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Retraction Watch

Tracking retractions as a window into the scientific process

Unglaublich! Boldt investigation may lead to more than 90 retractions

with 17 comments

Self-plagiarism alert: A very similar version of this post is being published online in Anesthesiology News, where one of us (AM) is managing editor.

Unglaublich is the German word for unbelievable, and it’s an apt description for the latest development in the case of Joachim Boldt.

Boldt, a prominent German anesthesiologist, has been at the center of a research and publishing investigation since last October, when the journal Anesthesia & Analgesia retracted a 2009 article of his over concerns of data manipulation. This morning, the German medical board overseeing the case, the Landesärztekammer Rheinland-Pfalz (LÄK-RLP),  released its findings — and they are truly stunning.

According to LAK, somewhere in the neighborhood of 90 of Boldt’s published articles might require retraction because the investigator failed to obtain approval from an institutional review board to conduct the research.

We don’t read German. But, fortunately, the LÄK-RLP announcement was accompanied by a joint letter posted to the websites of 11 major anesthesia journals. We do read English, and here’s what that letter says:

Based on today’s announcement, LÄK-RLP has reviewed 74 scientific articles describing
clinical trials subject to the requirements of the German Medicinal Act. This includes the article
by Professor Boldt recently retracted by Anesthesia & Analgesia and an article submitted by
Professor Boldt to Anaesthesia but not published. By law these studies required IRB approval.
Although the articles typically stated that IRB approval had been obtained, LÄK-RLP could not
find evidence of approval for 68 of these articles.

LÄK-RLP also identified 30 published articles that describe research that did not fall under the
jurisdiction of the German Medicinal Act but physicians performing such human research must
conform to the Code of Deontology, which includes a requirement for IRB review. Some articles
describing epidemiological studies with non-identifiable data did not require IRB review. For six
articles LÄK-RLP was able to document IRB approval. For the remaining articles LÄK-RLP has
not been able to document IRB approval.

LÄK-RLP has again contacted and asked the authors of published articles for which LÄK-RLP
cannot document IRB approval to provide evidence of such approval. LÄK-RLP is presently
awaiting documentation of IRB approval from the first/corresponding author of every questioned
article before making a final determination. LÄK-RLP will notify the respective journals of
articles describing clinical research for which there is no evidence of IRB approval.

We, the undersigned Editors-in-Chief, on behalf of our Editorial Boards, affiliated societies, and
publishers, affirm the commitment stated in our respective Guide for Authors to the ethical
conduct of research. Human research without IRB approval is unethical. If LÄK-RLP identifies
clinical studies in our respective journals that were conducted without IRB approval, those
articles will be retracted.

In addition to Anesthesia & Analgesia, the journals include Anesthesiology, Anaesthesia, Intensive Care Medicine and the Canadian Journal of Anesthesia, along with several European titles.

Should he be found guilty of violating the Code of Deontology, Boldt could face a fine of up to 100,000 Euros, and even jail time if he broke any laws. (We attempted to contact him by email about this story but have not received a reply.)

Questions about the veracity of Boldt’s data also have been raised. An editorial posted to Anesthesia & Analgesia‘s website (full disclosure: it’s where we found the word unglaublich) this morning about retracted 2009 paper calls the study “fabricated,” and says that Klinikum Ludwigshafen, from which Boldt was fired late last year, provided ample evidence to that effect. Quoting from the editorial:

1. There are no original patient data or laboratory data to support the findings in the study.

2. According to the head of the perfusionist team, no albumin has been used as a priming solution since
1999.

3. According to the pharmacy, no albumin has been delivered to the cardiac operating rooms for many
years.

4. All laboratory measurements, including IL-6, IL-10, intercellular adhesion molecule, neutrophil gelatinase-associated lipocalin, and alpha-glutathione-S-transferase, would have been performed in the clinical laboratory at the Klinikum Ludwigshafen. These assays have only been performed on patients receiving hydroxy-ethyl starch priming solutions. The laboratory could identify no assays from patients receiving albumin priming solutions.

5. Professor Boldt has admitted forging the signatures of the coauthors on the copyright transfer form submitted to Anesthesia & Analgesia.

6. The coauthors denied participation in the fabrication.

7. There is no convincing evidence that this study was performed at all.

However, LÄK-RLP’s mandate does not include investigating whether Boldt fabricated his data. That’s up to Klinikum Ludwigshafen, as the editors’ letter notes:

Retraction for lack of IRB approval does not address whether the published research was compromised by data fabrication, manipulation, or misrepresentation. A separate investigating committee at Klinikum Ludwigshafen is assessing the integrity of Professor Boldt’s published research. We will retract any article for which the data are found to be fraudulent.

Steven L. Shafer, editor-in-chief of Anesthesia & Analgesia, told Retraction Watch that although Germany and the United States might have different structures for overseeing science,

I believe the same thing could happen in the United States. We have a system of private IRBs that are paid for by investigators, and those IRBs are hired to review protocols and either approve it or not approve it. But for a hospital that assumes that investigators are using a private IRB — because they don’t have an IRBs themselves — there would be no way of checking up on this.

Udo Schuklenk, editor of Bioethics and Developing World Bioethics, agrees with Shafer.

The same thing could happen in the United States, don’t delude yourself. [Authors] just tick the box – yeah I got IRB approval — but do they have to submit an approval letter from the IRB chair? As journal editors we all ask, have you got ethics approval? They write back and say yes and we take it at face value that they are not lying to us.

Schuklenk, however, believes it’s not possible for journal editors to police these sorts of problems. Universities and research institutions, on the other hand, could do a better job of ferreting out fraud by paying more attention to the publishing activity of their faculty.

These guys almost certainly would have submitted their papers to the university as a way to say, ‘look, I’ve produced all this.’ The university could have said, ‘where is the corresponding ethics review.  The truth is, the universities don’t do this. They just take the credit and they’re happy — as long as there are not any scandals.

We asked Schuklenk whether lack of IRB approval on an otherwise scientifically sound study should trigger a retraction and not some other form of editorial sanction. His response was  unequivocal:

If people realize they can get away with this and if they get caught they will not be retracted, it is reasonable to assume that many more PIs would take short cuts … and that in the end destroys the system of ethics review in the first place.

Boldt, who has published nearly 350 articles, was a top figure in the world of fluid management during surgery. Many of his studies looked at a substance called hydroxyethyl starch (HES) and formed the basis of clinical guidelines for use of the therapy.

As Shafer says:

Boldt’s data primarily spoke to the safety issue. Boldt tended to dismiss safety claims about these colloidal solutions, and without his data, it would appear that these drugs are less safe than we think  they are.

In another editorial published on the website of Anesthesia & Analgesia, two fluid experts try to assess the potential fallout of the Boldt case on the risks calculus for HES.

Unfortunately, any scientific misconduct, no matter how trivial, casts a long shadow on the scientific work of all involved. In this particular case, a shadow is cast on a bulk of literature on HES safety and efficacy.

And, a little later:

A recent systematic review and meta-analysis from the Canadian Critical Care Trials Group concluded that critically ill patients receiving HES were more likely to receive renal replacement therapy, and identified a trend toward increased risk of death in association with HES for patients with severe sepsis. Because most of the studies by Boldt et al. included in these meta-analyses favored HES, their exclusion would increase the safety concerns of HES.

But despite the huge number of studies possibly requiring retraction, Shafer says the ultimate impact on patients won’t be as damaging as the case of Andrew Wakefield, who sparked a global antivaccine frenzy with his false claims that the measles-mumps-rubella vaccine caused autism.

How many parents withheld vaccinations from their children based on that report? And how many children died from that?

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Written by amarcus41

February 4, 2011 at 7:46 am

17 Responses

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  1. One sentence in this post is enough for me:Boldt who has published 350 papers-
    how old is Boldt- imagine himto have been publishing for 35 years- 10 papers a year? How does he get time to read them,and a fortiori, write them.I wonteven imagine whether he has timeto think about them.

    I think weshould have a limit on the number of papers which one can sign in a reputable journal
    and define the reputablejournals by their willingness to adoptthis policy-
    and as Iproposed before, nomore than 8 people in oneslab (dishwashers can be excluded)
    and journals paying reviewers.

    If you agree with any of this, please reply by answering this post- maybe we can set up a callto action on some of this
    ElaineNewman

    elaine newman

    February 4, 2011 at 11:08 am

    • Thank you for your comments – you are very insightful. I would agree with your proposal; it is ridiculous to say “So and so has 350 – 400 – 500 publications.”

      Unfortunately there is so much conflict of interest wrapped up in this – universities are the best placed to police this but they get rated on the number of publications they produce.

      Lynn epi

      February 4, 2011 at 12:28 pm

    • The person who investigated the alleged scientific misconduct at the Research Center Borstel (the Bulfone-Paus case as mentioned on this blogspot), an esteemed, prof. dr. dr. Werner Seeger (location Giessen), has 680 publications. Just go to PubMEd. What are we to make of this? If one were in an arethmetical frame of mind one might infer that if Fred Sanger (the protein and DNA sequencing man) had at total of 65 papers and won 2 nobel Prizes then professor dr. dr. Werner Seeger should have won 20 and 6/13ths Nobel Prizes.

      Beatrice Mueller

      February 6, 2011 at 8:27 am

    • Ghostwiting. Perhaps it is not the alleged authors who write so many papers, but other people. Cynthia Dunbar, the editor-in-chief of Blood, has written a considered piece on this subject for the new York Times:

      http://www.nytimes.com/2009/09/18/business/18ghost.html?scp=1&sq=cynthia%20dunbar%20ghostwriting&st=cse

      Sometimes people get to find out who is behind the scenes. Drug companies. That shouldn’t really be a surprize. They have the money and the motive. The “scientists” supply the reputable cover, nice clean white coats, for their activites. Drug companies like subjects where they can sell drugs. My suspicion is that drug companies may be at the bottom of the Boldt case (anaesthetics cost a lot) and the Bulfone-Paus case (there is always the hope that the immune system can be “manipulated” by drugs to be held out like the proverbial carrot to investors.)

      When Edward Bernays, Sigmund Freud’s nephew, and leading American advertising executive, was asked as an old man about the last time he had direct contact with the press he said somethin to the effect; “sixty years ago. What we do is sponsor some medical researchers whose work is later published by a newspaper. “Eggs and bacon are good for breakfast” reads the headline”. All he had to do was mention what was in the newspapers, and it was all at arms length.

      The pojnt is that this is a working hypothesis that needs to be investigated.

      Bernard Soares

      February 6, 2011 at 8:54 am

    • This “numbers” issue is definately something that has been bothering me for a while. Specifically, how is it possible for any physician-scientist to be prolific? My own experience suggests that it is not possible- unless you head a large and well established research lab/ group.

      Even then the question of HOW and WHEN you are going to be able to read/ plan/supervise/check/write/evaluate etc etc arises. The reality is that many, if not most of the other co-authors are likely to be students of some sort (and hence need very very close supervision before their work can be released for public consumption).
      So a prolific physician -PI/supervisor really needs to explain as to how the time was found.

      M.Naicker, Malaysia

      February 6, 2011 at 11:20 pm

  2. re: Shafer’s vaccine point in the quote at the end of your piece. Surely it is scaremongering pure and simple to ask “how many children died”? I am absolutely in favour of the MMR vaccine and always have been, but it is incorrect to hint or imply that “many children” have died from not being given the vaccine (though it is true that measles has resurfaced as a result – in the UK at least). There was one case a few months ago of a death, but an ambiguous case, not unequivocally linked to not having the MMR vaccine. I think that those accusing others of “anti science” must keep their own houses scrupulously in order and stick to the facts.

    Maybe you should be asking Mr Shafer if he is going to retract that statement, or provide some evidence for it?

    Maxine

    February 4, 2011 at 11:22 am

    • This is off-topic, given the nature of the Retraction Watch posting. In the interest of public health I will respond:

      Quoting from Global Measles Mortality, 2000-2008, Morbidity and Mortality Weekly Report 2009:58;1321-1326 “Because many unvaccinated children die from measles, routine measles vaccination coverage is used as an indicator of progress toward this goal. In 2008, all UN member states reaffirmed their commitment to achieving a 90% reduction in measles mortality by 2010 compared with 2000, from an estimated 733,000 deaths in 2000 worldwide to ≤73,300 by 2010.”

      Quoting from Eggertson L, Lancet retracts 12-year-old article linking autism to MMR vaccines CMAJ. 2010;182: E199–E200: “I think a lot of families were looking for a reason, so they were extremely vulnerable (to this explanation),” says Jeanette Holden, a geneticist at Queen’s University in Kingston, Ontario. Holden, whose brother is autistic, heads the Autism Spectrum Disorders —Canadian–American Research Consortium. “The problem is that this had dramatic health consequences, which was that people just didn’t vaccinate their children,” she adds. In the United Kingdom, the Health Protection Agency attributed a large measles outbreak in 2008 and 2009 to a concurrent drop in the number of children receiving the MMR vaccine. Pockets of measles — which can be fatal —have also cropped up in Canada and the United States as a result of parents’ refusal to vaccinate.”

      At the time the Wakefield article was published measles was responsible for nearly a million deaths yearly. As stated in the MMWR report, many unvaccinated children die from measles. As stated in the CMAJ report, pockets of measles have been linked to parents’ refusal to vaccinate.

      How many children died as a result of Wakefield’s fraudulent misrepresentations?

      Steven L. Shafer, MD
      Editor-in-Chief, Anesthesia & Analgesia
      Professor of Anesthesiology, Columbia University

      Steven L. Shafer

      February 4, 2011 at 1:00 pm

  3. How many of the 11 anesthesia journals who signed the joint letter require registration of a clinical trial in a clinical trials database such as Clinicaltrials.gov? Clinical trial registration is not foolproof, but would make it more difficult to conduct a study without IRB approval.

    Martin Fenner

    February 4, 2011 at 5:15 pm

  4. This is truly stunning, and I’m not only talking about the number of articles apparently ripe for retraction. The case implies that there has to be deep, deep anomalies within the German system of research ethical review. In my country, this guy would most probably go to jail for what he’s done.

    Christian Munthe

    February 4, 2011 at 7:18 pm

  5. Please, be enough wise to vanish the absurd term of “self-plagiarism”, at least in this blog. E.Newman thinks that it is moment to stablish our own limitations (the number of articles that I or you can write) as criteria of excellence. My Goodness, what a nonsense!!!

    Raúl Cruz-Mireles

    February 4, 2011 at 8:58 pm

    • Raul /Cruz-Morales, I understand that it seems ridiculous to you to limit GOOD papers. However I don’t know (m)any people who actually can manage to be up-to-date on more work in their lab than that. During my career in science I have seen the growth of enormous labs, requiring considerable grant money to maintain, and a gradual politicization of the granting process. To compete for jobs and grants, we expect an unduly large production ofpapers, and we count these rather than read them. We cannot find enough reviewers and the literature is corrupted with papers which are faked, or incompetent. There is less and less room for individual thinking people or small
      groups. PhDs have become supertechnicians.It is a waste of talent.
      I recognize of course the wonders that have occurred during that time- starting with my heroes,Jacob and Monod.However that period is regrettably over and it is time to find ways of restoring a more reasonable equilibrium. This will allow the blossoming of even more good research which we will all appreciate.

      elaine newman

      February 5, 2011 at 11:35 am

  6. I thank Prof Shafer for his reply. As I pointed out in my comment, as he also writes, yes there are pockets of measles in the UK, US and Canada (and possibly elsewhere) as a direct result of failure to vaccinate and this is terrible, both for the people infected and for those at risk as a result.

    But — In the UK I am aware of one, at most, death that could be attributed to failure to vaccinate with MMR. In the US I do not know if there are any deaths from measles – is there a published study?

    Just to note again, I write as a 100 per cent supporter of vaccination.

    Maxine

    February 5, 2011 at 5:43 am

  7. I must agree with Elaine Newman: the current procedures used in many countries to evaluate scientific work implies a lot of dangerous misconceptions, i.e. the equivalence of quality and quantity (some times slightly “adjusted” by impact factors). But the problem lies in the evaluation process, not in the lab work. In some fields it is easy to produce two dozen of GOOD papers/year (if you have enough students, coworkers or colaborations) although in others it is realy hard to produce one single paper in several YEARS, no matter the amount of money or people do you have. So, I realy think the solution to this situation implies an effective work of scientist on political and administrative arenas, the improvment of editorial teams, etc., but NOT the limitation of the quantity of research that a group or individual can publish in a journal.
    By the way, I also have deep sympathy for J. Monod; indeed, I just remember a quote: “You can be rational and immoral, or irrational and moral. If I don’t resolve this for myself, I will remain in pain either way” (Quoted by Melvin Cohen “In Memorian.” In Lwoff, A. & Ullman, A. “Origins of Molecular Biology. A Tribute to Jacques Monod” Academic Press, New York, 1979. There is a 2003 revised edition by Ullman) Greetings.

    Raúl Cruz-Mireles

    February 5, 2011 at 6:43 pm

  8. I have now expanded on the point about the broader research ethical ramifications of this case on my blog: http://philosophicalcomment.blogspot.com/2011/02/from-publication-ethics-to-big-time.html

    Christian Munthe

    February 6, 2011 at 5:37 am

  9. In view of the growing fraud in biology and medicine, shouldn’t the research part be separated from the clinical part? I mean – hospitals should conduct complete investigation of the papers and authors who propose the new drugs and methods. Hospitals should be held responsible for the introduction of these. Here should be your main peer review. The problem of course is that researchers have direct access to patients. And that should be stopped; I believe that just one case of Scott Reuben was enough to stop it.

    Michael Pyshnov

    February 8, 2011 at 11:56 am

  10. i READ THE ARTICLES ON “mEDICAL mADOFF”. DR. sTEVEN sHAFER HAS CONTACTED ANTHES. JOURNALS ABOUT THE FABRICATED RESEARCH. hOWEVER, hE ONLY CONTACTED THE SNTHES. JOURNAL. i HAVE READ SEVERAL ARTICLES ABOUT cELEBREX CAUSING MAJOR PROBLEMS AND THEY HAVE USED dR. ss REUBEN’S RSEARACH (WHICH IS FALSE). aLL THE MEDICAL JOURNSLAS NEED TO BE CONTACTED AS i CAN SEE WHERE dR. rEUBEN’S RESEARCH ARTICLES ARE QUOTED AND HAVE LEAD TO MISLEADING RESULTS ABOUT THE USE OF cELEBREX. tHERE ARE oRTHOPEDIC JOURNALS AND DENTAL JOURNALS WITH HIS RESEARCH WAS QUOTED AND IS REALLY MISLEADING THEIR RESEARCH. pLEASE NOTIFY ALL THE MEDICAL JOURNALS NOT JUST THE ANTHES. JOURNALS.

    mARILYN hAGEMANN

    February 11, 2011 at 3:38 pm

  11. The UK did a lot of ‘market research’ on the MMR. Before Wakefield’a Pulse article (before Lancet), the UK was close to ending endemic measles. That was lost after Wakefield.

    One of the interesting aspects is that Wakefield’s lawyer said this in the summing up:

    “Dr Wakefield was, as you know, a senior author of the Lancet paper, and publication of the paper, together with the commentary and the observations that he made at the press briefing, has led on the evidence that you have received to a downturn, or at least did turn to a downturn, in vaccination rates for the MMR vaccine. That is a fact. And it is a fact, even though Dr Wakefield may have been justified in publishing the paper; even though he held honest views about the safety of the MMR vaccine, and even though he advocated the use of a single vaccine. The fact of the linkage between the paper and the press briefing and the downturn is a fact, and it is not difficult to imagine that in some quarters he would be heavily criticised for that fact. ”
    day 130

    The Wakefield transcripts are now online as a single 10 mb zip file https://docs.google.com/leaf?id=0B9Ek8hRNlhrbNTk4MWI5YjktMDU3MS00MWU1LWFiZjQtZjA3MzI0ZDM0NTBl&hl=en
    At my blog, I’ve got links to the transcripts, the fact finding decision, the medical ethics guidelines and the sanctions decisions in one entry. http://vaccineswork.blogspot.com/p/wakefield-transcripts-and-gmc-documents.html

    sheldon101

    February 26, 2011 at 2:43 am


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