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