The contract research organization (CRO) Biotrial and Portuguese pharma partner Bial earn their place among the rotten tomatoes with patient fatalities. While absolute and final blame was not placed on the two companies, investigations into their actions found problems that should not be overlooked or deemed acceptable practice.
In fact, in light of what happened in France just over a year ago in January 2016, the European Medicines Agency (EMA) decided to reassess its early-stage trial policies to ensure this doesn’t happen again.
Let’s go back to the start: The CRO-pharma pair were testing a drug known as BIA 10-2474 as a treatment to block the enzyme FAAH, an approach believed to help treat forms of anxiety that is well-known in the industry. The med was under testing in Rennes, France, and as of January last year, around 100 patients had taken it.
But then, six trial participants took a higher-dose form of the treatment. One became brain-dead and later died, and the others grew acutely ill. These were not patients who had few treatment options or were dying of an advanced form of a terminal disease; the patient who died could potentially have lived for decades longer.
In France, this took on a major political significance, given its history with drug-associated deaths: In 2015, the French drugmaker Servier was found legally negligent after its obesity drug Mediator (benfluorex) was linked to up to 2,100 deaths.
Mediator was banned in France in 2009, much later than in other countries; at the time, it was already off the market in the U.S., Spain and Italy. The drug was also incorrectly prescribed to many patients who were not medically obese, but who merely wanted to lose weight—an unapproved use. Regulators faced allegations that the ban came so late because Servier's founder, Louis Servier, had close ties to the French government.
The country since has doubled down on drug safety, and it promptly launched a series of investigations into what happened with BIA 10-2474. Politicians also weighed in. What emerged was a complicated picture of a fundamental problem: The companies had followed the rules, but there was room within the rules for fatal errors.
That does not mean Bial and Biotrial were deemed blameless. Culpability has been shared, with the country’s health minister Marisol Touraine and France’s meds agency saying that both companies “lacked common sense,” and did not stop the trial quickly enough when it became apparent that things were going horribly wrong.
A few weeks after the fatal trial, Touraine said that Biotrial “should have halted the tests” after the first person was hospitalized. This didn’t happen, however, and five more people were given the medicine the next day. An initial report found that the first accident with the drug was on a Sunday evening, yet authorities were not alerted until the following Thursday.
Another report 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.
More investigations followed, and in May, a final report “confirmed that the conditions under which the test was approved did not breach existing legislation,” with much of the blame falling on the toxicity of the compound and its unprecedented effects.
But when announcing the report, Touraine added, “Inspectors consider, however, that Bial and Biotrial are responsible on several counts; regarding the dosage prescribed [...] and the time taken to alert authorities.” The EMA also got involved, telling FierceBiotech exclusively at the time that, given the seriousness of the death and its causes, it planned to rethink its phase 1 rules.
Biotrial also did not cover itself in glory as it repeatedly, and sometimes angrily, took issue with some of the investigations (namely those that put it in a bad light). Biotrial said the reports were flawed, and that investigators' failure to ask the CRO for input “removed credibility” from the process.