how patients found themselves guinea pigs in spite of themselves for prostheses still in test phase

A business leader and two surgeons who have decided to override the regulation on medical devices and violate the law: these are the new revelations of "Implant Files", Tuesday, November 27. The company Ceraver is being sued for having participated in 2011, with two surgeons also pursued, to the implantation of prostheses on patients whereas these implants not homologated were then in test on animals.

The "Implant Files" survey conducted by the international consortium of investigative journalists (ICIJ), of which Radio France is a partner, The world and First Lines ("Cash Investigation"), thus revealing what could be a scandal of medical fraud related to orthopedic implants.

An investigating judge has opened an investigation for biomedical research conducted without authorization and without consent of patients, violation of the regulations on implants and deception on the merchandise. For five years, the gendarmes of the Central Office for combating attacks on the environment and public health worked on the basis of phone tapping, searches, police custody … The story that they discover is eloquent.

A whistleblower who "can not stand to bail anymore"

It is not the European regulation on medical devices that has made it possible to reveal the case, any more than any monitoring devices of the National Agency for the Safety of Medicines and Health Products (ANSM). If it became public, it was only thanks to a whistleblower who anonymously testified to the ANSM in February 2013 of the "illegal acts" of which he was a witness. His mail lists all the shortcomings that will eventually be found by the ANSM and the investigators, and ends as follows: "I can not stand to endorse the operation of the company." His employer: Ceraver, a French laboratory that is then one of the largest French manufacturers of joint prostheses.

In May 2013, The Parisian reveals that hundreds of hip and knee prostheses were sold by Ceraver while the company did not hold the authorizations. There are also four patients implanted with uncertified Ceraver prostheses that were still being tested on animals.

Daniel Blanquaert, Ceraver's CEO, is organizing a press conference in front of his company headquarters in the Paris region. Wearing his white coat, the boss of this laboratory that produces prostheses says that the four patients are fine and, above all, that they were consenting. Problem: we know today that it is doubly false.

Prototypes of prostheses with inappropriate dimensions

In June 2011, when professors Alain Lortat-Jacob and Philippe Hardy, surgeons at Ambroise-Paré public hospital in Boulogne-Billancourt, operated hip Fernando V., Patrick G., Martine D. and Jeannine L., they do not give them essential information: the prosthesis they are about to receive is not approved. It has an antibacterial coating called Actisurf which is still in the testing phase. It was never discussed during preoperative appointments. Patients are not consenting. This will be recognized by surgeons during their custody.

In addition, two of the four patients will experience complications following their operation. "From the exit of the block", says Martine D. to the investigators. Pain that does not fade, even two years after the operation. Fernando V. has also lived "Hell" after his operation. This is the first to receive an unregistered Actisurf prosthesis. He suffered a first luxation of the hip two months after the operation, in August 2011. He suffered a second dislocation in September 2011. He will discover after the revelations of May 2013 that his prosthesis was undersized.

Despite their pain, Pr Hardy, in charge of the postoperative follow-up, tells them nothing about the Actisurf prostheses or the illegal test. It is rebaduring and explains that pains and even dislocations can happen after a hip operation. What is true. Just as it is true that their complications have no prior link with the Actisurf process itself. On the other hand, it is not known whether the experimental prostheses are manufactured at the time in sizes sufficiently diversified to cover all the morphologies of patients. It is also not known whether the surgeons, aware that they were performing acts partly tainted with serious irregularities, took the necessary time to carry out the operations.

Patients who feel like guinea pigs

Today, patients are angry with surgeons. Martine D. told the investigators her feeling of betrayal: "I trusted for something bbad and I found myself with ten years more (…) If I had to have surgery, I would refuse, I no longer trust at all in medicine."

Feeling shared by the family of Fernando V. He was supported by his two children, including Elisabeth whom we met. She says she feels hatred towards the two surgeons. "We really took a boat for two years," She launches. Today, she thinks she understands why the surgeons did not propose to remove the prosthesis that gave life "a hell" to his father and his family: "We have a report that evokes a cracking of the prosthesis and no one thinks that it is necessary to remove this prosthesis?" No. There is the test, the guinea pig test, which must be kept on the way. "

Instruction to use prostheses not yet approved

Beyond the role of the surgeons, the investigators were interested in the path of unapproved prostheses, from the Ceraver plant in Plailly (Oise), to the operating theater of the Ambroise-Paré hospital in Boulogne-Billancourt (Hauts-de-France). de-Seine). Because there are mandatory and strict procedures within AP-HP public hospitals in Paris to ensure the traceability of implants.

CEO Daniel Blanquaert brings together his heads of services in the meeting room and announces his decision to provide surgeons with prostheses not yet approved for implantation. Some collaborators protest, but Daniel Blanquaert requires them to find a solution for the implants to reach the operating room. "You are struggling, it's not my problem anymore," he says, according to a witness. Frames to find a solution. One of the collaborators proposes to falsify the label of the Actisurf prosthesis cartons in order to make them pbad for approved implants, with a CE marking in due form.

Remains to pbad the stage of the central pharmacy of the hospital, obligatory pbadage for all the implantable medical devices. The commercial manager of Ceraver takes care of this sensitive mission. He knows the place very well because he often comes to see Professors Hardy and Lortat-Jacob. He knows that the pharmacy opens at 8 o'clock in the morning. It is therefore sufficient to deliver the prostheses before, to be able to deposit the implants directly to the block.

An intellectual property issue

Why does the company and two surgeons, as all the investigations that have taken place since the beginning of this case seem to have decided, take such a risk? So far, everything was going as planned for the company. Ceraver has long sought legitimately to answer the last major problem of orthopedic surgery: the infection rate, which can reach 2% of operations.

The company has established a partnership with Véronique M., a researcher at the CNRS, who has her laboratory at Paris 13 University. She developed the process at the origin of Actisurf, for which patents have been filed. She will discover in the press in May 2013 that the company Ceraver has decided to "accelerate" the research by testing the process on humans. She explains to the investigators that she discovered the establishments in the press in 2013: "It's incomprehensible. For once, society is losing money, time and notoriety. "

The decision to operate patients is all the more surprising because at the same time, the company is finalizing an official request for a clinical trial. A doctor was even hired for this. Ironically, the request for a clinical trial is rejected by the AFSSAPS (now the ANSM) in October 2011 … for shortcomings of preclinical data. Four months after Ambroise-Paré's operations.

The truth about the motives of the company appears during the judicial investigation. CEO Daniel Blanquaert explains to the investigators that European and especially American manufacturers are starting to take an interest in the Actisurf process. : "I wanted to mark my territory on the intellectual property aspect."

In order not to dispute the paternity of the industrial process, he wants the operation to be performed by a surgeon whose competence is incontestable, Professor Lortat-Jacob, specialist in orthopedic infections. But there is a concern, he must retire. Hence the haste to operate. Facing the investigators, Daniel Blanquaert will say that the operation was a request from the surgeon. This one denies. In custody, Philippe Hardy explains that Ceraver and Alain Lortat-Jacob, jointly, wanted "take a date".

A transaction claimed by Ceraver in 2011

To mark its territory, Ceraver does not hesitate to communicate on these sites in the fall of 2011, at the annual conference of the French Society of Orthopedic and Traumatic Surgery (Sofcot) which brings together companies and surgeons. Ceraver has a large panel showing all its innovations for 40 years. Regarding the Actisurf hip prostheses, we can read: Actisurf bacterial anti-adhesion coating CNRS research – INSERM – Ceraver 2011: first implantations by A. Lortat-Jacob, Ph. Hardy, T. Bauer ".

"When we saw this sign at Sofcot, we thought that Daniel Blanquaert had necessarily obtained all the permissions and that he had hidden from us, says a former employee of Ceraver. At Sofcot, there are thousands of people including hospital pharmacists and people from the ANSM. It was too big."

A total of 1,885 implants without a valid certificate

Justice does not just reproach Ceraver with the history of the guinea pigs of Ambroise-Pare. The investigation revealed how the company would have disposed of several hundred knee and hip prostheses not covered by a valid certificate. Three deficiencies would thus be identified.

Ceraver orthopedic prostheses should have been the subject of a new application for certification following a change of clbadification decided in the framework of a European regulation of 2005. Clbad III, the most sensitive, is more restrictive for companies that wish to have their implants certified. Ceraver, and other companies involved, had until September 2009 to do what was necessary. Despite the written recommendations of the French certifying body LNE-GMED, Daniel Blanquaert's company would have ended up selling prostheses that were no longer covered by a valid certificate.

In a summary report, the investigators write that the company has even managed to sell to public institutions in Ile-de-France. "Despite the knowledge of the nonconformity of their products, the company Ceraver deceived the AGEPS [agence de l’AP-HP chargée des appels d’offres] stating that its implantable medical devices were Clbad III certified without the corresponding certification ", write the investigators.

According to these minutes, the AGEPS was also deceived by the company Ceraver, which provided false CE certificates. "There is neither the obligation nor the faculty to check the authenticity of the certificates", explains Renaud Cateland, Deputy Director of AGEPS.

In another case, Ceraver modified prostheses for which the company had valid CE certificates. But these changes, which were considered major by the certifying body, should have generated a new application for certification. What was not done since Daniel Blanquaert judged him that these changes were minor.

Finally, the investigators discovered that about forty Ceraver femoral stems were marketed without certificate from May 2010. It was only three years later that the company officially obtained a valid certificate.

Faced with the investigators, Daniel Blanquaert evokes "Errors" and "Oversights" to explain the breaches of the regulations. He will say in custody that the organization's certification timeframes are two years. Delays "Execrable" and "hardly acceptable". Following the inspection of the ANSM in 2013, Ceraver repeats in a letter of reply to have the "certainty (…) of the absence of danger" prostheses marketed without authorization.

A certainty that could be expensive for Ceraver. The investigators estimate the income related to this case to 1,140,209 euros. They arrived at this figure by adding the turnover achieved following the marketing of stems sold without authorization and reimbursed by social security, as well as the costs incurred by the implantation of the four patients of the hospital Ambroise- Parked in Boulogne-Billancourt and expenses related to the explantation of the prosthesis of Fernando V.

New tests … at Ambroise-Paré Hospital

The investigating judge dismissed during the investigation the dangerousness of the Actisurf process. After the revelation of the scandal, Ceraver waived the submission of a new application for a clinical trial to the Committee for the Protection of Persons (CPP) and the ANSM. Three years later, the CPP and the ANSM finally agreed at the end of 2016. "The first poses started in France in April 2017", says Ceraver on his website. A hundred patients participate. They are spread over three institutions: the University Hospital of Brest, the Lariboisière Hospital in Paris and … Ambroise-Paré Hospital in Boulogne-Billancourt.

"The AP-HP has signed a contract with the promoter Ceraver", recognizes Florence Favrel-Feuillade, Director of Delegation for Clinical Research and Innovation at AP-HP. But the choice to sign this contract with Ambroise-Paré Hospital does not seem to have raised any questions. The hospital, which was deceived by Ceraver and four patients have served as guinea pigs in spite of themselves, is working today with the same company, on the same procedure Actisurf, illegally implanted a few years earlier.

The APHP did not see fit to wait until the end of the judicial investigation and the trial to gauge the extent of the scandal and corporate liability before signing a contract with Ceraver. "What happened is serious, explains Florence Favrel-Feuillade. APHP learned from what happened. " But the scandal did not affect the decision to sign a contract with Ceraver for the Actisurf clinical trial.

An expected trial in 2019

The judicial part of this case could have ended quietly in a courtroom of the High Court of Pontoise, in October 2018. That day, Daniel Blanquaert and Alain Lortat-Jacob are at the helm, notes the investigation cell of Radio Fra, ce. They acknowledged the facts during the investigation and accepted the expedited plea-guilty procedure (CRPC). But at the hearing, the president refuses to homologate the proceedings following a disagreement between the civil parties and Alain Lortat-Jacob. The surgeon's lawyer explains that his client has agreed to recognize his responsibility for the implantation of a single patient, while the plaintiffs' lawyers claim that the surgeon is being sued for biomedical research concerning the four patients.

The business leader and the surgeon will be judged at a public hearing in September 2019, and they will have to go into detail about this case.

Outside the AP-HP, none of the actors and witnesses of this file did not wish to answer our questions, in spite of our numerous reminders. As for Professor Philippe Hardy, he died in September 2017.

The CEO of Ceraver sent us a few days before the publication of our article a message to answer us "for the sake of transparency". He is pointing out that "the appreciation of [la] society in these cases of non-compliance is still pending in court. " Daniel Blanquaert wants to clarify that "the absence of risk to the health of patients was emphasized by the health authorities in 2013."