INQUIRY. At the IHU, Didier Raoult’s little arrangements with ethics (and law)28 juillet 2021
Translation by Citizen4Science courtesy of L’Express – Link to the original article
Some studies published by the team of the famous professor border on, or even cross, the limits of the law that governs experiments on human beings. Some of them involve children.
At first sight, it is a banal study. In reality, it turns out to be the tree that hides the forest. Between 2017 and 2018, as part of a thesis directed by Prof. Jean-Christophe Lagier, of the IHU Méditerranée, a student is conducting a clinical trial in a medical practice in Carry-le-Rouet, near Marseille. Her work consists of taking nasopharyngeal swabs from people suffering from a respiratory disease, such as influenza, as well as from their contacts. She recruits 162 patients. 41 are minors, 15 of whom are under the age of 3. She then have the results analyzed at the IHU, and compares them with a similar trial conducted in two university hospitals in Marseille (AP-HM). « The protocol described in this thesis indicates that it is a Research Involving the Human Person (Recherche impliquant la personne humaine, RIPH), » says Philippe Amiel, a lawyer and member of the Inserm Research Ethics Committee and president of the College of Ethics of this institution. These experimental works are particularly regulated in France. The law classifies them in three categories: RIPH1, 2 and 3. All of them must be validated by one of the 39 Committees for the Protection of Individuals (Comités de Protection des Personnes, CPP) before they can start being carried out. The most sensitive ones, RIPH1, also require prior authorization from the French National Agency for the Safety of Medicines and Health Products (Agence nationale de sécurité des médicaments et des produits de santé, ANSM). A first problem emerges: on page 24 of the thesis, it is stated that a favorable opinion (#2016-016) has been granted by the « Ethics Committee of the IHU Méditerranée ». However, the latter is not a CPP and cannot replace it. Nevertheless, two other authorizations are mentioned in the consent forms intended to patients of legal age and to the representatives of minors, page 52 and 54. These documents, signed by the director of the IHU, Didier Raoult, indicate that « this research has obtained the agreement of the CPP Sud Méditerranée 1 and of the ANSM ». But no number or date is mentioned. Unusual. When contacted by a third party, the ANSM replied in an email obtained by L’Express that « no clinical trial corresponding to [this] request could be found ». When questioned by L’Express, the CPP Sud Méditerranée 1 confirmed that they had « not given a favorable opinion on the research mentioned on page 52 of the document transmitted », which means that this trial involving human subjects, including minors, has not received legal authorization. The fact of falsely claiming an authorization from a CPP is a serious ethical breach: the people who participate are deceived, » underlines Philippe Amiel. Moreover, conducting such a study without authorization is punishable by law. In this case, a prison sentence of up to 1 year and a 15,000 euro fine.
Excerpt of the mail sent by ANSM on 30 June 2021 © L’Express
Translation of the above excerpt :
Dear Sirs, By means of two emails dated April 25, 2021, you requested the following documents and information:
1. regarding a clinical trial sponsored but Assistance Publique-Hôpitaux de Marseille (AP-HM), entitled « Detection of respiratory virus (flu, RSV) in contact subjects of a confirmed case of viral respiratory infection »:
clinical trial authorization decision, synopsis of the protocol, files requesting substantial changes to the trial protocol, opinion of the Committee for the Protection of Persons (CPP) if available (or the reference and date of the CPP opinion);
In this regard, I would like to inform you that after wearching with my departments on the basis of the information you provided (sponsor and title of the trial), no clinical trial corresponding to your request could be found.
More surprisingly, L’Express found the same opinion number (#2016-016) of the IHU Ethics Committee in a scientific study published by the Marseille-based institute in 2018. This work is signed by Didier Raoult and several of his collaborators, some of whom are also the investigators of the student’s thesis. The experiments described are similar to those mentioned in the thesis, but this time they do not mention any authorization by ANSM or a favorable opinion from a CPP. When questioned by L’Express, the CPP Sud Méditerranée 1 indicated that it has not issued an opinion for this study. The authors of the study justify this by explaining that it is a study on samples collected in the context of care and not specifically for research. Except that this is not the case with samples from « controls » recruited specifically to have a comparison group. « And in this case, the entire research is normally qualified as RIPH and must gain a favorable opinion from a CPP, » observes Prof. Mathieu Molimard, a specialist in clinical pharmacology at Bordeaux University Hospital.
Two studies assessing Hydroxychloroquine
These shortcomings may seem anecdotal. But they appear to be common practice with the IHU. In 2020, when France was hit hard by the first wave of Covid-19, Didier Raoult and his team launched two studies on Hydroxychloroquine, the molecule presented as THE solution to Covid-19. The first, called « SARS-CoV2quine », plans to take nasopharyngealswabs and administer Hydroxychloroquine to 36 patients, including minors over 12 years of age, as confirmed by the European clinical trials registry. A formal authorization was requested and granted by the ANSM on March 5. The CPP Ile-de-France V issued afavorable opinion on March 6. But the results of the study, published on March 20 in the International Journal of Antimicrobial Agents – directed by Jean-Marc Rolain, a professor at the IHU and a close friend of Didier Raoult are surprising to many experts. Indeed, two 10-year-old children were included in the study and another drug, azithromycin, was tested, which was neither planned nor authorized.
The scholarly organization that oversees the International Journal of Antimicrobial Agents expressed concern in a note published on April 3, stating that « this study does not meet the standards for ensuring patient safety. The journal itself publishes, after the fact, a review by a Dutch researcher who calls the work « totally irresponsible« . Between the CPP’s opinion and the publication, there are only 14 days, and this timeframe does not allow us to assess properly the quality of the research work, nor the analysis work by the journal’s editorial board, » points out Hervé Maisonneuve, a doctor specializing in scientific integrity. The questioning also concerns the insurance of patients under 12 years of age and those receiving a drug not included in the protocol. Was there an amendment to the insurance contract? Does an insurer accept to insure patients outside the protocol? This information is missing ».
After this coup de force, the IHU is doing it again with a second study called « Azithroquine-covid19 », which aims to test the combination of hydroxychloroquine and azithromycin on 80 patients. The Marseille’s team requested new authorizations on March 19. However, two days later, ANSM and CPP Ile-de-France VI gave a negative response, this time justified by the flaws in the protocol and methodology presented, as revealed by Libération. Whatever the case, without changing their practice, the IHU team continued the trial and published their results on March 27 on the IHU website, then on April 11 in a scientific journal, one of the editors of which was Philippe Gautret, a physician at the IHU and a close collaborator of Didier Raoult. To justify ignoring the refusal of the ANSM and the CPP, the IHU team argues once again that the study does not involve intervention on human beings and therefore does not need authorizations. « However, it is enough to read the ‘methodology’ part written by the authors: they themselves describe an interventional study, a RIPH1 that requires an authorization from the ANSM and a favorable opinion from a CPP, it is an absolute evidence », according to Philippe Amiel, who had already developed his arguments in an article published on May 3, 2020 in Medicine/Sciences. « The protocol was not respected, patients -including children- and an additional drug were added at the last moment, it is no longer research, but cooking. « These tricks attracted the attention of several observers, including a pharmacist from outside the IHU who reported the matter to the Marseille public prosecutor’s office in April 2020. The judges then sought the opinion of ANSM. The Director General of the agency, Dominique Martin, replied in a letter dated May 20 that he had already conducted his investigation and questioned Didier Raoult directly. His conclusions are without appeal: « The methods of information […] do not comply with legal requirements ». The same day, the head of ANSM declared in the press that the IHU had not provided him with any proof that the second study was not an HPRI. On May 27, the ANSM therefore decided to refer the matter to the National Order of Physicians. But the institution, frequently criticized for their prudence, has still not given their verdict. The prosecutor of the Marseilles Public Prosecutor’s Office, Dominique Laurens, decided to close the case without further action. In a letter sent on November 12, 2020 that L’Expressa consulted, the magistrates and specialized assistants of the pole of public health judge that the elements are insufficiently constituted. The Prosecutor considers that the 10 years old children enrolled in the first study have « not been exposed to a possible risk of side effects », since they did not receive medication, but placebo. As for the second study, the judges consider that at the time, « in the context of an epidemic caused by an emerging virus », it was possible to consider the prescription of hydroxychloroquine as « routine care », which, in their opinion, is sufficient to consider the study not to be an RIPH. This is a very « local » reading of the Public Health Code that has provoked shock and anger in the research community. The National Conference of Committees for the Protection of Persons (CNCPP) even issued a vitriolic statement in December 2020 calling on the Public Prosecutor’s Office to reopen the investigation, but not without sweeping aside its legal arguments point by point. « The judges answer that the 10 year old children were in a placebo group, but that does not change anything: they should not have been included! », Bettina Couderc, a member of the CNCPP, storms. As for the second study, the protocol was refused, but the IHU still published a study that they qualified as non-interventional, even though this was not the case. Even considering that hydroxychloroquine would be a common care, there were nasopharyngeal samples that alone justify an authorization. »
Mail sent by the prosecutor’s office of Marseille to the parties to announce and justify the dismissal of the case.
Translation of the above excerpt :
In response to your letter of 3 November 2020, received on 12 November 2020, I have the honour of informing you that the procedure during which we carried out a preliminary analysis following a denunciation implicating clinical studies carried out within the IHU directed by Professor Didier RAOULT was the subject on 12 November 2020 of a decision to close the case without further action (insufficiently substantiated infractions).
This decision is based on the following elements:
The alert concerned, on the one hand, the irregular presence of children under 12 years of age in the list of patients in the preliminary report of a clinical study conducted in France by IHU Méditerranée Infection (IHU-MI) and, on the other hand, conducting a study that would be improperly categorised as « observational », conducted by the same sponsor and whose aim was to evaluate the efficacy of the combination of Hydroxycholoroquine and other drugs, tconducting a study that would be improperly categorised as « observational », conducted by the same sponsor and whose aim was to evaluate the effectiveness of the combination of Hydroxycholoroquine (PLAQUENIL©) and Azithromycin (ZITHROMAX© or other) in the treatment of Covid-19.
After analysis by the magistrates and specialised assistants of the public health unit, it appears that the offences relating to the above-mentioned facts are insufficiently established.
Indeed, firstly, if the IHU-MI team presents, in the preliminary results of its clinical trial n°2020-000890-25, results for two children aged ten, whereas the study protocol authorised by ANSM and validated by the Ile-de-France Commitee for the protection of persons excludes children under twelve, it appears that the children are part of the control group who did not receive PLAQUENIL© treatment and were not exposed to a possible risk of side effects associated with this drug.
Secondly, it is clear from the provisions of Article L.5121.12-1 of the Public Health Code (CSP) that the prescription of PLAQUENIL© outside of the marketing authorisation (AMM) is possible in the absence, for the patient, of an appropriate medicinal alternative with an AMM or a temporary authorisation for use, provided that the prescriber deems it essential, in the light of scientific evidence, to use this speciality to improve or stabilise the patient’s clinical condition.
In the context of an epidemic caused by an emerging, and therefore poorly known, virus, no drug had yet been authorised to treat Covid-19 or to prevent infection caused by the new SARS-CoV2 coronavirus.
Authorised medicines could therefore regularly be used outside the indication approved by their marketing authorisation (so-called « off-label use ») in the treatment of Covid-19, under the freedom of prescription of the physician and under his responsibility.
The conditions set out in Article L.5121-12-1 of the CSP are met with regard to the second study mentioned above.
Moreover, this study, which concerns retrospective data, does not fall within the legal framework of the JARDÉ law relating to biomedical research involving the human being.
Since then, new elements have appeared. And in particular a correction published in January 2021 in which the IHU admits that the number of patients included in the first study was not 36 as announced, but 42, and that there is not one, but two deaths in the group that received the hydroxychloroquine plus azithromycin treatment. « It seems through available documents that the protocol was not respected, patients including children and an additional drug are added, this is no longer research, but cooking », tackles Mathieu Molimard. The Express also found a testimony to say the least strange, published in the local press on 21 March 2020. Laetitia, 37 years old, a lawyer living in Aix-en-Provence, explains that she was hospitalized at the IHU on March 14, 2020 and that she participated in a clinical trial.
She says the HU made her sign a consent letter to agree to take hydroxychloroquine, have scans, and have stool and urine samples taken, which describes an RIPH. « A nurse laid the protocol on the bed for me and explained that it was in the research status, hence the need to sign. In shock and fear, I didn’t read anything, I didn’t think, I didn’t
I didn’t think about it, I just signed it », she explains. However, no 37-year-old woman is listed in the first study on hydroxychloroquine, the only one to have received the green light from a CPP and ANSM. Finally, a report of « Enquête exclusive » broadcast in January 2021 on M6, reports that lawyers of the IHU have threatened Elsevier – the publisher of the scientific journals that published Didier Raoult’s two studies – with legal action if these studies were retracted, i.e. officially disavowed. According to all experts interviewed by L’Express, as long as the Marseilles Public Prosecutor’s Office does not take up the case, it is up to ANSM to make a new report. Why such apathy on the part of the body that is supposed to represent the clinical trials police? Some people wonder about possible political pressure. After all, Didier Raoult has always been able to count on many supporters among the population, but also among politicians, from Philippe de Villiers to Renaud Muselier, and Nicolas Sarkozy, not forgetting Emmanuel Macron, who visited him on April 9, 2020 in Marseille, before distancing himself a few months later. Others evoke the desire not to throw oil on a fire that has already burned too much. « If there is no reaction from the authorities, it would be a very bad signal for the world of research, it is as if we were saying ‘there is no more law in this field’, » laments Philippe Amiel. « What will happen next? Researchers will create small local ethics committees that will authorize all their research by arrogating to themselves rights that they don’t have? », ironizes Mathieu Molimard.
From vaginal swabs on female students…
Especially since the IHU’s little arrangements with the rules don’t stop there. Microbiologist Elisabeth Bik, one of the world’s leading experts in detecting scientific fraud and manipulation, has found problems in more than 60 studies published by IHU in recent years, which she details in part in her blog. « I discovered, for example, that images in one of their studies that were supposed to represent results were duplicated and came from an image bank on the Internet, » the researcher told L’Express. I also raised potential problems of scientific ethics. In particular in studies where they take blood, skin or hair samples, but without indicating how they obtain the consent of the participants, or whether they have received authorization from a CPP or the ANSM. I’m not saying that these are necessarily deliberate manipulations, maybe they are errors or oversights, but the question deserves to be asked. »
L’Expresss also delved into dozens of studies published over the past twenty years by Didier Raoult or his collaborators. Some are particularly noteworthy. Like the one published in 2019 and dealing with the prevalence of respiratory, gastrointestinal and vaginal bacteria of 134 interns of the Faculty of Medicine of Aix-Marseille. The experiment took place between June and August 2018. The students, after signing a consent form, are invited to collect nasopharyngeal, fecal and vaginal samples themselves one week before their departure on vacation and the week of their return to France. Bis repetita in 2019, with another study involving the same samples on an even larger cohort of students (382). The results of these studies, which have not been published in a scientific journal, were released online on September 24, 2020. In each case, the authors note that the students signed a consent form. « The protocol classifies these two studies as RIPH, » says Mathieu Molimard. They should therefore benefit, at the very least, from the favorable opinion of a CPP ». But in both cases, the IHU team writes that « this protocol was authorized under the unique number n°2019-06 by our ethics committee », i.e. the IHU committee which has no authority in this matter. « And these medical students can be considered a ‘dependent population’ because they are hierarchically linked to the IHU, » the professor teases. « Without the vigilance of a CPP, which is going to guarantee that their consent is free? »
… to anti-lice briefs for the homeless
Another set of studies intrigues. The first runs from January 2011 to May 2012. Its purpose, detailed in the U.S. Clinicaltrials.gov registry, is to test anti-lice briefs on 125 homeless people and compare the results with a group wearing normal briefs. The study, published in December 2013, cites a 2011 approval from « our institutional ethics board » as #2010-A01406-33. First oddity, this number corresponds to an authorization by ANSM, and not to an opinion from a CPP. Contacted by L’Express, the CPP Sud Méditerranée 1 nevertheless confirms that a « favorable opinion was indeed issued for a study that was submitted to Afssaps », the ANSM at the time. So everything seems to be in order. Except that by searching for the number 2010-A01406-33 on the PubPeer website, which references works published in scientific journals, no less than 17 studies conducted between 2011 and 2020 appear. Some of them indicate that the authorization #2010-A01406-33 was granted by the ethics committee of Aix-Marseille University, others suggest that it comes from the ethics committee of the IHU or the AP-HM, or even simply do not specify this. However, an authorization number can only correspond to one study, with some exceptions. The general rule is: « one study, one authorization, one number, » explains Bettina Couderc. It can happen that a protocol is extended, but this only works if the trial is modified at the margin. However, if almost all of the 17 studies with #2010-A01406-33 concern homeless people or refugees, the subjects of the survey are most often far from the first study.
Did the IHU simply « forget » to mention the legal authorizations? Or would he have chosen to use the number 2010-A01406-33 dating from 2010 to justify all his studies? When questioned by L’Express, AP-HM explained that: « Among these 17 publications, only two actually correspond to the study number RCB 2010-AO1406-33, ERPOUPER. For the other 15 studies, the use of this number is erroneous ». Two of these studies are from another study promoted and correctly declared by the AP-HM, but incorrectly referenced by their author. For the last 13, there is no link with the study 2010-AO1406-33. « When contacted by the AP-HM research department, principal investigator Philippe Brouqui [researcher at the IHU, editor’s note] acknowledged that editorial errors had been made since these publications were not related to ERPOUPER (and therefore should not have been declared under this study number), » wrote the AP-HM. Prof. Philippe Brouqui then asserts that the 13 other studies « are the result of research carried out within the framework of annual surveys that were the subject of a favorable opinion, dated January 21, 2010, from the IFR 48 ethics committee (#10-005) ». According to him, « this reference should have been the one affixed to these articles which do not fall within the framework of the Jardé law, but are part of the epidemiological surveillance of the screening and care of a community of people ». In other words, these works were simply mislabeled and did not require a favorable opinion from a CPP. Except that, according to L’Express investigation, this line of defense does not hold for at least two studies. The first one, published on October 15, 2020, aims to detect cases of tuberculosis in the homeless through samples, scans and examinations. The second, published on February 13, 2021, and co-authored by Didier Raoult and Philippe Gautret, focuses on the prevalence of respiratory pathogens including Covid-19 for which nasal swabs were systematically taken. These two studies are undoubtedly RIPH, » analyze Mathieu Molimard and Philippe Amiel, « they should at least have the favorable opinion of a CPP. In other words, these studies fall within the framework of the Jardé law. As for the 11 other studies, a more detailed analysis would undoubtedly be worthwhile. In an email sent to L’Express, the AP-HM states that they have launched « a systematic review of all the studies in progress at the IHU and sponsored by AP-HM in order to ensure that each one is perfectly in line with the regulations ». These studies are of particular interest to me because in the United States, clinical trials on the homeless, who are considered ‘vulnerable’, are very closely monitored, » says Elisabeth Bik. The authorities make sure that they are not offered any treatment or protocol in exchange for shelter or money. I am not saying that the IHU has done this, but it is normal to ask whether authorizations have been granted.
An ongoing « investigation » by the authorities
When questioned, ANSM did not want to react to the fact that the Marseille public prosecutor’s office had dismissed the case, nor did they wish to refer the matter to the judges. Nor did they answer our questions about the potential problems of the studies cited in this investigation. However, the agency indicates that they have been « recently alerted », within the framework of their whistleblower system, about possible breaches of clinical trial regulations by the IHU of Marseille on certain studies of the Institute. « ANSM is conducting the necessary investigations and verifications. If these investigations reveal breaches of clinical trial regulations, we will take sanitary measures to guarantee the safety of participants and, if necessary, bring the matter to court, » we are told. Also contacted by L’Express, the IHU Méditerranée did not respond to our questions.
« One thing is certain, there are many problems with the IHU studies, » says Elisabeth Bik. When I started asking questions, Prof. Raoult could have simply said to me: ‘there is no technical or ethical problem, we simply forgot to publish the documents that attest to this, here they are’ and I would have moved on, but instead he attacked me on a personal and legal level. The professeur from Marseille has indeed decided to sue the researcher. Since then, Elisabeth Bik has been subjected to a terrifying wave of harassment on social netwokds. Her personal address has even been duvulgated by a well-known pro-Raoult Twitter account.
It is disturbing and it gives the impression that there is a wolf », says the researcher. Suspicions fueled by the unorthodox techniques used by Professor Raoult for years. In particular, his propensity to publish large numbers of poor quality studies in scientific journals of little renown and owned by close collaborators. An unethical, but legal process, allowing him to obtain 10 million euros per year on behalf of the AP-HM via the SIGAPS system, as explained by L’Express in an investigation published in June 2020. The two issues are at least partly linked and reveal the damage of the « race to publish », a phenomenon that has been growing for years and does not, unfortunately, only concern the IHU Méditerranée.