (Reuters) - Two U.S. lawmakers said on Tuesday they want to interview a former GlaxoSmithKline <a href="https://www.reuters.com/companies/GSK.L" style="margin: 0px; padding: 0px; border-width: 0px 0px 1px; border-top-style: initial; border-right-style: initial; border-bottom-style: dotted; border-left-style: initial; border-top-color: initial; border-right-color: initial; border-bottom-color: rgb(18, 143, 221); border-left-color: initial; border-image: initial; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; line-height: inherit; vertical-align: baseline; text-decoration-line: none;">GSK.L</a> official as they probe whether a prominent diabetes doctor was pressured by the company for criticizing its drug Avandia.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">Senate Finance Committee Chairman Max Baucus, a Montana Democrat, and Iowa Republican Charles Grassley are seeking information from former Glaxo research chief Tadataka Yamada, as they investigate whether the company tried to intimidate Dr. John Buse, now president of the American Diabetes Association.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">A New England Journal of Medicine analysis published in May suggested a 43 percent boost in heart attack risk linked to the diabetes drug.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">Last week, U.S. regulators slapped Avandia’s packaging with a black box warning about that risk, the strongest label the Food and Drug Administration gives to warn of side effects.Dr. Buse, also director of the University of North Carolina diabetes center, had spoken years earlier at medical meetings about Avandia’s potential negative impact on the heart. He also wrote a letter in 2000 to the FDA about his concerns.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">Glaxo has said that a fair examination of its interactions with Dr. Buse shows Glaxo was trying to correct inaccuracies about data on Avandia in a 1999 presentation by Dr Buse. It says the presentation was sponsored by Takeda Pharmaceutical <a href="https://www.reuters.com/companies/4502.T" style="margin: 0px; padding: 0px; border-width: 0px 0px 1px; border-top-style: initial; border-right-style: initial; border-bottom-style: dotted; border-left-style: initial; border-top-color: initial; border-right-color: initial; border-bottom-color: rgb(18, 143, 221); border-left-color: initial; border-image: initial; font-style: inherit; font-variant: inherit; font-weight: inherit; font-stretch: inherit; line-height: inherit; vertical-align: baseline; text-decoration-line: none;">4502.T</a>, maker of a competing drug called Actos.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">Yamada was research chief at Glaxo until recently joining the Bill and Melinda Gates Foundation.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">“You played a significant role in developing and implementing GSK’s (GlaxoSmithKline’s) strategy for dealing with Dr. Buse’s public airing of the his concerns about the cardiovascular risk associated with Avandia,” the senators wrote in a letter dated Nov. 16.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">A representative for Dr. Yamada said he would be willing to meet with congressional staff. g<span style="font-family: " times="Times" new="New" roman="Roman" font-size="font-size" large="large" font-style="font-style" inherit="inherit" font-variant-ligatures="font-variant-ligatures" font-variant-caps="font-variant-caps" font-weight="font-weight" letter-spacing="letter-spacing" px="px" text-transform="text-transform" uppercase="uppercase">laxoSmithKline spokeswoman was not available for comment.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">Dr. Buse was traveling on Tuesday and could not be reached for comment.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">At a congressional hearing in June, Buse testified he was quickly targeted by some employees of SmithKline Beecham, now a part of GlaxoSmithKline. He said it was mentioned that some in the company felt his actions were sufficient for him to be held liable for a loss in the company’s market capitalization.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">Buse said he later signed a clarifying statement drafted by the company.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">Glaxo said in a statement e-mailed to Reuters on Tuesday that because of the seriousness of Dr. Buse’s misstatements, a number of options were raised, including possible legal action, but ultimately he clarified and corrected his statements and the company also apologized to Dr. Buse.<p class="Paragraph-paragraph-2Bgue ArticleBody-para-TD_9x" style="margin: 30px 0px 30px 7vw; padding: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-stretch: inherit; line-height: 1.6; vertical-align: baseline; -webkit-font-smoothing: antialiased; overflow-wrap: break-word; word-break: break-word;">“Dr. Buse has publicly indicated that he has long since moved on from the events of 1999, and so has GSK,” the company said. (Reporting by Kim Dixon; Editing by Tim Dobbyn)</div><div>=</div><div>
</div><div>https://www.scoop.co.nz/stories/HL0708/S00239/fda-henchmen-protect-avandia-profits.htm<div>
</div><div>"...Evelyn PringleThe FDA's latest campaign to protect the profits of a drug company over the safety of Americans is unprecedented, and the organizers include a gang of current and former FDA officials largely credited with turning the nation's regulatory beagle into a lapdog for Big Pharma under the Bush Administration.FDA spokesman Douglas Arbesfeld, apparently the industry's new inside guy, kicked off the campaign by sending an e-mail to journalists which was intended to discredit Dr Steven Nissen and the Cleveland Clinic. Dr Nissen's study appeared online on May 21, 2007, in the New England Journal of Medicine and warned that GlaxoSmithKline's diabetes drug Avandia increased the risk of heart attacks by 43% and death from cardiovascular events by possibly 64%.The talking points for the media appear to have been formulated and agreed upon ahead of time between Arbesfeld and others (see below) because more than one story from ostensibly different sources later appeared in the media and on the internet referring to Dr Nissen with such names as "St Steven", "Patron Saint of Drug Safety" and "Saint Steven the Pure."In his email to journalists, Mr Arbesfeld pasted portions of an article which appeared on the Heartwire website, containing umpteen critical comments about Dr Nissen and the Avandia study, as well as comments made by an anonymous blogger on the internet who said that business at the Cleveland Clinic is run similar to a Mafia TV series. The full bog states:<div class="article-left-box-wrapper" style=""><div class="article-left-box" style="background-image: initial; background-position: initial; background-size: initial; background-repeat: initial; background-attachment: initial; background-origin: initial; background-clip: initial; float: left; clear: left; margin: 20px 0px 20px -20px; padding: 0px 20px 0px 0px;"><div class="headline-right" style=""><div id="div-gpt-ad-1493962836337-4" data-google-query-id="CNqHrsjelfMCFQoCoQodlCIDWQ" style=""><div id="google_ads_iframe/1688062/Scoop_Super-Rectangle_0container" style="border: 0pt none;"><div id="div-gpt-ad-1631171064832-0" style="background-color: white;">"Wake up pharmaceutical companies, this is a call from Dr. Nissen, if you don't hire the Cleveland Clinic for your big trials then you face the firing squad from Nissen and Company.""The Cleveland Clinic was one of the most respected names in medicine, now they are positioning themselves as candidates to take over for a new series on HBO to replace the Soprano's — the Clinico's 'next week who should we wack ......' — Bata bing bata boon. Comment by Brian A - May 22, 2007."However, it could just as easily be inferred that Mr Arbesfeld authored the slanderous blog and supplied it to Heartwire with the intention of quoting it later from a “reputable” web site. For its part, Heartwire has since removed what it says are "unsubstantiated remarks about Dr Nissen and the Cleveland Clinic," and states: "In retrospect we regret that we published those sentences, as they do not meet the highest standards of journalistic or scientific integrity or credibility."The smear campaign has federal lawmakers up in arms. At a June 6, 2007 hearing before the House Oversight and Government Reform Committee, in response to questions about Mr Arbesfeld sending the e-mail under his official title of FDA spokesman, FDA Commissioner Andrew von Eschenbach told the lawmakers, "It was an inappropriate and unfortunate act on the part of an individual which has been addressed through disciplinary procedures."Dr Nissen is none too happy about the stunt either. "I'm a pretty tough guy," he told ABC News on May 30, 2007, "but I'll tell you, having this kind of an e-mail that questions my motives, broadcast to the major journalists with whom I work and have established a reputation, is -- it's an outrage."As for his part, Mr Arbesfeld told the Boston Globe that the email reflected his own personal views and not the FDA's. Any assertion that the email reflected his own personal views is not quite credible considering that his previous employment was always promoting the views of the industry.A few articles in the media mentioned that Mr Arbesfeld worked for Johnson & Johnson, but his employment with public relations firm Manning Selvage & Lee was not noted. On December 16, 1999, the Healthcare Marketing & Communications Council reported that Mr Arbesfeld had joined Manning as Senior Vice President in New York.On January 5, 2001, the firm issued a press release to announce the promotion of Mr Arbesfeld and others and referred to Manning as "one of the largest healthcare practices worldwide and has a broad array of clients including Allergan, Amgen, Eli Lilly and Company, Genentech, Hoffmann La-Roche, Kaiser Permanente, Novartis, Pharmacia and Procter & Gamble."In reading the press release, Mr Arbesfeld's expertise with using the Internet is apparently a bi-product of his work for Manning. "In this role," it said, "Arbesfeld will help healthcare clients maximize internet-relations in the marketing and communications mix, and will expand the Practice's strategic e-product offerings."On August 5, 2002, Arbesfeld identified himself in a Reuters article as representing none other than Glaxo, along with six other drug giants including Bristol-Myers, Aventis, J&J, AstraZeneca, Abbott Labs and Novartis, in a campaign to promote the "Together Rx" prescription drug card program for senior citizens. In 2005, the Reporters Handbook listed him as the contact person for J&J subsidiaries, Janssen Pharmaceutica, Ortho-McNeil Pharmaceutical and Ortho Biotech Products.Less than a week after Mr Arbesfeld's hatchet job on Dr Nissen, ex-FDA Deputy Commissioner Dr Scott Gottlieb planted an editorial in the May 29, 2007, Wall Street Journal entitled, "Journalist Malpractice," accusing the New England Medical Journal of intentionally publishing the Nissen study to make the FDA look impotent. "The publication was timed," he wrote, "to get ahead of the Food and Drug Administration's more careful evaluation of the same issues.""The journal seemed bent on beating the FDA to the punch," Dr Gottlieb claimed."The goal?" he said, "Painting the FDA as impotent, in order to argue for legislation winding through Congress that would increase regulatory hurdles for drug approvals."The only problem with the Nissen-NEJM conspiracy theory is that the issue under investigation in Congress right now is why the FDA did not warn the public about Avandia heart risks six months before the Nissen study was ever published.In the end, when it comes to "Journalistic Malpractice," the larger question would seem to be how was it that so many industry shills were able to get the major media outlets and medical journals to immediately publish commentaries and editorials attacking the NEJM and the Nissen research with headlines splashing all over the internet.In his editorial, Dr Gottlieb notes that there are "questions" whether Avandia is associated with heart risks, but says they are "so far unsupported by more rigorous, randomized studies and extensive review by the FDA and other authorities around the world.""When it comes to the issue du jour, drug safety," he wrote, "no description of medical research in a medical journal comes close to the detail level or scrutiny imposed by the FDA on study results before approval."Assuming this is true, the problem is that the industry insiders running the FDA refuse to act on the advice of the agency's top scientists with first hand access to the underlying data. In a July 26, 2007 speech on the Senate floor, Senator Charles Grassley (R-Iowa), of the Senate Finance Committee, said that, in the case of Avandia, "Not only did the FDA disregard the concerns and recommendations from the office responsible for post-marketing surveillance, but I have found that it also attempted to suppress scientific dissent."In the past two months, he told his fellow senators, "I've had to write to the FDA regarding the suppression of dissent from not one but two FDA officials involved in the review of Avandia."The Heartwire website conveniently echoed Dr Gottlieb's sentiments by featuring portions of a May 23, 2007, unsigned editorial from the medical journal The Lancet, which claimed that the verdict on Avandia should await the results of a Glaxo sponsored trial called RECORD, not due out until 2009."Taken together," the editorial said of Dr Nissen's findings, "these results, although based on very small numbers of events, certainly raise a signal of concern and indicate the need for more reliable information about rosiglitazone's safety.""But the FDA, physicians, and patients can reasonably await the results of RECORD, a phase 3 trial designed specifically to study cardiovascular outcomes," it said."Until the results of RECORD are in," the Lancet noted, "it would be premature to overinterpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses."The problem with waiting two years for the results of the RECORD trial is that FDA scientist Dr David Graham reviewed the results of this study thus far and told an FDA advisory panel that the study design is so flawed that the results should not be considered in any risk benefit analysis of Avandia now, or in 2009.In fact, Dr Graham says the RECORD study is so useless that it is probably unethical to allow it to continue because no possible benefit can be achieved by allowing it to go on and that Avandia should be pulled off the market now because thousands of patients are being injured each month by using the drug.At the end of his editorial, Dr Gottlieb lists himself as a physician and a resident fellow at the American Enterprise Institute, as well as former Deputy Commissioner of the FDA from 2005 to 2007. However, back on August 24, 2005, the Seattle Times provided a much better picture of his background and highlighted the oddity of the FDA hiring him in the first place in light of his solid alliance with the industry. "Only a month ago," the article states, "Dr Scott Gottlieb was a Wall Street insider, promoting hot biotech stocks to investors."At the time, the Times noted, "Now Gottlieb holds the No. 2 job at the federal agency that approves new drugs, oversees their safety and affects the fortunes of companies he once touted.""Now, as one of three deputy commissioners," the article said, "Gottlieb will help oversee such major policies as the FDA's fast-track approval process for drug and biotech products, a priority for many Wall Street funds and the pharmaceutical industry."The Times also noted that a half-dozen current and former FDA officials said they did not know of anyone else from Wall Street ever moving directly into such a high-level job at the agency.A couple months later, the November 12, 2005, Boston Globe reported that Dr Gottlieb could not participate in formulating the nation's defense plan against the avian flu due to conflicts of interest. He "was recused from key parts of the planning effort because his past consulting work for Manning Selvage & Lee involved companies whose products would be used to combat a flu pandemic," it said. Yes, the very same Manning Selvage & Lee at which Arbesfeld held the Senior Vice President position. Does anyone smell a rat (or several)?The article pointed out that Dr Gottlieb's former clients included Roche, the manufacturer of Tamiflu, and Sanofi-Aventis, the parent company of the nation's sole flu vaccine maker.According to the Globe, Manning paid Gottlieb a $12,500 monthly retainer for nine months for projects that included eight companies, and he was also paid $9,000 for private consulting work for VanGen Inc, a firm that won a $878-million contract to supply the US government with 75 million doses of anthrax vaccine.Dr Nissen and Dr Gottlieb's disputes are not new. In fact, on August 2, 2006, they participated in a debate on the topic: "Government Science Panels: Fair and Balanced?" sponsored by the Center for Science in the Public Interest, and reported on by Russell Mokhiber and Robert Weissman in Common Dreams.Likewise, lawmakers have mentioned in their communications with the FDA that they found it "troubling" that Mr Arbesfeld might be trying to settle old scores with Dr Nissen because they were on opposite sides regarding the approval of the heart failure drug Natrecor.Much to his credit, Dr Nissen openly communicated his objections to the industry's infiltration of the FDA. While sitting right next to Dr Gottlieb, he candidly described the conflicts of interest, which he stated were "evident at the highest levels of the FDA.""For years," he said of FDA leadership, "we had an interim FDA Commissioner, Lester Crawford, who shortly after confirmation, abruptly resigns, apparently because he and his wife owned stock in regulated companies.""Then the administration appointed Andrew von Eschenbach as interim commissioner creating another conflict," he said. "In his role as director of the National Cancer Institute, von Eschenbach must seek FDA approval for human testing or approval of new cancer drugs, an obvious conflict," he noted."But even worse," Dr Nissen stated, "the administration appointed Scott Gottlieb as deputy commissioner.""He came to this job with no regulatory experience, directly from Wall Street, where he served as a biotech analyst and stock promoter," Dr Nissen told the audience.Dr Gottlieb's response to Dr Nissen's comments was, in essence, that he would not dignify the comments with a response.Firms with which Dr Gottlieb was involved prior to his gig at the FDA, according to the Globe, also include the Inamed Corp, one of two companies that were seeking to return silicone gel implants to the market and on November 17, 2006, the FDA announced that it would lift restrictions on the sale of the implants.When Dr Gottlieb left the FDA, he headed right back to greener pastures with the drug giant Novartis. The press release to announce his hiring read: "Bench International Places Eminent Regulatory Advisor Scott Gottlieb, M.D., as Senior Counsel to Novartis.""Under an exclusive consulting agreement," the release stated, "Scott Gottlieb, M.D., will provide advisory services to Novartis on matters of global regulatory policy and strategy."
Two more members of FDA’s alumni, Peter Pitts and Robert Goldberg took another swipe at Dr. Nissen in a June 6, 2007 commentary in the Washington Times, using the same talking points as the anonymous blogger, likewise referring to Dr. Nissen as a “self-appointed and media-anointed Patron Saint of Drug Safety” and “Saint Steven the Pure.”For much of the childish commentary, they poke fun at Dr Nissen because he acknowledged in the NEJM that he consults for many drug companies but said he "requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction."At the end of the commentary, Mr Pitts says he is a former FDA associate commissioner, and both men list their affiliation with the Center for Medicine in the Public Interest; but as usual, that listing really does not give credit where credit is due.On its web site, the Center describes itself as "a non-partisan, non-profit educational charity," and Mr Pitts is indeed listed as President, but his bio also says he is the Senior Vice President for Global Health Affairs at none other than Manning, Selvege & Lee.The Manning firm apparently fills two important roles. It's a breeding ground for industry moles preparing to enter "public service" and serves as an employment hub for industry shills once they finish their on average 2- to 3-year stint inside the Bush Administration.In his CMPI bio, Mr Pitts describes his duties as the FDA's Associate Commissioner from 2002 to 2004 as serving as the agency's "Chief Messaging Officer."On June 7, 2007, Mr Pitts had this to say in defense of fellow hit-man Mr Arbesfeld on the Pharmalot web site: "I know Doug Arbesfeld and he is a guy devoted to advancing the public health."According to Mr Pitts, in sending the derogatory e-mail about Dr Nissen to journalists, Mr Arbesfeld was just standing up for the FDA and that people should know about the sacrifice he made by accepting a job in government."He is also a guy," Mr Pitts says, "who took a pretty significant pay cut to put in some time in public service."Some would no doubt argue that it's difficult to imagine that Mr Arbesfeld will end up in the poor house as a result of serving as the top industry mole inside the FDA.Mr Pitts' sidekick, Mr Goldberg, is indeed listed as the vice president of CMPI, but Mr Goldberg's bio also says he used to be Director of the Manhattan Institute's Center for Medical Progress and Chairman of its 21st Century FDA Task Force.In fact, a review of the CMPI web site turned up a whole nest of ex-moles who served the industry in one capacity or another in the Bush Administration's FDA. For instance, Daniel Troy, the former FDA Chief Counsel, also known as the "Godfather of Preemption," sits on this "charity's" Advisory Board.Troy’s bio points out that he "played a principal role in FDA’s generally successful assertion of preemption in selected product liability cases."This "assertion of preemption" says that, as long as the FDA has approved a drug and its label, private citizens in state courts cannot sue the drug company for failing to warn about a product's serious health risks, even in cases where it can be shown that the company concealed studies that revealed the risk from the public and the FDA.Now that he's switched back to private practice, Mr Troy's CMPI bio says he currently specializes in constitutional and appellate litigation, as well as strategic counseling with "particular focus" on what else - clients regulated by the FDA.The Advisory Board also includes, Tomas Philipson, whose bio says he served as the Senior Economic Advisor to the commissioner of FDA during 2003 and 2004 and as the Senior Economic Advisor to the administrator of the Centers for Medicare and Medicaid Services in 2004 and 2005.That would mean that Mr Philipson served Mark McClellan, and they are now apparently joined at the hip because, as part of a program called "Patient-Centric and Prospective Medicine," CMPI says it has created the Patient-Centric Health Forum and that Mr McClellan, "former Medicare administrator and FDA commissioner, will chair the group."So, it would appear that anyone looking for the retirement home for industry hit men who served in the Bush Administration's FDA can find it right in the middle of cyberspace on the CMPI web site.Persons seeking legal advice regarding Avandia can contact Baum, Hedlund, Aristei, Goldman & Menzies Law Firm at: (800) 827-0087; <a href="http://www.baumhedlundlaw.com/" target="blank" style="text-decoration-line: none;">http://www.baumhedlundlaw.com/</a>
<a href="http://www.avandia-heart-lawyers.com/" target="blank" style="text-decoration-line: none;">http://www.avandia-heart-lawyers.com/</a>.<center style="background-color: white;">*</center><a name="a">Evelyn Pringle
evelyn-pringle@sbcglobal.net</a>(Evelyn Pringle is a columnist for OpEd News and an investigative journalist focused on exposing corruption in government and corporate America)
(This article is part of the Avandia Update series sponsored by the Baum Hedlund law firm)=clASS ACTION?<a href="https://www.bloomberg.com/news/articles/2010-07-13/glaxosmithkline-is-said-to-pay-460-million-to-settle-avandia-damage-suits">https://www.bloomberg.com/news/articles/2010-07-13/glaxosmithkline-is-said-to-pay-460-million-to-settle-avandia-damage-suits</a>
Bloomberg BusinessGlaxo Said to Pay $460 Million to End Avandia SuitsJef Feeley and Trista KelleyJuly 13, 2010, GlaxoSmithKline Plc agreed to pay about $460 million to resolve a majority of lawsuits alleging the company’s Avandia diabetes drug can cause heart attacks and strokes, people familiar with the accords said.Glaxo, the U.K.’s biggest drugmaker, agreed to settle about 10,000 suits for an average of at least $46,000 apiece, the people said. The company had been facing more than 13,000 suits alleging Glaxo hid the drug’s heart-attack risk, according to a UBS AG analyst. The settlements come as Glaxo is set to face its first Avandia trial in federal court in Philadelphia in October.<div style="background-color: white;">
</div>=odd no mention of crime settlement?https://www.fiercepharma.com/pharma/gsk-s-avandia-free-and-clear-at-fda-8-years-after-heart-safety-controversy-beganfiercePharma no lnxGSK's Avandia is free and clear at the FDA, 8 years after heart-safety controversy beganby Tracy Staton | Dec 17, 2015 The long saga of Avandia's disgrace is over. The FDA has lifted the final layer of safety measures on the GlaxoSmithKline ($GSK) diabetes drug, 8 years after researchers flagged an apparent increase in the risk of heart attack, and at least three years too late to make a difference in sales. The safety questions drove Avandia revenues down from a peak of $3 billion before the controversy to $183 million in 2011, just before generics hit the market.In a safety communication Wednesday, the FDA said its "continued monitoring" of Avandia, Avandamet and Avandaryl had turned up "no new pertinent safety information" about the drug.An outcry over those red flags--prompted by a meta-analysis published by the New England Journal of Medicine--spurred the agency to slap harsh limits on the drug in 2010. Those restrictions essentially shrank Avandia's market to the very few patients whose doctors were willing to brave the red tape necessary to write a script. European regulators withdrew the drug altogether.Avandia sales plummeted from a $3 billion peak to $680 million in 2010, and GSK took a $2.4 billion charge that year to cover related litigation costs. As of February 2015, the company had settled most of the Avandia-related liability claims, GSK's annual report notes.But in 2013, GlaxoSmithKline persuaded the FDA to take another look at the data on Avandia, citing concerns about how that study, known as Record, was designed. An FDA advisory panel met for two days to hash over the data and then voted to remove most of those restrictions.The agency determined that the data didn't prove an increased risk of heart attack with Avandia and its combo meds, compared with the standard diabetes meds metformin and sulfonylurea.The only additional precautions that remained were requirements for GSK (and any generics makers) to educate doctors and other prescribers about "the current state of knowledge" about Avandia's cardiovascular risks."Manufacturers have since fulfilled these requirements," the FDA said in Wednesday's notice, and the risk-management measures in place are "no longer necessary to ensure that the benefits of rosiglitazone medicines outweigh their risks."The last time GSK disclosed the Avandia franchise's sales was 2012, when they amounted to £6 million, or about $9 million at today's exchange rates; that was a decline from £123 million ($183 million) in 2011. Generics had hit the market in the second quarter of 2012, siphoning away the brand's revenue.
- see the FDA notice
Special Reports: Top 15 pharma companies by 2014 revenue - GSK=see scott gottleib<a href="https://www.ucsusa.org/resources/glaxosmithkline-tried-silence-scientist-who-exposed-dangers-its-drug-avandia">https://www.ucsusa.org/resources/glaxosmithkline-tried-silence-scientist-who-exposed-dangers-its-drug-avandia</a>
oct 2017
when Dr. John Buse found that a diabetes drug had the side effect of higher risk of heart disease, GlaxoSmithKline officials threatened his integrity and career.In July 2010, an FDA advisory committee recommended a recall of Avandia, a drug used to treat Type-2 diabetes, and placed severe restrictions on its availability. GlaxoSmithKline, Avandia’s manufacturer, had long known about the drug’s potentially life-threatening side effects. But the company used its power to silence scientists rather than protecting its customers by bringing the harm to light.A decade earlier, in 1999, Dr. John Buse at the University of North Carolina found that Avandia users had a high risk of heart disease, and published his findings. In response, Buse alleges, a representative from the company contacted his boss, accused him of lying, and threatened to sue him for a $4 billion drop in the company’s stock valuation.A Senate Finance Committee report confirmed Buse’s charges, revealing that a GlaxoSmithKline official emailed Tadataka Yamada, then the company’s chairman of research and development, urging him to write a “firm letter” to Buse. It would contain a warning that “the punishment will be that we will complain up his academic line and to the CME [continuing medical education] granting bodies that accredit his activities.” Yamada wrote back, “I think there are two courses of action. One is to sue him for knowingly defaming our product even after we have set him straight as to the facts—the other is to launch a well-planned offensive on behalf of Avandia.” Yamada also called Fred Sparling, the chairman of Buse's department at UNC, and communicated the threat of lawsuits.After this blatant harassment, Buse felt he had no choice but to sign a letter drafted by the company which walked back his scientific findings. It stated that his comments on the drug “had been taken out of context” and that “only years of use, greater patient exposure and comparative clinical trials” would provide the data needed to allow any drug “into proper perspective.” The letter was used by the industry to persuade financial analysts to change their safety assessment of Avandia, which resulted in its staying on the market another decade.In 2007, a meta-analysis of 42 randomized controlled trials of the drug confirmed Buse’s findings and revealed that there was a 43 percent increase in the risk of heart disease among diabetics taking Avandia. When questioned on its intimidation of Buse by the Senate Finance Committee in 2007, GlaxoSmithKline released a statement saying, “perhaps we could have handled interactions with Dr. Buse better,” but otherwise denied that it had retaliated against the scientist. After reviewing extensive documents from Buse, the Committee concluded that the behavior of the company was “troubling” and “had Buse been able to continue voicing his concerns, without being characterized as a ‘renegade’ and without the need to sign a ‘retraction letter,’ it appears that the public good would have been better served.”Ultimately, this case—including the ultimate corroboration of Buse’s findings—spawned thousands of lawsuits charging that GlaxoSmithKline’s handling of the drug caused death and illness in patients. The company has already paid at least $90 million to settle some of them.
Further ReadingHow Corporations Corrupt Science at the Public’s Expense=<a href="https://abcnews.go.com/Health/Diabetes/story?id=3428577&page=1">https://abcnews.go.com/Health/Diabetes/story?id=3428577&page=1</a><header class="ArticleHeader" style="background-color: rgb(255, 255, 255); -webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; margin-bottom: 20px;"><div class="ArticleHeadline" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; margin-bottom: 20px;"><h1 class="ArticleHeadlineTitle" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; margin: 0px; line-height: 43px; padding-bottom: 12px;">FDA Panel: Avandia Should Remain on Market</h1>Docs on the panel say the benefits of the diabetes drug outweigh its risks.</div><div class="ArticleHeaderMeta" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; display: flex; -webkit-box-align: center; align-items: center; -webkit-box-pack: justify; justify-content: space-between; flex-wrap: nowrap;"><section class="Byline flex items-center" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; display: flex; -webkit-box-align: center; align-items: center;"><div class="BylineContent" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box;"><div aria-label="By JOSEPH BROWNSTEIN and DAN CHILDS">
ABC News Medical Unit" class="BylineGroup" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; -webkit-box-align: center; align-items: center;">By JOSEPH BROWNSTEIN and DAN CHILDS
ABC News Medical Unit</div><div class="BylineTimestampWrapper" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; justify-content: left; line-height: normal; display: flex; -webkit-box-orient: horizontal; -webkit-box-direction: normal; flex-direction: row;"><div class="BylineMeta BylineMeta--publishDate" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; line-height: 20px; opacity: 0.8;">January 7, 2009, </div></div></div></section><section class="Share flex flex-no-wrap ArticleHeaderShare" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; display: flex; flex-wrap: nowrap;"><button aria-label="Share to Facebook" class="Button Button--default Button--icon-noLabel ShareItem ShareItem--facebook" tabindex="0" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: inherit; line-height: 1; margin: 0px; overflow: hidden; appearance: button; -webkit-box-align: center; align-items: center; cursor: pointer; display: flex; font-weight: 600; height: 40px; -webkit-box-pack: center; justify-content: center; max-width: 414px; padding: 0px; position: relative; white-space: nowrap; width: 40px; border-width: 0px; border-style: initial; border-color: initial; outline: 0px;"><svg focusable="false" aria-hidden="true" class="ShareIcon iconsvg" viewbox="0 0 24 24" /><use xlink:href="#iconsocialfacebook" xmlns:xlink="xlink" /></button><button aria-label="Share to Twitter" class="Button Button--default Button--icon-noLabel ShareItem ShareItem--twitter" tabindex="0" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: inherit; line-height: 1; margin: 0px; overflow: hidden; appearance: button; -webkit-box-align: center; align-items: center; cursor: pointer; display: flex; font-weight: 600; height: 40px; -webkit-box-pack: center; justify-content: center; max-width: 414px; padding: 0px; position: relative; white-space: nowrap; width: 40px; border-width: 0px; border-style: initial; border-color: initial; outline: 0px;"><svg focusable="false" aria-hidden="true" class="ShareIcon iconsvg" viewbox="0 0 24 24" /><use xlink:href="#iconsocialtwitter" xmlns:xlink="xlink" /></button><button aria-label="Email this article" class="Button Button--default Button--icon-noLabel ShareItem ShareItem--email" tabindex="0" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: inherit; line-height: 1; margin: 0px; overflow: hidden; appearance: button; -webkit-box-align: center; align-items: center; cursor: pointer; display: flex; font-weight: 600; height: 40px; -webkit-box-pack: center; justify-content: center; max-width: 414px; padding: 0px; position: relative; white-space: nowrap; width: 40px; border-width: 0px; border-style: initial; border-color: initial; outline: 0px;"><svg focusable="false" aria-hidden="true" class="ShareIcon iconsvg" viewbox="0 0 24 24" /><use xlink:href="#iconemail" xmlns:xlink="xlink" /></button></section></div></header><section class="Article__Content story" style="background-color: white; -webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; line-height: 28px;">July 30, 2007 — -- A panel of outside experts recommended to the FDA on Monday afternoon that the diabetes drug Avandia should be kept on the market, despite concern over its heart risks.Though 20 of the 23 panelists agreed that use of the drug increased heart risks for those with diabetes, 22 out of 23 said that the balance between the drugs benefits and risks supported its continued use in the United States.But nearly all the panelists agreed that the drug's warning label should be strengthened to reflect its potential risks.Dr. Scott Gottlieb, a resident fellow at the American Enterprise Institute for Public Policy Research and former Deputy Commissioner for Medical and Scientific Affairs for the FDA, said the panel's recommendation in light of the evidence at hand was the proper move."Putting additional warnings on the drug label is prudent, given the suggestion that there is an increased risk with this drug," he said. "But it will take additional studies to establish that risk, and so the advisory committee I believe prudently called for additional research."However, not all agreed that the panel's decision made sense."I find the panel's voting confusing and strange," said ABC News Medical Editor Dr. Tim Johnson."If you really believe that Avandia increases the risk for a heart attack -- as they voted -- then why would you keep the drug on the market given that there are other drugs available to lower blood sugar? We obviously need better data after drugs like Avandia are approved -- and the data in this case is still confusing."<div class="AdPlaceholder" style="background-color: rgb(255, 255, 255); -webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box;"><div data-box-type="fitt-adbox-incontentTeads2" style="-webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box;">One prominent FDA expert, Dr. David Graham -- one of the loudest voices calling for the withdrawal of the pain medicine Vioxx in 2004 -- said the drug, which is manufactured by GlaxoSmithKline and used by about 1 million Americans, should be pulled off the market.But other physicians said the fears about the drug are thus far unsubstantiated and believe that removing it from the market may deprive diabetes patients of effective medication.Concerns over the drug were first raised in May with an analysis showing a 43 percent increased risk of heart attack in those taking it.In a hearing held last month, Rep. Henry Waxman, D-Calif., summarized the issue of whether to take Avandia off the market."Diabetes is a serious illness, and Avandia is an effective medication for lowering blood sugar," he said. "Sounding a false alarm about the dangers of the drug has the potential to cause serious harm to patients."On the other hand, there have been repeated warnings -- from the day of approval forward -- about the potential cardiac risks associated with Avandia. And these should not be ignored."<h4 style="background-color: rgb(255, 255, 255); -webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; margin: 0px; line-height: 25px; scroll-margin-top: 72px;">Avandia Prescriptions Down</h4>Since the Avandia analysis was published, many doctors are wary and have decided not to write new prescriptions. Others say they are going so far as to take their patients who are already taking Avandia off of the drug.According to the market research firm ImpactRx, Inc., new prescriptions of Avandia dropped from roughly 15 percent of the market before the study's announcement to below 5 percent now.This means that in mid-May, about one out of every seven new prescriptions for an oral diabetes medication was for Avandia. Since then, this figure has tumbled to less than one in 20.And the panel's recommendation may have little effect on some doctors' choices for their patients."I will not use [Avandia] and I am aware of other physicians who have made that decision," said Dr. Neil Brooks, past president of the American Academy of Family Physicians."The information from the FDA is disturbing," he said. "I believe that most physicians will discontinue the use of Avandia. This is especially true since [Actos, another oral diabetes drug] is available and seems to have a better safety profile."Actos, a drug made by Takeda Pharmaceuticals in the same class as Avandia but with a different chemical makeup, has benefited significantly from Avandia's decline. Actos held a share of roughly 12 percent of new prescriptions before the announcement of Avandia's association with heart attacks and now holds around 22 percent.Data show that nearly 60 percent of all switches in diabetes medication were to Actos just two weeks after the announcement -- an increase of around 45 percentage points during that time.<h4 style="background-color: rgb(255, 255, 255); -webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; margin: 0px; line-height: 25px; scroll-margin-top: 72px;">Do Benefits Outweigh the Risks?</h4>But while some physicians want Avandia off the market, others say that Avandia is not much different from many other drugs that have side effects. So as long as the benefits outweigh the risks, they say nothing should change."I am very worried about how people will interpret these findings," said Dr. Anne Peters, the director of the clinical diabetes programs at the University of Southern California's Keck School of Medicine. "All drugs have side effects. All drugs can kill you. But the diseases we are treating are far more dangerous."I think there is much more danger in patients who are well-treated being pulled off medication," she said.And Gottlieb said focusing too much on the risks of certain useful drugs could turn out to be both expensive and counterproductive."I fear that the task of uncovering these kinds of latent risks -- which is the sort of risk Avandia is believed by some to harbor -- the kinds of risks that can only be unmasked with prolonged use of a drug, is going to be much, much harder and more expensive and cause the delay of a lot of potentially useful medicines," he said.<h4 style="background-color: rgb(255, 255, 255); -webkit-tap-highlight-color: rgba(0, 0, 0, 0); box-sizing: border-box; margin: 0px; line-height: 25px; scroll-margin-top: 72px;">Company Fires Back</h4>As Graham and other researchers made the case for the removal of Avandia from the market, GSK fired its own salvo of studies at the FDA expert panel asserting the drug's safety and benefits."We certainly believe that Avandia is an important treatment option for physicians," Mary Anne Rhyne, a spokesperson for GSK, told ABCNEWS.com Monday morning.The centerpiece of GSK's defense is a company-funded study, the results of which were released after the May analysis. The study, which GSK said took into account data on more than 400,000 type 2 diabetes patients, provides safety evidence contrary to the findings published in NEJM.The company-funded study "provides strong evidence that Avandia is not associated with the increased risk of heart attack suggested as part of a previously published meta-analysis," according to a statement by the company.Rhyne said GSK would not respond specifically to Graham's call for the drug to be pulled off the market.But why the discrepancy between the NEJM analysis and the studies presented by GSK? Rhyne said these contradictions can be explained by a difference in study design."The biggest thing is that a meta-analysis is designed to raise questions, while these other studies are designed to answer those questions," she said. "We believe that a long-term clinical trial designed to look at cardiovascular risk is the best way to answer these questions."Those sentiments were echoed by Dr. John Messmer of the University Physician Group in Palmyra, Pa., who said that an analysis of studies not designed to look at heart attack risk in Avandia patients should not draw any conclusions about it."I think the FDA should advise physicians that there is a suggestion of increased cardiac risk and to exercise caution in prescribing it," he said."I do not think the FDA should state that Avandia causes heart attacks. There is no proof of that -- just a trend in the data in some studies. It would be ammunition for unscrupulous lawyers to trawl for cases if the FDA makes a bigger deal out of this than it really is."Messmer, who said he is "very selective" in the way he uses Avandia, added that he feels the drug should be left on the market so that physicians can weight the benefits of the drug on a case-by-case basis."Physicians must judge risk versus benefit every day," he said. "Let it be up to us to make the best decision."</div></div></section>=
<a href="https://www.justice.gov/opa/pr/glaxosmithkline-plead-guilty-and-pay-3-billion-resolve-fraud-allegations-and-failure-report">https://www.justice.gov/opa/pr/glaxosmithkline-plead-guilty-and-pay-3-billion-resolve-fraud-allegations-and-failure-report</a>very long ...avandia: In its civil settlement agreement, the United States alleges that GSK promoted Avandia to physicians and other health care providers with false and misleading representations about Avandia’s safety profile, causing false claims to be submitted to federal health care programs. Specifically, the United States alleges that GSK stated that Avandia had a positive cholesterol profile despite having no well-controlled studies to support that message. The United States also alleges that the company sponsored programs suggesting cardiovascular benefits from Avandia therapy despite warnings on the FDA-approved label regarding cardiovascular risks. GSK has agreed to pay $657 million relating to false claims arising from misrepresentations about Avandia. The federal share of this settlement is $508 million and the state share is $149 million.
all: </div></div></div></div>FOR IMMEDIATE RELEASEMonday, July 2, 2012GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety DataLargest Health Care Fraud Settlement in U.S. HistoryGlobal health care giant GlaxoSmithKline LLC (GSK) agreed to plead guilty and to pay $3 billion to resolve its criminal and civil liability arising from the company’s unlawful promotion of certain prescription drugs, its failure to report certain safety data, and its civil liability for alleged false price reporting practices, the Justice Department announced today. The resolution is the largest health care fraud settlement in U.S. history and the largest payment ever by a drug company.
GSK agreed to plead guilty to a three-count criminal information, including two counts of introducing misbranded drugs, Paxil and Wellbutrin, into interstate commerce and one count of failing to report safety data about the drug Avandia to the Food and Drug Administration (FDA). Under the terms of the plea agreement, GSK will pay a total of $1 billion, including a criminal fine of $956,814,400 and forfeiture in the amount of $43,185,600. The criminal plea agreement also includes certain non-monetary compliance commitments and certifications by GSK’s U.S. president and board of directors. GSK’s guilty plea and sentence is not final until accepted by the U.S. District Court.GSK will also pay $2 billion to resolve its civil liabilities with the federal government under the False Claims Act, as well as the states. The civil settlement resolves claims relating to Paxil, Wellbutrin and Avandia, as well as additional drugs, and also resolves pricing fraud allegations.“Today’s multi-billion dollar settlement is unprecedented in both size and scope. It underscores the Administration’s firm commitment to protecting the American people and holding accountable those who commit health care fraud,” said James M. Cole, Deputy Attorney General. “At every level, we are determined to stop practices that jeopardize patients’ health, harm taxpayers, and violate the public trust – and this historic action is a clear warning to any company that chooses to break the law.”“Today’s historic settlement is a major milestone in our efforts to stamp out health care fraud,” said Bill Corr, Deputy Secretary of the Department of Health and Human Services (HHS). “For a long time, our health care system had been a target for cheaters who thought they could make an easy profit at the expense of public safety, taxpayers, and the millions of Americans who depend on programs like Medicare and Medicaid. But thanks to strong enforcement actions like those we have announced today, that equation is rapidly changing.”This resolution marks the culmination of an extensive investigation by special agents from HHS-OIG, FDA and FBI, along with law enforcement partners across the federal government. Moving forward, GSK will be subject to stringent requirements under its corporate integrity agreement with HHS-OIG; this agreement is designed to increase accountability and transparency and prevent future fraud and abuse. Effective law enforcement partnerships and fraud prevention are hallmarks of the Health Care Fraud Prevention and Enforcement Action Team (HEAT) initiative, which fosters government collaboration to fight fraud. 
Criminal Plea AgreementUnder the provisions of the Food, Drug and Cosmetic Act, a company in its application to the FDA must specify each intended use of a drug. After the FDA approves the product as safe and effective for a specified use, a company’s promotional activities must be limited to the intended uses that FDA approved. In fact, promotion by the manufacturer for other uses – known as “off-label uses” – renders the product “misbranded.”Paxil: In the criminal information, the government alleges that, from April 1998 to August 2003, GSK unlawfully promoted Paxil for treating depression in patients under age 18, even though the FDA has never approved it for pediatric use. The United States alleges that, among other things, GSK participated in preparing, publishing and distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18, when the study failed to demonstrate efficacy. At the same time, the United States alleges, GSK did not make available data from two other studies in which Paxil also failed to demonstrate efficacy in treating depression in patients under 18. The United States further alleges that GSK sponsored dinner programs, lunch programs, spa programs and similar activities to promote the use of Paxil in children and adolescents. GSK paid a speaker to talk to an audience of doctors and paid for the meal or spa treatment for the doctors who attended. Since 2004, Paxil, like other antidepressants, included on its label a “black box warning” stating that antidepressants may increase the risk of suicidal thinking and behavior in short-term studies in patients under age 18. GSK agreed to plead guilty to misbranding Paxil in that its labeling was false and misleading regarding the use of Paxil for patients under 18.
Wellbutrin: The United States also alleges that, from January 1999 to December 2003, GSK promoted Wellbutrin, approved at that time only for Major Depressive Disorder, for weight loss, the treatment of sexual dysfunction, substance addictions and Attention Deficit Hyperactivity Disorder, among other off-label uses. The United States contends that GSK paid millions of dollars to doctors to speak at and attend meetings, sometimes at lavish resorts, at which the off-label uses of Wellbutrin were routinely promoted and also used sales representatives, sham advisory boards, and supposedly independent Continuing Medical Education (CME) programs to promote Wllbutrin for these unapproved uses. GSK has agreed to plead guilty to misbranding Wellbutrin in that its labeling did not bear adequate directions for these off-label uses. For the Paxil and Wellbutrin misbranding offenses, GSK has agreed to pay a criminal fine and forfeiture of $757,387,200.
Avandia: The United States alleges that, between 2001 and 2007, GSK failed to include certain safety data about Avandia, a diabetes drug, in reports to the FDA that are meant to allow the FDA to determine if a drug continues to be safe for its approved indications and to spot drug safety trends. The missing information included data regarding certain post-marketing studies, as well as data regarding two studies undertaken in response to European regulators’ concerns about the cardiovascular safety of Avandia. Since 2007, the FDA has added two black box warnings to the Avandia label to alert physicians about the potential increased risk of (1) congestive heart failure, and (2) myocardial infarction (heart attack). GSK has agreed to plead guilty to failing to report data to the FDA and has agreed to pay a criminal fine in the amount of $242,612,800 for its unlawful conduct concerning Avandia.“This case demonstrates our continuing commitment to ensuring that the messages provided by drug manufacturers to physicians and patients are true and accurate and that decisions as to what drugs are prescribed to sick patients are based on best medical judgments, not false and misleading claims or improper financial inducements,” said Carmen Ortiz, U.S. Attorney for the District of Massachusetts.“Patients rely on their physicians to prescribe the drugs they need,” said John Walsh, U.S. Attorney for Colorado. “The pharmaceutical industries’ drive for profits can distort the information provided to physicians concerning drugs.  This case will help to ensure that your physician will make prescribing decisions based on good science and not on misinformation, money or favors provided by the pharmaceutical industry.”
Civil Settlement AgreementAs part of this global resolution, GSK has agreed to resolve its civil liability for the following alleged conduct: (1) promoting the drugs Paxil, Wellbutrin, Advair, Lamictal and Zofran for off-label, non-covered uses and paying kickbacks to physicians to prescribe those drugs as well as the drugs Imitrex, Lotronex, Flovent and Valtrex; (2) making false and misleading statements concerning the safety of Avandia; and (3) reporting false best prices and underpaying rebates owed under the Medicaid Drug Rebate Program.Off-Label Promotion and Kickbacks: The civil settlement resolves claims set forth in a complaint filed by the United States alleging that, in addition to promoting the drugs Paxil and Wellbutrin for unapproved, non-covered uses, GSK also promoted its asthma drug, Advair, for first-line therapy for mild asthma patients even though it was not approvedor medically appropriate under these circumstances. GSK also promoted Advair for chronic obstructive pulmonary disease with misleading claims as to the relevant treatment guidelines. The civil settlement also resolves allegations that GSK promoted Lamictal, an anti-epileptic medication, for off-label, non-covered psychiatric uses, neuropathic pain and pain management. It further resolves allegations that GSK promoted certain forms of Zofran, approved only for post-operative nausea, for the treatment of morning sickness in pregnant women. It also includes allegations that GSK paid kickbacks to health care professionals to induce them to promote and prescribe these drugs as well as the drugs Imitrex, Lotronex, Flovent and Valtrex. The United States alleges that this conduct caused false claims to be submitted to federal health care programs.GSK has agreed to pay $1.043 billion relating to false claims arising from this alleged conduct. The federal share of this settlement is $832 million and the state share is $210 millionThis off-label civil settlement resolves four lawsuits pending in federal court in the District of Massachusetts under the qui tam, or whistleblower, provisions of the False Claims Act, which allow private citizens to bring civil actions on behalf of the United States and share in any recovery.
Avandia: In its civil settlement agreement, the United States alleges that GSK promoted Avandia to physicians and other health care providers with false and misleading representations about Avandia’s safety profile, causing false claims to be submitted to federal health care programs. Specifically, the United States alleges that GSK stated that Avandia had a positive cholesterol profile despite having no well-controlled studies to support that message. The United States also alleges that the company sponsored programs suggesting cardiovascular benefits from Avandia therapy despite warnings on the FDA-approved label regarding cardiovascular risks. GSK has agreed to pay $657 million relating to false claims arising from misrepresentations about Avandia. The federal share of this settlement is $508 million and the state share is $149 million.Price Reporting: GSK is also resolving allegations that, between 1994 and 2003, GSK and its corporate predecessors reported false drug prices, which resulted in GSK’s underpaying rebates owed under the Medicaid Drug Rebate Program. By law, GSK was required to report the lowest, or “best” price that it charged its customers and to pay quarterly rebates to the states based on those reported prices. When drugs are sold to purchasers in contingent arrangements known as “bundles,” the discounts offered for the bundled drugs must be reallocated across all products in the bundle proportionate to the dollar value of the units sold. The United States alleges that GSK had bundled sales arrangements that included steep discounts known as “nominal” pricing and yet failed to take such contingent arrangements into account when calculating and reporting its best prices to the Department of Health and Human Services. Had it done so, the effective prices on certain drugs would have been different, and, in some instances, triggered a new, lower best price than what GSK reported. As a result, GSK underpaid rebates due to Medicaid and overcharged certain Public Health Service entities for its drugs, the United States contends. GSK has agreed to pay $300 million to resolve these allegations, including $160,972,069 to the federal government, $118,792,931 to thestates, and $20,235,000 to certain Public Health Service entities who paid inflated prices for the drugs at issue.
Except to the extent that GSK has agreed to plead guilty to the three-count criminal information, the claims settled by these agreements are allegations only, and there has been no determination of liability.“This landmark settlement demonstrates the Department’s commitment to protecting the American public against illegal conduct and fraud by pharmaceutical companies,” said Stuart F. Delery, Acting Assistant Attorney General for the Justice Department’s Civil Division. “Doctors need truthful, fair, balanced information when deciding whether the benefits of a drug outweigh its safety risks.  By the same token, the FDA needs all necessary safety-related information to identify safety trends and to determine whether a drug is safe and effective.  Unlawful promotion of drugs for unapproved uses and failing to report adverse drug experiences to the FDA can tip the balance of those important decisions, and the Justice Department will not tolerate attempts by those who seek to corrupt our health care system in this way.”
Non-monetary Provisions and Corporate Integrity Agreement
In addition to the criminal and civil resolutions, GSK has executed a five-year Corporate Integrity Agreement (CIA) with the Department of Health and Human Services, Office of Inspector General (HHS-OIG). The plea agreement and CIA include novel provisions that require that GSK implement and/or maintain major changes to the way it does business, including changing the way its sales force is compensated to remove compensation based on sales goals for territories, one of the driving forces behind much of the conduct at issue in this matter. Under the CIA, GSK is required to change its executive compensation program to permit the company to recoup annual bonuses and long-term incentives from covered executives if they, or their subordinates, engage in significant misconduct. GSK may recoup monies from executives who are current employees and those who have left the company.  Among other things, the CIA also requires GSK to implement and maintain transparency in its research practices and publication policies and to follow specified policies in its contracts with various health care payors.
“Our five-year integrity agreement with GlaxoSmithKline requires individual accountability of its board and executives,” said Daniel R. Levinson, Inspector General of the U.S. Department of Health and Human Services. “For example, company executives may have to forfeit annual bonuses if they or their subordinates engage in significant misconduct, and sales agents are now being paid based on quality of service rather than sales targets.”    “The FDA Office of Criminal Investigations will aggressively pursue pharmaceutical companies that choose to put profits before the public’s health,” said Deborah M. Autor, Esq., Deputy Commissioner for Global Regulatory Operations and Policy, U.S. Food and Drug Administration. “We will continue to work with the Justice Department and our law enforcement counterparts to target companies that disregard the protections of the drug approval process by promoting drugs for uses when they have not been proven to be safe and effective for those uses, and that fail to report required drug safety information to the FDA.”“The record settlement obtained by the multi-agency investigative team shows not only the importance of working with our partners, but also the importance of the public providing their knowledge of suspect schemes to the government,” said Kevin Perkins, Acting Executive Assistant Director of the FBI’s Criminal, Cyber, Response and Services Branch. “Together, we will continue to bring to justice those engaged in illegal schemes that threaten the safety of prescription drugs and other critical elements of our nation’s healthcare system.”“ Federal employees deserve health care providers and suppliers, including drug manufacturers, that meet the highest standards of ethical and professional behavior,” said Patrick E. McFarland, Inspector General of the U.S. Office of Personnel Management. “Today’s settlement reminds the pharmaceutical industry that they must observe those standards and reflects the commitment of Federal law enforcement organizations to pursue improper and illegal conduct that places health care consumers at risk.”“Today’s announcement illustrates the efforts of VA OIG and its law enforcement partners in ensuring the integrity of the medical care provided our nation’s veterans by the Department of Veterans Affairs,” said George J. Opfer, Inspector General of the Department of Veterans Affairs. “The monetary recoveries realized by VA in this settlement will directly benefit VA healthcare programs that provide for veterans’ continued care.”
“This settlement sends a clear message that taking advantage of federal health care programs has substantial consequences for those who try,”  said Rafael A. Medina, Special Agent in Charge of the Northeast Area Office of Inspector General for the U.S. Postal Service. “The U.S. Postal Service pays more than one billion dollars a year in workers' compensation benefits and our office is committed to pursuing those individuals or entities whose fraudulent acts continue to unfairly add to that cost.”
A Multilateral EffortThe criminal case is being prosecuted by the U.S. Attorney’s Office for the District of Massachusetts and the Civil Division’s Consumer Protection Branch. The civil settlement was reached by the U.S. Attorney’s Office for the District of Massachusetts, the U.S. Attorney’s Office for the District of Colorado and the Civil Division’s Commercial Litigation Branch. Assistance was provided by the HHS Office of Counsel to the Inspector General, Office of the General Counsel-CMS Division and FDA’s Office of Chief Counsel as well as the National Association of Medicaid Fraud Control UnitsThis matter was investigated by agents from the HHS-OIG; the FDA’s Office of Criminal Investigations; the Defense Criminal Investigative Service of the Department of Defense; the Office of the Inspector General for the Office of Personnel Management; the Department of Veterans Affairs; the Department of Labor; TRICARE Program Integrity; the Office of Inspector General for the U.S. Postal Service and the FBI.This resolution is part of the government’s emphasis on combating health care fraud and another step for the Health Care Fraud Prevention and Enforcement Action Team (HEAT) initiative, which was announced in May 2009 by Attorney General Eric Holder and Kathleen Sebelius, Secretary of HHS. The partnership between the two departments has focused efforts to reduce and prevent Medicare and Medicaid financial fraud through enhanced cooperation. Over the last three years, the department has recovered a total of more than $10.2 billion in settlements, judgments, fines, restitution, and forfeiture in health care fraud matters pursued under the False Claims Act and the Food, Drug and Cosmetic Act.Court documents related to today’s settlement can be viewed online at www.justice.gov/opa/gsk-docs.html .
Related Materials:Remarks by the Deputy Attorney General James M. Cole at the GSK Press ConferenceRemarks by Acting Assistant Attorney General for the Civil Division Stuart F. Delery at the GSK Press Conference</div><div>=</div><div>blog md</div><div>http://weblogdofraga.blogspot.com/2007/05/</div><div><h2 class="date-header" style="margin: 0px -15px 1px; position: static; font-variant-numeric: normal; font-variant-east-asian: normal; font-weight: normal; font-stretch: normal; line-height: normal; min-height: 0px; padding: 0px; border-bottom: 1px solid transparent; background-image: none; background-position: left top; background-size: initial; background-repeat: no-repeat; background-attachment: scroll; background-origin: initial; background-clip: initial; border-top: 0px solid rgb(238, 238, 238); border-top-left-radius: 0px; border-top-right-radius: 0px; bottom: 100%; right: 15px;"><span style="font-variant-numeric: normal; font-variant-east-asian: normal; font-stretch: normal; line-height: normal; display: block; padding: 0.5em 15px; border-left: 0px solid rgb(238, 238, 238); border-right: 0px solid rgb(238, 238, 238);">thursday, May 31, 2007</h2><div class="date-posts" style="margin: 0px -15px; padding: 8px 15px 0px; clear: both; border-top: 1px solid rgb(238, 238, 238);"><div class="post-outer" style="border-top: none; margin: 0px -15px; padding: 0px 15px 10px;"><div class="post hentry uncustomized-post-template" itemprop="blogPost" itemscope="itemscope" itemtype="http://schema.org/BlogPosting" style="position: relative; min-height: 0px;"><a name="4294651385979791540" /><h3 class="post-title entry-title" itemprop="name" style="margin: 0px; position: relative; font-variant-numeric: normal; font-variant-east-asian: normal; font-stretch: normal; line-height: normal;"><a href="http://weblogdofraga.blogspot.com/2007/05/fda-still-unsettled-in-wake-of-new.html" style="text-decoration-line: none; font-variant-numeric: normal; font-variant-east-asian: normal; font-stretch: normal; line-height: normal;">F.D.A. Still Unsettled in Wake of New Questions</a></h3><div class="post-header" style="line-height: 1.6; margin: 0px 0px 1em;"><div class="post-header-line-1"><div class="post-body entry-content" id="post-body-4294651385979791540" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">ROCKVILLE, Md., May 30 — When Dr. Andrew C. von Eschenbach took over the <a title="More articles about the U.S. Food And Drug Administration." href="http://topics.nytimes.com/top/reference/timestopics/organizations/f/food_and_drug_administration/index.html?inline=nyt-org" style="text-decoration-line: none;">Food and Drug Administration</a> in 2005, the agency had a crisis over drug approvals that had missed or ignored dangerous side effects in Vioxx, antidepressants and other prominent medications.
Dr. von Eschenbach promised improvements, and agency officials said they would no longer be caught flatfooted on drug safety.
But this month, The <a title="More articles about New England Journal of Medicine" href="http://topics.nytimes.com/top/reference/timestopics/organizations/n/new_england_journal_of_medicine/index.html?inline=nyt-org" style="text-decoration-line: none;">New England Journal of Medicine</a> published a study suggesting that a major <a title="Recent and archival health news about diabetes." href="http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/diabetes/index.html?inline=nyt-classifier" style="text-decoration-line: none;">diabetes</a> pill, Avandia, might increase the risk of heart attacks.
Concerns over that drug and others have led <a title="More articles about Republican Party" href="http://topics.nytimes.com/top/reference/timestopics/organizations/r/republican_party/index.html?inline=nyt-org" style="text-decoration-line: none;">Republicans</a> and Democrats in the House and the Senate to call for investigations. A House hearing is planned for June 6.
Dr. von Eschenbach said in a briefing on Wednesday that his agency needed to collaborate more closely with drug companies.
“The point is that we need to look at the role of the F.D.A. in being a bridge to the future, not a barrier to the future,” he said at his office here.
Responding to a suggestion that promoting collaborations with drug makers, including an effort to modernize human testing and find genetic markers to predict suffering from side effects, may not be politic, Dr. von Eschenbach said the agency was not working solely with pharmaceutical companies.
“It’s with everyone,” including government agencies and independent scientists, he said.
He defended the agency in the Avandia case, saying, “I believe we did it right with regard to Avandia.”
Hints of the heart risks from Avandia were, however, present from the beginning. The original trials, overseen by <a title="More information about GlaxoSmithKline P.L.C." href="http://topics.nytimes.com/top/news/business/companies/glaxosmithkline_plc/index.html?inline=nyt-org" style="text-decoration-line: none;">GlaxoSmithKline</a>, the drug’s maker, showed that patients taking the drug had more than twice the rate of ischemic <a title="Recent and archival health news about heart disease." href="http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/heartdisease/index.html?inline=nyt-classifier" style="text-decoration-line: none;">heart disease</a> as recipients of placebos.
The medical reviewer for the F.D.A. expressed concerns, but in a further analysis decided that it was less of a problem.
The hearing next week may highlight the growing internal dissension between officials who approve drugs and those who track the safety of drugs after they have been approval. Tension between the groups has long been common, but in recent months it has erupted into sniping.
Congressional investigators said the safety group recommended months ago that the drug agency put its severest warning on Avandia. The review group, which holds sway, has not done so.
The sniping became public in an exchange at an advisory committee hearing last month on whether to approve a new <a title="Recent and archival health news about arthritis and rheumatism." href="http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/arthritisandrheumatism/index.html?inline=nyt-classifier" style="text-decoration-line: none;">arthritis</a> drug.
On one side was Dr. David Graham, author of an internal report that found that Avandia substantially increased the risks of heart attack, findings similar to the medical journal’s report.
On the other, Dr. Robert J. Meyer, an office director in the drug review division, and his boss, Dr. John Jenkins, were in a group deciding against warning about the potential risks.
There was little chance that the advisory committee or the drug agency would approve the arthritis drug, Arcoxia, at the hearing.
Behind the scenes, agency officials were battling over Avandia. Dr. Graham told the committee that top agency officials had demanded an unreasonable level of certainty about a drug’s risks before agreeing to warn the public.
“They assume it’s safe,” Dr. Graham said of the top officials’ analyses of safety data. “Which is just looking at things all the way wrong.”
Dr. Jenkins said Dr. Graham’s “characterization of how we look at safety data is simply false.”
“We make our best informed judgment about what the regulatory action should be,” Dr. Jenkins added.
Senator <a title="More articles about Charles E. Grassley." href="http://topics.nytimes.com/top/reference/timestopics/people/g/charles_e_grassley/index.html?inline=nyt-per" style="text-decoration-line: none;">Charles E. Grassley</a>, Republican of Iowa, and others on Capitol Hill, say the rift between the approval office and the safety office means that the two must separate and that the safety group must have more power. Mr. Grassley proposed such a split in an amendment this month; it failed by one vote.
Top House staff members said the Avandia case had breathed new life into Mr. Grassley’s proposal, because the House will soon debate changing the drug agency.
Curt Furberg, a professor of public health sciences at Wake Forest and a co-author of the New England Journal of Medicine’s editorial on Avandia, said the agency remained broken.
“Safety is just not a high priority for them,” said Dr. Furberg, who serves on the F.D.A. Drug Safety and Risk Management Advisory Committee.</div><div class="post-footer" style="line-height: 1.6; margin: 1.5em 0px 0px;"><div class="post-footer-line post-footer-line-2">Labels: <a href="http://weblogdofraga.blogspot.com/search/label/Avandia" rel="tag" style="text-decoration-line: none;">Avandia</a></div><div class="post-footer-line post-footer-line-3"></div></div></div></div><div class="post-outer" style="border-top: 1px solid rgb(238, 238, 238); margin: 0px -15px; padding: 15px 15px 10px;"><div class="post hentry uncustomized-post-template" itemprop="blogPost" itemscope="itemscope" itemtype="http://schema.org/BlogPosting" style="position: relative; min-height: 0px;"><a name="4962781936656406601" /><h3 class="post-title entry-title" itemprop="name" style="margin: 0px; position: relative; font-variant-numeric: normal; font-variant-east-asian: normal; font-stretch: normal; line-height: normal;"><a href="http://weblogdofraga.blogspot.com/2007/05/drug-maker-defends-rosiglitazone-in.html" style="text-decoration-line: none; font-variant-numeric: normal; font-variant-east-asian: normal; font-stretch: normal; line-height: normal;">Drug-Maker Defends Rosiglitazone in Letter to The Lancet</a></h3><div class="post-header" style="line-height: 1.6; margin: 0px 0px 1em;"><div class="post-header-line-1"><div class="post-body entry-content" id="post-body-4962781936656406601" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">KING OF PRUSSIA, Pa., May 30 -- Despite reports linking rosiglitazone (Avandia) to increased risk of cardiac events, the data safety monitoring boards assessing that risk in three studies of the drug agreed that the trials should continue.
Ronald L. Krall, M.D., chief medical officer of GlaxoSmithKline, maker of rosiglitazone, disclosed the decisions of the safety panels in a letter released online today by The Lancet.
The disclosure that all three trials -- RECORD, BARI 2D, and ACCORD -- will continue as planned could be construed as the most reassuring news about rosiglitazone since May 21 when the New England Journal of Medicine published online a meta-analysis that found a 43% increase in relative risk of myocardial infarction for patients using rosiglitazone.
Or, it may simply indicate the studies have reached their pre-specified safety stopping points.
Dr. Krall said the relative safety of rosiglitazone could also be gleaned from a balanced cohort observational study of 33,363 patients in a managed care database who began treatment with oral antidiabetic drugs from 2000 to 2004. That study, commissioned by GSK, assessed the risk of MI, coronary revascularization or both among patients taking rosiglitazone, metformin, or sulfonylurea monotherapy, or combinations of those drugs.
"The incidence of composite cardiovascular endpoint was 1.75 events per 100 patient-years for rosiglitazone-containing regimen and 1.76 events per 100 patient-years for the non-rosiglitazone-containing regiment (hazard ratio 0.93, 95% CI 0.80-1.10), he wrote.
Dr. Krall concluded that the company believed "these studies provide clear evidence of the cardiovascular safety of rosiglitazone and that the estimates of cardiovascular morbidity from the meta-analyses are not robust."
The system for drug approval and safety monitoring of drugs, he said, "is working," said Dr. Krall.
The meta-analysis in the NEJM was conducted by Steven Nissen, M.D., of the Cleveland Clinic, and colleagues.
In the week since the NEJM published his study, Dr. Nissen has been both lionized and lambasted. Tonight ABC News reported that Douglas Arbesfeld, a senior communications consultant at the FDA, sent emails to several reporters suggesting that Dr. Nissen targeted pharmaceutical companies that didn't fund Cleveland Clinic research.
Dr. Nissen, meanwhile, has not retreated from his findings. He said the furor that followed publication has been the ugliest in his personal experience and that he was especially offended by slurs directed at the clinic.
The FDA said the Arbesfeld email did not reflect the FDA's position but was merely private correspondence from a consultant.
That GSK statement will be closely scrutinized on June 6 when Rep. Henry Waxman (D-Calif.) opens a congressional hearing into FDA oversight of rosiglitazone from its initial approval in 1999 through post-marketing surveillance. Dr. Nissen will testify.
The FDA has already confirmed that its own ongoing meta-analysis of rosiglitazone studies will also show an increased cardiac event rate for patients using rosiglitazone. But the agency has also maintained that its review of preliminary data from RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes), provided evidence that contradicted the meta-analyses.
A week ago, The Lancet published an unsigned editorial -- also released online -- urging calm until results of prospective trials, such as RECORD are available.
Dr. Krall, who said he was responding to The Lancet editorial, conceded that the company's own meta-analyses conducted in 2005 and 2006 found hazard ratios "in the same direction" as Dr. Nissen's meta-analysis.
But he pointed out that there was "a very low frequency of events (0.6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0.1%."
Dr. Krall said data from ADOPT (A Diabetes Outcomes Progression Trial) and DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) offer more reliable evidence of rosiglitazone safety than findings from meta-analyses.
In support of that assertion, he presented data from a GSK post hoc analysis of the ADOPT database. "Our analysis, which adjusted for medication exposure, found that such events were rare in this population and that all treatments were comparable," he wrote.
ADOPT compared rosiglitazone to metformin or glyburide. The hazard ratios "varied from 0.58 to 1.52 and 95% CIs for all comparisons included unity," Dr. Krall wrote.
Initial published findings from the DREAM trial, which used a 2 x2 design that randomized patients to rosiglitazone plus placebo, rosiglitazone plus ramipril, ramipril plus placebo or placebo-placebo found no significant difference in cardiovascular endpoints. But a post hoc cell-level intention-to-treat analysis found an increase in cardiovascular events among patients in the rosiglitazone-ramipril arm, a finding that Dr. Krall said "is currently unexplained."<a class="comment-link" href="https://www.blogger.com/comment.g?blogID=4055230499735545325&postID=4962781936656406601&isPopup=true" style="font-family: " times="Times" new="New" roman="Roman" font-size="font-size" large="large" white-space="white-space" nowrap="nowrap" text-decoration-line="text-decoration-line" none="none"> </a></div><div class="post-footer" style="line-height: 1.6; margin: 1.5em 0px 0px;"><div class="post-footer-line post-footer-line-2">Labels: <a href="http://weblogdofraga.blogspot.com/search/label/Avandia" rel="tag" style="text-decoration-line: none;">Avandia</a></div><div class="post-footer-line post-footer-line-3"></div></div></div></div><div class="post-outer" style="border-top: 1px solid rgb(238, 238, 238); margin: 0px -15px; padding: 15px 15px 10px;"><div class="post hentry uncustomized-post-template" itemprop="blogPost" itemscope="itemscope" itemtype="http://schema.org/BlogPosting" style="position: relative; min-height: 0px;"><a name="3416213662534547980" /><h3 class="post-title entry-title" itemprop="name" style="margin: 0px; position: relative; font-variant-numeric: normal; font-variant-east-asian: normal; font-stretch: normal; line-height: normal;"><a href="http://weblogdofraga.blogspot.com/2007/05/rosiglitazone-meta-analysis-continues.html" style="text-decoration-line: none; font-variant-numeric: normal; font-variant-east-asian: normal; font-stretch: normal; line-height: normal;">Rosiglitazone Meta-Analysis Continues to Drive Controversy in Second Week</a></h3><div class="post-header" style="line-height: 1.6; margin: 0px 0px 1em;"><div class="post-header-line-1"><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">May 30, 2007 (New York, NY) - The fallout continues from the publication in the New England Journal of Medicine (NEJM) last week of a meta-analysis of rosiglitazone (Avandia, GlaxoSmithKline [GSK]), which suggested it increases the risk of MI and cardiovascular death [1].
As reported by heartwire, many experts have said the data were far from perfect and have expressed concern about the manner in which they were released. But new reports go one step further--suggesting that FDA whistleblowers coordinated with politicians critical of the agency and the study authors to get damaging data into the public arena before the FDA could issue a safety statement on rosiglitazone.
And damage has certainly been done in the form of a battering of the stock of GlaxoSmithKline, as Avandia was until now a $3-billion-a-year drug. Shares of the company were today at their lowest level in two years, following the sixth drop in seven trading days. Prescriptions for Avandia have also plummeted, with its slice of new oral diabetes prescriptions dropping from 10% to almost zero in the two days following the NEJM report.
As part of the company's response to the controversy, chief medical officer of GSK, Dr Ronald L Krall, has written a letter, published online in the Lancet today [2]. In support of the cardiovascular safety of rosiglitazone, he cites, among other things, the decision by the independent data safety monitoring board to continue the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, which is specifically designed to look at cardiovascular outcomes with rosiglitazone.
However Krall told the New York Times last week that the RECORD study could be under threat because some of the patients have dropped out of the trial due to safety concerns following last week’s events [3].</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
Conspiracy theories
An in-depth feature in a biotechnology weekly newsletter relates the tale of who knew what and when with regard to the rosiglitazone saga. US politicians have “portrayed Avandia as the quintessential. . . . Washington scandal, complete with maverick outsider who exposes wrongdoers and alerts congressional guardians of the public health,” writes Steve Usdin in BioCentury [4].</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
But according to an editorial by former FDA deputy commissioner Scott Gottlieb, published May 29, 2007 in the Wall Street Journal, the truth is that the study authors, the NEJM, and politicians with their own motives tried to upstage the FDA in an attempt to influence public debate [5].</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
According to Gottlieb, lead author Dr Steve Nissen (Cleveland Clinic, OH) submitted his manuscript to the NEJM on May 1 and did not inform either the FDA or GSK. The journal expedited the review of the paper and commissioned a commentary from two well-known critics of FDA’s drug safety record, Drs Curt Furberg (University of Washington, Seattle) and Bruce Psaty (Wake Forest University, Winston-Salem, NC) [6]. The paper and commentary were published online by the NEJM on May 21, a move Gottlieb says was “timed to get ahead of the FDA’s more careful evaluation of the same issues.”</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
The FDA had planned to issue a safety statement about Avandia around May 23, according to an unnamed drug safety official cited in the article by Usdin. Following publication of the NEJM paper, the FDA issued a statement on May 21 saying that its analyses were ongoing and that it would convene an advisory committee on the issues as soon as possible.</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
Gottlieb says the NEJM claims to have made the decision to publish quickly because of the medical importance of the research but, if that were the case, he wonders why it did not inform the FDA about its publication or the findings.
“When it comes to the issue du jour, drug safety, no description of medical research in a medical journal comes close to the detail level or scrutiny imposed by the FDA on study results before approval. Yet NEJM and other journals have tried on other occasions to upstage FDA investigations through well-timed but much less complete publications,” he asserts.</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
He adds that there was no mention in the NEJM paper or editorial of rosiglitazone’s benefits or of how doctors should advise patients.
Steven Galson (director of the FDA’s Center for Drug Evaluation and Research) told Usdin: “Medical journals have to take their job seriously. They have a responsibility to patients and physicians to publish information in a responsible and balanced manner. I’m not sure that responsibility was adequately executed in this instance.”</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
But NEJM editor Dr Gregory Curfman told BioCentury that his journal is not responsible for the media reactions to the rosiglitazone paper and commentary: “We are a scholarly journal, not a news outlet. What happens in the media is beyond our control.”</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
RECORD study may have to be halted</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
Despite an interim review of RECORD finding no safety flags with the drug, GSK medical director Dr Ronald L Krall told the New York Times that the independent research committee overseeing the trial is examining what steps can be taken to prevent people from leaving the study.</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
RECORD is an open-label six-year cardiovascular outcomes trial with prospectively defined cardiovascular end points in 4458 patients. It began in 2000 and is scheduled to run until next year.
He said he did not yet know how many patients had withdrawn from the study as a result of last week’s events.</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
The Times points out that neither GSK nor the FDA has released any details of this interim assessment of RECORD, which was apparently conducted within the past few weeks. But in his letter to the Lancet today, Krall says the manuscript regarding this interim assessment is “in preparation.”</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
He adds that other cardiovascular-outcomes trials--such as the 2368-patient Bypass Angioplasty Revascularization Investigation Type 2 Diabetes trial (BARI 2D) and the 10 251-patient Action to Control Cardiovascular Risk in Diabetes (ACCORD) study--“will further inform the cardiovascular safety profile of rosiglitazone.”</div><div class="post-body entry-content" id="post-body-3416213662534547980" itemprop="description articleBody" style="width: 586px; position: relative; line-height: 1.4;">
The data safety monitoring boards of both of these studies have also confirmed that they should continue, he notes, concluding: “We should stay the course and allow ongoing trials to provide their definitive answers.”
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; DOI:10.1056/NEJMoa072761. Available at: <a href="http://www.nejm.org/" target="blank" style="text-decoration-line: none;">http://www.nejm.org</a>.
Krall RL. Cardiovascular safety of rosiglitazone. Lancet 2007; DOI: 10.1016/S0140-6736 (07) 60824-1. Available at: <a href="http://www.thelancet.com/" target="blank" style="text-decoration-line: none;">http://www.thelancet.com</a>.
Saul S. Test of drug for diabetes in jeopardy. New York Times, May 26, 2007. Available at: <a href="http://www.nytimes.com/" target="blank" style="text-decoration-line: none;">http://www.nytimes.com</a>.
Usdin S. Political defibrillator. BioCentury, May 28, 2007. Available at: <a href="http://www.biocentury.com/" target="blank" style="text-decoration-line: none;">http://www.biocentury.com</a>.
Gottlieb S. Journalistic malpractice. Wall Street Journal, May 29, 2007. Available at: <a href="http://www.wsj.com/" target="blank" style="text-decoration-line: none;">http://www.wsj.com</a>.
Psaty B and Furberg C. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; DOI:10.1056/NEJMe078099. Available at: <a href="http://www.nejm.org/" target="_blank" style="text-decoration-line: none;">http://www.nejm.org</a>.</div><div class="post-footer" style="line-height: 1.6; margin: 1.5em 0px 0px;"><div class="post-footer-line post-footer-line-2">Labels: <a href="http://weblogdofraga.blogspot.com/search/label/Avandia" rel="tag" style="text-decoration-line: none;">Avandia</a></div></div></div></div></div></div><div>===</div></div></div></div></div></div></div></div></div></div></div></div>