
French drug trial leaves six hospitalized, one brain-dead - manyoso
http://www.nytimes.com/2016/01/16/world/europe/french-drug-trial-hospitalization.html?_r=0
======
kauffj
The unfortunate nature of the seen and the unseen is that we will always
notice the times we approved a drug too early or tested too aggressively, but
we will never notice the deaths that happen because we were too timid or
cautious in our approach.

While this case should be studied to ascertain whether process changes could
prevent it, the solution is absolutely not further testing, control, and
regulation. Hundreds of thousands of people already die or suffer every year
because of the paternalistic, conservative policies governing medicine.

~~~
tomkinstinch
_Primum non nocere_ (first, do no harm[1])

Medical research is conservative, cautious, and regulated because we strive to
move beyond the ugly abuses of our past[2]. It should not be the Wild West.

For insight into modern medical ethics, read the Belmont Report[3]. It's what
contemporary researchers must read before conducting any studies involving
human subjects. Where I work, we're tested on it.

(This is opinion, but...) Harm today is in research guided more by profit than
by benefit. Chronic disease is more profitable than cures or prevention. With
rapidly-emergent antibiotic resistance there is little private incentive to
develop new antibiotics. We must rely on and expand research in the public
interest (funded by NIH, philanthropy, and so on) to balance private
biomedical research.

1\.
[https://en.wikipedia.org/wiki/Primum_non_nocere](https://en.wikipedia.org/wiki/Primum_non_nocere)

2\.
[https://en.wikipedia.org/wiki/List_of_medical_ethics_cases](https://en.wikipedia.org/wiki/List_of_medical_ethics_cases)

3\.
[http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html](http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html)

~~~
Houshalter
I'm really surprised that this is news, or that it's being upvoted on HN.
Apparently deaths during trials are really rare. From the article:

>A meta-analysis of non-cancer Phase 1 drug trials, published last year in The
British Medical Journal, found serious adverse events in only 0.31 percent of
participants, and no life-threatening events or deaths.

And the last event comparable to this, according to the article, happened in
2006 in a different country.

I was surprised by this. I would not have expected drug trials to be risk
free, in fact I thought that was the whole point. Apparently they are already
super conservative and safe. I'm not sure why people are alarmed or calling
for more regulation.

It's probably impossible to 100% safety, and certainly not desirable. Parent
comment is definitely right that we kill more people through inaction and need
to be far more liberal. Total lives saved is all that should matter.

Somehow one person dying out of many drug trials over many years is news
that's on the front page of HN. But the 22,000 people that died of cancer
today isn't.

~~~
Fomite
Part of the issue is, medically, _we_ (where we = the medical community)
killed those people, whereas cancer killed the other 22,000.

Medical ethics are expressly meant to protect subjects from experimentation
purely on the basis of "This will probably help more people than it hurts."
Given the events that prompted the development of those guidelines, I'm not
sure they're wrong.

~~~
selestify
> experimentation purely on the basis of "This will probably help more people
> than it hurts."

And why is this bad?

~~~
anigbrowl
Because people are actually kind of shitty at estimating probabilities, and
overconfidence in this area is likely to kill or injure a lot of people. I'm a
utilitarian by temperament, but a deontologist in practice because I'm aware
that my powers of foresight are actually quite limited and I will very rarely
be presented with neatly predictable conflicting imperatives as in the trolley
problem. Many self-professed utilitarians _wildly_ overestimate their own
intellectual and analytical abilities and come to grief on the rocks of failed
predictions. Unfortunately this also tends to involve a lot of innocent
casualties too.

~~~
Houshalter
On a case by case basis you might have a point, but over time we have tons of
statistics on how many drug trials fail and hurt people, vs succeed and save
people. It would be relatively easy to calculate the risk/benefit objectively.

That's also an ideal use case for prediction markets, if you want to get
really good predictions.

Also, I've heard this argument used before in other contexts. Do people really
believe that because you can't make perfect predictions, you should default to
inaction? That's just silly. You do the best with what you know and believe.

And if you really believe your predictions are wrong, then you can just adjust
them accordingly and make them correct. If you don't believe that, then you
obviously wouldn't find that argument convincing in the first place.

~~~
Fomite
We don't default to inaction. We default to careful action. There's a vast
difference.

------
csours
The drug in question is a Monoclonal Antibody (mab) intended to boost immune
response. [1] Mabs do have a tendency to runaway reactions. [2].

Mab treatments are likely to explode in coming years as immunomodulators to
both boost the immune system to fight disease and suppress immune reactions in
autoimmune diseases (some arthritis, asthma, severe allergies, etc)

You have to dig to find this information, posting it here for visibility.

1\.
[https://en.wikipedia.org/wiki/TGN1412](https://en.wikipedia.org/wiki/TGN1412)

2\.
[http://www.ncbi.nlm.nih.gov/pubmed/20305665](http://www.ncbi.nlm.nih.gov/pubmed/20305665)

~~~
awalton
I found a French website claiming the drug is BIA 10-2474, with reference to a
patient who received an offer to join this trial but decided not to:
[http://www.breizh-info.com/2016/01/15/rennes-biotrial-
biales...](http://www.breizh-info.com/2016/01/15/rennes-biotrial-bialessai-
therapeutique/)

And of course, the information around this particular drug is completely
missing or intentionally vague. edit: there seems to be a lot of people who
believe the drug is a FAAH2 inhibitor, based on previous work from the same
company, Bial Pharmaceuticals out of Portugal. The drug works on/around
endocannabinoids, which might be why the media was confused about this being
cannibis related.

~~~
gerbilly
In the video they say that the drug in question is intended to control pain
via the endocannabinoid system.

She was also very careful to insist that the drug neither contains cannabis or
any substance derived from cannabis.

------
cstross
Note from the NYTimes:

 _Contrary to several reports in the French news media, the drug was not a
cannabis-based painkiller, Ms. Touraine said._

Early reports in The Guardian, the BBC, and elsewhere called it a cannabinoid-
based painkiller. (That sounded rather implausible because (a) cannabinoids
have a _ridiculously_ high therapeutic index -- ratio of medically effective
dose to toxic dose -- and (b) with cannabis decriminalization spreading
internationally, the commercial benefit of patenting a drug in the same space
as a cheap non-proprietary alternative would appear to be small.)

Edit: The Guardian amended their piece to state that it was a monoclonal
antibody targeting the brain's endocannabinoid receptors. (Interesting idea,
but Mabs have some really lethal failure modes, notably triggering a cytokine
storm in some cases, cf. TGN1412.)

~~~
refurb
_cannabinoids have a ridiculously high therapeutic index_

 _Some_ cannabinoids have a high therapeutic index. Some of the THC analogues
being used as "fake weed" are quite toxic.

Also, there is a huge market for cannabinoid-like drugs. If you have chronic
pain, would you want to be stoned all day? Or take a drug that provides pain
relief, but doesn't alter your mood?

------
cowsandmilk
There are some oddities here.

(1) It sounds like the trial started on July 9

(2) These 6 people all started receiving the drug January 7 and all got sick

(3) 90 people total have received the drug, so I assume 84 people safely
received the drug.

This sounds like there was a bad batch that hospitalized everyone who received
the drug on January 7.

~~~
wins32767
It could well be a trial where they gradually increase the dose to find out
what a safe dose is.

------
milkcircle
Just some background about clinical trials that may yield more insight into
the drug approval process:

Phase I: intended to determine a loose range of safe doses for patients.
Subjects enrolled in Phase I clinical trials are informed that it is unlikely
for the drug to benefit them. Normally, subjects are healthy volunteers that
are put into buckets of different doses to determine the Maximal Tolerated
Dose (MTD).

Phase II: Intended to characterize the efficacy of the drug (on a small
scale). There are several methods of conducting Phase II trials; some are
simply longitudinal case studies, and others are structured more like
randomized controlled trials (the type of clinical trial generally considered
the most valid [i.e. maintains the highest internal validity]).

Phase III: Randomized controlled trial. Patients are randomized into the test
group vs. placebo/current standard of care to determine whether the new drug
is effective. The best RCTs are double-blinded though this is not always the
case.

This drug, a monoclonal antibody intended to alter the immune response, was
halted in the Phase I clinical trial.

------
epmatsw
While I do worry about the state of the FDA and prescription drugs in the US,
things like this make me feel glad that drug companies have a well regulated
process to catch issues like this before they can become more widespread.

~~~
MBCook
It's all the supplements and other homeopathic exemption stuff that worries
me. Not only do they not have to prove they're effect (at all, let alone more
effective than the standard treatment), but they've had serious safety issues
in the past. Ephedra is a classic example. Plus there are so many times people
do tests that find supplements don't contain what they claim.

~~~
SixSigma
Or contain more than they should.

Reading the FDA recall database is quite illuminating

[http://www.fda.gov/Drugs/DrugSafety/DrugRecalls/default.htm](http://www.fda.gov/Drugs/DrugSafety/DrugRecalls/default.htm)

The food one is also an eye opener, 8 so far in 2016

[http://www.fda.gov/Food/RecallsOutbreaksEmergencies/Recalls/...](http://www.fda.gov/Food/RecallsOutbreaksEmergencies/Recalls/default.htm)

Last year I scraped the whole database and read every one to analyse the
reasons for a Uni project. I'm surprised anyone is still alive!

------
ajb
One of the recommendations from the previous episode (TGN1412) was that in the
first trial on humans, the administrations should be staggered so that if
there is an unexpected adverse reaction, you only get one or two patients
down. It sounds like that may not have been taken on board.

------
Aissen
FYI, the drug being tested was for Parkinson's disease (nytimes doesn't say
that but lemonde does):
[http://www.lemonde.fr/societe/article/2016/01/15/essai-
thera...](http://www.lemonde.fr/societe/article/2016/01/15/essai-
therapeutique-a-rennes-un-volontaire-en-etat-de-mort-
cerebrale_4848001_3224.html)

~~~
sjg007
Seems weird to do a Phase I trial in healthy volunteers for a monoclonal
antibody targeted to Parkinson's.

~~~
chrisseaton
This is the whole point of a Phase 1 trial.

[https://en.wikipedia.org/wiki/Phases_of_clinical_research#Ph...](https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_I)

~~~
sjg007
You don't test Phase 1 anticancer drugs in healthy volunteers. So likewise
monoclonal antibodies for Parkinson's should probably be first tested in the
affected population.

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678815/](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678815/)

~~~
intrasight
Perhaps they do - if all Phase 1 is done on healthy human guinea pigs. Better
question is why do we allow otherwise healthy people to be guinea pigs?

~~~
Fomite
Because we need to know about drug side effects, and it's extremely difficult,
if not impossible, to parse out those effects in people who are already very
sick. Additionally, those side effects are likely far less dangerous in an
otherwise healthy individual.

------
tokenadult
This is why for years here on Hacker News I have been more than a little
skeptical about university press releases announcing that this or that group
of researchers has discovered a new breakthrough for curing this or that human
disease. It is wonderful that medical researchers continue to do basic
research better to understand physiology, genetics, and biochemistry. And it
is especially wonderful that researchers doing basic research sometimes think
about translational research to apply to basic science findings to clinical
medicine. But that takes a lot of time and careful work.

Here on Hacker News, we all like to be excited by possible breakthroughs that
will help us or our loved ones to enjoy longer, healthier lives. But an
announcement of a laboratory result in cultured cell lines or in mice or some
other preliminary model is a LONG way from a demonstration of safety and
effectiveness for a new treatment of a human disease. Let's keep funding and
celebrating basic research, and let's keep advancing the frontier in clinical
trials on human patients, but let's reality-check every step of the way to
make sure that proposed new treatments really do good, and really do more good
than harm.

For perspective on this, it's important to note that age-adjusted all-cause
mortality has been steadily going DOWN all over the world. Life expectancy at
age 40, at age 60, and at even higher ages is still rising throughout both the
developed countries and the still developing countries of the world.[1] Right
now, the number-one thing we can do to reduce our own risk of disability or
death is to take action on known individual preventive measures that raise
likelihood of good health and to set up institutional incentives for doctors
and other practitioners to use best-practice means of preventing and treating
disease. Steady incremental improvements of many kinds are increasing healthy
human lifespan all over the world at all ages.[2]

[1] "The Biodemography of Human Ageing" by James Vaupel

[http://www.demographic-
challenge.com/files/downloads/2eb51e2...](http://www.demographic-
challenge.com/files/downloads/2eb51e2860ef54d218ce5ce19abe6a59/dc_biodemography_of_human_ageing_nature_2010_vaupel.pdf)

[2]
[http://www.slate.com/articles/health_and_science/science_of_...](http://www.slate.com/articles/health_and_science/science_of_longevity/2013/09/life_expectancy_history_public_health_and_medical_advances_that_lead_to.html)

~~~
refurb
I think your perspective is exactly right. Most of the articles you see on HN
are about pre-clinical work (not done in humans). This is so early in the
development time that the chance of the technology failing is huge.

Keep in mind that for drugs that actually enter human trials, the success rate
is typically less than 5%.

------
xiaoma
Seeing this reminds me of how there is never an exciting story to publish for
the far greater of number who suffer great illness or death because of
regulators being _too_ cautious about allowing trials of new treatments.

~~~
Retric
There are plenty of stories published with exactly that message. Granted, they
might not be exciting, but hit pieces are fairly common.

------
graeham
A sobering report for biotech entrepeneurs (and the industry in general).
Hopefully more details become avalible, not for blame but to learn from it.

There is a duty of care and caution needed in medicine. Of course this needs
to be balanced with the damage from slowing or preventing innovation.

~~~
searine
The realities of biotech made real.

Somehow, "move fast and break things" doesn't quite translate to biology.

~~~
SCHiM
Sure it does, only too aptly.

------
magicmu
"British regulators approved the trial in just 17 days, and the testing
company, based in Massachusetts, did not have an adequate response plan in the
event of a disastrous adverse reaction, British investigators concluded."

This seems like a bit of an issue.

EDIT: Not the same trial, I'm a fool.

~~~
colanderman
That paragraph is referring to a previous incident. The current incident
occurred in France in behalf of a Portuguese firm.

------
lemmings19
Here is more information on the trial mentioned in the last two paragraphs:
[https://en.m.wikipedia.org/wiki/TGN1412](https://en.m.wikipedia.org/wiki/TGN1412)

------
jszymborski
While this is truly a sad event, there are some things to note here,
primarily:

This was a Stage 1 trial, whose sole goal is to determine the minimum-tolerate
dose. The idea here is that after we've identified a possible drug, we do
preliminary tests in animals and follow some well established dosage-scaling
formulas to determine human dosages.

They then scale that waayy down, and gradually scale up the drug in different
patients until side-effects are noticed.

Although the article describes the patients as being healthy, people who
volunteer for these types of studies usually have exhausted all possible
alternatives and aren't usually given good prognosis.

If a study is conducted ethically, they aren't given any hope that the drug
will positively effect them in any way, and that they are truly doing this for
the possible benefit of Stage >1 patients.

Usually, toxicity is found before patients die (although that happens). What
makes this unprecedented, imho, is that so many died. What makes it personally
disheartening is that one is brain-dead, which is a special kind of hell for a
family to go through.

While these patients weren't told "this drug will murder you, or maybe leave
you brain-dead, with high-likelihood", however, in a Phase I trial, that is
very much the risk you're running at such an early stage of drug development.

~~~
tremon
_people who volunteer for these types of studies usually have exhausted all
possible alternatives and aren 't usually given good prognosis._

According to other comments here (e.g.
[https://news.ycombinator.com/item?id=10910698](https://news.ycombinator.com/item?id=10910698)),
this is incorrect. Stage 1 is given to otherwise healthy patients, to
ascertain adverse effects of the drug. Stage 2 is where the positive effects
of the drug are tested, that seems like the case you're describing here.

~~~
jszymborski
You are correct, and I beleive I mentioned in my comment that the sole purpose
of Stage I is to asses the minimal tolerated dosage.

What I meant by the sentence you quoted is that because of the unknown human
physiological consequences of the drug, it is usually only used on those who
have no other recourse. Patients that have a clear course of treatment undergo
those clear courses, and do not assume the risk of a Phase I drug.

------
hyperliner
Can someone smart (I am not it) explain how can something that you ingest
orally create brain damage? What is an example of something simpler that we
all may be familiar with that could cause a similar effect, and the process
through which it happens?

In advance, thank you for educating me.

~~~
jo909
Not quite on the same scale, but maybe more relatable: alcohol can have quite
an effect on the brain. Luckily most of it is reversible.

~~~
gus_massa
Somewhat related, drinking methanol (wood alcohol) can make you blind or kill
you. More information in Wikipedia:
[https://en.wikipedia.org/wiki/Methanol#Toxicity](https://en.wikipedia.org/wiki/Methanol#Toxicity)

Layman translation: Methanol is transformed into Formate, that is another
substance. Formate mess with the functions of the mitochondria, that are the
parts of the cells that use the oxygen. So each cell dies like it would die if
you can't breath oxygen.

(I suppose that the neurons are more sensible, and the visual problems are
easier to spot, so one of the first symptoms of Methanol poisoning is
blindness.)

------
tacon
When it is the first use in humans, and the main point of Phase 1 is safety,
why is there not an exponential turn on of the trial to avoid widespread harm?
For example Patient 1 gets medicine for a week (or whatever), then patients 2
& 3 start their trial, etc. Where is the economic analysis of length of test
vs risk of harm by various turn on strategies?

------
jhartmann
Some information about the trial seems to be here: [http://www.breizh-
info.com/2016/01/15/rennes-biotrial-biales...](http://www.breizh-
info.com/2016/01/15/rennes-biotrial-bialessai-therapeutique/)

------
rplnt
This (HN) title is incorrect as it would make 7 "affected" instead of 6 as is
written in article.

~~~
manyoso
Fixed, thanks. Yay, counting!

~~~
rplnt
Huh, I didn't even know you can edit titles.

------
thrownunder
I can't seem to find the name of nature of the drug in question, does anyone
know it? I ask because full CB1 agonists are already known to be problematic,
but none of the articles mention anything other than endocannabinoid

~~~
TacticalMalice
There's speculation the structural family was disclosed in Bial's patent
application
[http://www.freepatentsonline.com/20150174103.pdf](http://www.freepatentsonline.com/20150174103.pdf)

------
trhway
>Ms. Touraine said the drug had previously been tested on animals, including
chimpanzees

testing an animals beside being a cruel practice that has to be stopped, is
also useless even when the animals are that close to humans.

~~~
dnautics
It's a series of filters - you test on animals before testing on humans. Of
course some percentage of things that are not toxic to animals have a special
toxicity in humans. To claim that it is "useless" means that you also believe
there to be a large proportion of candidates which are toxic in animals that
aren't toxic in humans.

I don't have the data on this, but, without necessarily defending the practice
of animal testing, I suspect that toxicity in animals _is_ a good predictor
for toxicity in humans in the forward direction.

------
intrasight
Are all Phase 1 trials done on healthy human guinea pigs. Why do we allow
otherwise healthy people to be guinea pigs? Presumably there are patients who
have the disease this drug targets.

~~~
stan_rogers
Parkinson's is a toughie - you don't _really_ know what a patient is suffering
from, just the syndrome they're exhibiting. I "have Parkinson's", by which I
mean I have a series of symptoms that aren't related to any known purely-
genetic disease (there are several, and I've been tested for all of them),
tumors or structural issues in the brain (lived many a night in various
scanning devices), are similar in general tone to those common to Parkinson's
sufferers, and which respond well to treatments for Parkinson's. The syndrome
itself, though, is a bit idiosyncratic, and may in fact be a constellation of
similar diseases rather than a single disease. Diagnosis is still mostly a
process of observation and elimination, despite what a few optimistic studies
may have reported.

------
dawnbreez
What _was_ the drug?

~~~
TacticalMalice
Some investigation of recent patents by Bial points to a probable candidate
[http://cdsouthan.blogspot.nl/2016/01/the-unfortunate-case-
of...](http://cdsouthan.blogspot.nl/2016/01/the-unfortunate-case-of-
bia-10-2474.html)

~~~
dawnbreez
So it might be an FAAH inhibitor? _one quick google search later_

So one of the things that FAAHs do is handle "endocannabinoids", which are
chemicals that activate cannabinoid receptors, which are (as the name implies)
also triggered by cannabis. That'd explain why people thought it was a
cannabis-based painkiller.

------
mrfusion
Keep in mind you never hear about all of the deaths from being too
conservative in testing and approving medications but it's probably a lot.

