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02 Feb 2016

Safety protocols for human drug trials are coming under renewed scrutiny after one man died and three may have suffered permanent brain damage in a French test that went badly wrong.

In one of the most serious reported incidents in years, six men taking part in the Phase 1 clinical trial of an experimental molecule developed by the Portuguese pharmaceutical firm Bial were rushed to hospital in Rennes, north-west France after suffering severe adverse reactions to the drug.

One man who was declared brain dead has subsequently died, and University Hospital of Rennes Chief Neuroscientist Dr Pierre-Giles Edan said MRIs conducted on three other volunteers, who were all healthy males aged between 28 and 40 years, showed deep cerebral haemorrhage and necrosis. Dr Edan warned the damage “might be irreversible”.

A fifth man was suffering neurological problems and a sixth was being monitored but was in a stable condition.

A subsequent update reported that one volunteer with no symptoms had been discharged from hospital, two others had been transferred to hospitals closer to home, while the two still being treated at the University Hospital of Rennes “present a positive scenario”.

French Health Minister Marisol Touraine described the situation as “an accident of exceptional gravity”, and pledged to “get to the bottom” of it.

Three separate investigations, including one by the French prosecutor, have been launched to determine whether the tragedy was caused by the drug itself or by an error in the way the trial, being conducted by the private Rennes-based firm Biotrial for Bial, was conducted.

The trial was the first time the Bial compound BIA 10-2474 had been used on humans following a series of tests involving laboratory animals.

It had begun in July, and the company said 108 people had taken the drug without experiencing any “moderate or serious” adverse reaction before the six men received an oral dose on 7 January. Phase 1 trials are to test for the safety of novel treatments, and typically involve taking escalating doses. Experts suspect the men received a higher dose than previous recipients.

One of the issues likely to be the focus of investigation is why the six men received the dose at the same time, rather than staggered over time.

Bial designed the drug to provide relief from pain and anxiety by acting on cannabinoid receptors in the brain.

The six volunteers each received 1900 euros ($A3000) to take part in the trial.

In a statement, Bial said that as soon as the five volunteers showed severe symptoms, “they were immediately transferred [to hospital]”.

“Our main concerns at this time are with the monitoring of the trial participants, in particular the five hospitalised volunteers,” the company said.

The company subsequently expressed “deep regret” over the death of the volunteer, and said it was “continually and closely following the health state conditions of the other five volunteers”.

Bial said the trial had been approved by French regulatory authorities, and had been conducted “since the beginning in accordance with all the good international practices [sic] guidelines”.

It said results, including the completion of toxicology tests in the pre-trial phase, had “permitted the start of the clinical trials in humans”.

The company said it was committed to ensuring the well-being of participants and to determine “thoroughly and exhaustively the causes which are at the origin of this situation”.

The Daily Mail has reported that French authorities have registered only 10 drug trial incidents since 2000, all with consequences far less serious than those in Rennes.

The incident has drawn parallels with a drug trial in Britain in 2006, in which six volunteers developed serious health problems and two were left in a critical condition. One, Ryan Wilson, spent 147 days in hospital after suffering multiple organ failure, and had to have all his toes and several fingers amputated. The German company that made the drug collapsed.

The accident reinforced calls for doses to be staggered over time, so that an adverse reaction in one subject could be detected before exposing others to the same risk.

Adrian Rollins

Published: 02 Feb 2016