Fwd: Avandia, a Deadly Case of Déjà vu all over again

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ALLIANCE FOR HUMAN RESEARCH PROTECTION A Catalyst for Public Debate: Promoting Openness, Full Disclosure, andAccountability http://www.ahrp.org FYIOnce again, a front page report in The New York Times (below) lays bareunseemly facts about the pharmaceutical industry’s deadly norm and practiceof concealing fatal risks of drugs that millions of patients consume as aresult of aggressive marketing campaigns. Once again, the FDA is shown to be complicit in turning a blind eye when adrug manufacturer, in this case, GlaxoSmithKline, concealed documented risksof heart attacks linked to its adjuctive diabetes drug, Avandia(rosiglitazone), putting of patients in harm’s way.Gardiner Harris reports that a fierce debate that has been brewing for yearswithin the FDA about “what to do about Avandia:” inasmuch as thepreponderance of evidence shows patients taking the drug suffer cardiacharm. Once again, a detailed Senate Finance Committee investigation reveals thetrue magnitude of the potentially deadly cardiac risks involving Avandia, anaggressively marketed diabetes drug whose sales reached $3.2 billion in2006, but whose deadly risks the manufacturer, GlaxoSmithKline, concealedfrom patients and physicians for YEARS.” See Senate Finance Committee PressRelease packet: http://finance.senate.gov/press/Gpress/2010/prg022010b.pdf The report, overseen by Senator Max Baucus, a Democrat, and Senator CharlesE. Grassley, a Republican., examined 250,000 internal GSK documents,concluded that instead of issuing a warning—as is a drug manufacturer’sduty--“G.S.K. executives attempted to intimidate independent physicians,focused on strategies to minimize or misrepresent findings that Avandia mayincrease cardiovascular risk, and sought ways to downplay findings that acompeting drug might reduce cardiovascular risk.” See Senate Finance Committee letter to FDA Commissioner (below). The Committee packet posted on its website includes a comprehensivebenefit-risk assessment report (2008. 75 pp.) by FDA safety officers, Dr.David Graham and Dr. Kate Gelperin. They report that the preponderance of evidence showed that "there was noevidence that rosiglitazone [Avandia] confers any unique health benefit overpioglitzone [Actos] while there was strong evidence that [Avandia] confersan increased risk of AMI [acute myocardial infarction] and heart failurecompared to [Actos]. The evidence led these expert FDA safety officers toconcluded that the drug “should be removed from the market” inasmuch as anestimated 500 heart attacks and 300 cases of heart failure would be avertedEVERY MONTH, if patients took another diabetes drug.” See FinanceCommittee packet Attachment B:http://finance.senate.gov/press/Gpress/2010/prg022010a.pdfAvandia’s cardiac risk was in evidence as early as November 2003, when GSKcompleted a study in which “diabetics given Avandia had far more heartproblems than those given placebos.” European regulators ordered GSK toconduct a study to examine Avandia’s heart risks, but when the study showedharm (2004), GSK conducted a meta-analysis which it submitted to the FDA in2005, and updated in 2006. The analysis showed that “Avandia increased therisks of serious heart problems by nearly a third.” However, despite the totality of evidence, from company studies, adverseevent reports filed with FDA’s Medwatch, and FDA safety evaluationscorroborating Avandia’s deadly cardiac risks, the agency continued to dragits feet, “negotiating” with GSK, rather than pulling the drug off themarket or, at the very least, issuing public warnings. Even worse, in 2007, after the New England Journal of Medicine published areport warning of the cardiovascular risk for patients taking Avandia; andafter warnings were issued in several countries--including Canada, theEuropean Union, and Australia--that Avandia was CONTRAINDICATED in patientswith acute coronary syndrome; FDA officials, in collusion and collaborationwith GSK, approved an unethical and exploitative clinical trial—TIDE, whichis on-going. See:http://clinicaltrials.gov/ct2/show/NCT00879970?term=nct00879970 & rank=1 The trial does not meet the ethical principle of equipoise—requiring that sofar as is known, benefit-risk of each comparator were equal. The accumulatedevidence showed that Avandia posed higher risks than Actors. Furthermore,the FDA-approved trial allows the enrollment of very high risk patients withischemic heart disease—for whom Avandia is contraindicated in severalcountries See: Attachment C:http://finance.senate.gov/press/Gpress/2010/prg022010a.pdfThe Informed Consent form given to patients is deceptive by commingling therisks of Avandia with the comparator drug, Actos (pioglitzone), which doesnot pose the cardiac risk that Avandia does. See Finance CommitteeAttachment D: http://finance.senate.gov/press/Gpress/2010/prg022010a.pdfCorporate tactics of intimidation are, once more, in evidence: The Senate Finance Committee report states that “GSK executives intimidatedindependent physicians” who suggested in public that Avandia might haveserious risks. It’s difficult to tell whether GSK took a leaf from Merck’stactics of intimidation—such as, Merck’s physician “hit list” of doctors whopublicly raised concerns about Vioxx cardiac risks—or whether intimidationof honest physicians is but “the norm and practice” within thepharmaceutical industry.FDA’s consistent failure to act in the public interest continues unabatedunder the Obama administration, much as it did under the BushAdministration. Avandia--and an untold number of other drugs that damage theheart--continue to be aggressively marketed, killing thousands of consumers:FDA officials continue to diddle.Contact: Vera Hassner Sharavveracare212-595-8974~~~~~~~~~~~~~~~~~http://finance.senate.gov/press/Gpress/2010/prg022010a.pdfUnited States SenateCommittee on FinanceVia Electronic TransmissionThe Honorable Margaret A. Hamburg, MDCommissionerU.S. Food and Drug AdministrationWhite Oak Building 110903 New Hampshire AvenueSilver Spring, MD 20993Dear Commissioner Hamburg:As senior members of the United States Senate and Chairman and RankingMember of the Committee on Finance (Committee), we have a duty under theConstitution to conduct oversight into the actions of executive branchagencies, includingthe Food and Drug Administration (FDA). In this capacity, we must ensurethat FDAproperly fulfill their mission to advance the public’s welfare, safeguardthe nation’s drugsupply, and protect patients participating in clinical trials.We recently released a report raising concerns about Avandia, a diabetesdrugmade by GlaxoSmithKline (GSK). We began this inquiry after the New EnglandJournalof Medicine published a study in May 2007 warning of the possiblecardiovascular risk ofAvandia.Our report was based on a review of hundreds of thousands of pages ofinternalGSK documents and concluded:The totality of evidence suggests that GSK was aware of the possible cardiacrisksassociated with Avandia years before such evidence became public.… Based onthis knowledge, GSK had a duty to sufficiently warn patients and the FDA ofitsconcerns in a timely manner. Instead, GSK executives intimidated independentphysicians, focused on strategies to minimize findings that Avandia mayincreasecardiovascular risk, and sought ways to downplay findings that the rivaldrugACTOS (pioglitazone) might reduce cardiovascular risk.In 2007, the FDA asked GSK to perform a cardiovascular safety trial, calledTIDE (Thiazolidinedione Intervention With Vitamin D Evaluation), to compareAvandiato other diabetes treatments such as ACTOS (piolglitazone). According toclinicaltrials.gov, the TIDE trial is currently recruiting patients.[ATTACHMENT A]In response to several document requests made to the FDA, we received andreviewed an analysis conducted by two FDA safety officials. It is ourunderstanding thatthis analysis, conducted in October 2008, reviewed all available studiescomparingrosiglitazone (Avandia) to pioglitazone (ACTOS). The analysis by these FDAofficialsraise some alarms. For instance, they wrote:[T]here is no evidence that rosiglitazone confers any unique health benefitsoverpioglitazone while there is strong evidence that rosiglitazone confers anincreasedrisk of [heart attacks] and heart failure compared to pioglitazone.[ATTACHMENT B]Even more alarming, they concluded that “any proposed head-to-head trial ofrosiglitazone vs. pioglitazone would be unethical and exploitative.”Two days after releasing this analysis, one of these same safety officersreviewedthe protocol for the TIDE trial. This safety officer wrote that because ofcardiovascularconcerns with Avandia “the safety of the study itself cannot be assured, andis notacceptable.” [Attachment C]After reading these documents, we would like to know what steps the FDA hastaken to protect patients in the TIDE trial, and why this trial is allowedto continue. Wewould also like to know if the Office for Human Research Protection (OHRP)wasnotified about the safety concerns of the TIDE trial identified by the FDA.Further, wewere alarmed to learn that the warnings from these safety officers do notappear to beaddressed in the consent form that was handed out to patients that wereenrolled in thestudy. [Attachment D]We look forward to hearing from you by no later than March 4, 2010. Alldocuments responsive to this request should be sent electronically in PDFformat toBrian_Downey. If you have any questions, please donothesitate to contact Chris Law (Senator Baucus) or Paul Thacker (SenatorGrassley) at(202) 224-4515.Sincerely,Max Baucus Charles E. GrassleyChairman Ranking Memberhttp://www.nytimes.com/2010/02/20/health/policy/20avandia.html THE NEW YORK TIMESFebruary 20, 2010Controversial Diabetes Drug Harms Heart, U.S. Concludes By GARDINER HARRISHundreds of people taking Avandia, a controversial diabetes medicine,needlessly suffer heart attacks and heart failure each month, according toconfidential government reports that recommend the drug be removed from themarket.The reports, obtained by The New York Times, say that if every diabetic nowtaking Avandia were instead given a similar pill named Actos, about 500heart attacks and 300 cases of heart failure would be averted every monthbecause Avandia can hurt the heart. Avandia, intended to treat Type 2diabetes, is known as rosiglitazone and was linked to 304 deaths during thethird quarter of 2009.“Rosiglitazone should be removed from the market,” one report, by Dr. DavidGraham and Dr. Kate Gelperin of the Food and Drug Administration, concludes.Both authors recommended that Avandia be withdrawn. The internal F.D.A. reports are part of a fierce debate within the agencyover what to do about Avandia, manufactured by GlaxoSmithKline. Some agencyofficials want the drug withdrawn because they believe there is a saferalternative; others insist that studies of the drug provide contradictoryinformation and that Avandia should continue to be an option for doctors andpatients. GlaxoSmithKline said that it had studied Avandia extensively andthat “scientific evidence simply does not establish that Avandia increases”the risk of heart attacks. The battle has been brewing for years but has been brought to a head bydisagreement over a new clinical trial and a Senate investigation thatconcluded that GlaxoSmithKline should have warned patients earlier of thedrug’s potential risks. Avandia was once one of the biggest-selling drugs in the world. Driven inpart by a multimillion-dollar advertising campaign, sales were $3.2 billionin 2006. But a 2007 study by a Cleveland Clinic cardiologist suggesting thatthe drug harmed the heart prompted the F.D.A. to issue a warning, and salesplunged. A committee of independent experts found in 2007 that Avandia mightincrease the risk of heart attack but recommended that it remain on themarket, and an F.D.A. oversight board voted 8 to 7 to accept that advice. Hundreds of thousands still take the medicine, although some topendocrinologists say they have sworn off the drug.Since 2007, more studies have been done. In a December 2009 internalmemorandum, Dr. Janet Woodcock, director of the F.D.A.’s drug center, wrotethat “there are multiple conflicting opinions” about Avandia within theagency, and she ordered officials to assemble another advisory committee,expected this summer, to reconsider whether the drug should be sold.“I await the recommendations of the advisory committee,” the agency’scommissioner, Dr. Margaret Hamburg, said Friday night. “Meanwhile, I amreviewing the inquiry made by Senators Baucus and Grassley and I am reachingout to ensure that I have a complete understanding and awareness of all ofthe data and issues involved.”The bipartisan multiyear Senate investigation — whose results are expectedto be released publicly on Monday but which were also obtained by The Times— sharply criticizes GlaxoSmithKline, saying it failed to warn patientsyears earlier that Avandia was potentially deadly. “Instead, G.S.K. executives attempted to intimidate independent physicians,focused on strategies to minimize or misrepresent findings that Avandia mayincrease cardiovascular risk, and sought ways to downplay findings that acompeting drug might reduce cardiovascular risk,” concludes the report,which was overseen by Senator Max Baucus, a Montana Democrat, and SenatorCharles E. Grassley, an Iowa Republican.Mr. Baucus said of the report, “Patients trust drug companies with theirhealth and their lives, and GlaxoSmithKline abused that trust.”In response, GlaxoSmithKline said that it disagreed with the Senateinvestigation’s conclusions. The company said that it could not comment oninternal F.D.A. documents but that “the official ruling from F.D.A. is thatAvandia remain on the market.” In the wake of the controversy, agency officials ordered GlaxoSmithKline toundertake a study comparing how many heart attacks, strokes andheart-related deaths occur among patients given either Avandia, Actos or aplacebo. Studies suggest that Actos, made by Takeda, lowers blood sugar aswell as Avandia but without hurting the heart as much. But Dr. Graham and Dr. Gelperin, working in the F.D.A.’s office ofsurveillance and epidemiology, argued in two separate internal reports thatthe new GlaxoSmithKline study, called TIDE, is “unethical and exploitative”because patients given Avandia face far greater risks than those givenActos, with no promise of any additional benefit. The trial may includepatients who have had heart attacks or chest pains even though some foreigndrug authorities have warned against Avandia’s use by precisely suchpatients, the reports note.“Although the proposed TIDE trial is motivated by a desire for definitiveanswers regarding the cardiovascular safety of the drug rosiglitazone, thesafety of the study itself cannot be assured and is not acceptable,” one ofthe reports concludes.These concerns, in internal reports dated October 2008 but not made publicuntil now, were later overruled by other agency officials, andGlaxoSmithKline is currently enrolling patients in the TIDE trial. The trialis not expected to be completed until 2020, although the company is hopingto report some results to the F.D.A. by 2014. The company’s patent onAvandia expires in 2012, and generic versions will probably swallow mostremaining profits.In a letter sent Thursday to Dr. Hamburg, the Food and Drug Administrationcommissioner, Mr. Baucus and Mr. Grassley asked “what steps the F.D.A. hastaken to protect patients in the TIDE trial” and said the trial’s patientshad never been told about the concerns raised by the agency’s own safetyofficers.Mr. Grassley said the internal agency battle showed that the agency neededto be restructured to give more power to safety officials like Dr. Grahamand Dr. Gelperin over their counterparts who approve medicines and deal moredirectly with drug makers.“It doesn’t make any sense to have these experts who study drugs after theyhave been on the market for several years under the thumb of the officialswho approved the drug in the first place and have a natural interest indefending that decision,” Mr. Grassley said. “The Avandia case may be themost alarming example of the problem with this setup.”The question of when and how to communicate possible drug risks has longbedeviled drug makers and regulators. Hints are common that drugs may causeinjuries; thousands of drug injury reports pour into the Food and DrugAdministration every week. For example, Avandia ranked first among allprescribed drugs in the number of serious, disabling and fatal problems —including 304 deaths — reported to the agency in the third quarter of 2009,according to an analysis done by the Institute for Safe Medication Practice,a drug safety oversight group.But companies say that such reports do not offer proof of a problem and thathighlighting them can scare patients away from needed treatment, so theyoften argue that more certainty is needed before alarms are raised.GlaxoSmithKline said a “vast majority” of the recent reports regardingAvandia was related to litigation.The Senate investigation — the result of years of digging through more than250,000 internal company documents — concludes that GlaxoSmithKline and byextension the F.D.A. delayed far too long in this process. In November 2003, for instance, the company completed a study in whichdiabetics given Avandia had far more heart problems than those givenplacebos. Two months later, the World Health Organization sent the companyan alert linking Avandia to heart ailments. In a June 2004 meeting, thecompany’s Global Safety Board said a hard look should be taken at allAvandia clinical trials for more signs of heart problems, documents show.European regulators had earlier ordered GlaxoSmithKline to conduct a study —called the Record trial — to examine Avandia’s heart risks because hints ofthese problems appeared in the company’s earliest trials.. But the Senatereport shows that by at least 2004, company executives were aware that theRecord trial was going so poorly that it would never answer the heartquestion with any kind of certainty.So company executives gathered dozens of Avandia studies and sifted theircombined data. Called a meta-analysis, this combined look found first in2005 and in an updated look in 2006 that Avandia increased the risks ofserious heart problems by nearly a third, the Senate investigation shows.Because two-thirds of diabetics die of heart problems, this was hugelyworrying.In 2005, executives revealed the results of their meta-analysis to theF.D.A., and in 2006 they provided the agency with the underlying data. Two large company-sponsored trials — called Dream and Adopt — were publishednear the end of 2006, and each provided more hints that Avandia hurts theheart, the documents show. In a March 2007 meeting of the company’s DiabetesFranchise Cardiology Advisory Board, advisers called the safety worriesfound in these many studies “disquieting.” Negotiations with agencyofficials about how and whether to alert the public continued.Meanwhile, the company continued to market and advertise Avandiaaggressively. The Senate inquiry concludes that the company threateneddoctors who suggested in public that Avandia might have serious risks. In 1999, for instance, Dr. John Buse, a professor of medicine at theUniversity of North Carolina, gave presentations at scientific meetingssuggesting that Avandia had heart risks. GlaxoSmithKline executivescomplained to his supervisor and hinted of legal action against him,according to the Senate inquiry. Dr. Buse eventually signed a documentprovided by GlaxoSmithKline agreeing not to discuss his worries aboutAvandia publicly. The report cites a separate episode of intimidation ofinvestigators at the University of Pennsylvania. GlaxoSmithKline said that it “does not condone any effort to silence”scientific debate, and that it disagrees with allegations that it tried tosilence Dr. Buse. Still, it said the situation “could have been handleddifferently.”Copyright 2010 The New York Times Company FAIR USE NOTICE: This may contain copyrighted (© ) material the use of whichhas not always been specifically authorized by the copyright owner. Suchmaterial is made available for educational purposes, to advanceunderstanding of human rights, democracy, scientific, moral, ethical, andsocial justice issues, etc. It is believed that this constitutes a 'fairuse' of any such copyrighted material as provided for in Title 17 U.S.C.section 107 of the US Copyright Law. This material is distributed withoutprofit. =====In accordance with Title 17 U.S.C. Section 107, this material is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.