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

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

Sun, 11 Dec 2005

Two major cases of medical research fraud on each side of the Atlantic involve evidence of fraud and data tampering by pharmaceutical company giants. Both cases provide insight into the way in which academics are used by pharmaceutical companies that are desperate to obtain a stamp of respectability to their drug research. Companies commission academics to pen their name to published reports in prestigious journals. But those reports do not reflect the actual clinical trial data. Both industry and the academics who serve as their lackeys are destroying the very basis of that respectability. The positions taken by the scientists involved in these two cases are a study in contrast.

The U.S. press is focused on stunning revelations of fraud and data tampering that were uncovered during Vioxx court proceedings. Merck – “once the most esteemed name in the pharmaceutical business” – and its contracted academic scientists were shown to have deleted data linking Vioxx to cardiovascular damage from the major VIGOR report published in The New England Journal of Medicine in 2000. The NEJM is viewed as the most authoritative scientific journal.

Forbes reports (below) that Dr. Gregory Curfman, Executive Editor of the NEJM said 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.” The New York Times editorial states:

“What aroused the ire of the journal’s editors was an internal company memo revealing that the researchers knowingly suppressed data on three additional heart attacks among Vioxx users that was available months before the paper was published. Had that data been included, Vioxx would have looked five times as risky as naproxen, not four times, and would have looked potentially dangerous even in patients deemed at low risk of heart attacks.” See: http://www.nytimes.com/2005/12/11/opinion/11sun2.html

However, Forbes reports that following the withdrawal of Vioxx, NEJM editors stumbled upon the evidence by examining a disc containing an earlier version with the cardiovascular data that was subsequently deleted from the final published version. The Journal editors remained silent about the evidence of data manipulation in a major report in its Journal that though they “talked internally” about the deletion of data they did not alert readers of the Journal who rely on the Journal’s review process to protect the integrity of scientific reports within its covers: “We did not feel we had sufficient evidence to act on it.”

From Forbes, we learn, that The NEJM editors saw fit to alert readers only after Dr. Curfman was deposed (on Nov. 21, 2005) in Boston by lawyers from the firm of Lieff Cabraser Heimann and Bernstein, at which time he was confronted with “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.”

Merck’s defense is that the company had submitted all the data to the FDA – as is its legal obligation. From that we are left to conclude that scientists who pen their name to journal articles do not feel similarly obliged to disclose ALL. The lead author of the VIGOR study, Dr. Claire Bombardier, (at the University of Toronto) appears to have been a willing servant of commercially driven misleading presentation of research. How many other such misleading reports are polluting the scientific literature?

On the other side of the Atlantic, a similarly worrying new and important case is unfolding at the University of Sheffield in the United Kingdom. The case involves a collision between a senior clinician and respected scientist, Dr Aubrey Blumsohn, who was the lead scientist for a clinical study of a Procter & Gamble Pharmaceuticals (P&G) drug, Actonel (risedronate). Dr. Blumsohn blew the whistle on data concealment and ghostwritten journal reports with his name appended.

The case has attracted intensive press coverage: “A war between one of Britain’s most experienced academics and one of the world’s most successful drugs companies. At issue is a highly significant report on a drug to treat a debilitating disease which the academic says was published under his name when he had not seen analysis of the research it was based on. The drugs firm denies anything untoward has happened.”
http://observer.guardian.co.uk/uk_news/story/0,6903,1657275,00.html

After Dr. Blumsohn’s data collection efforts for this study, P&G refused to provide him with randomization codes or to allow an independent 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 and statistical reports on behalf of the University academics while denying them access to data upon which those reports were based. Data was required by the academics to verify scientific reports, statistical analyses, meeting abstracts, and draft publications “ghost written” in their names.

Refusal of access to data under such circumstances is unprecedented, and violates all norms of proper conduct and procedure in science. It interfered with the ability of academics to discharge their duties as responsible scientists and clinicians, and prevented proper publication and correction of the scientific literature. It appeared that “fair” analysis of the data might not have yielded findings desired by the sponsor. The company violated the norms of science under whose banner they claim to sell their products.

Repeated attempts to obtain the required data were not successful, and information emerged that the data analysis had been misleading. Blumsohn eventually made his concerns known about his inability to access the data to several senior officials at his university but was apparently repeatedly ignored. Because, however, the University charged that he did not go through proper channels, and eventually talked to the news media, the University of Sheffield suspended him.

Victimization of academics raising such difficult issues is sadly only too familiar. Particularly important was the UK Observer report of a taped conversation Blumsohn had with Professor Richard Eastell, head of the university’s bone and metabolism unit and also Research Dean of his Medical 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 relationship with P&G. Because we are… we have the big Sheffield Centre Grant which 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. So if Ian [Barton] is unhappy it goes to Arkadi [Chines, global medical director of P&G Pharmaceuticals] and before we know it, there is an issue, there is a problem.”

The matter was discussed extensively in the House of Commons (UK Parliament) on 8th of December 2005.

Different aspects of the Sheffield case are reported in the UK including: Times Higher Education Supplement (a UK academic newspaper), and the Observer (a UK Sunday paper). It has also been the focus of discussion in Parliament.

When access to data is a real bone of contention 
http://www.thes.co.uk/search/story.aspx?story_id=2026307

How the drugs giant and a lone academic went to war
http://observer.guardian.co.uk/uk_news/story/0,6903,1657275,00.html

Doctor accuses drugs giant of ‘unethical’ secrecy
http://observer.guardian.co.uk/uk_news/story/0,6903,1657302,00.html
The Observer, UK – Dec 3, 2005

Contact: Vera Hassner Sharav
212-595-8974

FORBES
Sciences and Medicine
Merck’s Deleted Data
Robert 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 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.”

~~~~~~~~~~

How the drugs giant and a lone academic went to war

Worrying power games are at the heart of Procter and Gamble’s relationship with academics, alleges the scientist investigating its billlion-dollar osteoporosis treatment, reports Jo Revill

Sunday December 4, 2005
The Observer

Every medicine prescribed in Britain is offered to patients only after years collecting data from clinical trials to show a drug’s safety and effectiveness.

Increasingly, medical research in the UK is a collaborative effort between big pharmaceutical companies and universities. Although there will be a commercial contract between the two, much of that relationship is built on trust.

For patients everywhere it is essential that the way research is conducted is open and transparent. This is an account of what happens when the relationships break down, when academics believe they have not been given access to the data and when the relationship between universities and the drugs companies which provide much of their funding for research becomes mired in controversy. This issue – and the influence of the pharmaceutical industry – will be debated in parliament this week.

At its heart is the practice of ‘ghost writing’, pharmaceutical companies hiring writers to produce reports which academics give permission for their name to be put to.It is rare for tensions in the highly sensitive world of scientific drugs research to break into the open. But an Observer investigation has uncovered a story of a war between one of Britain’s most experienced academics and one of the world’s most successful drugs companies. At issue is a highly significant report on a drug to treat a debilitating disease which the academic says was published under his name when he had not seen analysis of the research it was based on. The drugs firm denies anything untoward has happened.

In the summer of 2002, Dr Aubrey Blumsohn, a senior lecturer and honorary consultant in metabolic bone disease at Sheffield University, was preparing to lead a major research project. One of the world’s largest pharmaceutical firms, Procter and Gamble, had just signed a £180,000 deal for his research team to carry out a study on one of their drugs, Actonel.

Actonel is a highly successful medication prescribed by doctors to nearly one million women around the world every year to treat osteoporosis. Also known as risedronate, it has been licensed as a treatment in the UK since 2002, and is known to be safe, with a good record of reducing the risk of broken hips, spines and wrists.

Blumsohn, who was born in South Africa, joined the Sheffield centre for bone metabolism research five years ago. He was to lead a third thorough investigation into the drug to look at how it was affecting the bones of thousands of women. To do the study, thousands of blood and urine samples, taken from women in more than 100 research centres around the world, were analysed in Blumsohn’s laboratory in September 2002.

More than 3,000 pages of laboratory data and electronic records had to be put together by the researchers. Their aim was to look at the samples collected over a period of three years from women who were on Actonel, to determine which patients suffered fractures, and match that to changes in their bone turnover and bone density with their treatment. Bone turnover, the rate at which the body replaces its own bone material, is an important factor in osteoporosis.

The data was sent off in December 2002 to be analysed by statisticians at Procter and Gamble’s headquarters in Egham, Surrey. Blumsohn’s colleague, Richard Eastell, professor of bone metabolism at Sheffield, had worked on previous collaborations with the company, and had published data prepared by them.

A great deal was at stake for Procter and Gamble, a US company with headquarters in Cincinnati, Ohio. Its fortune was built on soap and candles made by the Englishman, William Procter, and the Irishman, James Gamble, more than 170 years ago. With shrewd investment and its ownership 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 company between $500m and $1bn each year. But there is intense competition with its main rival, the drug Fosamax, manufactured by another pharmaceuticals giant, New Jersey-based Merck.

There has been much debate over how these drugs actually work. It is known that they do two things: increase the mineral content of the bone, known as bone mineral density (BMD), and reduce the rate of bone turnover. Bone is a living tissue which constantly regenerates itself, by losing and gaining calcium and protein. Bones are always developing tiny holes which are filled in as new material grows, but as women grow older the holes are not filled in properly and the bones are weakened. Both Fosamax and Actonel are ‘anti-resorptive agents’ – they prevent the bones from losing material too fast.

Blumsohn asked at an early stage if he could see the way in which the analysis of his research was being carried out by P&G. The contract he and Eastell had signed with the company stipulated that their final written report would include all data, and any interpretation necessary for analysis.

Although the two experts were providing the raw data from their laboratory, the numbers were meaningless in themselves because they were 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 are decoded – and P&G possessed the key. xxxxxxxxx cut xxxxx

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a ‘fair use’ 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 without profit.