It was supposed to be safe!

Yesterday I heard the very disturbing newsthat a clinical trial in France, has gone terribly wrong leaving one human volunteer brain dead.

“The chief neuroscientist at the hospital in Rennes, Dr. Gilles Edan, said in addition to the brain-dead man, three other men could have "irreversible" brain damage. A fifth man is suffering from neurological problems and a sixth man is being kept in the hospital but is in less critical condition, he said.”

The men were included in 90 healthy volunteers participating in a Phase 1 clinical trial of a new drug, code named BIA 10-2474, to treat pain and anxiety by Biotrial - a drug evaluation company based in Rennes, on behalf of the Portuguese pharmaceutical company Bial.

 

The remaining volunteers are being contacted.

The French Health Minister Marisol Touraine has suggested the incident is “unprecedented” and stated of the catastrophe “We'll do everything to understand what happened. I don't know of any other event like this.”

Perhaps the minister is not aware of the TGN 1412 disaster in 2006 whereby six healthy males suffered major organ failure and are now at higher risk of cancer and autoimmune diseases; nor the recall of Vioxx, a drug shown to be cardio-protective in mice yet caused heart attacks in humans; or even Thalidomide, the anti-morning sickness drug which was tested on animals yet caused tens of thousands of physical deformities in children; or perhaps even Diethylstillbestrol, a synthetic estrogen prescribed to pregnant women to prevent miscarriage, but instead Increased spontaneous abortions, premature births and neonatal deaths and also increased risk of vaginal cancer in daughters and granddaughters of users.

These are only those well publicised failures but there are many others recalled on a regular basis due to unexpected side effects not predicted in preclinical trials.

A Phase 1 clinical trial is the first step after pre-clinical (animal) trials have deemed the test substance safe. This particular drug, like those listed above, had undergone extensive animal tests – in this instance including chimpanzees – genetically, our closest relatives!

So, if the animal tests are a precautionary measure to evaluate the safety of these drugs, prior to administering them to humans, why have these unfortunate men been exposed to such a horrendous outcome?

Considering that 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them[1] it is becoming increasingly clear that our methods of testing need to change, and instead of focusing on animals with different genetics and metabolism to us, we need to embrace the technologies that are specific to humans – not monkeys or mice – because it’s quite obvious that animal tests provide dangerously misleading data.

A paper published this week in ATLA titled “Predicting Human Drug Toxicity and Safety via Animal Tests: Can Any One Species Predict Drug Toxicity in Any Other, and Do Monkeys Help?” is timely.  The paper looks at whether tests on animals, including monkeys, can predict human outcomes. It reveals that drug tests on monkeys are just as poor as those using any other species in predicting the effects on humans. The chances of a getting it right are no better than a coin-toss.

The authors of the study, FRAME Life President Professor Michael Balls and Dr Jarrod Bailey and Michelle Thew of Cruelty Free International, argue that animal testing for human drugs is not ‘fit-for-purpose’. They hope the paper will lead to discussions in the pharmaceutical industry about using more reliable testing methods not involving animals.

I certainly agree, because if we continue using the current flawed system based on animal trials, sadly we are likely to see similar tragedies unfold and far slower progress toward genuine medical cures.

Update:
Since publishing this post one of the volunteers has sadly died and the others who remain hospitalised are at risk of brain damage.

Scientific experts have responded to the news with the suggestion that the risks may have been identified through computational tests:

'Sean Ekins, PhD, who writes at Collaborative Chemistry, has run the BIA 10-2474 structure through two computational algorithms to identify potential protein targets other than FAAH to which the drug might bind. While he stresses that these are simply computational analyses that have not been confirmed experimentally, Ekins writes

“These high scores for many protein targets in humans could suggest the molecule is highly promiscuous and there may not be a single pathway interfered with. Vesicular acetylcholine transporter is slightly lower down in the list which also makes you wonder how many GPCRs might be impacted too. For now this is all idle speculation until we hear more about exactly what happened. Perhaps this compound could be profiled both computationally and experimentally to answer these questions of what the target/s of the toxicity are.”

If Bial performed similar experiments for their drug–biochemical or computational–no similar data has been published or otherwise made available publicly.'

For further information about animal experiments: Please visit www.HumaneResearch.org.au
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[1] Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work Thomas Hartung, Altex 30, 3/13 (http://altweb.jhsph.edu/altex/30_3/FFTHartung.pdf)