The European Medicines Agency is to undertake a large-scale review of trial practices alongside the French drugs agency as a result of the recent disastrous trial in France which saw a study participant die. This will form the basis of a wider public consultation on the possible changes to how early-stage studies are undertaken.
There have already been a number of reports from France investigating how one patient died and 5 others were seriously injured after taking Bial’s FAAH anxiety drug BIA 10-2474 back in January.
A lot of blame has been shared, with the country’s health minister Marisol Touraine and France’s meds agency saying that both the CRO running the trial and the Portuguese pharma company Bial--which owns the drug compound being studied--lacked common sense, and did not stop the trial quickly enough when it became apparent that things were going horribly wrong.
But fundamentally, neither Bial nor Biotrial acted outside of the current rules--leading French authorities to demand a shakeup of the laws to ensure that the death and injuries which occurred in Rennes can never happen again.
In the latest report, released by France's social affairs inspectorate (IGAS) yesterday, experts found that the company had not properly informed volunteers and had followed a “flawed testing protocol.”
But Touraine, speaking to journalists as the report was published, said that while the “inspectors considered […] that Bial and Biotrial are responsible on several counts; regarding the dosage prescribed [...] and the time taken to alert authorities,” a final investigation report “confirms that the conditions under which the test was approved did not breach existing legislation.”
In lieu of this, France’s government said it would now seek talks with the European Medicines Agency and the European Commission, the central agencies responsible for most drugs and trials across the European Union, to improve study practices at an international level.
The EMA told FierceBiotech today that it has in fact already started a review of the guidelines that describe first-in-human clinical trials, and the data needed to enable their appropriate design and allow initiation. “The Agency will look at which areas may need to be revised, in light of the tragic incidents which occurred during the Phase I first-in-man clinical trial in Rennes in January 2016,” the agency said.
The EMA said that this review will take into account the findings of two in-depth investigations into what went wrong during this trial: one carried out by the Temporary Specialist Scientific Committee (TSSC) set up by the French medicines agency ANSM and the other by IGAS.
“EMA’s work will focus on best practices and guidance,” the agency said. “The review has started with two groups of experts carrying out preparatory work. One group is looking at preclinical aspects and the other at clinical aspects of the design of first-in-human trials and how these could be improved to better ensure the safety of human volunteers taking part in these trials. This will lead into the EU-wide expert group discussion on the revision of guidelines.”
The agency said its aim is to agree on a concept paper by July that “identifies areas for change and proposals to further minimize the risk of similar accidents […] The concept paper will form the basis for an EU-wide review of the guidelines. This process will include targeted discussions with stakeholders and a public consultation on proposed changes towards the end of 2016.”
Touraine has also demanded that French CRO Biotrial provide an action plan within a month to guarantee that “major breaches” cannot happen again. “If they don’t, we will suspend their activities. If this report is handed in, we will carry out verifications by the end of the year”, Touraine said in a news conference on Monday.
Biotrial has reacted angrily to the claims against it, however, saying it “contests the conclusions” from the IGAS report.
In late April, a report ordered by the French National Agency for Medicines and Health Products Safety (ANSM) found common sense “was lacking” from the two companies, but ultimately blamed the toxicity of the compound--and its unprecedented effects--as being the primary culprit for the death and the injuries. Biotrial welcomed this particular report.
But the ANSM too said that a major overhaul of safety standards should be made to stop this from happening again, saying the fallout from the trial will likely require new best practice codes for all future drug studies to reduce any similar accidents and fatalities.
The report’s authors also urged a tougher selection process for volunteers when testing drugs on humans for the first time, given that the dead man had previously suffered a head injury, and another of the victims had hypertension--ailments that should have ruled them out of the study, the report said.
"The seriousness of the accident at Rennes justifies changes to the regulations and international best practice," the report noted.
This is not the first time a native French company has been at the center of a drug death. The French drugmaker Servier was last year found legally negligent after its obesity drug Mediator (benfluorex) was linked to up to 2,100 deaths. It was later banned in France in 2009 after being taken by millions of patients. It is also long been banned in the U.S. Spain and Italy.
But its removal from the French market took much longer than in other countries--where the drug was also incorrectly prescribed to many patients who were not medically obese, but merely wanted to lose weight--something that was not allowed on its label. There have also been lingering allegations that the ban took so long because of the close ties between Servier's founder, Louis Servier, and the French government.
Observers have pointed out that less than a year before Mediator was withdrawn, Servier was awarded France's highest state honour, the Legion d'Honneur, by France’s former president Nicolas Sarkozy--who also once acted as Servier’s personal lawyer.
More recently, the country has also had to deal with the fallout from the PIP silicone breast implants scandal, made by the French company Poly Implant Prothese (PIP).
A U.K. report published back in 2012 found the PIP implants, made from unauthorised silicone filler, had double the rupture rate of other implants.
The boss of the French company which distributed the defective breast implants around the world has since been sentenced to four years in prison for fraud.
And a German firm responsible for granting European safety certificates for the implants has been ordered by a French court to pay compensation to hundreds of women.
Both the Mediator and PIP scandal left a lasting scar across the country and it has become highly sensitive to any drug-related safety issues, hence the rapidity and volume of its reports, and sharp criticism coming from the health ministry.
- see the IGAS report (in French)