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Dear Stephen, Though the entire trial database was held by Schering Plough, the PI Dr John Kastelein always insisted in his public interviews that the data had not been unblinded before the end-point was changed. However Scientific Misconduct Blog ridiculed this assertion in its Blog and wrote:'Lead investigator of the study, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) stated that "The suggestion that the results are being suppressed because they are negative is simply wrong. People are assuming that anyone can take a peek at the data, but how can they do that if it hasn't even been unblinded and there are 40 000 images to analyze?" With respect Dr Kastelein, the assertion that altering endpoints before unblinding cannot cause bias is obvious and utter nonsense. 1. Firstly, we have no confidence (P=0.3) that the study has not in fact been secretly unblinded. This lack of confidence is the logical assumption following numerous odd events and data alterations which have taken place in the past. Unblinding codes are presumably held by the same entity holding the raw data (I guess). That same entity has a huge financial stake in the outcome. That entity is not yourself Dr Kastelein. Nor is that entity a secure impartial honest third party (a complete guess). 2. Secondly, as an experienced scientist you will be fully aware it is perfectly easy to fiddle the results of a randomized trial given a "blinded" study database even without the un-blinding codes. Ezetimibe has many side "effects" that distinguish it from placebo apart from it's intended clinical benefit (LDL lowering is itself such a "side effect"). It would be easy for an individual "exploring" the data to examine the relationship between LDL lowering and various "primary endpoints" without unblinding to get a pretty good idea of the "primary" endpoints to reject, exclusion criteria to be applied, or even the variables that might require a little "recoding". ............... You might also make some comment about the need for company statisticians to be involved with the data at all'. The other curious thing about the whole affair is that Schering and Merck did not list the trial on the government Web site clinicaltrials.gov, which is supposed to have records of all clinical studies, until asked by Forbes.com about its absence. The companies stated that it was an oversight resulting from the fact that ENHANCE began before the industry listed every study online. After Forbes published a story on Vytorin (Ezetimibe) in its magazine, Merck and Schering-Plough issued a press release saying that they had convened an expert panel on Nov. 16 2007 to offer advice on how to analyze the ENHANCE trial. The panel recommended focusing only on arteries in the neck, not in both the neck and the thigh. However, the drug companies resolutely refused to publicly disclose the names of the members of that panel. Regards. Ash From: Stephen Senn <[log in to unmask]> >To: [log in to unmask] >Sent: Saturday, 20 August 2011, 9:35 >Subject: Re: Ezetimibe/Simvastatin > >Does anybody know if the endpoint was changed before or after unblinding of the data? >Stephen > > >Stephen Senn > >Professor of Statistics >School of Mathematics and Statistics >Direct line: +44 (0)141 330 5141 >Fax: +44 (0)141 330 4814 >Private Webpage: http://www.senns.demon.co.uk/home.html > >University of Glasgow >15 University Gardens >Glasgow G12 8QW > >The University of Glasgow, charity number SC004401 >________________________________________ >From: Evidence based health (EBH) [[log in to unmask]] On Behalf Of Michael Power [[log in to unmask]] >Sent: 20 August 2011 06:20 >To: [log in to unmask] >Subject: Re: Ezetimibe/Simvastatin > >Ash > >Does the NHS have in its purchasing contracts for drugs and devices a clause to the effect that money paid will be reclaimed (with interest and damages if appropriate) if products are found to be misleadingly marketed on the basis of biased or incomplete evidence on effectiveness and safety? > >Could people from outside the UK tell us what their country’s healthcare purchaser’s practices are. > >michael > > >From: Evidence based health (EBH) [mailto:[log in to unmask]] On Behalf Of Ahmed M. Abou-Setta, MD >Sent: 19 August 2011 23:31 >To: [log in to unmask] >Subject: Re: Ezetimibe/Simvastatin > >Hi Ash, > >Thanks for the background on this paper. It came out right before we actually began the review and our clinical leads had said that they had been anticipating this trial for some time. Interesting enough from the text of the trial report in the NEJM, it doesn’t read like the authors were at all outside of the loop: > >“The image database was generated and housed in the Core Echo Laboratory at the Academic Medical Center in Amsterdam, and the clinical database was maintained by the sponsors. All data were analyzed independently by an investigator at the Department of Clinical Epidemiology and Biostatistics at the Academic Medical Center. Although the authors allowed the sponsors to review the manuscript, all data analyses and interpretation of the results are those of the academic investigators.” > >Ahmed > >From: Evidence based health (EBH) [mailto:[log in to unmask]] On Behalf Of Ash Paul >Sent: Friday, August 19, 2011 2:35 PM >To: [log in to unmask] >Subject: Re: Ezetimibe/Simvastatin > >Dear Ahmed, >Many thanks for your clarification and for the reference to your AHRQ study. >Ezetimibe's claim to fame is that it does not work like statins, so patients unable to tolerate statins can usually take it safely. It also is better at selectively lowering "bad" (LDL) cholesterol than statins alone. Proof that it lowered LDL was enough for the FDA to approve it. >The infamous ENHANCE Trial, now regarded as a classical example of grave scientific research misconduct, did not measure cholesterol levels as a primary or secondary end-point. >What it set out to do was to measure the growth of atherosclerotic plaque in patients taking only a statin versus patients taking both the statin and ezetimibe. The thickness of plaque is still a "surrogate endpoint" rather than an actual disease outcome; but many believed that it was a reasonable predictor of whether the drug would actually work. >Apart from the abnormal delay in reporting results, the companies had sole control of the trial data, and until they analyzed it all and elected to release it, there was no way that the Principal Investigator Kastelein himself could access it. The companies then decided to change the study's primary endpoint. Initially they had planned to focus attention on a combination of plaque thickness measuements at three different points in the carotid artery. They then suddenly announced that they intended to report as the primary endpoint the thickness at only one point. This, they claimed, would allow faster reporting of the results and would be just as reliable. They said that they would still report the three separate places in the carotid, but as a secondary and not as a primary endpoint. >Kastelein hinted in the interviews that he was personally not very happy with the change in endpoints. To determine that this was the right thing to do, the companies brought in an outside expert advisory panel. The panel concluded that the endpoint should be changed. However, oddly, the drug companies refused to disclose who was on the panel. >Many trial experts were highly critical of the endpoint shift. As a rule such a shift is very suspicious because it raises fears that you are deciding what counts as a successful trial result only after you know what some of the data show. It is analogous to hitting a bull's-eye with a bow and arrow by first shooting the arrow, then drawing the bull's-eye around the arrow wherever it happens to land (quotation taken from Prof Howard Brody). >The rest, as the saying goes, is history! >Regards, >Ash >From: Ahmed Abou-Setta <[log in to unmask]<mailto:[log in to unmask]>> >To: [log in to unmask]<mailto:[log in to unmask]> >Sent: Friday, 19 August 2011, 18:23 >Subject: Ezetimibe/Simvastatin >Hi Paul, > >I don’t want to get off topic, but just a note of clarification. We performed a large comparative effectiveness review for AHRQ a couple of years ago and found that Ezetimibe/simvastatin does in fact decrease cholesterol levels more than simvastatin alone, BUT this was a surrogate outcome (not our primary outcome). What we didn’t find is a difference in important patient oriented outcomes (e.g. mortality, stroke, MI, etc.). If anyone is interested the full report is available on the AHRQ website (http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=170) and a subsequent report in Annals of Internal Medicine (http://annals.org/content/151/9/622.abstract?sid=738e55b3-c9f2-4c27-a11f-7270dc38306c). What drug companies, and others so I am not pointing fingers, often do is use surrogate outcomes in place of clinically important long-term outcomes to prove their case of efficacy and effectiveness. The concept is like offering infertile couples a treatment plan will 100% guarantee of a clinical pregnancy, but at the same time will 100% guarantee an abortion before the baby can survive outside the womb. Would patients or clinicians find this drug to be the golden standard because it works 100% of the time for a surrogate outcome, or an injustice because it fails 100% of the time to provide the needed final result (the birth of a healthy child)? I am hoping no one on this list is picking the former. > >Ahmed > > >From: Evidence based health (EBH) [mailto:[log in to unmask]]<mailto:[mailto:[log in to unmask]]> On Behalf Of Ash Paul >Sent: August 19, 2011 5:24 AM >To: [log in to unmask]<mailto:[log in to unmask]> >Subject: Re: Something else does indeed need to be done > >Dear Richard, > >The best example of a recent non-disclosure that comes to mind is that of Ezetimibe (which brilliantly illustrates Rakesh's point made previously about trial publication within a specified time period). > >According to the ENHANCE trial, the results of which were published a full two years after it finished, and then only because the US Congress threatened to subpoena the pharmaceutical company MSD who were deliberately withholding and refusing to release the unfavourable trial results, Ezetimibe is essentially a worthless drug. The FDA is now investigating and re-evaluating the drug: >http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070779.htm >Following on from this, on 15th July 2009, Merck and Schering Plough struck a $5.4 million deal with 35 US State Attorneys General to resolve an investigation into the companies' lengthy delay in releasing negative results from the ENHANCE trial, which showed that Ezetimibe combined with cholesterol-lowering Simvastatin was no better than Simvastatin alone. As I mentioned earlier, the trial was completed in May 2006, but the results were not announced until January 2008. > >During the lengthy delay, the companies engaged in aggressive direct-to-consumer (DTC) marketing of their two Ezetimibe products, Zetia and Vytorin, spending $200 million on DTC marketing in 2007 alone, according to a study (http://content.nejm.org/cgi/content/abstract/358/17/1819) published last year in the New England Journal of Medicine. >The settlement extends the terms that Merck agreed to in 2008 in its settlement with the states over its marketing of Rofecoxib (Vioxx) to marketing of Ezetimibe. > >According to a press release (http://www.ag.state.il.us/pressroom/2009_07/20090715.html ) issued by the Illinois Attorney General, the settlement requires the companies to: > >* Obtain pre-approval from the FDA for all DTC television advertisements, and comply with FDA suggestions to modify the advertising >* Register clinical trials and post their results >* Refrain from ghostwriting articles for medical journals >* Reduce conflicts of interest for members of data safety monitoring boards >* Comply with detailed rules prohibiting the deceptive use of clinical trials >The company was found guilty by the US Attorneys General on all the above counts in relation to Ezetimibe. >The settlement resolves only a small portion of the litigation and governmental investigations the companies face over their flawed handling of the ENHANCE trial. > >Tom Jefferson from our Group has also raised a very interesting question as to why/when Medtronic have agreed to this new proposal (before or after the court case?) > >Regards, > > >Ash >Dr Ash Paul >Medical Director >NHS Bedfordshire >21 Kimbolton Road >Bedford >MK40 2AW >Tel no: 01234897224 >Email: [log in to unmask]:[log in to unmask] >