Scientific Fraud & Corruption on Both sides of Atlantic: Merck / Proctor & Gamble

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Scientific Fraud & Corruption on Both sides of Atlantic: Merck /Proctor & Gamble ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)Promoting Openness, Full Disclosure, and Accountabilitywww.ahrp.org FYI Two major cases of medical research fraud on each side of the Atlanticinvolve evidence of fraud and data tampering by pharmaceuticalcompany giants. Both cases provide insight into the way in whichacademics are used by pharmaceutical companies that are desperate toobtain a stamp of respectability to their drug research. Companiescommission academics to pen their name to published reports inprestigious journals. But those reports do not reflect the actualclinical trial data. Both industry and the academics who serve astheir lackeys are destroying the very basis of that respectability. The positions taken by the scientists involved in these two cases area study in contrast. The U.S. press is focused on stunning revelations of fraud and datatampering that were uncovered during Vioxx court proceedings.Merck-"once the most esteemed name in the pharmaceutical business"-andits contracted academic scientists were shown to have deleted datalinking Vioxx to cardiovascular damage from the major VIGOR reportpublished in The New England Journal of Medicine in 2000. The NEJM isviewed as the most authoritative scientific journal. Fortune reports (below) that Dr. Gregory Curfman, Executive Editor ofthe NEJM said he was "stunned to find out that data linking Vioxx tocardiovascular risk was deleted from a major study his journalpublished five years ago--and that it appears that Merck researchers may have deleted that data." The New York Times editorial states: "What aroused the ire of the journal's editors was an internal companymemo revealing that the researchers knowingly suppressed data on threeadditional heart attacks among Vioxx users that was available monthsbefore the paper was published. Had that data been included, Vioxxwould have looked five times as risky as naproxen, not four times, andwould have looked potentially dangerous even in patients deemed at lowrisk of heart attacks." See:http://www.nytimes.com/2005/12/11/opinion/11sun2.html However, Fortune reports that following the withdrawal of Vioxx, NEJMeditors stumbled upon the evidence by examining a disc containing anearlier version with the cardiovascular data that was subsequentlydeleted from the final published version. The Journal editors remainedsilent about the evidence of data manipulation in a major report inits Journal that though they "talked internally" about the deletion ofdata they did not alert readers of the Journal who rely on theJournal's review process to protect the integrity of scientificreports within its covers: "We did not feel we had sufficient evidenceto act on it." From Fortune, we learn, that The NEJM editors saw fit to alert readersonly after Dr. Curfman was deposed (on Nov. 21, 2005) in Boston bylawyers from the firm of Lieff Cabraser Heimann and Bernstein, atwhich time he was confronted with "an internal Merck document datedJuly 5, 2000--after the VIGOR manuscript was submitted to the journal,but well before the study went to press." Merck's defense is that the company had submitted all the data to theFDA-as is its legal obligation. From that we are left to concludethat scientists who pen their name to journal articles do not feelsimilarly obliged to disclose ALL. The lead author of the VIGOR study,Dr. Claire Bombardier, (at the University of Toronto) appears to havebeen a willing servant of commercially driven misleading presentationof research. How many other such misleading reports are polluting thescientific literature? On the other side of the Atlantic, a similarly worrying new andimportant case is unfolding at the University of Sheffield in theUnited Kingdom. The case involves a collision between a seniorclinician and respected scientist, Dr Aubrey Blumsohn, who was thelead scientist for a clinical study of a Procter & GamblePharmaceuticals (P & G) drug, Actonel (risedronate). Dr. Blumsohn blewthe whistle on data concealment and ghostwritten journal reports withhis name appended. The case has attracted intensive press coverage: "A war between oneof Britain's most experienced academics and one of the world's mostsuccessful drugs companies. At issue is a highly significant report ona drug to treat a debilitating disease which the academic says waspublished under his name when he had not seen analysis of the researchit was based on. The drugs firm denies anything untoward hashappened."http://observer.guardian.co.uk/uk_news/story/0,6903,1657275,00.html After Dr. Blumsohn's data collection efforts for this study, P & Grefused to provide him with randomization codes or to allow anindependent analysis of this data. This, according to Dr. Blumsohn,was in breach of the company's contract with the institution.Furthermore, P & G wrote meeting abstracts, draft publications andstatistical reports on behalf of the University academics whiledenying them access to data upon which those reports were based. Datawas required by the academics to verify scientific reports,statistical analyses, meeting abstracts, and draft publications "ghostwritten" in their names. Refusal of access to data under such circumstances is unprecedented,and violates all norms of proper conduct and procedure in science. Itinterfered with the ability of academics to discharge their duties asresponsible scientists and clinicians, and prevented properpublication and correction of the scientific literature. It appearedthat "fair" analysis of the data might not have yielded findingsdesired by the sponsor. The company violated the norms of scienceunder whose banner they claim to sell their products. Repeated attempts to obtain the required data were not successful, andinformation emerged that the data analysis had been misleading.Blumsohn eventually made his concerns known about his inability toaccess the data to several senior officials at his university but wasapparently repeatedly ignored. Because, however, the Universitycharged that he did not go through proper channels, and eventuallytalked to the news media, the University of Sheffield suspended him. Victimization of academics raising such difficult issues is sadly onlytoo familiar.Particularly important was the UK Observer report of a tapedconversation Blumsohn had with Professor Richard Eastell, head of theuniversity's bone and metabolism unit and also Research Dean of hisMedical School about his attempts to get the data from P & G. Eastell said: "The only thing that we have to watch all the time is our relationshipwith P & G. Because we are... we have the big Sheffield Centre Grantwhich is a good source of income, we have got to really watch it. So,the reason why I worry is the network within P & G is like lightning. Soif Ian [barton] is unhappy it goes to Arkadi [Chines, global medicaldirector of P & G Pharmaceuticals] and before we know it, there is anissue, there is a problem." The matter was discussed extensively in the House of Commons (UKParliament) on 8th of December 2005. Different aspects of the Sheffield case are reported in the UKincluding: Times Higher Education Supplement (a UK academicnewspaper), and the Observer (a UK Sunday paper). It has also been thefocus of discussion in Parliament. When access to data is a real bone of contention http://www.thes.co.uk/search/story.aspx?story_id= 26307 How the drugs giant and a lone academic went to warhttp://observer.guardian.co.uk/uk_news/story/0,6903,1657275,00.html Doctor accuses drugs giant of 'unethical' secrecyhttp://observer.guardian.co.uk/uk_news/story/0,6903,1657302,00.htmlThe Observer, UK - Dec 3, 2005 Contact: Vera Hassner Sharav212-595-8974veracare FORBEShttp://www.forbes.com/home/sciencesandmedicine/2005/12/08/merck-vioxx-lawsuits_cx_mh_1208vioxx.html Sciences and MedicineMerck's Deleted DataRobert Langreth and Matthew Herper, 12.08.05, 8:10 PM ET NEW YORK - A top editor of The New England Journal of Medicine says that he was stunned to find out that data linking Vioxx to cardiovascular risk was deleted from a major study his journal published five years ago--and that it appears that Merck researchers may have deleted that data. "I was somewhere between surprised and stunned," Dr. Gregory Curfman, executive editor of The Journal, says. "They allowed us to publish an article that was just incomplete and inaccurate in some respects and was misleading and may have contributed to the detriment to the public health." The discovery (see: "Merck's Slanted Study?") comes as the company faces a flood of lawsuits following its decision to pull the drug from the market in September 2004. Merck recalled Vioxx after its own study linked long-term use of the drug to an increased risk of heart attacks and strokes. Now, the question is if that alarm should have been sounded much earlier. Just days after Merck recalled Vioxx from the market, editors at The Journal discovered a diskette containing earlier versions of a manuscript for a crucial Vioxx clinical trial called VIGOR that they had published in November 2000. The early versions of the manuscript contained a blank table entitled "CV events"--which is standard jargon for cardiovascular events. Time stamps in the software indicated that the table was deleted two days before the manuscript was submitted to The New England Journal on May 18, 2000. "When you hover the cursor over the editing changes, the identity of the editor pops up, and it just says 'Merck,'" Curfman says. The editors weren't sure what to make of the finding, so they kept quiet. It wasn't clear that the information that had been in the table would have changed the conclusions of the study. The published version of the study noted a higher heart attack rate in patients who took Vioxx compared with those who took naproxen, an older painkiller that is sold over the counter as Aleve. But the report provided relatively few details. "We talked internally. Should some action be taken? We did not feel we had sufficient evidence to act on it," Curfman says. But on Nov. 21, 2005, Curfman was deposed in Boston by lawyers from the firm of Lieff Cabraser Heimann and Bernstein, who represent plaintiffs in one of the Vioxx suits. During the deposition, which also included attorneys for the drugmaker, they showed Curfman an internal Merck document dated July 5, 2000--after the VIGOR manuscript was submitted to the journal, but well before the study went to press. It indicated that two Merck authors on the VIGOR study knew of three additional heart attacks among Vioxx patients in the study, which had not been disclosed to The New England Journal of Medicine. The heart attacks occurred in the final five weeks of the trial and in patients at low risk for heart problems. The plaintiff's lawyers also showed him early versions of the manuscript containing the original version of the deleted table, he says. This version also revealed more cardiovascular problems potentially connected to Vioxx than those had been discussed in the published study. Curfman says the editors had assumed that the VIGOR manuscript only included limited data on heart attacks because that was all that was available at the time. "It turns out that they had quite a bit more already worked up," he says. He raced back to the office and spent the next few weeks analyzing all the VIGOR drafts, raw data and correspondence. At 3:00 P.M. today, Curfman and two other editors released an editorial on The New England Journal's Web site entitled "_Expression of Concern," which calls on the VIGOR authors to submit a correction of the 2000 manuscript. "Taken together, these inaccuracies and deletions call into question the integrity of the data on adverse cardiovascular events in this article," it read. Curfman says he called lead author Claire Bombardier of the University of Toronto, on Monday, indicating that the statement would be published. She told him that she would begin working on a correction. However, in an e-mail to Forbes.com, Bombardier said that the VIGOR paper appropriately disclosed the data and that the authors were working on finalizing a response to the editorial. Catharine Whiteside, dean of medicine at the University of Toronto, said today that she has yet to talk to Dr. Bombardier. "In the event that information is brought to light in which we would need to investigate Dr. Bombardier, we would initiate due process," Whiteside says. Hints that Vioxx might cause heart attacks had existed for years, as basic research pointed to a mechanism by which the drug might cause more clots. When VIGOR was published in The New England Journal of Medicine, there were already questions among scientists about the potential of Vioxx and related drugs made by Pfizer (nyse: PFE - news - people ) to cause heart attacks. Later on, the data about the VIGOR manuscript led researchers at the Cleveland Clinic to sound the alarm about Vioxx's heart risk. Some analysts have estimated Merck's potential liability in the tens of billions of dollars. Others say that the risk to the drugmaker, once the most esteemed name in the pharmaceutical business, is impossible to know. The news that the once-popular arthritis drug may have caused thousands of heart attacks led to a firestorm about drug safety. In a statement, Merck disputed The New England Journal analysis. "The VIGOR publication, which was peer-reviewed, fairly and accurately described the results of the study as of the prespecified cutoff for analysis. The additional events referred to in the editorial were events that were reported after the prespecified cutoff date and, therefore, these were not included in the primary analysis reported in the article. "Nevertheless, the additional events were disclosed to the FDA in 2000, presented publicly to the FDA's Advisory Committee in February 2001 and included in numerous press releases subsequently issued by Merck. We also note that these additional events did not materially change any of the conclusions in the article." Curfman responded, "We're not buying into that." © Fortune~~~~~~~~~~How the drugs giant and a lone academic went to war Worrying power games are at the heart of Procter and Gamble'srelationship with academics, alleges the scientist investigating itsbilllion-dollar osteoporosis treatment, reports Jo Revill Sunday December 4, 2005The ObserverEvery medicine prescribed in Britain is offered to patients only afteryears collecting data from clinical trials to show a drug's safety andeffectiveness. Increasingly, medical research in the UK is a collaborative effortbetween big pharmaceutical companies and universities. Although therewill be a commercial contract between the two, much of thatrelationship is built on trust. For patients everywhere it is essential that the way research isconducted is open and transparent. This is an account of what happenswhen the relationships break down, when academics believe they havenot been given access to the data and when the relationship betweenuniversities and the drugs companies which provide much of theirfunding for research becomes mired in controversy. This issue - andthe influence of the pharmaceutical industry - will be debated inparliament this week. At its heart is the practice of 'ghost writing', pharmaceuticalcompanies hiring writers to produce reports which academics givepermission for their name to be put to.It is rare for tensions in thehighly sensitive world of scientific drugs research to break into theopen. But an Observer investigation has uncovered a story of a warbetween one of Britain's most experienced academics and one of theworld's most successful drugs companies. At issue is a highlysignificant report on a drug to treat a debilitating disease which theacademic says was published under his name when he had not seenanalysis of the research it was based on. The drugs firm deniesanything untoward has happened. In the summer of 2002, Dr Aubrey Blumsohn, a senior lecturer andhonorary consultant in metabolic bone disease at Sheffield University,was preparing to lead a major research project. One of the world'slargest pharmaceutical firms, Procter and Gamble, had just signed a£180,000 deal for his research team to carry out a study on one oftheir drugs, Actonel. Actonel is a highly successful medication prescribed by doctors tonearly one million women around the world every year to treatosteoporosis. Also known as risedronate, it has been licensed as atreatment in the UK since 2002, and is known to be safe, with a goodrecord of reducing the risk of broken hips, spines and wrists. Blumsohn, who was born in South Africa, joined the Sheffield centrefor bone metabolism research five years ago. He was to lead a thirdthorough investigation into the drug to look at how it was affectingthe bones of thousands of women. To do the study, thousands of bloodand urine samples, taken from women in more than 100 research centresaround the world, were analysed in Blumsohn's laboratory in September2002. More than 3,000 pages of laboratory data and electronic records had tobe put together by the researchers. Their aim was to look at thesamples collected over a period of three years from women who were onActonel, to determine which patients suffered fractures, and matchthat to changes in their bone turnover and bone density with theirtreatment. Bone turnover, the rate at which the body replaces its ownbone material, is an important factor in osteoporosis. The data was sent off in December 2002 to be analysed by statisticiansat Procter and Gamble's headquarters in Egham, Surrey. Blumsohn'scolleague, Richard Eastell, professor of bone metabolism at Sheffield,had worked on previous collaborations with the company, and hadpublished data prepared by them. A great deal was at stake for Procter and Gamble, a US company withheadquarters in Cincinnati, Ohio. Its fortune was built on soap andcandles made by the Englishman, William Procter, and the Irishman,James Gamble, more than 170 years ago. With shrewd investment and itsownership of leading brands in washing powders and disposable nappies,it has become a major player in pharmaceuticals. Actonel is one of P & G's 16 'billion-dollar brands', making the companybetween $500m and $1bn each year. But there is intense competitionwith its main rival, the drug Fosamax, manufactured by anotherpharmaceuticals giant, New Jersey-based Merck. There has been much debate over how these drugs actually work. It isknown that they do two things: increase the mineral content of thebone, known as bone mineral density (BMD), and reduce the rate of boneturnover. Bone is a living tissue which constantly regenerates itself,by losing and gaining calcium and protein. Bones are always developingtiny holes which are filled in as new material grows, but as womengrow older the holes are not filled in properly and the bones areweakened. Both Fosamax and Actonel are 'anti-resorptive agents' - theyprevent the bones from losing material too fast. Blumsohn asked at an early stage if he could see the way in which theanalysis of his research was being carried out by P & G. The contract heand Eastell had signed with the company stipulated that their finalwritten report would include all data, and any interpretationnecessary for analysis. Although the two experts were providing the raw data from theirlaboratory, the numbers were meaningless in themselves because theywere coded. As in all cases of this type of work, the researcher is'blind' to the details of the data because they might be 'influenced'by that knowledge. The results cannot be understood until they aredecoded - and P & G possessed the key. xxxxxxxxx cut xxxxx