Medical study ploys  Elsevier

Joan Cranmer’s Fateful Decisions and the Suppression of Autism Science

By Mark Blaxill

March 02, 2010

On February 12, 2010 the journalNeurotoxicology made a quiet change on its web-site to an “in-press” article that had previously been available as an “epub ahead of print.”  There was no press release or public announcement, simply an entry change. The entry for the article, “Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing Hepatitis B vaccine: Influence of gestational age and birth weight”, was first modified to read “Withdrawn” and has since been removed altogether from the Neurotoxicology web-site. The only remaining official trace of the paper is now the following listing on the National Library of Medicine’s “PubMed” site.

Neurotoxicology. 2009 Oct 2. [Epub ahead of print] [2009 pdf] Hewitson... Wakefield. Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing Hepatitis B vaccine: Influence of gestational age and birth weight

WITHDRAWN: Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing Hepatitis B vaccine: Influence of gestational age and birth weight.

Hewitson L, Houser LA, Stott C, Sackett G, Tomko JL, Atwood D, Blue L, White ER, Wakefield AJ.

Department of Obstetrics and Gynecology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States; Thoughtful House Center for Children, Austin, TX 78746, United States.

This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause.

How can a scientific study simply vanish? This paper had cleared every hurdle for entry into the public scientific record: it had passed peer review at a prestigious journal, received the editor’s approval for publication, been disseminated in electronic publication format (a common practice to ensure timely dissemination of new scientific information), and received the designation “in press” as it stood in line awaiting future publication in a print version of the journal. Now, and inexplicably, it has been erased from the official record. For practical scientific purposes it no longer exists.

The answer, of course, is that this is no ordinary scientific study.  Age of Autism reported previously on its importance HERE, where we noted that “one likely tactic of critics of the study will include attempts to nullify the evidence based on the alleged bias of those involved.” The obvious risk, of course, was that a co-investigator on the paper, Dr. Andrew Wakefield, might make the study a target, especially in light of the hearings then underway at the U.K.’s General Medical Council (GMC).  In the wake of last month’s GMC findings of misconduct, we also reported on the calls by Generation Rescue to recognize the even greater importance of Dr. Wakefield’s work on this primate project, an analysis of the health outcomes of vaccinated and unvaccinated macaque monkeys (see HERE and HERE)). Sadly, true to our prediction, and despite the quality of the work and the importance of the findings, it appears that the “attempts to nullify the evidence” have been successful.

Over the least several weeks, Age of Autism has tried repeatedly to contact the journal and spoke briefly with Joan Cranmer, the editor-in-chief of Neurotoxicology. She declined comment on the issue. We have obtained evidence, however, that Cranmer has participated in two separate communications on her decisions regarding the primate paper. The first of these came last November, in the form of a response to a threatening letter she had received, at which time Cranmer gave a strong defense of Neurotoxicology’s review procedures.

“As Editor of Neurotoxicology this is to inform you that the referenced manuscript has been subjected to rigorous independent peer review according to our journal standards.   If you have issues with the science in the paper please submit them to me as a Letter to the Editor which will undergo peer review and will be subject to publication if deemed acceptable.”

That response, of course, came before the subsequent media storm over the GMC findings and the decision by another journal, The Lancet to retract a paper co-authored by Dr. Andrew Wakefield, the last listed author (a slot typically reserved for a project’s senior scientist) on the primate paper.

Shortly before the primate paper vanished in February, a second communication involving Cranmer took place, when she received a query from Lyn Redwood of SafeMinds who had learned from the study authors that there might be a problem with publication. As a co-funder of the project, Redwood wrote to Cranmer asking why Neurotoxicology would consider not publishing the primate paper.  This time, Cranmer declined comment and instead referred Redwood to an Elsevier executive named Elizabeth Perill (Elsevier is a division of Reed Elsevier PLC, a large scientific publishing corporation and owner of Neurotoxicology). Perill wrote the following note to Ms. Redwood on February 4th.

Dear Dr. Redwood [sic],
Aside from any authorship concerns, on reflection the paper is not suitable for publication in this journal. The decision was based on the fact that the paper should not have been accepted in Neurotoxicology and the paper is not suitable for the audience of Neurotoxicology.
Kind regards,
Elizabeth Perill
Publisher, Toxicology,
360 Park Av. South, New York, NY 10010

It’s hard to find much evidence to substantiate Perill’s claim. Quite the contrary, available evidence shows that the primate paper lies squarely within Neurotoxicology’s  suitable topic range: a recent search of the journal’s publication history identified 17 papers on thimerosal, 280 papers on mercury, 12 papers on vaccines, 738 papers on animal models, 64 papers on primates, 28 papers on autism and 63 papers on neurodevelopment. Furthermore, this oddly inconsistent sequence of decisions by the editor-in-chief of a leading scientific journal--to publish a scientific study on vaccine safety, to defend that decision to a critic and then to refer questions to her publisher once the journal reversed its previous decision--raises an important question. Did Cranmer make her publication decisions based on the scientific merits of the work involved or did Elsevier contravene Cranmer’s editorial authority with a corporate decision to suppress unpopular research? Any way one looks at it, the need for an Elsevier executive to speak for Joan Cranmer on this subject raises important questions about her own editorial independence. And in a world where autism science, especially the science surrounding controversial questions of vaccine safety, is increasingly influenced by the pervasive power of the medical industry, Cranmer’s decisions deserve more explanation than she has been willing to provide.

The unique importance of the primate project
In the ongoing controversy over the potential role of vaccines and their components in autism causation, the publication of the Neurotoxicology article in October provided a crucial pivot point. Despite the oft-repeated talking points from public health officials and medical industry representatives that any and all concerns have been “asked and answered”, the scientific support for these assurances is weak. Such claims rely exclusively on a controversial set of epidemiology studies of varying quality, ignore epidemiology that provides contradictory evidence and neglect the fact that none of the exculpatory evidence considers the interactions between different elements of the expanding childhood vaccine program. Instead, the studies (reviewed in depth HERE) cover only one vaccine product (the MMR vaccine) and one vaccine component (thimerosal) in isolation.

For many years, autism parents have called for higher quality research into vaccine safety. Inspired in part by Age of Autism Editor Dan Olmsted’s pioneering work on the low frequency of autism in less-vaccinated populations such as the Amish, parent groups have long called for human studies comparing vaccinated and unvaccinated populations. These calls have received support from many quarters. Representative Carolyn Maloney (Dem. NY) has introduced a bill in front of Congress asking for a vaccinated/unvaccinated study. In June of last year, the National Vaccine Advisory Group (NVAC) issued a similar call, asking the CDC to consider the “strengths and weaknesses, ethical issues and feasibility including timelines and cost of various study designs to examine outcomes in unvaccinated, vaccine delayed and vaccinated children.” So far, however, little progress has been made.

One important alternative to epidemiology studies that investigate vaccine safety in human populations is to conduct more invasive research using animal models. Animal models offer many advantages over human epidemiology studies; the vaccine exposures and outcomes can be tightly controlled and measured, while precise biological outcomes can be measured in far greater detail in tissue since the animals can be sacrificed. We’ve reported extensively on recent animal studies that address vaccine safety concerns, much of it focused on rodents (mice, hamsters and rats) and thimerosal HERE and HERE).. A number of years ago, however, private funding emerged for the gold standard animal experiment on vaccine safety, this one using primates. This multi-year project has been conducted by some of the nation’s leading primate researchers and led by scientists affiliated with Thoughtful House of Austin, Texas.

From the beginning of the primate project, Andrew Wakefield has been a senior scientist. With philanthropic support from autism families, he started Thoughtful House in 2005. Even before that, work on the primate project had already begun. The first results from the team’s research were reported at an autism conference in London in May 2008  (see HERE). Then, in October 2009, the first peer-reviewed output of the effort, the Neurotoxicology paper, was published (see HERE).. In that initial paper (clearly the first of many), Wakefield and his colleagues reported convincing evidence that the birth dose of thimerosal-containing hepatitis B vaccine caused developmental delay involving brainstem damage in infant primates. Despite the obvious importance of these animal experiments, Age of Autism has been virtually the sole news outlet covering this story.

When Joan Cranmer accepted the primate paper in Neurotoxicology, her decision could not have been an easy one. The study subject and one of the study authors, Andrew Wakefield, were known to be highly controversial. All of the information about the GMC proceedings and the accusations against Wakefield were well known to the editors and peer reviewers. Despite that knowledge and the risks involved, Cranmer and her editorial team judged the science to be sound and decided to go ahead. We complimented them at the time, noting that “the journal editors at Neurotoxicology have taken a courageous stand in publishing what is sure to be unwelcome evidence in some circles.” It appears, however, that Cranmer’s superiors within Elsevier did not share those views.

Did Reed Elsevier interfere in the editorial decisions of Neurotoxicology?

In wake of last month’s GMC findings, a rapid-fire series of events followed. The editor-in-chief of The Lancet, Richard Horton, issued a retraction of Wakefield’s case series report published by the journal in 1998. Although regrettable the retraction was not especially surprising, since Horton’s well-documented betrayal of Wakefield has placed him at the center of what we have called the Wakefield Inquisition (see HERE). Although Horton has consistently defended hisscientific judgments in public, including the decision to publish the 1998 case series, Horton claimed to be surprised to learn that Wakefield was assisting autism parents in the U.K.’s equivalent of vaccine court. He then used the occasion to set the Inquisition in motion, admitting in his 2004 book, MMR: Science and Fiction, to meeting with an unnamed medical regulator and counseling him on how to build their case against Wakefield (see HERE) Unlike Cranmer, Horton has made himself one of the primary agents in the suppression of inconvenient science.  In scientific terms, however, The Lancetcase series carries far less significance than the primate paper. Contrary to the bulk of media coverage on this issue, the 1998 “early report” provided neither evidence nor claims of causation. By contrast, the Thoughtful House primate project was carefully designed to test causation hypotheses.

So if Horton’s decision to retract the 1998 paper was unsurprising,Neurotoxicology’s decision not to proceed with publication of the primate paper was a different story; it shocked many of those close to the project. Despite protests from study participants, on February 2nd, the same day Horton announced The Lancet’s decision,Neurotoxicology informed the primate study authors of their decision not to proceed with publication in the print edition and soon removed the epub from its web-site. In a further ripple effect, within days of the Neurotoxicology decision, Thoughtful House announced Wakefield’s resignation. In the middle of the media frenzy sparked byThe Lancet’s actions, the decision at Neurotoxicology went largely unnoticed.

At first glance, the two journals--The Lancet and Neurotoxicology--couldn’t be more different: The Lancet, a general purpose medical journal founded in 1823 and named after a device used to bleed patients under the now obsolete theory of the humors, is headquartered in London; Neurotoxicology, founded in 1979 and headquartered in Arkansas, is a specialized journal focused on “dealing with the effects of toxic substances on the nervous system of humans and experimental animals of all ages.” There is, however, a critical connection between the two. Both journals are published by Elsevier, a division of publishing giant Reed Elsevier, a multi-billion dollar corporation. Elsevier publishes close to 2400 scientific journals and also distributes millions of scientific articles through its online site ScienceDirect. According to Reed Elsevier’s 2008 Annual Report, “ScienceDirect from Elsevier contains over 25% of the world’s science, technological and medical information.”

As a leading publisher of scientific and medical journals, Reed Elsevier possesses enormous power over what studies actually make it into the scientific record. Moreover, in its quest for profits, the company has displayed an inclination to provide privileged access to that record to its commercial partners. In 2009, Elsevier acknowledged publishing nine journals, with titles such as “Australasian Journal of Bone and Joint Medicine" that were entirely sponsored by mostly undisclosed pharmaceutical advertisers (one was solely sponsored by Merck and published articles favorable to products like Vioxx and Fosamax). Although Reed Elsevier doesn’t manufacture drugs or vaccines, as a for-profit publisher it clearly has an interest in generating revenue from commercial partners in the medical industry.

Suspicions over the editorial independence of Reed Elsevier on the question of vaccine safety draw support from evidence of board level conflicts of interest involving Reed Elsevier’s CEO, Sir Crispin Davis. Davis, who retired in 2009 as CEO of Reed Elsevier, has served since July 2003 on the board of directors of GlaxoSmithKline (GSK) a major vaccine manufacturer (also recently appointed to the board of GSK is James Murdoch, publisher of News Corp., which owns The Times of London, the newspaper which launched the media attack on Wakefield). In 2008, vaccines accounted for 12.5% of GSK’s worldwide revenues. And although Reed Elsevier has no known vaccine liability risk, GSK has been directly exposed to two of the most prominent autism/vaccine controversies. GSK manufactured Pluserix, a version of the MMR vaccine introduced in the UK in 1989 and withdrawn in 1992 due to safety concerns. GSK also produced a thimerosal containing vaccine similar to the one examined in the primate paper (which was a Merck product) named Engerix B, for hepatitis B. GSK lists its financial exposure to thimerosal litigation in the U.S. under the “legal proceedings” section in its 2008 Annual Report.

Tensions between publishers, who attend to a publication’s profitability, and editors, who attend to independent content, are well known. In their normal operations, there is little reason to believe that Reed Elsevier executives might involve themselves in the scientific review process. However, when scientific publications that can threaten the profitability (and commercial sponsorship) of valued partners of Reed Elsevier such as Glaxosmithkline and Merck are suppressed, Reed Elsevier’s actions should raise concerns among the scientists who lend their names and reputations to the journals the company distributes.

What should Joan Cranmer do?
In October 2008, Neurotoxicology hosted its annual conference in Rochester, New York. One of the featured speakers at the meeting was an elderly pediatrician named Herbert Needleman. Now in his eighties, Needleman is revered in neurotoxicology circles as the man responsible for identifying the developmental risk of lead exposure in children. His pioneering work led to the removal of lead additives from paint and gasoline. I had the opportunity to attend the conference and even to meet Needleman briefly. As I watched him speak I observed with interest the high regard with which the other attendees held him. It was clear that Needleman has attained iconic status in the field of neurotoxicology.

One of the reasons that Needleman is revered in the neurotoxicology community is because he had to surmount formidable obstacles and fight powerful opponents in order to protect children from dangerous exposures to heavy metals.  Like Wakefield, Needleman once served as an expert witness in a legal proceeding, in this case on behalf of a child from Utah who had been injured by lead pollution. Also like Wakefield, Needleman found himself facing off against powerful industry forces, in this case the oil and gas industry and their suppliers of lead, companies such as Ethyl Corp and E.I. DuPont de Nemours. Most notably, in order to defend their profits, the lead industry mounted an aggressive effort to discredit Needleman. In 1991, he was called before the Office of Scientific Integrity at the National Institutes of Health (NIH) on charges of scientific misconduct.

NIH referred the hearings to his university, a fortunate turn of events for Needleman, who was able to blunt a skillfully orchestrated private attack by opening up the proceedings to the public and to his university colleagues (interestingly, he noted that in a crisis “you learn who your friends are. My friends were not people in the medical school but the faculty in the university at large”). Even more fortunately for the health of children, Needleman successfully defended his work and reputation and prevailed in the trial. As a consequence, we now all fuel our cars with unleaded gasoline and decorate our houses with lead free paint. Yet despite Needleman’s victory, the ruthless industry attacks he endured clearly disturbed and offended him, and he subsequently wrote an account of his experiences for the journal Pediatrics in a paper he called, “Salem Comes to the National Institutes of Health: Notes From Inside the Crucible of Scientific Integrity.” The title speaks to the intensity of emotion that Needleman brought to the conflict and the jeopardy in which he felt himself.

We like to assume that in conflicts like this the good guy always wins. But what if that isn’t always the case? What if the product involved hadn’t been leaded gasoline and the companies Needleman was up against were more influential than the oil and gas industry? What if the hearings had been closely controlled by commercial interests and the committee that investigated Needleman had gone against the evidence and found him guilty of misconduct? What if the scientific record he created had been erased and his work on lead “withdrawn” from scientific journals? The progress in eliminating dangerous toxins from our environment is something we now take for granted, but Needleman certainly didn’t see the situation that way. Looking back, however, the difficulties Needleman faced seem almost quaint by comparison to the blitzkrieg-style character attacks of our modern media; the story of his conquest over the evils of corporate America appearing nostalgically Capra-esque when compared to the slick public relations techniques of the global corporation. Indeed, since Needleman’s experiences twenty years ago, the threat of corporate power has become far more menacing and the opportunity for miscarriages of justice many times greater.

Seen from this perspective, what if the next-generation incarnation of Herbert Needleman is Andrew Wakefield, but in today’s version of the story, the balance of power has shifted in critical ways? In Wakefield’s case the product is neither gasoline nor paint, but vaccines, one of the most privileged product categories ever invented, products that are produced and promoted by the medical industry with missionary zeal. In contrast to the limited scientific influence of the oil and gas industry, the medical industry Wakefield faces is far more powerful, pursues its interests with greater skill, controls the flow of scientific information and effectively dictates media coverage.  It appears now that the medical industry is so powerful that it can rewrite scientific history when it wants and even erase important scientific publications in a reputable journal.

This is a pessimistic view of course, for scientists can and do stand up against corporate influence and frequently do the right thing for children. But taking a stand can be more difficult in some situations than others. When it is difficult to stand for scientific principle, the toughest moral choices often fall to individuals who find themselves caught in the middle. In the area of vaccine safety, these moral choices have flowed most clearly to two journal editors. One, Richard Horton made his choice in favor of industry and has successfully turned much of the world against Andrew Wakefield. Another, Joan Cranmer, now faces a different choice. Last October, she made an honorable, science-based decision and then found her editorial judgment superseded last month by Elsevier. This reversal represents a clear violation of scientific values, the values of the neurotoxicology community and the interests of children. But Joan Cranmer is not a passive participant in this controversy. She has a moral choice to make herself.

So what should Joan Cranmer do?
I submit the answer is obvious. Cranmer should oppose the corporate interventions of Elsevier. She should defend the primate project, the health of children and her previous decision to publish the primate paper. More than any other human being on the planet, she can make a statement showing that medical science need not cower before the power of the medical industry. The best way to do that is for her to resign as editor of Neurotoxicology in protest over Elsevier’s interference.

What better way to honor the legacy of Herbert Needleman?

UPDATE: After publishing the article, Age of Autism received this statement from Joan Cranmer.

“Scientific integrity and good science are fundamental principles for publication of research articles in Neurotoxicology.   Although rare, the journal withdraws papers whenever these essential principles are cast into doubt. The January 28, 2010 UK General Medical Council ruling of research dishonesty by Dr. Andrew Wakefield cast into doubt the scientific integrity of a new related paper co-authored by Wakefield*.  However, it would be inappropriate for either me or the other editors to discuss the specific factors publicly.

 Professor Joan M. Cranmer, Editor, Neurotoxicology

Mark Blaxill is Editor-at-Large of Age of Autism and a Director of SafeMinds. He is a co-author of a paper published in Neurotoxicologyand a past presenter at Neurotoxicology conferences. SafeMinds is a co-funder of the primate project and has been a sponsor of pastNeurotoxicology conferences