Elsevier has weighed in on the handling of a controversial paper about the utility of hydroxychloroquine to treat Covid-19 infection, defending the rigor of the peer review process for the article in the face of concerns that the authors included the top editor of the journal that published the work.
On April 3, as we reported, the International Society of Antimicrobial Chemotherapy issued an expression of concern (without quite calling it that) about the paper, which had appeared in March in the International Journal of Antimicrobial Agents, which the ISAC publishes, along with Elsevier. According to the society, the article, by the controversial French scientist Didier Raoult, of the University of Marseille, and colleagues:
did not meet the [society’s] expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.
Critics of the paper have also noted that one of Raoult’s co-authors on the article, Jean-Marc Rolain, serves as editor-in-chief of the journal.
The second statement from the society now includes Elsevier, but doesn’t add much to the original other than noting that the publisher is now investigating the work:
Concerns have been raised regarding the content, the ethical approval of the trial and the process that this paper underwent to be published within International Journal of Antimicrobial Agents.
In response, we want to clarify that the journal’s standard peer review process was followed in the publication of this paper. To minimize potential bias, as one of the paper’s authors is the Editor in Chief of the journal, the Editor in Chief was not involved in the peer review of the manuscript, and that following the established standard process, the manuscript’s peer-review was delegated to an Associate Editor.
At present, additional independent peer review is ongoing to ascertain whether concerns about the research content of the paper have merit. Given this process of post-publication assessment is on-going, it would be premature to comment at this time. The study authors have been contacted and asked to address the concerns. Depending on the nature of their response, a correction to the scientific record may be considered in accordance with the policies of Elsevier and the Committee on Publication Ethics (COPE): https://www.elsevier.com/editors/perk/corrections-to-the-record.
We asked Andrew Davis, a spokesman for Elsevier, why the company decided to weigh in after the society had already issued its statement, and whether any legal or political pressure played a role. His reply:
It is a joint statement because Elsevier is a co-owner of the journal with the ISAC.
We do not have further to add at this time.
By way of background, Elsevier owns some journals outright — eg The Lancet, Cell — co-owns others, as in this case, and publishes some under contract without any ownership. For all journals published under any of these models by Elsevier, a committee, with input from company lawyers, reviews complaints that could lead to retraction, and has at least a strong hand in writing retraction notices. While editors theoretically have the final say, they often defer to Elsevier on such matters — and in discussing them with news outlets, including Retraction Watch.
About that peer review process: We also asked Davis how likely it was that the reviewers weren’t aware of whose work they were reviewing and if that might undermine the idea that the process was “standard”. (Perhaps it was “standard” after all … which isn’t exactly an endorsement).
He did not respond.
The journal appears to have gone all-in on the hydroxychloroquine hypothesis. Raoult, Rolain and a colleague also co-wrote an editorial in March for the IJAA in which they declared:
In the current episode of novel coronavirus (SARS-CoV-2) emergence, we find a spectacular example of possible repositioning of drugs, particularly chloroquine. … If clinical data confirm the biological results, the novel coronavirus-associated disease will have become one of the simplest and cheapest to treat and prevent among infectious respiratory disease.
Meanwhile, Raoult and his colleagues continue to post data from their ongoing project.
Like Retraction Watch? You can make a tax-deductible contribution to support our work, follow us on Twitter, like us on Facebook, add us to your RSS reader, or subscribe to our daily digest. If you find a retraction that’s not in our database, you can let us know here. For comments or feedback, email us at team@retractionwatch.com.
Having worked in clinical research for >30 yrs, it strikes me as impossible that a clinical trial in a disease that had been around for less than 3 mths could be performed and the results analysed, written, submitted to AND published in a peer-reviewed journal in these same 3 mths. Drafting a protocol (with all aspects of defining in-/exclusion criteria, data-capture and -analysis, …), preparing trials meds, having it reviewed by an ethics committee, … would take far longer than 3 mths, even in emergency conditions. Only after ethics and regulatory approval can a clinical trial start including patients.
At best, this paper sounds very “iffy” to me!
Raoult’s editorial is claiming chloroquine drugs could *prevent* COVID-19, based on no studies in healthy individuals whatsoever, and ignoring the fact that (at least in the doses used in the trials) they are toxic enough that many people would die from the treatment–a very careful analysis would be needed to find if there were any risk groups where the benefit outweighed the risk. And this he refers to as “simple.”
I think it was horrendously irresponsible to publish this editorial.
“To minimize potential bias, as one of the paper’s authors is the Editor in Chief of the journal, the Editor in Chief was not involved in the peer review of the manuscript, and that following the established standard process, the manuscript’s peer-review was delegated to an Associate Editor. ”
I sure hope it is not one of the two Associate editors that are also co-authors on the paper.
It’s difficult for common man, I fell sorry for those thay lost there life’s .
Wait, he could be right:
1. https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1
2. https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
Both of the articles say some effect of hydroxychloroquine
3.http://www.zjujournals.com/med/EN/10.3785/j.issn.1008-9292.2020.03.03
This third study says no effect but the patients were “common” meaning “mild” in both groups, and comparison was not possible.
One reanalysis says Raoult could be right but the original analyses overestimated.
https://www.medrxiv.org/content/10.1101/2020.03.22.20040949v2
Don’t have time for for double blinded, placebo controlled randomized, cross over chi square etc.
This is the difference between clinical medical during a pandemic and researchers.
The interest in HCQ stems from being studied for the first SARS Covid. It showed some promising results but wasn’t pursued cause the virus dropped off.
So this application of HCQ is not unorthodox for SARS COVID. It appears that its most beneficial effect is from its ability to reduce inflammatory markers, which in turn effects respiratory function.
Also, many anti virals can have cross over effect since they can block a certain percent of a virus, especially if its not specifically designed for a specific pathogen. This variation can explain differences in viral load. But viral load is the wrong end point.
What the primary endpoint should is respiratory function as well mortality. One study done with over 700 patients over age 70 with a physician in NYC showed zero deaths.
There have been studies in France, South Korea, Italy, NYC, Minnesota, South Dakota and yes China look at the effect of HCQ, Zpak etc.. The mounting CLINICAL evidence points to favorable results.
Lastly, please explain to me the safety concern?? We have drug developed in the 30’s used in the 50’s with expanded usage in lupus and RA for extended use.
Well, cardiac effects, such as ventricular fibrillation sounds like a safety concern to me.
The drug worked, the patient died sounds more like a deleterious side effect, not a desired outcome.
Blindness is another known side effect that sounds like a safety concern, quality of life and all.
That’s just for hydroxychloroquine.
That whole cardiac conduction issue rears its head with azithromycin as well.
Excuse the lack of abbreviation, where I worked, abbreviation was discouraged, due to potential and very real pharmacy errors resulting in patient harm.
I do conditionally disagree in points of data, viral load should be monitored, but as you said, the primary goal is restoring respiratory function. Not as an endpoint, but as a data point, as monitoring should continue after function is restored.
The outcome of patient recovered, was discharged and died would be captured.
https://www.sciencedirect.com/science/article/pii/S0924857920300996
All patients in Marseille center were proposed oral hydroxychloroquine sulfate 200 mg, three times per day during ten days …
Ocular toxicity
https://reference.medscape.com/drug/plaquenil-hydroxychloroquine-sulfate-343205
Rheumatoid Arthritis: … not exceed 600 mg or 6.5 mg/kg (5 mg/kg base) per day, whichever is lower, as the incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded
https://reference.medscape.com/drug/plaquenil-hydroxychloroquine-sulfate-343205#5
Irreversible retinal damage observed; significant risk factors for retinal damage include daily doses of hydroxychloroquine sulfate > 6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use > 5 years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate and concurrent macular disease
Cardiac disorders
https://www.mediterranee-infection.com/procedure-de-securisation-de-la-prescription-du-traitement-hydroxychloroquine-azithromycine/
The combination of hydroxychloroquine and azithromycin is proposed in the treatment of COVID-19. Insofar as this association could lead to lengthening of the QT interval and therefore to torsades de pointes (malignant ventricular arrhythmia), it was decided at the request of Professor Raoult’s team to set up in the urgently a pragmatic procedure for securing this prescription.
The QT interval was measured on the first EKG and corrected according to the Bazett formula. The recommendations were as follows:
* Prescription authorization if the corrected QT was less than 460 ms
* Case-by-case discussion of the risk benefit in the event of corrected QT 460 ms and 500 ms
* Contraindication in the event of corrected QT greater than or equal to 500 ms.
In the above paper that you cited:
None of the patients in the study had ocular toxicity which would be rare in the doses and time needed to treat Covid.
There were no incidences of clinically significant prolongations of the Qtc interval or problematic drug related arrhythmias.
The combo of hydroxychloroquine and azithromycin are cheap and have an excellent risk benefit ratio. There are so many physicians reporting anecdotal success that I think anyone who wants to refuse this early in the disease is a fool.
You report partial truths with your toxicity statements that are not in context with the risks associated with current treatment protocols. Don’t take these drugs yourself but what is your incentive trying to influence others to refuse it. For those unfortunate enough to get the virus follow- follow you dpcs recommendations. If he/she is not using it ask why not.
“None of the patients in the study had ocular toxicity which would be rare in the doses and time needed to treat Covid.”
You do not know as the effects of Covid itself introduces other adverse potentials like coagulopathy that will likely worsen adverse effects of medications being introduced.
“So this application of HCQ is not unorthodox for SARS COVID. It appears that its most beneficial effect is from its ability to reduce inflammatory markers, which in turn effects respiratory function.”
Why are people pushing HCQ for what looks to be a minor improvement at most?
What I don’t understand is why people are not pushing the use of statins(which reduce both possible infection and level of infection) with the possible addition of a ACE inhibitor/ARB if it’s not contradicted.
Both of these drugs are of proven safety, available everywhere and in the case of the statins will little effect on the body. The ACE inhibitors/ARB will of course cause a reduction in blood pressure to some degree.
An American of Cardiology study out of the University of California – San Diego showed that with “use of statins prior to admission was associated with a more than 50% reduction in risk of developing severe COVID-19”
A Heart article out of Oxford University showed a reduced possibility of hospitalization with the prior use of a ACE inhibitor/ARB.
There at plenty of other studies supporting those outcomes.
https://www.ajconline.org/article/S0002-9149%2820%2930947-4/fulltext
https://heart.bmj.com/content/106/19/1503
The following note was published by Yanis Roussel and Didier Raoult.
https://www.mediterranee-infection.com/actualite-du-traitement/
The fight against the COVID-19 epidemic has involved the exploration of numerous therapeutic avenues, which have given rise to research in vitro and in vivo. However, practitioners worldwide have not waited for the results of this research to use what appeared to them to be the most adequate treatment (1). This means being quick in carrying out research and then disseminating the results to doctors confronted with the epidemic in the field, to guide their therapeutic management of patients.
The use of potential treatments on patients makes it possible to produce data, which can then be used in research. In the scientific community, conducting randomized double-blind clinical trials has become the gold standard for validating the effectiveness of a treatment. However, when the urgency is to treat life-threatening patients, it is unethical to give them a placebo when the state of the art gives the doctor the intimate conviction that the risk-benefit balance is in favor of the administration of the treatment that he wishes to experience. We must therefore not forget that single-arm studies, without randomization, can be just as convincing as randomized studies.
Two elements appear crucial to us for a study carried out without randomization to be significant. First, it must study clearly identified endpoints. For COVID19, we identify three: mortality, going into intensive care, and viral load. It must also be comparative. The study needs to compare the results following the use of a treatment to a series of historical results, or to a series of results in other health care centers.
(1) https://www.sermo.com/press-releases/category/week-of-0413/
“The use of potential treatments on patients makes it possible to produce data, which can then be used in research.”
Where does informed consent for the use of highly experimental treatment that may prove utterly ineffective fall into your model of medical ethics?
https://www.sciencedirect.com/science/article/pii/S0924857920300996
The study was conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines of good clinical practice, the Helsinki Declaration, and applicable standard operating procedures.
World Medical Association Declaration of Helsinki
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
Informed Consent (from 25 to 32)
25 Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary …
26 … The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal …
ICH Safety Guidelines
https://www.ich.org/page/safety-guidelines
As of today, you report on 15 COVID-19 studies since Jan 31 that have been retracted. Do you know what percentage of COVID-19 studies these 15 represent?