French clinical trial leaves one dead and others with brain damage

An experimental painkiller that killed one volunteer and severely damaged the brains of five others in a clinical trial in Rennes, France, may have acted on parts of the brain that it was not supposed to, a committee investigating the incident has concluded. It recommends that safety rules for clinical trials be tightened up globally.

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This story was upsetting to me on many levels. You have people in pain and those who relieve them of it. The bond between a user and their dealer can be a strong, but an unstable relationship. Tolerances grow over time and emotions fade, which can leave a person feeling empty. There is desperation on both sides, seeking what each want from the other, with the exception of the user having limited choices. Many become addicted and some drugs just don't work for some people. Subjecting yourself to these kinds of trials may just take away your pain forever. How sad...

The trial was looking at a drug called BIA 10-2474, a painkiller developed by Portuguese firm Bial. In total, 90 volunteers received the drug. The six who were harmed received the highest total dose: 50 milligrams per day up to cumulative amounts of between 250 and 300 milligrams, at which point symptoms rapidly kicked in.

In a stupid declaration of obvious proportions, the French National Agency for Medicines and Health Products Safety concluded that the damage was almost certainly “an off-target effect.” I hope they got paid a bunch of money to reach that conclusion. Don't expect much recourse, though I doubt their informed consent was given based on the knowledge of possible death.

The investigators suspect that at the high doses some volunteers received – 40 times above what is needed to block all FAAH – the drug may start disrupting brain enzymes other than FAAH. Another possibility is that the surplus anandamide may cause damage either by activating other molecules in the brain or by breaking down into harmful substances.

The same committee called for stricter rules for future trials and a ban on doses that vastly exceed those needed to achieve the intended effect. The committee is going to meet again on March 24th and release a more detailed report that following Monday.

Here's a not so fun fact,

Anandamide, also known as N-arachidonoylethanolamine or AEA, is a fatty acid neurotransmitter derived from the non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid) an essential polyunsaturated fatty acid. The name is taken from the Sanskrit word ananda, which means "joy, bliss, delight", and amide.

All I can do is quote James Joyce, "hot baths of sentiment followed by cold showers of irony."

The reality is that clinical trials are necessary to proof drugs. I'm not making excuses for this trial but they are part of the process. I have to do more digging but if they were giving 40X the does needed then that should be criminal IMHO

I have dealt with this personally. (Just as a side note)

In the span of 10 years my wife and I lost all 4 parents, 3 of which dies of leukemia. My mother was first. She underwent a trial of a drug that would become Vidaza. It did not work on her. But 8 years later my father was able to keep his symptoms at bay for over 2 years till he succumbed to AML as well. My mom held no illusions about her chances but the opportunity to help others down the road was irresistible to her......

What is wrong with an aspirin again? Seems like everything that replaces it is much more of a problem. They increased the dosage in aspirins, it used to be one hundred and I used to take three, now they are three hundreds and they say to take two. I think they caused the problems aspirins have so they could sell more expensive things.

a reply to: FredT

The reality is that clinical trials are necessary to proof drugs. I'm not making excuses for this trial but they are part of the process. I have to do more digging but if they were giving 40X the does needed then that should be criminal IMHO.

We'll have to see what new information comes out in a couple of weeks. The drug had already been tested on animals, but I don't know if they endured the same amount that was given to those who were injured. It makes me wonder if any damage was done to those who took less, but showed no immediate adverse side effects. I'm sorry for what you have been through and you're right, incidents like this only make it safer for the next guy. A hard sacrifice to swallow.

a reply to: rickymouse

Well some people are allergic to Aspirin and not all pain can be helped with aspirin. Speaking as a pharmaceutical chemist, I wonder what phase of trials this was? Because if it is an early phase (I or II) chances are they have very little idea of effects, though they should have something from the Toxicological studies.

a reply to: Noinden

Speaking as a pharmaceutical chemist, I wonder what phase of trials this was?

The drug is being developed by Portuguese firm Bial. It was a “phase one” trial, in which a new drug that has been tested in animals is tested for the first time in humans. The idea is to make sure it is safe, and to measure its effects. Usually a range of relatively low doses are used in such trials.

I guess low means high in France.

You may get something out of this: Link

a reply to: eisegesis

Most pain killers are toxins in high doses.

It sounds like those given the highest doses were worst affected and the testing was to determine toxicological effects.

I also notice that the drug generally targets the Fatty Acid Amide Hydrolase (FAAH) in the endocannabinoid system (normally affected by Tetrahydrocabanninol or THC), but BIA 10‐2474 (the drug under test) was notedly less specific in targeting FAAH (indicating that it could have many other interractions and targets).

It is sad that people were hurt. I would assume that toxicology reports in vitrio would have missed the specific interactions that caused brain damage. Either way, it does sound like careless and excessive dosing at 40x.

a reply to: chr0naut

Hmm, who the hell at Bial decided it was ethical to endanger innocent people, especially after destroying so many animals back at the laboratory! I wonder what emotions you have to be lacking in order to work in that type of environment?

This is why I want to see more details. Most pain medications, and meds in general are tested way beyond normal doses. This drug should be no exception IMHO.

originally posted by: chr0naut
a reply to: eisegesis

Most pain killers are toxins in high doses.

It sounds like those given the highest doses were worst affected and the testing was to determine toxicological effects.

I also notice that the drug generally targets the Fatty Acid Amide Hydrolase (FAAH) in the endocannabinoid system (normally affected by Tetrahydrocabanninol or THC), but BIA 10‐2474 (the drug under test) was notedly less specific in targeting FAAH (indicating that it could have many other interractions and targets).

It is sad that people were hurt. I would assume that toxicology reports in vitrio would have missed the specific interactions that caused brain damage. Either way, it does sound like careless and excessive dosing at 40x.

I agree. The personal ability of a body to detox something should be checked first. In a newer class of drug like this that could be a little hard. They gained a lot of knowledge of this on usage of drugs over time and many are taken off the market because of this reason.

This may be a good drug for treating for some people but they probably ruined the chances of it hitting the market by overdoing it in the testing. Many meds on the market are toxic at twenty times the dose. Some are even toxic at five times the dose.

I posted a thread back in January here when the story was first breaking.

This is a nice update to it!

a reply to: eisegesis

It can happen in Phase 1, but that is very unusual, and more fool them. BIal is NOT a new start up. But given what they were studying, I am not shocked. At least it did not go to market. This seems harsh, but when you sign up to be a test subject in Phase 1, 2, 3 and possibly 4 (last stage before being approved or nixed) testing it's a crap shoot.

I just make the new drugs for these tests (I'm part of a CRO/CMO (Contract Research Organsiation/COntract Manufacture Organisation) , but every project I've worked that is for these 4 phases of testing, tends to have a well defined set of side effects to worry about. I've never had an issue, some of the early study stuff usually has "effects unknown" listed in the SDS (safety data sheets) they supply