[Tamiflu] Fwd: BMJ Demands Raw Data from Pharma Clinical Trials

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ALLIANCE FOR HUMAN RESEARCH PROTECTION A Catalyst for Public Debate: Promoting Openness, Full Disclosure, andAccountability http://www.ahrp.org FYIThe controversy surrounding the frenzied promotion of the drug, Tamiflu(oseltamivir) has exploded in several scientific venues and even in the USand UK media. The controversy may be even more instructive about thesystemic issues that undermine the integrity of the drug and vaccine reviewand analysis process than the Vioxx catastrophe.This week's BMJ contains six articles detailing the essential issuesinvolved in the Tamiflu controversy: included are independent critics'analyses as well as company counterclaims, and two editorials (excerptsbelow) that critique the current system which not only fails to detectserious adverse effects, the system allows manufacturers to control thetrials and conceal the safety data. Physicians and the public are misledwith a false sense of security about the safety and effectiveness ofpatented drugs and vaccines. The deception is orchestrated by companymarketing masquerading as evidence which prominent industry-paid academicphysicians promote as "science-based" information. For example, a much cited favorable analysis by Kaiser et al (2005) wasfunded by the drug's manufacturer Roche. The analysis was based entirely on10 trials funded by Roche: of which only two had been published in peerreviewed journals. All 10 trials were authored by Roche employees and paidacademic consultantsThe system has provided companies an opportunity to make spectacular profitsfrom the widespread use of defective drugs and vaccines that have causedirreversible harm."The current system isn't working. Worse than that, it gives a false senseof security. The system's failures have left a legacy of drug evaluationsfor which, in the absence of better information, we must assume the samelevels of confusion and uncertainty as for oseltamivir. The drug industrydirectly or indirectly undertakes the majority of all drug evaluations, somost of the evidence used to support drug policy and treatment remainsshrouded in secrecy. In only a minority of cases will the data have beensubject to full independent analysis and interpretation. In many if not mostcases, the only people who have seen the entire dataset are companyemployees." See: Editorial, Why don't we have all the evidence on oseltamivir? BMJ2009;339:b5351 http://www.bmj.com/cgi/content/full/339/dec08_3/b5351Indeed, we learn how independent Cochrane Collaboration reviewers werehoodwinked into trusting a company funded meta-analysis of unpublisheddata--data that was undisclosed to the Cochrane reviewers:"The previous reviewers endorsed the conclusion that oseltamivir reducescomplications such as pneumonia and bronchitis by implicitly trusting thatthe unpublished data were verifiable. This trust now seems naive. The factthat a trust in unpublished data extends to many systematic reviews ofneuraminidase inhibitors by other researchers and was not questioneduntil... a paediatrician from Japan, Keiji Hayashi, submitted a comment tothe Cochrane Collaboration that would ultimately leave us doubtful about theability of systematic reviews to deal with the challenges of contemporarypharmaceutical evaluation...""The previous Cochrane review placed its trust in publications and includedKaiser's unpublished data, but to do so once again, despite our inability toobtain data sufficient to perform an independent analysis, would haveshifted our position from that of trust in publication to that of trust insecrecy." The revised review dropped Kaiser's paper from its analysis.Notwithstanding the positive spin provided by the Kaiser analysis, whichconcluded that Tamiflu reduces complications, Roche, apparently did notitself make any such claims about complications. A Tamiflu.com webpagereads, "Treatment with TAMIFLU has not been proven to have a positive impacton these outcomes," referring to pneumonia, other respiratory diseases, andinfluenza related death.However, a footnote on that website undermines the company's pretense ofcandor: "THIS [WEB]SITE IS INTENDED FOR U.S. AUDIENCES ONLY." On its global website, Roche.com, it asserts that "Tamiflu delivers ... [a]67 percent reduction in secondary complications such as bronchitis,pneumonia and sinusitis in otherwise healthy individuals." BMJ editor, Fiona Godlee, challenges Roche to disclose the drug's completeclinical trial data so that independent scientists can evaluate the actualrisk / benefit of the vaccine--on the basis of scientific data, not thehearsay of the manufacturer and its financially compromised scientists.Her challenge is really directed at the pharmaceutical industry, not justRoche. It gets to the heart of the systemic corruption of science, clinicalpractice, government healthcare policies that have encouraged system widefraud."We don't know yet whether this episode will turn out to be a decisivebattle or merely a skirmish in the fight for greater transparency in drugevaluation. But it is a legitimate scientific concern that data used tosupport important health policy strategies are held only by a commercialorganisation and have not been subject to full external scrutiny and review.It can't be right that the public should have to rely on detective work byacademics and journalists to patch together the evidence for such a widelyprescribed drug. Individual patient data from all trials of drugs should bereadily available for scientific scrutiny."Contact: Vera Hassner Sharavveracare212-595-8974http://www.bmj.com/cgi/content/full/339/dec10_2/b540510 December 2009BMJ 2009;339:b5405Editor's ChoiceWe want raw data, nowFiona Godlee, editor, BMJfgodleeThis week's BMJ is dominated by a cluster of articles on oseltamivir(Tamiflu) (doi:10.1136/bmj.b5351, doi:10.1136/bmj.b5387,doi:10.1136/bmj.b5106, doi:10.1136/bmj.b5164, doi:10.1136/bmj.b5248,doi:10.1136/bmj.b5364). Between them the articles conclude that the evidencethat oseltamivir reduces complications in otherwise healthy people withpandemic influenza is now uncertain and that we need a radical change in therules on access to trial data.Briefly, in updating their Cochrane review, published this week(doi:10.1136/bmj.b5106), Tom Jefferson and colleagues failed to verifyclaims, based on an analysis of 10 drug company trials, that oseltamivirreduced the risk of complications in healthy adults with influenza. Theseclaims have formed a key part of decisions to stockpile the drug and make itwidely available.Only after questions were put by the BMJ and Channel 4 News has themanufacturer Roche committed to making "full study reports" available on apassword protected site. Some questions remain about who did what in theRoche trials, how patients were recruited, and why some neuropsychiatricadverse events were not reported. A response from Roche is published in ourletters pages (doi:10.1136/bmj.b5364) and their full point by point responseis published online (doi:10.1136/bmj.b5374).Should the BMJ be publishing the Cochrane review given that a more completeanalysis of the evidence may be possible in the next few months? Yes,because Cochrane reviews are by their nature interim rather than definitive.They exist in the present tense, always to be superseded by the next update.They are based on the best information available to the reviewers at thetime they complete their review. The Cochrane reviewers have told the BMJthat they will update their review to incorporate eight unpublished Rochetrials when they are provided with individual patient data.Where does this leave oseltamivir, on which governments around the worldhave spent billions of pounds? The papers in this week's journal relate onlyto its use in healthy adults with influenza. But they say nothing about itsuse in patients judged to be at high risk of complications-pregnant women,children under 5, and those with underlying medical conditions; anduncertainty over its role in reducing complications in healthy adults stillleaves it as a useful drug for reducing the duration of symptoms. However,as Peter Doshi points out (doi:10.1136/bmj.b5164), on this outcome it hasyet to be compared in head to head trials with non-steroidal inflammatorydrugs or paracetamol. And given the drug's known side effects, therisk-benefit profile shifts considerably if we are talking only in terms ofsymptom relief.We don't know yet whether this episode will turn out to be a decisive battleor merely a skirmish in the fight for greater transparency in drugevaluation. But it is a legitimate scientific concern that data used tosupport important health policy strategies are held only by a commercialorganisation and have not been subject to full external scrutiny and review.It can't be right that the public should have to rely on detective work byacademics and journalists to patch together the evidence for such a widelyprescribed drug. Individual patient data from all trials of drugs should bereadily available for scientific scrutiny.Cite this as: BMJ 2009;339:b5405~~~~~~~http://www.bmj.com/cgi/content/full/339/dec08_3/b5351EditorialsWhy don't we have all the evidence on oseltamivir?Fiona Godlee, editor in chief1, Mike Clarke, director2 The full data from drug trials must be available for scrutiny by thescientific communityThis week the BMJ publishes an updated Cochrane review on neuraminidaseinhibitors in adults with influenza.1 The review and a linked investigationundertaken jointly by the BMJ and Channel 4 News2 cast doubt not only on theeffectiveness and safety of oseltamivir (Tamiflu) but on the system by whichdrugs are evaluated, regulated, and promoted.In the process of updating their review, Jefferson et al found severalimportant inconsistencies. Prompted by a reader of their previous update,3they attempted to reconstruct the evidence from a much cited analysis onwhich they had based their previous conclusions. The analysis, by Kaiser etal,4 looked specifically at the effects of oseltamivir on the risk ofhospital admission and complications (pneumonia and other lower respiratorytract infections) in people with influenza. Jefferson et al noted that theKaiser analysis was funded by the drug's manufacturer Roche and was basedentirely on 10 trials funded by Roche, only two of which had been publishedas articles in peer reviewed journals. All 10 included trials were authoredby Roche employees and paid academic consultants. The Cochrane reviewerscould find no independently funded trials of oseltamivir in healthy adults.Other questions also arose, as outlined by one of the Cochrane reviewersPeter Doshi5 and by Deborah Cohen in our feature.2 Which authors of thetrials had seen the raw data? Why were key authors of the published papersand abstracts not named in company documents submitted for drug approval,while people named in these documents were not included in the publishedpapers? Were ghost writers involved in some of the manuscripts, as allegedby former employees of the medical communication company hired by Roche? Whywere the rates of influenza infection in the trials so high? And why wereserious adverse events under-reported?...........This case exposes how much of the evidence on drug safety and effectivenessis taken on trust. Governments and international bodies have relied heavilyon the Kaiser et al analysis and on observational studies to justify thestockpiling and widespread use of oseltamivir.2 7 10 No doubt they assumedthat others had looked critically and comprehensively at the completedataset. Those others might include drug regulators and health technologyassessors such as NICE, as well as journal editors and Cochrane reviewers.But that isn't how the system works........FAIR USE NOTICE: This may contain copyrighted (C ) 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. _____________Infomail1 mailing listto send a message to Infomail1-leave =====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.