Miscellaneous Articles

The following are three articles published by Medscape in January, 2011. They report on the three corresponding articles published by BMJ (British Medical Journal) during the first three weeks of January, 2011.

Autism and MMR Vaccine Study an 'Elaborate Fraud', Charges BMJ

First article. Published online January 06, 2011.
Deborah Brauser is a freelance writer for Medscape.
Deborah Brauser has disclosed no relevant financial relationships.

January 6, 2011 — BMJ is publishing a series of 3 articles and editorials charging that the study published in The Lancet in 1998 by Andrew Wakefield and colleagues linking the childhood measles-mumps-rubella (MMR) vaccine to a "new syndrome" of regressive autism and bowel disease was not just bad science but "an elaborate fraud."

According to the first article published in BMJ today by London-based investigative reporter Brian Deer, the study's investigators altered and falsified medical records and facts, misrepresented information to families, and treated the 12 children involved unethically.

In addition, Mr. Wakefield accepted consultancy fees from lawyers who were building a lawsuit against vaccine manufacturers, and many of the study participants were referred by an antivaccine organization.

In an accompanying editorial, BMJ Editor-in-Chief Fiona Godlee, MD, Deputy BMJ Editor Jane Smith, and Associate BMJ Editor Harvey Marcovitch write that there is no doubt that Mr. Wakefield perpetrated fraud. "A great deal of thought and effort must have gone into drafting the paper to achieve the results he wanted: the discrepancies all led in 1 direction; misreporting was gross."

A great deal of thought and effort must have gone into drafting the paper to achieve the results he wanted: the discrepancies all led in 1 direction; misreporting was gross.

Although The Lancet published a retraction of the study last year right after the UK General Medical Council (GMC) announced that the investigators acted "dishonestly" and irresponsibly," the BMJ editor’s note that the journal did not go far enough.

"The Lancet retraction was prompted by the results from the [General Medical Council] hearing and was very much based on the concerns about the ethics of the study," Dr. Godlee told Medscape Medical News.

"What we found was that it was definite fraud and that is a very important thing for the world to know. This article shows that the science was falsified and should be discounted," continued Dr. Godlee.

This evidence "should now close the door on this damaging vaccine scare," the editorial authors add.

Damage to Public Health

Although it included only 12 patients, faced almost immediate criticism, and never had its findings replicated, the study received wide media coverage and set off a panic among parents, with the result that MMR vaccinations decreased dramatically.

The 2003 to 2004 vaccination rate of 80% has now recovered slightly in the United Kingdom, but it is still well below the recommended 95% level recommended to ensure "herd immunity." A measles epidemic was also declared in England and Wales in 2008.

"Perhaps as important as the scare's effect on infectious disease is the energy, emotion, and money that have been diverted away from efforts to understand the real cause of autism and how to help children and families who live with it," the editorialists write.

Mr. Deer did his first investigative stories on the Wakefield paper in 2004 for the Sunday Times in London and a UK television network. On the basis of his findings, the GMC's Fitness to Practice panel convened in 2007 and heard from 36 witnesses during a period of 2 and a half years.

At the end of January last year, as reported by Medscape Medical News, the panel used strong language in condemning the study's methods and noted that Mr. Wakefield and 2 other colleagues had broken guidelines.

The Lancet issued its retraction 5 days later, citing the panel's findings that the participants were not consecutive patients seeking treatment and that the study had falsely reported being approved by an ethics committee.

Although the GMC later found that Mr. Wakefield and coauthor John Walker-Smith committed serious misconduct and struck them off the medical register, Mr. Wakefield has repeatedly denied doing anything wrong. In addition, he was not among the 10 of 13 coauthors who disavowed the study's findings in 2004.

"Instead, although now disgraced and stripped of his clinical and academic credentials, he continues to push his views. Meanwhile, the damage to public health continues," the editorialists write.

Multiple Discrepancies Found

Last spring, the BMJ went to Mr. Deer to ask if there was more to this story. In this newest article, he reports that "multiple discrepancies" were found, including the following:

Only one of the studied 9 children actually had clear regressive autism and 3 did not have a diagnosis of any autism type;

Five had preexisting development concerns — although all 12 were classified in the study as "previously normal"; and

The exclusion of important allegations helped create "the appearance of a 14-day temporal link."

In addition, none of the 12 patients were "free of misreporting or alteration," he writes.

It cost a tremendous amount of time and money to penetrate the veil of confidentiality that surrounded just these 12 children. So how on earth would anybody penetrate the veil over other larger medical research? When Wakefield did what he did, it was on the assumption that no one would ever be able to find out the truth.

"My number 1 takeaway is that it cost a tremendous amount of time and money to penetrate the veil of confidentiality that surrounded just these 12 children. So how on earth would anybody penetrate the veil over other larger medical research? When Wakefield did what he did, it was on the assumption that no one would ever be able to find out the truth," Mr. Deer told Medscape Medical News.

BMJ fact-checked Mr. Deer's article against the 6 million–word transcript of the GMC panel's hearing. Dr. Godlee said she is now calling for reexamination of all of Wakefield's past studies to determine whether others should be retracted. "Past experience tells us that research misconduct is rarely isolated behavior," she writes.

But how did a small case-control study like this set off such a panic in the first place? "I think a lot of people would like to know the answer to that," said Dr. Godlee.

"I think Andrew Wakefield is a terrifically good publicist. He managed to convince his institution to run a press conference for this very small piece of research. The media attention for this grew, and concerns were raised with his subsequent publications."

In addition, she said that many parents have questions about why their children have developed autism and are looking for reasons to explain the onset of its behavioral symptoms. "MMR is a very common intervention, it seemed to fit the picture, and it's very hard to prove that something is safe despite overwhelming evidence that there is no link.

"If you're looking for an explanation, this may seem plausible, although the science is nonsense. Overall, I think it's a combination of very desperate parents looking for answers and a very clever man who was willing to lie and cheat, who was willing to try to advance his own career and financial benefits," noted Dr. Godlee.

Editor's Dread

With questions raised almost from the start, how culpable is The Lancet? And how can other journals protect themselves from publishing falsified studies?

"That is the dread of any editor," said Dr. Godlee. "I think editors' main responsibility is to make sure that what is published is valid in terms of being good research. And I think The Lancet's decision to publish this is the first place was a very questionable decision, especially as it dealt with such a serious issue.

"Why publish research that is not going to advance science and is going to create a vaccine scare? I think there is culpability there. But as for fraud, that is very tricky because science is based on trust," she added.

"None of us go back and ask for the case records of patients involved. But we need to become aware that any article that comes in could be fraudulent. And we have to be absolutely vigilant and investigate properly when concerns are raised. It's a constant cycle of oversight that needs to be done."

Medscape Medical News contacted The Lancet for its reaction to the BMJ series of articles, but officials there had "no comment on this."

Dr. Godlee said that she would also hope that coauthors would serve as backup for honesty in reporting and that all of this study's investigators "failed in their duties as authors" — especially since there were only 12 patients involved.

Adding a name to a paper carries a responsibility to ensure that no fraud has been committed. This should serve as a wake-up call for other researchers in the future. It's their reputation that can be damaged if they are found to be associated with someone else's failures of integrity.

"Adding a name to a paper carries a responsibility to ensure that no fraud has been committed. This should serve as a wake-up call for other researchers in the future. It's their reputation that can be damaged if they are found to be associated with someone else's failures of integrity."

Diversion of Research Funds

The editors write that although a breach of trust this large is "almost certainly rare," it raises questions about what could have been done earlier, what further inquiry is needed, and what can be done to keep it from happening again.

Future BMJ articles in the series, to be published during the next 2 weeks, will deal with these questions and The Lancet's actions from study publication through retraction.

"We wanted to also look at what motivated Andrew Wakefield, looking at the commercial schemes he established to exploit the MMR scare, and then we examine what happened when the issues of concern were first raised back in 2004 and why it was not taken more seriously at that time," explained Dr. Godlee.

"To people who might ask why we're interested in all of this now, the answer is that what Brian Deer has unearthed is much more substantial than what most of us knew or what came out in the GMC hearing. This study was not only bad research but fraudulent as well. And it's taken an enormous amount of time and effort and money away from legitimate lines of inquiry," she concluded.

Mr. Deer's original investigation was funded by the Sunday Times of London and the Channel 4 television network. The current articles were funded by the BMJ. He reported receiving no other funding except for legal costs from the Medical Protection Society on behalf of Mr. Wakefield. The editorial authors have disclosed no relevant financial relationships.

BMJ. Published online January 6, 2011.

Investigator Planned to Make Vast Profit From Autism/MMR Vaccine Scare.

Second article. Published online January 11, 2011.

January 13, 2011 — Andrew Wakefield, the lead author on the 1998 study that reported a link between the measles-mumps-rubella (MMR) vaccine and a new condition of regressive autism and bowel disease called autistic enterocolitis (AE), was planning to market a pre-study diagnostic testing kit with expected yearly sales of 28 million pounds (43 million US dollars), a new paper published online January 11 in the BMJ reports.

In the second of a series of 3 investigative articles examining the MMR vaccine scare, UK journalist Brian Deer reports that Mr. Wakefield planned several businesses to develop not only the new test but also immunotherapeutic and a "safer single measles shot" — which he held a patent for. Mr. Deer writes that these would only be successful if public confidence in the MMR vaccine was damaged.

There was hope of a financial gain from all these businesses that were set up and I think the important thing was that these commercial dealings were undisclosed. Some of the people at the Royal Free Hospital where Wakefield worked were involved and others were aware. Yet these dealings remained undisclosed as the vaccine scare unfolded.

"I think this new article very clearly lays out the extent of the financial motivation behind what we now know was a falsified paper," Fiona Godlee, MD, BMJ editor-in-chief, told Medscape Medical News.

"There was hope of a financial gain from all these businesses that were set up, and I think the important thing was that these commercial dealings were undisclosed. Some of the people at the Royal Free Hospital where Wakefield worked were involved and others were aware. Yet these dealings remained undisclosed as the vaccine scare unfolded," said Dr. Godlee.

Following the Money

In the first article in the BMJ series, published last week and reported by Medscape Medical News at that time, Mr. Deer reported that the investigators altered and falsified medical records of the 12 children involved. This study was published in The Lancet in 1998 and subsequently retracted early last year.

In this new article, Mr. Deer "follows the money." He found that although the first study patient was still in the hospital, Mr. Wakefield met with managers from the Royal Free Medical School in London, England, to discuss forming a joint business. A week after publication of his research, he brought in business associates to the Royal Free to continue negotiations.

A prospectus obtained by Mr. Deer that was aimed at raising an initial 700,000 pounds from investors says, "it is estimated that the initial market for the diagnostic will be litigation driven testing of patients with AE from both the UK and the USA.

Dr. Fiona Godlee

"In view of the unique services offered by the company and its technology, particularly for the molecular diagnostic, the assays can command premium prices," adds the document.

Several other businesses were planned and/or registered, including Carmel Healthcare Ltd, which was named after Mr. Wakefield's wife.

"His magnitude of ambition was really quite surprising to find. I had no idea that there was this scale of commercial involvement," said Dr. Godlee.

The article also explains in detail how a lawyer hoping to bring a lawsuit against vaccine manufacturers funded much of the study on the MMR vaccine.

"The lawyer...was forthright when later asked. He said he paid for The Lancet research," writes Mr. Deer.

Other new details unearthed include the following drug industry support for Mr. Wakefield during 1999:
  • Overseas airfare from Axcan Pharma Inc
  • Consultancy negotiations with Johnson & Johnson
  • "Longstanding connections" with both Merck and SmithKline Beecham

However, the "commercial deals" ended when Mr. Wakefield received a letter voicing concern that conflicts existed between his academic employment and involvement with Carmel, especially as "the company's business plan appears to depend on premature, scientifically unjustified publication of results."

Although the school offered Mr. Wakefield a year's paid absence and help to try to replicate his results with a validated study of up to 150 patients, he did not do the work, citing a need for "academic freedom."

Damaging Health Scare

He's still promoting his ideas and I think it's important for people to know that the science behind them is fraudulent and that he had extremely sophisticated and well-developed plans to benefit from this personally in ways that were not made apparent.

"This isn't personal. We're focusing on what Wakefield has done, and he has fueled a very damaging health scare," said Dr. Godlee.

"He's still promoting his ideas, and I think it's important for people to know that the science behind them is fraudulent and that he had extremely sophisticated and well-developed plans to benefit from this personally in ways that were not made apparent," she said.

The third and final article in their series will be published next week and will focus on what happened when study concerns were first raised by Mr. Deer in 2004 and why they weren't taken more seriously.

"None of what has appeared in the BMJ should imply for a moment that we don't sympathize with parents making very difficult decisions. What we're left with is that we need much better research into the cause of autism," said Dr. Godlee.

[As a result of the Wakefield study], a generation of parents and their children have grown up afraid of vaccines, and the resulting outbreaks of measles and mumps have damaged and destroyed young lives.

In a new "Perspectives" article published online January 13 in the New England Journal of Medicine, 2 clinicians from the Mayo Clinic write that there has been opposition since the very first vaccine was introduced, with particular mistrust over the smallpox vaccine in 1910.

"Little has changed since that time, although now the antivaccinationists' media of choice are typically television and the Internet...which are used to sway public opinion and distract attention from scientific evidence," write Gregory A. Poland, MD, and Robert M. Jacobson, MD, from the Mayo Clinic Vaccine Research Group and the Department of Pediatric and Adolescent Medicine in Rochester, Minnesota.

"Even though more than a dozen studies have demonstrated an absence of harm from MMR vaccination, Wakefield and his supporters continue to steer the public away from the vaccine," they add.

"As a result, a generation of parents and their children have grown up afraid of vaccines, and the resulting outbreaks of measles and mumps have damaged and destroyed young lives."

The editorialists note several recommendations to "hasten the funeral of antivaccination campaigns," including the following:
  • Fund and publish studies that investigate vaccine safety concerns
  • Maintain monitoring programs, including the Vaccine Adverse Events Reporting System
  • Instruct healthcare workers, parents, and patients how to counter false claims
  • Expand public education

"We believe that antivaccinationists have done significant harm to the public health. Ultimately, society must recognize that science is not a democracy in which the side with the most votes or the loudest voices gets to decide what is right," conclude the editorial authors.

Mr. Deer's original investigation was funded by the Sunday Times of London and the Channel 4 television network. The current articles were funded by the BMJ. He reported receiving no other funding except for legal costs from the Medical Protection Society on behalf of Mr. Wakefield. The Perspective authors report several financial disclosures, which are listed in the original article.

BMJ. Published online January 11, 2011.
N Engl J Med. Published online January 13, 2011.

Medical Establishment Buried Concerns About MMR/Autism Study, BMJ Charges

Third article. Published online January 20. 2011.

January 20, 2011 — The medical establishment "closed ranks" to protect Andrew Wakefield, the researcher whose 1998 study linked the measles-mumps-rubella (MMR) vaccine to autism, according to a third and final article of a special investigative series published online January 18 in the BMJ.

UK journalist Brian Deer alleges that when he approached The Lancet editor Richard Horton in 2004 with concerns about potential issues of research fraud, conflicts of interest, and unethical treatment of children discovered while researching an article about the study for the Sunday Times, The Lancet failed to ensure that a formal, independent investigation was conducted.

In his most recent BMJ article, Mr. Deer writes that failure to conduct such an investigation and the series of denials issued by Mr. Wakefield, his coauthors, and the Royal Free Hospital led to the public being "misled for 6 years" about the credibility of the article before The Lancet finally retracted it in February 2010.

"That's really the nubbin of this story — the failing of The Lancet and the Royal Free to investigate adequately when questions were raised back in 2004," Fiona Godlee, MD, BMJ editor-in-chief, told Medscape Medical News.

"Although it was discredited in some ways, this damaging article still sat in the literature for 6 years. And the GMC [General Medical Council] went through this incredibly lengthy and expensive investigation, which potentially might have been avoided to some extent," added Dr. Godlee.

The Lancet Responds

Although it was discredited in some ways, this damaging article still sat in the literature for 6 years. And the GMC went through this incredibly lengthy and expensive investigation, which potentially might have been avoided to some extent.

In a statement, The Lancet disputes Mr. Deer's "portrayal of events" in 2004. "We strongly disagree with his assessment and firmly stand by our actions and decisions," they write.

The Lancet also notes that the original 1998 article did not assert that MMR caused autism and that it was at a separate press conference where Mr. Wakefield suggested this association.

"It is the role of medical journals to foster debate, even disagreeable debate, and we took this role seriously and responsibly," says The Lancet release.

What none of us knew at the time, including many of his coauthors, was the extraordinary part that Andrew Wakefield had been playing in this affair and the part that he was about to play. At no point did we actively defend [his] public statements about the link between MMR and autism."

What none of us knew at the time, including many of his co-authors, was the extraordinary part that Andrew Wakefield had been playing in this affair and the part that he was about to play. At no point did we actively defend [his] public statements about the link between MMR and autism.

No matter how the events unfolded, Dr. Godlee writes in her Editor's Choice editorial this week that a new process is needed in the United Kingdom to ensure research integrity. Although the UK Research Integrity Office was established in 2006, it lacks mandatory powers and is running out of funding.

"Other countries have models we could adapt, [such as] the US Office of Research Integrity, which has a mandate to oversee institutional investigations of publicly funded research," she writes.

"In America, you've got a process set up that could possibly be improved, but in Britain we haven't got a good set-up at all. I think this case should be used as a springboard for really improving and raising our game on that score," she added.

In the first article in the BMJ series, as reported by Medscape Medical News, Mr. Deer wrote that the investigators altered and falsified medical records of the 12 children involved.

In the second article, reported last week, Mr. Deer "followed the money." He found that while the first study patient was still in the hospital, Mr. Wakefield met with managers from the Royal Free Medical School to discuss forming a joint business.

In this last piece, Mr. Deer writes that he first approached The Lancet in assumed confidence on advice from his editor at the Sunday Times for comment and "to be sure we were getting it right."

False Reassurance

We were falsely reassured. We were told by authoritative sources...that an investigation had been done and cleared Wakefield of most charges. But as shown by documents obtained under the Freedom of Information Act, there was no proper investigation, merely a 48-hour 'scramble' to protect reputations and discredit the story.

According to the BMJ article, within 48 hours of this meeting, an editor from The Lancet met with the study's 3 senior authors and the journal published "a 5000-word avalanche of denials in statements unretracted to this day."

Further statements reported that an investigation was undertaken by the Royal Free Hospital that "cleared Wakefield of wrongdoing."

However, according to documents obtained under the Freedom of Information Act, the investigation was actually conducted internally by the coauthors themselves. Both the Royal Free Hospital and Medical School have now confirmed that no formal investigation was performed, no physicians were ever interviewed, and no documents generated.

"We were falsely reassured," writes Dr. Godlee. "We were told by authoritative sources...that an investigation had been done and cleared Wakefield of most charges. But as shown by documents obtained under the Freedom of Information Act, there was no proper investigation, merely a 48-hour 'scramble' to protect reputations and discredit the story."

The Lancet statement also says that it followed the guidelines by the Committee on Publication Ethics when speaking to the study authors after Mr. Deer brought his concerns to them in 2004 and published a partial retraction by 10 of the study's coauthors soon after.

Major Flaws in Peer Review Process

According to the BMJ article, the GMC became involved soon after the allegations were made, but it took the panel 6 years to substantiate the allegations.

"Were it not for the GMC case, which cost a rumored 6 million pounds, the fraud by which Wakefield concocted fear of MMR would forever have been denied and covered up," writes Mr. Deer.

"It is hard to escape the conclusion that this represents institutional and editorial misconduct, and its impact has been substantial. The international damage might have been lessened by earlier definitive action," adds Dr. Godlee.

"This case reveals major flaws in pre- and post-publication peer review," said Dr. Godlee in a release. "Allegations of research misconduct must be independently investigated in the public interest. But it's still too easy for institutions to avoid external scrutiny, and editors can fail to adequately distance themselves from work they have published and then defended."

She noted that "this is where coauthors become crucially important. If coauthors are going to sign their names to a paper, I think they need to have real knowledge and understanding of the entire study."

Dr. Godlee added that "it was interesting" that the Wakefield study had case reports on just 12 children but had 13 authors. "One would think it would be difficult to be fraudulent with so many coauthors, but he's obviously a person who is very compelling and persuasive and managed to achieve this without them being alerted to it."

Need for Healthy Skepticism

In an accompanying article, clinicians from Seattle, Washington, write that there is an urgent need to fix a research system that failed to protect its subjects and the public from the consequences of fraudulent science.

"So much has been written about Wakefield himself, but we felt that, especially in light of Deer's articles, there were a lot of unindicted coconspirators here," Douglas J. Opel, MD, MPH, acting assistant professor at the Treuman Katz Center for Pediatric Bioethics at Seattle Children's Research Institute, Washington, told Medscape Medical News.

"I think it's important...to look into and investigate why these existing safeguards that are meant to protect research subjects didn't do their job. Wakefield was able to circumvent them and conduct unethical and fraudulent research. We need to understand what those defects are, fix them, and prevent situations like this from happening again," added Dr. Opel.

The editorialists offer several suggestions for preventing future "research adverse events" including the following:
  • Empower everyone in research to raise questions throughout the process
  • Train research leaders to manage inquiries once raised
  • Not allow journal editors to "take the word" of researchers after allegations are made against them
  • Train research leaders to recognize that they may have conflicts of interest in looking into allegations

I think it's important...to look into and investigate why these existing safeguards that are meant to protect research subjects didn't do their job. Wakefield was able to circumvent them and conduct unethical and fraudulent research. We need to understand what those defects are, fix them, and prevent situations like this from happening again.

"We perhaps need a paradigm shift in the research world. We need to look to what we're doing in the clinical world with respect to quality improvement and patient safety and determine whether some of those can be applied to the research realm to protect human subjects," said Dr. Opel.

"We...need to rethink and reform our customs and culture. The disastrous impact that Wakefield's study has had on vaccine coverage, recrudescence of disease, public trust, and, most of all, science requires that we do so in haste," write the editorial authors.

Dr. Godlee added that when it comes to medical journals, clinicians should also maintain a healthy skepticism.

"We work hard to make sure that what we publish is accurate, and I'm sure the same is true with The Lancet. One is aware that clinicians are going to be reading this and using the information to treat and advise their patients. Yes, there can be inaccuracies, and we know that there will be fraud. But how often that happens is almost impossible to judge," she said.

"So physicians need to, one hopes, not be cynical but absolutely question. The whole scientific enterprise is organized skepticism, where we all are meant to look at what's put in front of us and submit it to a process of questioning internally in terms of whether this is valid and relevant," she concluded.

Mr. Deer's original investigation was funded by the Sunday Times of London and the Channel 4 television network. The current articles were funded by the BMJ. He reported receiving no other funding except for legal costs from the Medical Protection Society on behalf of Mr. Wakefield. The editorial authors have disclosed no relevant financial relationships.

BMJ. Article and editorial published online January 18, 2011.
BMJ. Editor's Choice published online January 19, 2011.